Inibidores da via JAK‐STAT na dermatologia | Anais Brasileiros de Dermatologia

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AA, Alopecia areata; AD, Atopic dermatitis; DM, Dermatomyositis; PSO, Psoriasis; VITI, Vitiligo; HS, Hidradenitis suppurativa; GVHD, Graft-versus-host disease; Abro, Abrocitinib; Upa, Upadacitinib; Bari, Baricitinib; TDelgo, Topical Delgocitinib; Tofa, Tofacitinib; TRuxo, Topical Ruxolitinib; Ruxo, Ruxolitinib; Ritle, Ritlecitinib; Deucra, Deucravacitinib; Solci, Solcitinib; Itaci, Itacitinib; Deuruxo, Deuruxolitinib" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Hélio Amante Miot, Paulo Ricardo Criado, Caio César Silva de Castro, Mayra Ianhez, Carolina Talhari, Paulo Müller Ramos" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Hélio Amante" "apellidos" => "Miot" ] 1 => array:2 [ "nombre" => "Paulo Ricardo" "apellidos" => "Criado" ] 2 => array:2 [ "nombre" => "Caio César Silva" "apellidos" => "de Castro" ] 3 => array:2 [ "nombre" => "Mayra" "apellidos" => "Ianhez" ] 4 => array:2 [ "nombre" => "Carolina" "apellidos" => "Talhari" ] 5 => array:2 [ "nombre" => "Paulo Müller" "apellidos" => "Ramos" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "pt" => array:9 [ "pii" => "S2666275223001418" "doi" => "10.1016/j.abdp.2023.05.018" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "pt" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2666275223001418?idApp=UINPBA00008Z" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0365059623001149?idApp=UINPBA00008Z" "url" => "/03650596/0000009800000005/v1_202307281023/S0365059623001149/v1_202307281023/en/main.assets" ] ] "itemSiguiente" => array:18 [ "pii" => "S2666275223001376" "issn" => "26662752" "doi" => "10.1016/j.abdp.2023.05.014" "estado" => "S300" "fechaPublicacion" => "2023-09-01" "aid" => "780" "copyright" => "Sociedade Brasileira de Dermatologia" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "pt" => array:10 [ "idiomaDefecto" => true "cabecera" => "Cartas ‐ Investigação" "titulo" => "Série de casos: psoríase em pacientes transplantados de órgãos sólidos e agentes imunobiológicos" "tienePdf" => "pt" "tieneTextoCompleto" => "pt" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "678" "paginaFinal" => "681" ] ] "contieneTextoCompleto" => array:1 [ "pt" => true ] "contienePdf" => array:1 [ "pt" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 930 "Ancho" => 2925 "Tamanyo" => 354037 ] ] "descripcion" => array:1 [ "pt" => "(A) Placas eritematosas no abdome. 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(A) Diversas citocinas e fatores de crescimento presentes no meio extracelular dependem de receptores transmembrana para dar início ao processo de sinalização celular e transcrição nuclear dos genes associados a cada via. (B) O acoplamento da citocina com o domínio extracelular do receptor transmembrana leva a mudança em sua conformação e fosforilação dos dímeros de JAK, situados no domínio intracelular do receptor, e que transfosforilam seus resíduos terminais de tirosina. Esse processo induz a dimerização e fosforilação de unidades inativas de STAT, que migram para o núcleo e medeiam a transcrição de genes relacionados à via da citocina específica. (C) Inibidores da via de sinalização JAK‐STAT (iJAK) impedem a fosforilação da JAK, interrompendo a sinalização nuclear da citocina ou fator de crescimento. Fonte: os autores" ] ] ] "textoCompleto" => "IntroduçãoA via de sinalização Janus Quinase (JAK) e transdutor de sinal/ativador da transcrição (STAT) compreende uma família de moléculas ligadas aos domínios intracelulares dos receptores de diversas citocinas e fatores de crescimento, que medeiam sua sinalização até o núcleo.<a class="elsevierStyleCrossRef" href="#bib0690">1</a> A denominação dessas quinases como Janus refere‐se ao deus romano que representava o início ou abertura de um processo. Janus tinha duas faces, que estão associadas aos dois domínios das JAK: um catalítico e um semelhante à quinase. Historicamente, o início do dia, do mês e do ano era destinado em sacramento a Janus; assim, segundo a lenda, o mês de janeiro origina‐se de seu nome.A via JAK‐STAT pertence a um complexo sistema de proteína quinases, conservado evolutivamente, em que mediadores extracelulares controlam a expressão de genes específicos envolvidos em diversas funções celulares como mitose, diferenciação, apoptose, hematopoese, desenvolvimento do sistema imune (inato e adaptativo) e atividade de glândulas exócrinas. Além disso, participa de respostas celulares a agressões como hipoxia, irradiação ultravioleta, estímulo por endotoxinas, estresse oxidativo e hiperosmolar.<a class="elsevierStyleCrossRef" href="#bib0695">2</a>Desse modo, diversas dermatoses inflamatórias ou autoimunes são alvo de estudo para a indicação de inibidores da via JAK‐STAT (iJAK).<a class="elsevierStyleCrossRef" href="#bib0700">3</a> Uma vez que essa classe terapêutica se revelou promissora em substituir o uso crônico dos imunossupressores clássicos (p. ex., ciclosporina, azatioprina, micofenolato, metotrexato, corticosteroides) em virtude de sua seletividade de ação, os iJAK devem, paulatinamente, ocupar espaço na prescrição dermatológica.Esta é uma revisão narrativa que englobou artigos publicados sobre iJAK com direcionamento para as principais doenças dermatológicas nas bases de dados MEDLINE, SciELO e Google Scholar, que avaliou o período de 1992 (dos primeiros fundamentos do processo de sinalização intracelular) até os dias atuais. Apresentamos os principais medicamentos disponíveis, seus efeitos imunológicos e suas características farmacológicas relacionadas à eficácia clínica e de segurança, a fim de substanciar a melhor prática dermatológica.Via JAK‐STATAs enzimas JAK são tirosina quinases agregadas aos domínios intracelulares dos receptores transmembrana de certas citocinas e fatores de crescimento. Após o acoplamento das moléculas nos domínios extracelulares de seus receptores ocorre modificação conformacional em sua estrutura, que leva à fosforilação de resíduos específicos de tirosina nos dímeros de JAK. Essa fosforilação possibilita o recrutamento de proteínas como os fatores de transcrição STAT, que se dimerizam e são translocadas para o núcleo das células (via Ran de importação nuclear) a fim de regular a transcrição de genes específicos (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0705">4</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Cada subtipo de JAK contém um resíduo de tirosina específico para a fosforilação ATP‐dependente. Essa especificidade as diferencia entre si e entre as mais de 500 tirosinas quinases humanas.<a class="elsevierStyleCrossRef" href="#bib0710">5</a>Os principais componentes da via JAK‐STAT constituem quatro enzimas JAK (JAK1, JAK2, JAK3 e tirosina quinase 2 [Tyk2]), e sete enzimas STAT (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B e STAT6). Elas se distribuem como dímeros cuja composição varia de acordo com o tipo de receptor transmembrana e o tipo celular envolvido.<a class="elsevierStyleCrossRef" href="#bib0690">1</a> Logo, de acordo com o padrão de inibição para diferentes JAK‐STAT, diferentes perfis de sinalização de citocina são afetados.O bloqueio seletivo da sinalização de grupos de citocinas é uma característica do efeito imunomodulador dos iJAK em comparação com os imunossupressores convencionais (p. ex., ciclosporina ou corticosteroides), que suprimem uma vasta gama de mediadores; ou com os imunobiológicos, que suprimem, especificamente, uma citocina.<a class="elsevierStyleCrossRef" href="#bib0715">6</a> A <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a> apresenta as principais citocinas e os fatores de crescimento afetados pelo bloqueio dos subtipos de JAK.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Como as unidades JAK estão acopladas apenas a receptores de citocinas tipos I e II, os iJAK não medeiam, diretamente, a sinalização de TNF (α, β), TGF (α, β), EGF, quimiocinas (p. ex., IL‐8, CXC, CX3C), PDGF e IL‐1 (α, β), que são patogênicas em uma série de dermatoses.<a class="elsevierStyleCrossRefs" href="#bib0720">7,8</a>A via de sinalização JAK‐STAT constitui profícua linha de pesquisa em biologia celular envolvendo aspectos ligados ao comportamento de variantes mutantes de suas enzimas, a regulação intracelular por inibidores/ativadores, efeitos da ativação não canônica e interação com outras vias inflamatórias, apoptóticas ou de crescimento celular que são assuntos clinicamente relevantes, porém que ultrapassam o escopo deste texto.<a class="elsevierStyleCrossRefs" href="#bib0730">9–16</a>Principais características dos iJAK na dermatologiaOs iJAK são moléculas pequenas (< 500 kD), o que favorece sua absorção intestinal e permeação cutânea, apesar de serem pouco lipofílicas (log p entre 1,5 e 2). Por constituírem medicamentos finais e não dependerem de metabolização para o efeito farmacológico, sua rápida absorção leva a efeito clínico precoce; porquanto, seus picos plasmáticos e meia‐vidas de eliminação também são breves (< 18 horas).<a class="elsevierStyleCrossRef" href="#bib0770">17</a>Nas formulações tópicas, iJAK não implicam em níveis séricos elevados dos medicamentos, minimizando efeitos adversos (EA) sistêmicos e interações medicamentosas.<a class="elsevierStyleCrossRefs" href="#bib0770">17,18</a> Além disso, atingem alta concentração na epiderme e derme superior, o que justifica sua eficácia em eczemas, psoríase e vitiligo, conforme discutido adiante. Entretanto, recomenda‐se não ultrapassar 20% da superfície cutânea, utilizar camada fina e não prolongar seu uso, com o intuito de reduzir a chance de efeitos sistêmicos.<a class="elsevierStyleCrossRef" href="#bib0770">17</a>Quanto à seletividade, os iJAK podem ser classificados como de primeira geração (p. ex., tofacitinibe, baricitinibe) ou não seletivos, ou de segunda geração (p. ex., upadacitinibe, abrocitinibe, ritlecitinibe), considerados os mais seletivos para um dos subtipos de JAK. Além disso, os iJAK diferem quanto ao bloqueio enzimático (reversível ou covalente) e o sítio de ligação (tipo I, II e alostérico).<a class="elsevierStyleCrossRef" href="#bib0780">19</a>Quando consideradas suas estruturas moleculares, os iJAK podem ser agrupados como iJAKα (baricitinibe, delgocitinibe, ruxolitinibe, tofacitinibe) ou iJAKβ (abrocitinibe, upadacitinibe, filgotinibe, deucravacitinibe). Os iJAKα têm estrutura semelhante à purina e sistema bicíclico condensado formado por heterociclos de pirimidina/pirrol. Todas essas substâncias exibem um grupo cianeto nucleofílico para o sítio de ligação da quinase. Dada a semelhança dos segmentos JH1 entre as isoformas JAK, os iJAKα as inibem todas, apesar de diferentes afinidades. Os iJAKβ foram especificamente sintetizados por modelagem química para otimizar as ligações, na tentativa de combinar a estrutura dos iJAKβ com um respectivo sítio de ligação, gerando maior seletividade. Porém, os iJAKβ são menos comparáveis entre si quanto à estrutura química.<a class="elsevierStyleCrossRef" href="#bib0785">20</a>Em virtude da semelhança estrutural das enzimas do grupo JAK, os diferentes iJAK exercem algum efeito inibitório em todos os seus quatro subtipos, de acordo com a concentração utilizada. A <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a> resume as características farmacológicas dos principais iJAK de uso atual na dermatologia. Entretanto, a maior parte dos indicadores farmacológicos e farmacodinâmicos é estimada por ensaios em que as concentrações inibitórias são realizadas por testes in vitro que empregam diferentes metodologias, sem considerar variações metabólicas ligadas a sexo, faixa etária, ascendência étnica, composição corporal, comorbidades e uso de medicamentos concomitantes. Essas características justificam cautela em sua prescrição e seguimento de longo prazo, uma vez que os resultados de farmacovigilância das principais substâncias ainda estão em andamento em virtude da recente aprovação (menos de cinco anos) pelas agências regulatórias internacionais.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Segurança e tolerabilidade dos iJAKTal como ocorre com outras medicações, exceto em reações imunologicamente mediadas, os EA e riscos ligados a medicamentos que interferem nas vias de sinalização e transcrição de citocinas, fatores de crescimento celular e indução da apoptose celular são diretamente proporcionais aos seguintes condicionantes: (i) ocorrência de doenças concomitantes (tuberculose latente, infecção por HIV, HTLV‐1, doença de Chagas, doenças autoimunes, doença intestinal inflamatória [DII], trombofilias, hepatopatias, nefropatias e hematológica); (ii) dose da medicação; (iii) longevidade do tratamento, e (iv) vias metabólicas alteradas por polimorfismo gênico (deficiência da glicose‐6‐fosfato desidrogenase, acetilador lento, HLA de predisposição a reações adversas graves como no caso do abacavir, HLA‐B*5701).<a class="elsevierStyleCrossRef" href="#bib0790">21</a>Mesmo assim, muitos EA podem ser pouco frequentes, ou mesmo não estar presentes em estudos de fase III com limitado número de pacientes e curta exposição ao fármaco, que somente serão identificados pelos relatos de farmacovigilância, já que a maioria dos iJAK tem menos de cinco anos de comercialização.<a class="elsevierStyleCrossRef" href="#bib0795">22</a> Cabe ao dermatologista estar atento à possibilidade de EA oriundos do uso prolongado desses fármacos, assim como identificar subgrupos de pacientes suscetíveis e, principalmente, a possibilidade de interações medicamentosas.Interações medicamentosasO envelhecimento populacional e a disponibilidade de novos fármacos favorecem o uso concomitante de medicamentos pela população, o que maximiza a possibilidade de interações medicamentosas, por exemplo, via citocromo P450 (CYP).<a class="elsevierStyleCrossRef" href="#bib0800">23</a>Em pacientes com artrite reumatoide (AR) que receberam iJAK, identificou‐se em mais de 10% deles a prescrição concomitante de medicamentos com potencial interação medicamentosa, como inibidores da bomba OAT3 (organic anion transporter 3), inibidores potentes do CYP3A4 e CYP2C19.<a class="elsevierStyleCrossRef" href="#bib0800">23</a>Enquanto os iJAK são primariamente metabolizados no fígado pelo sistema CYP, via enzimas metabolizadoras do CYP3A4, a extensão do metabolismo por essas vias e outras enzimas varia de acordo com o iJAK utilizado, bem como seu nível de excreção renal. A <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a> fornece uma extensa lista de medicamentos que, potencialmente, interferem com CYP3A4, CYP2C19 e bomba OAT3 e que devem ser considerados no uso concomitante de iJAK.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Destaque‐se que fazem parte dessa lista medicamentos de uso corriqueiro, como ansiolíticos, antidepressivos, antifúngicos, antilipemiantes e anti‐hipertensivos, e os dermatologistas devem ponderar os riscos dessas interações. Inclusive, substâncias de uso recreativo (p. ex., Cannabis sp.) e extratos vegetais (p. ex., Echinacea purpurea, Hypericum perforatum), que são frequentemente omitidos pelos pacientes, têm efeito sobre a metabolização hepática de medicamentos.<a class="elsevierStyleCrossRefs" href="#bib0805">24,25</a> No entanto, o breve uso concomitante de iJAK com potenciais substâncias que promovem interação, como fluconazol para candidose vulvovaginal, não implica em prejuízo.Diferentes iJAK de uso sistêmico têm particularidades farmacocinéticas e metabólicas dependentes de sua fração de ligação com proteínas plasmáticas, taxa de metabolização hepática e atividade dos seus metabólitos (<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>).O tofacitinibe é rapidamente absorvido por via oral, com pico de concentração plasmática em 1 hora, atingindo equilíbrio (steady‐state) em até 48 horas. Sua biodisponibilidade oral é de 74%, independente da ingesta de alimentos, e 40% da substância se ligam a proteínas plasmáticas.<a class="elsevierStyleCrossRef" href="#bib0785">20</a> É eliminado principalmente via hepática (70%) e renal (30%), o que demanda doses menores em hepatopatas e nefropatas. A principal via de metabolização utiliza o CYP3A4, com pequena contribuição do CYP2C19, além de ser substrato da glicoproteína‐P. Não foram demonstradas interações com midazolam, contraceptivos orais ou metformina.<a class="elsevierStyleCrossRef" href="#bib0815">26</a>O upadacitinibe é absorvido em ampla faixa de pH (entre 1‐7,5) sem grande interferência alimentar, e apenas 52% se ligam às proteínas plasmáticas; portanto, não são esperadas interações relevantes dependentes do deslocamento proteico. Nenhum ajuste de dose é necessário para indivíduos com insuficiência renal ou hepática leve ou moderada.<a class="elsevierStyleCrossRef" href="#bib0820">27</a> O upadacitinibe é metabolizado pela CYP3A4, com participação menor de CYP2D6. O uso concomitante com cetoconazol aumenta a concentração máxima (Cmáx) do medicamento e a curva de concentração plasmática (AUC) no tempo em 70% e 75%, respectivamente. O uso concomitante com rifampicina diminui a Cmáx e AUC em 50% e 60%, respectivamente. Não há interação medicamentosa com varfarina, omeprazol, midazolam e etinilestradiol+levonorgestrel.<a class="elsevierStyleCrossRef" href="#bib0815">26</a>O abrocitinibe, após absorção, liga‐se em 37% às proteínas plasmáticas; a excreção é principalmente renal (85%) e fecal (9,5%). Quanto à forma não metabolizada, 0,6% são excretadas nos rins e 0,3% nas fezes.<a class="elsevierStyleCrossRef" href="#bib0785">20</a> A coadministração deve seguir a seguintes recomendações: (i) uso concomitante com inibidores do CYP2C19 – a dose do abrocitinibe deve ser reduzida pela metade; (ii) uso concomitante com indutores potentes do CYP2C9/CYP2C19 – não recomendado; (iii) inibidores do OAT3 – sem necessidade de ajuste.<a class="elsevierStyleCrossRef" href="#bib0825">28</a> Como exemplos, atenção especial: (i) fluconazol, fluoxetina, fluvoxamina e ticlopidina (inibidores do CYP2C19); (ii) apalutamida e rifampicina (uso não recomendado); e (iii) probenecida e teriflunomida (sem necessidade de ajuste de dose).<a class="elsevierStyleCrossRef" href="#bib0825">28</a> Insuficiência hepática não tem efeito clinicamente relevante na farmacocinética e segurança do abrocitinibe, autorizando seu uso sem ajuste da dose em casos de insuficiência hepática leve ou moderada.<a class="elsevierStyleCrossRef" href="#bib0830">29</a>O baricitinibe é rapidamente absorvido por via oral em jejum, com pico plasmático em 1 hora e biodisponibilidade de 80%. Alimentos gordurosos e calóricos diminuem sua absorção em 29%, atrasando o pico plasmático para 3 horas. Ocorre ligação de 50% às proteínas plasmáticas, e steady‐state é atingido em até 48 horas. Menos de 10% do baricitinibe ingerido sofrem metabolismo pelo CYP3A4, não se detectando metabólitos no plasma, o que dispensa ajuste de dose na insuficiência hepática leve ou moderada. O baricitinibe é excretado sem alteração na urina (69%) e nas fezes (15%), enquanto 6% da dose são excretados como metabólitos. A filtração glomerular é o principal mecanismo de excreção e secreção ativa pelo OAT3, glicoproteína‐P, BCRP e pela MATE2‐K. Assim, a concentração plasmática do baricitinibe aumenta em pacientes com disfunção renal leve (1,4×) e moderada (2,2×). Em pacientes com clearence de creatinina entre 30‐60mL/min, a dose do baricitinibe deve ser reduzida para 2mg/dia, e não é recomendado quando o clearance de creatinina for<30mL/min.<a class="elsevierStyleCrossRef" href="#bib0835">30</a>O ajuste nas doses do tofacitinibe ou baricitinibe, mas não do upadacitinibe, é necessário com a progressão da gravidade da insuficiência renal. Embora a dose do tofacitinibe precise ser ajustada para pacientes com insuficiência hepática moderada, não é o caso do baricitinibe ou do upadacitinibe.<a class="elsevierStyleCrossRef" href="#bib0840">31</a> Insuficiência renal moderada e grave levaram a maior exposição à porção ativa do abrocitinibe, sugerindo que a dose de abrocitinibe deva ser reduzida pela metade nesses casos.<a class="elsevierStyleCrossRef" href="#bib0845">32</a>Infecções e eventos adversos geraisOs efeitos farmacológicos dos iJAK são proporcionais às doses utilizadas, de modo que sua prescrição deve levar em consideração a menor dose clinicamente eficaz, a fim de minimizar os riscos associados à imunossupressão ou à inibição da JAK2, associada aos EA hematológicos.O uso de iJAK tópicos demonstrou poucos EA sistêmicos, porém acne, já relatada em pacientes com iJAK orais, foi observada em alguns relatos e séries de casos.<a class="elsevierStyleCrossRef" href="#bib0700">3</a>A maioria dos eventos infecciosos relacionados aos iJAK é relatada pelo uso do tofacitinibe, liberado para comercialização em 2012, de modo que se torna evidente o maior tempo e o grande número de doentes expostos a essa medicação e, consequentemente, o maior número de publicações na literatura.<a class="elsevierStyleCrossRefs" href="#bib0850">33–36</a>O estudo ORALSURV envolveu 4.362 indivíduos com AR, com mais de 50 anos e pelo menos um fator de risco cardiovascular. Doentes em uso prévio de metotrexato foram alocados para receber tofacitinibe 5mg, 2×/dia; tofacitinibe 10mg, 2×/dia; ou anti‐TNFα (etanercepte ou adalimumabe). Em relação às infecções, o estudo demonstrou que tofacitinibe conferia risco similar de infecções em relação aos anti‐TNFα, exceto pela propensão em reativar vírus latentes (p. ex., varicela‐zóster, herpes simplex e citomegalovírus).<a class="elsevierStyleCrossRef" href="#bib0850">33</a>Com relação aos eventos infecciosos graves (EIG), o ORALSURV identificou risco semelhante para a dose de 5mg de tofacitinibe e os anti‐TNFα, mesmo em pacientes com mais de 65 anos.<a class="elsevierStyleCrossRef" href="#bib0850">33</a> Os dados dos EIG no estudo foram consistentes com os dados dos programas de desenvolvimento dos iJAK e agentes biológicos modificadores do comportamento da AR (bDMARD) atualmente aprovados, nos quais as taxas de EIG foram semelhantes (3‐4 EIG/100 pacientes‐ano), com taxas mais elevadas em idosos.<a class="elsevierStyleCrossRefs" href="#bib0850">33,37</a>Os EAs mais comuns relatados nos estudos de fase III dos iJAK sistêmicos foram cefaleia, náuseas e nasofaringite. Infecções virais como herpes simples (HSV, herpes simplex virus), erupção variceliforme de Kaposi (eczema herpético [EH]) e herpes‐zóster (HZ) constituem os EA dermatológicos mais comuns em pacientes com dermatite atópica (DA) sob tratamento com iJAK.<a class="elsevierStyleCrossRef" href="#bib0750">13</a> A maioria dos dados sobre infecção pelo HSV procede do uso do tofacitinibe na AR, artrite psoriásica e DII. No entanto, há menor incidência de infecção pelo HSV, HZ e EH nos ensaisos clínicos de iJAK1 (seletivos) em pacientes com DA.<a class="elsevierStyleCrossRefs" href="#bib0875">38,39</a>No estudo JADE REGIMEN foram incluídos 1.233 pacientes com DA moderada a grave emfase aberta (12 semanas) em monoterapia com abrocitinibe 200mg/dia.<a class="elsevierStyleCrossRef" href="#bib0880">39</a> Ao final de 12 semanas, 798 pacientes (64,7%) foram considerados respondedores ao medicamento e aleatoriamente alocados no estudo cego com abrocitinibe 200mg/dia, 100mg/dia ou placedo (40 semanas). Considerando a fase de estudo aberto (indução) e cego, os pacientes completaram 52 semanas de seguimento. Na fase de indução (12 semanas), foram observados EIGs em seis pacientes (0,5%), com HZ em nove pacientes (0,7%). Na fase cega (40 semanas), as taxas de EIG e HZ variaram entre os pacientes alocados nos três diferentes grupos: (i) placebo, 267 pacientes, foram observados EIG em dois casos (0,7%) e em HZ dois casos (0,7%); (ii) abrocitinibe 100mg/dia, 265 pacientes, EIG em dois casos (0,8%) e HZ em dois casos (0,8%); (iii) abrocitinibe 200mg/dia, 266 pacientes, foram observados EIG em cinco casos (1,9%), e HZ em nove casos (3,4%). Somando‐se os três grupos da fase cega (20 semanas; 798 pacientes), foram foram nove casos (1,1%) de EIG e 13 (1,6%) de HZ.<a class="elsevierStyleCrossRef" href="#bib0880">39</a>Em metanálise sobre a eficácia e segurança de abrocitinibe, baricitinibe e upadacitinibe em pacientes com DA moderada a grave, os autores concluíram que quando se analisou o número total de EA (TEAE; do inglês, treatment‐emergent adverse events), o upadacitinibe e o abrocitinibe demonstraram maior incidência que o grupo placebo, e o abrocitinibe esteve associado a aumento nos TEAE, quando comparado com o baricitinibe. No entanto, quando se analisaram esses iJAK em relação aos TEAE e dose da medicação utilizada, apenas a dose de 30mg/dia do upadacitinibe aumentou a incidência dos TEAE: odds ratio (OR)=13,64. Ainda na metanálise de rede, a comparação dos eventos adversos de abrocitinibe versus placebo resultou em OR=5,57; baricitinibe versus placebo, OR=2,92; abrocitinibe versus baricitinibe, OR=1,92; abrocitinibe versus upadacitinibe, OR=0,41; e baricitinibe versus upadacitinibe, OR=0,21. Os autores da metanálise ressaltam que a maioria dos estudos de ensaios clínicos foi conduzida com avaliações de eficácia e segurança em um período curto de avaliação, sem comparação ainda em estudos entre eles, e que estudos de eficácia e segurança de longo prazo devem ser conduzidos.<a class="elsevierStyleCrossRef" href="#bib0885">40</a>Como exemplos de estudos de fase III publicados com casuística considerável, randomizados e placebo‐controlados, Measure Up1 e Measure Up2 avaliaram, respectivamente, 847 e 836 pacientes com DA moderada a grave alocados em grupos recebendo 30mg/dia, 15mg/dia de upadacitinibe ou placebo. Os desfechos primários de eficácia foram avaliados na semana 16, e os EA foram registrados (<a class="elsevierStyleCrossRef" href="#tbl0020">tabela 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>No que se refere às complicações infectocontagiosas, é importante considerar que as prevalências das doenças variam com a epidemiologia de cada país. A via JAK‐STAT faz a transmissão de sinalização intracelular de mais de 50 citocinas e fatores de crescimento e é considerada a via de comunicação central do sistema imune, inclusive na defesa contra patógenos.A alteração funcional do sistema JAK‐STAT pode ocorrer não apenas por ação farmacoterápica, mas também por mutações germinativas de perda ou ganho de função, as quais determinam diversos fenótipos imunes e doenças mieloproliferativas. Como exemplos: (i) mutações com perda de função da JAK3 são relacionadas com imunodeficiência combinada grave (SCID; do inglês, severe combined immunodeficiency); (ii) perda de função por mutações na STAT1 pode gerar deficiência de respostas ligadas às interferonas (IFN), tipo 1 (α e β) e IFN‐γ, ocasionando aumento na suscetibilidade de infecções virais; (iii) mutações com perda da função da JAK1, TYK2, STAT1 e STAT5B determinam infecções bacterianas intracelulares, e a deficiência da STATB5 pode ocasionar pneumonias de repetição; e (iv) mutação com ganho de função da STAT1 pode determinar infecções recorrentes por Candida spp., pois a STAT1 antagoniza os efeitos antifúngicos mediados pela IL‐17 via STAT3, suprimindo essa sinalização intracelular.<a class="elsevierStyleCrossRef" href="#bib0905">44</a>Pacientes com dermatoses crônicas inflamatórias apresentam maior risco de infecção em decorrência tanto de sua própria doença (p. ex., disbiose cutânea com colonização de estafilococos na DA) quanto pelo tratamento ao qual são submetidos, em particular imunossupressores como ciclosporina, azatioprina, micofenolato e metotrexato.<a class="elsevierStyleCrossRef" href="#bib0905">44</a> Como exemplo, na AR há o dobro de risco de esses pacientes apresentarem infecções graves, particularmente broncopulmonares e geniturinárias, que contribuem para maior mortalidade.<a class="elsevierStyleCrossRef" href="#bib0910">45</a> Assim, ao prescrever iJAK, um dos fatores a se considerar são os potenciais EAs dessas substâncias, mas também a idade do paciente (imunossenescência), comorbidades associadas e aspectos da patogênese da doença.Apesar de as infecções oportunistas se mostrarem mais frequentes em todas as classes de iJAK, não foram observadas diferenças em relação ao risco de EIGs em uma recente análise de rede de ensaios clínicos.<a class="elsevierStyleCrossRef" href="#bib0910">45</a> Contudo, os ensaios clínicos individuais não foram desenvolvidos para examinar desfechos raros.Uma análise dos estudos de extensão de longo prazo (EELP) sobre o tofacitinibe encontrou incidência de EIGs de 2,7 casos por 100 pacientes‐ano.<a class="elsevierStyleCrossRef" href="#bib0915">46</a> Quando os iJAK foram associados a drogas antirreumáticas modificadoras da doença (DMARDs; do inglês, disease‐modifying antirheumatic drugs) em um registro nos EUA com 21.832 pacientes com AR, houve maior ocorrência de EIGs com tofacitinibe associado a outro DMARD na taxa de 3,67 vs. 2,01 EIG para cada 100 pacientes‐ano entre os pacientes em uso apenas do DMARD. A incidência de EIG na associação tofacitinibe+DMARD foi, inclusive, maior que nos pacientes que utilizaram tofacitinibe+anti‐TNFα: 3,67 casos/100 pacientes‐ano vs. 2,16 casos/100 pacientes‐ano.<a class="elsevierStyleCrossRefs" href="#bib0920">47,48</a> Entretanto, esses dados ainda não estão disponíveis em doenças dermatológicas tratadas com iJAK.Dados de vida real de pacientes com DA comparando os perfis de segurança do baricitinibe e tofacitinibe confirmaram HZ como evento adverso mais frequente (5,6% tofacitinibe×4,9% baricitinibe).<a class="elsevierStyleCrossRef" href="#bib0885">40</a> O risco é maior em idosos e na coadministração com corticosteroides ou metotrexato.<a class="elsevierStyleCrossRef" href="#bib0905">44</a> No entanto, são poucos os casos de herpes disseminado ou acometendo vários dermátomos, sem evidência de doença visceral ou óbito pela infecção herpética. Os estudos clínicos demonstraram que o upadacitinibe apresentou maior risco de HZ comparado a indivíduos que utilizavam imunobiológicos e DMARDS.<a class="elsevierStyleCrossRef" href="#bib0905">44</a> Tal como nos iJAK de primeira geração, o upadacitinibe em pacientes com AR apresentou risco maior de HZ quando prescrito em doses elevadas, nas quais o HZ é mais provável ocorrer e ser mais grave e de natureza a envolver vários dermátomos.<a class="elsevierStyleCrossRef" href="#bib0930">49</a>Assim, a vacinação contra o vírus do HZ é um meio importante, embora imperfeito, de reduzir o impacto da infecção pelo HZV.<a class="elsevierStyleCrossRef" href="#bib0905">44</a> Porém, tanto a vacina contra varicela (Varivax®, para indivíduos não imunes com menos de 50 anos) quanto a vacina contra zóster (Zostavax® para indivíduos ≥ 50 anos) utilizam vírus vivos (assim como a da febre amarela) e, como tal, recomenda‐se administrar pelo menos três a quatro semanas antes do início dos iJAK.<a class="elsevierStyleCrossRef" href="#bib0905">44</a>No Brasil, já está disponível a vacina recombinante contra o HZV, Shingrix®, para pacientes com mais de 50 anos, adultos maiores de 18 anos com imunossupressão ou que vão receber imunossupressores, como os iJAK. Essa vacina confere taxas de proteção de 91,3% para pessoas com 70 anos ou mais, e de 67,3% em imunocomprometidos com mais de 50 anos. A vacina é composta pelo antígeno glicoproteína E (gE) da superfície viral e deve ser oferecida em duas doses (0‐2 meses). Como não utiliza partículas vivas, pode ser administrada em concomitância com o tratamento iJAK.<a class="elsevierStyleCrossRef" href="#bib0935">50</a>Estudos de eficácia sobre o uso de Shingrix® em uma população imunocomprometida ≥ 65 anos e em indivíduos tratados para DII com imunossupressores e ≥ 50 anos mostraram boa proteção contra HZ. Como ambos (iJAK e Shingrix®) estão recentemente disponíveis, o seguimento de longo prazo dessa associação deve revelar detalhes do perfil de imunização nesses pacientes.Os iJAK reduzem as diferentes citocinas e a sinalização dos receptores do fator de crescimento, dependendo do tipo de inibição de JAK. Tofacitinibe, um inibidor de JAK1/3, tem efeitos importantes no desenvolvimento dos linfócitos B naïve. Isso sugere perda na capacidade de imunização contra novos antígenos. Encontrou‐se resposta imune diminuída à vacina pneumocócica polissacarídica 23‐valente (PPSV‐23), especialmente em pacientes recebendo metotrexato concomitantemente: tofacitinibe, 45,1% vs. controles saudáveis 68,4%. A interrupção temporária do tofacitinibe por duas semanas (uma semana antes e uma após a vacinação) não restaurou a eficácia da vacina pneumocócica. Já os resultados para a vacina da influenza não foram afetados pelo uso do tofacitinibe.<a class="elsevierStyleCrossRef" href="#bib0940">51</a>No entanto, a maioria dos pacientes com psoríase tratada com tofacitinibe desenvolveu imunidade adequada contra infecção pneumocócica (vacina pneumocócica conjugada‐13) e vacina contra o tétano. A vacinação com a pneumocócica conjugada (PCV‐13) foi bem‐sucedida em 68% dos pacientes com AR tratados com o baricitinibe, enquanto apenas 43% alcançaram aumento ≥ 4×nas concentrações da IgG antitetânica. Contudo, a maioria dos pacientes também fazia uso de metotrexato (89%) e/ou corticosteroides (30%). Resultados semelhantes foram encontrados para upadacitinibe, com resposta humoral satisfatória (aumento ≥ 2×nos níveis de anticorpos) para a vacina PCV‐13 em 12 semanas em 65% e 55%,respectivamente, entre os pacientes em uso de 15mg/dia e 30mg/dia.<a class="elsevierStyleCrossRef" href="#bib0940">51</a>Assim, a opinião dos autores desta revisão é de que todo o calendário vacinal seja atualizado ao menos três a quatro semanas antes do início do uso dos iJAK sistêmicos, conforme orientações da autoridade de saúde local, inclusive aquelas do Ministério da Saúde do Brasil. E, durante o tratamento com iJAK, seja cumprido o calendário vacinal (exceto para vírus vivos), sem interrupção do tratamento.Tal como ocorre com outros imunossupressores e com imunobiológicos anti‐TNFα, há preocupação de infecção por Mycobacterium tuberculosis com o uso de iJAK,<a class="elsevierStyleCrossRef" href="#bib0770">17</a> e todos os pacientes que vão iniciar seu uso devem ser examinados e investigados quanto à tuberculose latente ou ativa.<a class="elsevierStyleCrossRef" href="#bib0905">44</a> O risco de infecção por tuberculose é dependente do risco epidemiológico de cada região. A incidência de tuberculose com tofacitinibe foi maior em regiões endêmicas (0,75/100 pacientes‐ano) em relação às regiões de menor risco (0,02/100 pacientes‐ano).<a class="elsevierStyleCrossRefs" href="#bib0905">44,52</a>Como o Brasil apresenta taxas endêmicas de tuberculose, que pode permanecer latente por décadas, a vigilância deve ocorrer previamente e durante o uso de imunossupressores como iJAK por meio do teste PPD (prova da tuberculina/Mantoux) ou dos ensaios de liberação da IFN (IGRA: ELISPOT, Quantiferon gold, Quantiferon gold plus), que apresentam performance discretamente superior.<a class="elsevierStyleCrossRefs" href="#bib0950">53,54</a> Testes de rastreio de tuberculose positivos devem ser referenciados ao infectologista a fim de considerar o tratamento da tuberculose latente com isoniazida, por nove meses, já que 5%‐10% apresentam ativação, especialmente em pacientes sob imunossupressão.No âmbito do uso de iJAK, essas medicações conferem maior risco de infecções gerais, risco de infecções oportunistas como pneumonia por Pneumocystis jirovecii, HZ, tuberculose, citomegalovirose e infecções por Epstein‐Barr vírus. Recomenda‐se: 1) rastreamento de infecção pelo vírus da hepatite B previamente ao tratamento; 2) profilaxia para P. jirovecii em pacientes com fatores de risco adicionais, como uso de corticosteroides; 3) rastreamento de tuberculose latente; 4) monitorização da carga viral em pacientes HBsAg negativos porém anti‐HBcAg positivos em virtude do risco de reativação de infecção oculta pelo vírus da hepatite C; 5) ao longo do uso crônico de iJAK, os médicos devem estar atentos para o aumento de outras infecções oportunistas, como infecções fúngicas invasivas, especialmente em pacientes que já apresentam risco adicional por fatores como uso prévio ou concomitante de corticosteroides, baixa contagem de linfócitos no hemograma ou terapia dependente de altas doses de iJAK.<a class="elsevierStyleCrossRef" href="#bib0960">55</a>Infecções fúngicas invasivas foram detectadas em EELP e nos ensaios com tofacitinibe em 15 casos entre 9.291 pacientes; infecção por Candida spp. foi a mais comum, seguida por critptococose, histplasmose e P. jirovecii.<a class="elsevierStyleCrossRef" href="#bib0905">44</a>Eventos tromboembólicosBaricitinibe, tofacitinibe, ruxolitinibe e upadacitinibe incluem advertências para potencial eventos de trombose venosa profunda, embolia pulmonar e trombose arterial.<a class="elsevierStyleCrossRef" href="#bib0965">56</a> Embora esses riscos pareçam ser baixos e dependentes da dose, estudos adicionais são necessários para determinar o mecanismo exato por trás de seus efeitos trombóticos.A descoberta pelo estudo ORALSURV de risco aumentado de tromboembolismo venoso (TEV) com dose de 10mg/dia do tofacitinibe em relação aos anti‐TNFα corrobora esse fato, observado pela primeira vez em ensaios clínicos com pacientes com AR na dose de 4mg/dia de baricitinibe, o que fortalece o conceito de que o TEV pode ser um verdadeiro evento adverso relacionado ao uso de iJAK em pacientes com AR.<a class="elsevierStyleCrossRef" href="#bib0905">44</a>Embora ainda falte plausibilidade biológica, é razoável especular que maior modulação de JAK2, observada com doses mais altas de tofacitinibe e baricitinibe, mediaria os efeitos trombóticos.<a class="elsevierStyleCrossRef" href="#bib0905">44</a> Contudo, de modo tranquilizador, os iJAK usados na AR, em suas doses atualmente aprovadas, ainda não parecem apresentar risco excessivo de eventos tromboembólicos.<a class="elsevierStyleCrossRef" href="#bib0905">44</a>O estudo ORALSURV relatou que 5mg/dia de tofacitinibe e o uso de anti‐TNFα estão associados a risco semelhante de TEV, e isso é consistente com dados do mundo real.<a class="elsevierStyleCrossRef" href="#bib0905">44</a> Além disso, as taxas de incidência de TEV observadas nos estudos principais de tofacitinibe e upadacitinibe foram semelhantes (e foram menores nos estudos de filgotinibe), e as taxas nos grupos de comparadores ativos desses programas (metotrexato ou adalimumabe) não foram superiores. Mesmo para o baricitinibe, para o qual o desequilíbrio inicial no risco de TEV entre as doses de 2mg/dia e 4mg/dia nas primeiras 12 semanas dos ensaios de fase III levantou suspeitas, taxas de incidência de longo prazo semelhantes foram relatadas para ambas as doses, de 0,5/100 pacientes‐ano, em linha com estudos de base populacional de AR.<a class="elsevierStyleCrossRefs" href="#bib0905">44,57</a>Por fim, baricitinibe 4mg/dia administrado por duas semanas não aumentou o risco de TEV no tratamento da COVID‐19, uma condição per se com risco aumentado de TEV no início do estudo.<a class="elsevierStyleCrossRef" href="#bib0975">58</a> Como as descobertas do ORALSURV sugerem haver risco dose‐dependente com tofacitinibe em relação aos anti‐TNFα, até que pesquisas mais fundamentadas sejam realizadas com cada um desses compostos, é prudente evitar os iJAK em pacientes com risco elevado de TEV, particularmente aqueles com história de TEV que não estejam atualmente anticoagulados.<a class="elsevierStyleCrossRef" href="#bib0905">44</a>Em 2021, a Food and Drug Administration (FDA) emitiu uma comunicação de segurança e exigiu revisões de preucaução na embalagem para os iJAK tofacitinibe, baricitinibe e upadacitinibe, que incluía informações sobre o risco de eventos cardíacos graves, câncer, trombose e óbito.<a class="elsevierStyleCrossRef" href="#bib0960">55</a>Neoplasias malignasA taxa geral de ocorrência de neoplasias malignas com o uso dos iJAK em ensaios clínicos randomizados envolvendo pacientes com AR e estudos de extensão de longo prazo foi semelhante à observada com bDMARD.<a class="elsevierStyleCrossRef" href="#bib0850">33</a>No estudo ORALSURV, a taxa de incidência de malignidade (por 100 pacientes‐ano) foi de 1,13 para pacientes tratados com tofacitinibe 5mg, 2×/dia e 1,13 com tofacitinibe 10mg, 2×/dia, em comparação com 0,77 para os anti‐TNFα.<a class="elsevierStyleCrossRefs" href="#bib0850">33,44</a>O maior risco de malignidades foi impulsionado por taxas diferenciais de vários tipos de câncer (particularmente câncer de pulmão e linfoma), observados principalmente nos grupos norte‐americanos do estudo (em comparação com o restante do mundo), entre indivíduos mais idosos e com histórico de tabagismo.<a class="elsevierStyleCrossRef" href="#bib0850">33</a> Também foi notado risco aumentado de câncer de pele não melanoma, observado anteriormente com o uso da dose de 10mg/dia de tofacitinibe na colite ulcerativa.<a class="elsevierStyleCrossRef" href="#bib0980">59</a> Entretanto, taxas mais altas de melanoma foram observadas em pacientes usando anti‐TNFα 0,09 vs. 0,02 para qualquer dose do tofacitinibe.<a class="elsevierStyleCrossRef" href="#bib0980">59</a>O mecanismo pelo qual os iJAK podem estar associados a alguns tipos de câncer é desconhecido, mas especula‐se que alguns iJAK, dependendo de sua seletividade e efeito nas células natural killer (NK), poderiam diminuir a imunovigilância do hospedeiro, tornando um câncer existente ou de novo com maior possibilidade de evolução, como ocorre com os outros imunossupressores<a class="elsevierStyleCrossRef" href="#bib0985">60</a>Em resumo, quando os iJAK orais são avaliados de modo geral, as taxas de TEV relatadas variaram de nenhum evento a 0,1%‐0,5% em ensaios clínicos específicos de dermatologia de fase III em comparação com nenhum evento no placebo. As taxas de eventos cardiovasculares variaram de nenhum evento a 0,4%‐1,2% em comparação com nenhum evento a 0,5%‐1,2% no placebo. As taxas de infecções graves foram de 0,4%‐4,8% em comparação com nenhum evento a 0,5%‐1,3% no placebo. As taxas de câncer de pele não melanoma variaram de nenhum evento a 0,6%‐0,9% em comparação com nenhum evento no placebo. As taxas de câncer de pele não melanoma variaram de nenhum evento a 0,2%‐0,7% em comparação com nenhum evento a 0,6% no placebo. A maioria dos pacientes que desenvolveram esses eventos adversos tinha fatores de risco para o evento específico. Os EA mais habituais foram infecções das vias aéreas superiores, náuseas, cefaleia, acne e dislipidemia.<a class="elsevierStyleCrossRef" href="#bib0990">61</a>Contraindicações aos iJAKA principal contraindicação aos iJAK é a incerteza no diagnóstico da doença inflamatória que se deseja tratar.<a class="elsevierStyleCrossRef" href="#bib0995">62</a> Várias dermatoses inflamatórias podem simular linfoma cutâneo de células T, como DA e psoríase; alopecias podem se relacionar a sífilis; hidradenite supurativa, a processos infecciosos como tuberculose, actinomicose, paracoccidioidomicose e doença de Crohn metastática. O uso inadvertido dos iJAK nessas condições pode desencadear desfechos graves.Outras contraindicações dos iJAK incluem: (i) hipersensibilidade aos componentes das medicações (p. ex., Tween 80); (ii) tuberculose; (iii) função renal alterada (baricitinibe); (iv) alteração grave da função hepática (upadacitinibe e abrocitinibe); (v) neutropenia <500 células/mm<a class="elsevierStyleCrossRef" href="#bib0700">3</a> (baricitinibe) ou <1.000 células/mm<a class="elsevierStyleCrossRef" href="#bib0700">3</a> (upadacitinibe e abrocitinibe); (vi) anemia (hemoglobina ≤ 9g/dL); (vii) processos infecciosos ativos; (viii) gestantes, mulheres com desejo de engravidar ou com vida sexual ativa sem uso de método contraconceptivo; (ix) plaquetopenia <50.000mm3 (abrocitinibe).<a class="elsevierStyleCrossRef" href="#bib0995">62</a>A prescrição também deverá ser reconsiderada caso o paciente se mostre impossibilitado de realizar exames de rastreamento infeccioso antes do início do tratamento ou acompanhamento regular durante o tratamento.Avaliação dos pacientes antes e durante o uso dos iJAKAnamnese e exame clínico geral, além do dermatológico, devem ser realizados em virtude das potenciais complicações com doenças infecciosas virais, bacterianas e fúngicas, além de neoplasias.Avaliar histórico de perda ponderal de causa não esclarecida, contatos profissionais ou familiares com doenças infectocontagiosas (tuberculose, doença de Chagas, hanseníase), não realização de exames periódicos de prevenção de câncer indicados para a faixa etária do paciente e antecedentes familiares de câncer ou de erros inatos da imunidade (imunodeficiências).<a class="elsevierStyleCrossRef" href="#bib0995">62</a>A palpação das cadeias linfonodais, fígado, baço, ausculta pulmonar e cardíaca, sinal de Giordano são essenciais a cada consulta. Outros dados a serem verificados antes do tratamento estão incluídos na <a class="elsevierStyleCrossRef" href="#tbl0025">tabela 5</a>.<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>Antes do tratamento e periodicamente, a cada dois meses, os pacientes em uso de iJAK sistêmicos devem realizar exames de sangue (hemograma, lipidograma, função hepática e renal), radiografia do tórax antes do tratamento, repetindo‐se quando indicado.Manejo de eventos durante o tratamento com os iJAKOs iJAK podem promover aumento dos lípides séricos, com aumento do colesterol total, LDL, HDL e triglicérides.<a class="elsevierStyleCrossRef" href="#bib0995">62</a> Os níveis do colesterol e triglicérides devem ser monitorados durante o tratamento, de modo que, quando necessário, antilipemiantes orais sejam utilizados, de acordo com os protocolos clínicos.<a class="elsevierStyleCrossRef" href="#bib1000">63</a>É comum a elevação da creatinofosfoquinase (CPK) durante o tratamento, geralmente não relacionado à miopatia, o que demanda atenção quanto aos resultados no seguimento laboratorial.<a class="elsevierStyleCrossRef" href="#bib0995">62</a> Postula‐se que o aumento nos níveis da CPK durante o uso do updacitinibe ocorra porque o iJAK1 inibe a ação fisiológica da oncostatina M (OSM), que bloqueia a diferenciação dos mioblastos a miócitos, onde se produz mais CPK. Uma vez que se perca essa via inibidora, mais mioblastos se diferenciam em miócitos e aumenta a síntese da CPK, sem rabdomiólise, apenas pela diferenciação celular. Acredita‐se que inclusive a OSM em níveis elevados determine a sarcopenia nos pacientes com AR. A suspeita de rabdomiólise decorrente do iJAK deve seguir mialgia, câimbras e escurecimento da urina, configurando urgência clínica.<a class="elsevierStyleCrossRef" href="#bib0995">62</a>Pacientes recebendo iJAK devem ser monitorados quanto à elevação das transaminases e orientados a procurar atendimento médico caso apresentem sintomas sistêmicos: náusea/vômitos/anorexia, como sintomas digestivos, e erupção cutânea/prurido/icterícia.<a class="elsevierStyleCrossRef" href="#bib0995">62</a>O risco de citopenias é maior entre pacientes> 65 anos. O iJAK deve ser interrompido em casos de neutropenia (< 1.000 neutrófilos/mm<a class="elsevierStyleCrossRef" href="#bib0700">3</a>), linfopenia (< 500 linfócitos/mm<a class="elsevierStyleCrossRef" href="#bib0700">3</a>), anemia (hemoglobina <8g/dL) ou plaquetopenia (< 50.000mm3).<a class="elsevierStyleCrossRef" href="#bib0995">62</a> Neutropenia e linfopenia aumentam os riscos de infecção, e o paciente deve ser orientado a procurar atendimento médico em caso de febre, calafrios ou dor de garganta ou tosse. Caso ocorram sintomas de fadiga, mal‐estar, palpitações, tonturas ou dispneia, dor abdominal de início abrupto, náuseas, vômitos ou anorexia, o paciente também deve buscar atendimento médico, pelo risco de perfuração intestinal. Em pacientes com doença diverticular do cólon, a perfuração gastrintestinal pode suceder uma diverticulite; esses pacientes devem ser instruídos e cautelosamente acompanhados.<a class="elsevierStyleCrossRef" href="#bib0995">62</a>Sintomas como tosse seca, dispneia ao exercício e febre devem alertar o paciente a procurar atendimento médico, sob risco de pneumopatia intersticial. Nesse caso, exames de sangue devem ser solicitados: PCR, DHL, Krebs von den Lungen‐6 (KL‐6) e SP‐D (surfactante protein D) – os níveis séricos dessas duas últimas são muito sensíveis no diagnóstico de pneumonite de hipersensibilidade medicamentosa.<a class="elsevierStyleCrossRef" href="#bib1005">64</a> Além disso, radiografia ou tomografia computadorizada do tórax e gasometria devem ser solicitados, devendo ser descontinuado o iJAK até o diagnóstico.Pneumonia por P. jirovecci pode ocorrer, e a dosagem dos níveis de β‐D‐glucana podem auxiliar o diagnóstico. Além disso, deve‐se afastar influenza, COVID‐19, infecções por Mycoplasma, Chlamydia e Legionella em pacientes com imagens radiológicas de padrão parenquimatoso intersticial, o que pode configurar pneumonia atípica não pneumocística. Excluídas causas infecciosas, pneumonia de doença pulmonar reumática induzida por medicamento deve ser considerada. Imagens radiológicas exsudativas no pulmão podem indicar pneumonia bacteriana ou tuberculose.<a class="elsevierStyleCrossRef" href="#bib0995">62</a>iJAK nas dermatoses inflamatórias e autoimunesA maior parte das dermatoses inflamatórias ou autoimunes não decorre do efeito de uma única citocina, porém, segue perfis inflamatórios que podem ser inibidos pela modulação da via JAK‐STAT. A base imunológica e os resultados clínicos dos principais iJAK, na dermatologia, são apresentadas adiante. A <a class="elsevierStyleCrossRef" href="#tbl0030">tabela 6</a> apresenta os iJAK com indicações dermatológicas descritas na literatura, e a <a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a> resume as principais substâncias com ensaios clínicos para uso na dermatologia.<elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Dermatite atópicaA DA apresenta alta prevalência, especialmente em crianças e adultos jovens. Seu curso crônico e redicivante, associado a comorbidades alérgicas e psicológicas, infligem importante impacto na qualidade de vida.<a class="elsevierStyleCrossRef" href="#bib1010">65</a> Sua patogênese é complexa e depende da interação de vários elementos. Em cerca de 80% dos pacientes ocorrem falha da barreira cutânea, especialmente por perda de função do gene da filagrina. Perda transepidérmica de água, alterações no microbioma cutâneo, em conjunto com permeabilidade a antígenos e hiper‐reatividade neural favorecem a exacerbação da resposta inflamatória local, manifesta especialmente como eczema e prurido.<a class="elsevierStyleCrossRefs" href="#bib1015">66,67</a>Apesar de ser considerada doença inflamatória com predominância do padrão Th2, diversas citocinas atuam conjuntamente para formar e manter um ambiente de hiper‐reatividade cutânea e que variam também entre as fases da doença.<a class="elsevierStyleCrossRef" href="#bib0700">3</a> O envolvimento no microambiente cutâneo, especialmente de IL‐4, IL‐5, IL‐10, IL‐13, IL‐31, IFN‐γ, IL‐17, IL‐22 e IL‐33, é indício do potencial dos iJAK, (principalmente JAK1) em seu tratamento.<a class="elsevierStyleCrossRefs" href="#bib1020">67,68</a>Modelos experimentais demonstraram que o tratamento da DA com iJAK levou à rápida supressão do prurido, melhora da barreira cutânea, das fibras nervosas cutâneas, redução do infiltrado linfocitário e das citocinas inflamatórias (p. ex., IL‐4 e IL‐13).<a class="elsevierStyleCrossRef" href="#bib1030">69</a>No Brasil, baricitinibe, abrocitinibe e upadacitinibe são aprovados para uso oral na DA moderada a grave; ruxolitinibe 1,5% creme está disponível no mercado dos EUA, e delgocitinibe 0,5% creme deve ser aprovado em 2023. Apesar de eficaz no tratamento da DA, não foram desenvolvidos ensaios clínicos com tofacitinibe oral – a maioria dos estudos é de relatos e séries de casos.<a class="elsevierStyleCrossRef" href="#bib1020">67</a> A <a class="elsevierStyleCrossRef" href="#tbl0035">tabela 7</a> resume os resultados de ensaios clínicos pivotais dos principais iJAK na DA.<elsevierMultimedia ident="tbl0035"></elsevierMultimedia>Nos estudos clínicos, todos os iJAK sistêmicos tiveram desempenho superior ao placebo, com rápido controle do prurido, melhora da qualidade de vida e do sono e redução da área de eczema. Doses mais altas e associação dos iJAK com corticosteroides tópicos promoveram melhor desempenho dos tratamentos, porém maior taxa de EA.Na comparação dos estudos individuais, abrocitinibe e upadacitinibe orais apresentaram maior proporção de redução de escores clínicos que baricitinibe.<a class="elsevierStyleCrossRefs" href="#bib0885">40,76</a> Apesar das diferenças entre os estudos nas faixas etárias e etnias dos pacientes, na duração e nas diferentes estratégias de resgate, espera‐se que ≥ 60% daqueles em uso de upadacitinibe nas doses de 15mg/dia e ≥ 70% na dose de 30mg/dia atinjam a redução ≥ 75% do Índice de Área e Gravidade do Eczema (EASI75).<a class="elsevierStyleCrossRefs" href="#bib0885">40,43</a> Já no abrocitinibe 100mg/dia e 200mg/dia, espera‐se que esses valores sejam ≥ 40% e ≥ 60%. E, no baricitinibe 2mg/dia e 4mg/dia, que sejam ≥ 18% e ≥ 21%.<a class="elsevierStyleCrossRef" href="#bib0885">40</a>A extensão por 52 semanas do estudo AD UP incluiu 901 pacientes entre 12 e 75 anos, com DA moderada ou grave, randomizados em três grupos: upadacitinibe 15mg/dia, 30mg/dia e placebo (primeiras 16 semanas), todos associados a corticosteroide tópico de baixa potência ou inibidor de calcineurina, 2×/dia. Na semana 52, a proporção de pacientes que atingiu EASI75 foi de 50,8% para o grupo upadacitinibe 15mg/dia e 69,0% para o grupo de 30mg/dia; 7,4% dos pacientes do grupo upadacitinibe 15mg/dia e 2,5% do grupo de 30mg/dia abandonaram o estudo por falta de eficácia.<a class="elsevierStyleCrossRef" href="#bib1035">70</a>No estudo BREEZE‐AD3, que faz o seguimento por 52 semanas de 292 pacientes do estudo BREEZE‐AD7 (16 semanas) em uso de baricitinibe 2 ou 4mg/dia e corticosteroides tópicos, observou‐se uma leve perda de eficácia: EASI75 51% na semana 16 para 43% na semana 68. Até 17,8% dos pacientes tratados com baricitinibe 2mg/dia e 28,4% dos tratados com baricitinibe 4mg/dia abandonaram o seguimento por falta de eficácia.<a class="elsevierStyleCrossRef" href="#bib1070">77</a>Em estudo de vida real que incluiu 44 pacientes adultos com DA tratados com baricitinibe, confirmou‐se a eficácia e perfil de segurança do medicamento; entretanto, o seguimento longitudinal revelou que o percentual de pacientes que atingiu EASI75 foi de 53% na semana 4, e 33% na semana 16; 7% dos pacientes abandonaram o estudo por eficácia insuficiente.<a class="elsevierStyleCrossRef" href="#bib1075">78</a> Esses dados apontam para a possibilidade de uma leve perda de eficácia dos tratamentos a partir da quarta semana.Ainda não há estudos randomizados comparando os iJAK orais a outros imunossupressores (p. ex., ciclosporina, azatioprina e metotrexato) na DA. Também não são disponíveis dados relativos à associação de iJAK tópico e sistêmico ou esquemas posológicos variáveis, como a utilização de doses altas nas primeiras semanas, com posterior redução das doses ou troca de estratégia para minimizar custo e EA.O estudo Heads up comparou 692 adultos com DA, randomizados para usar upadacitinibe oral 30mg/dia vs. dupilumabe 300mg a cada 14 dias, por 24 semanas. Na semana 16, o EASI75 foi atingido por 71% dos pacientes usando upadacitinibe e por 61% daqueles em uso de dupilumabe. Os demais desfechos clínicos seguiram essa superioridade do upadacitinibe, com destaque à maior e mais precoce redução do prurido. Na semana 24, o EASI75 do grupo upadacitinibe reduziu para 64%, enquanto o dupilumabe resultou em 59%. Ambos os grupos demandaram tratamentos de resgate antes da semana 16: upadacitinibe 20,3% e dupilumabe 17,5%.<a class="elsevierStyleCrossRef" href="#bib1080">79</a>Nessas doses, ao fim de 24 semanas, o estudo evidenciou maior frequência de acne (18,4% vs. 3,2%), HSV (0,9% vs. 0,0%) e HZ (3,4% vs. 1,2%) no grupo upadacitinibe, enquanto conjuntivite foi mais frequente no grupo dupilumabe (10,2% vs. 1,4%). Um participante do grupo upadacitinibe faleceu em decorrência de broncopneumonia associada à infecção pelo vírus influenza. No grupo upadacitinibe, houve maior frequência de alterações laboratoriais. Elevação das transaminases ocorreu em 3,4% vs. 1,1%, e dois participantes do grupo upadacitinibe descontinuaram o estudo por esse motivo. Anemia (2,0% vs. 0,3%), neutropenia (1,7% vs. 0,6%) e elevação da CPK (7,5% vs. 3,2%) também prevaleceram no upadacitinibe.<a class="elsevierStyleCrossRef" href="#bib1080">79</a> O perfil de segurança de longo prazo do dupilumabe permite recomendar sua administração sem a necessidade de seguimento laboratorial ou risco de interação medicamentosa.<a class="elsevierStyleCrossRefs" href="#bib1020">67,76</a>O estudo JADE DARE comparou abrocitinibe 200mg/dia vs. dupilumabe 300mg a cada 14 dias, em 726 pacientes com DA moderada a grave, por 26 semanas. Ao final do estudo, 73% dos pacientes do grupo abrocitinibe vs. 72% do grupo dupilumabe atingiram o EASI75. Conjuntivite foi mais prevalente no grupo dupilumabe (11% vs. 3%). No grupo abrocitinibe, foram mais frequentes: acne (13% vs. 3%), náuseas (19% vs. 2%), HSV (6% vs. 5%), HZ (3% vs. 0%) e cefaleia (13% vs. 7%).<a class="elsevierStyleCrossRef" href="#bib1085">80</a>Os iJAK tópicos (ruxolitinibe e delgocitinibe) ratificaram o rápido início de efeito (< 24 horas para redução do prurido), com alta taxa de eficácia, segurança e tolerabilidade. Até o momento, iJAK tópicos são indicados em quadros com menos de 20% da área corporal afetada e uso não prolongado.<a class="elsevierStyleCrossRefs" href="#bib0775">18,75,81</a> A eficácia dos iJAK tópicos aumenta com a concentração do ativo e o número de aplicações diárias. A boa tolerabilidade e o perfil de segurança podem revelar‐se oportunos no resgate de pacientes jovens com DA moderada a grave, que geralmente dependem de corticosteroides tópicos para tal. O uso estendido de ruxolitinibe 1,5% creme por até 44 semanas, com 1.249 adultos orientados a usar nas lesões, se necessário, resultou em bom perfil de tolerabilidade e segurança, sem evidências de efeito sistêmico. Entre 74% e 78% atingiram o fim do estudo com IGA 0/1.<a class="elsevierStyleCrossRef" href="#bib1095">82</a>Quando comparados os desempenhos dos iJAK tópicos em estudos clínicos individuais, tofacitinibe 2%, delgocitinibe 3% e ruxolitinibe 1,5% apresentaram maior redução de escores de DA que os esperados para os inibidores da PDE4 (p. ex., crisaborol).<a class="elsevierStyleCrossRefs" href="#bib1075">78,83</a>Em uma comparação duplo‐cega envolvendo 51 pacientes com DA usando triancinolona creme 0,15%, 2×/dia, sob diferentes concentrações e regimes de ruxolitinibe creme por oito semanas, tanto a triancinolona quanto as diferentes posologias de ruxolitinibe evidenciaram superioridade em relação ao veículo e incremento do efeito em função do tempo. EASI75 ocorreu em 56% dos pacientes do grupo que utilizou ruxolitinibe 1,5%, 2×/dia vs. 47% dos que usaram triancinolona.<a class="elsevierStyleCrossRef" href="#bib1105">84</a>De modo geral, os iJAK ainda não são liberados para crianças menores de 12 anos, exatamente a população mais afligida pela DA, porém os estudos de segurança têm avançado para ampliar a faixa etária de uso.Por fim, os iJAK orais ou tópicos revelaram‐se opções terapêuticas valiosas para a DA, com bom perfil de segurança, porém sua indicação em DA precisa ser bem definida frente aos demais imunossupressores, imunobiológicos e fototerapia.PsoríaseA patogênese da psoríase envolve tanto o sistema imune inato quanto o adaptativo, a partir de uma complexa interação entre queratinócitos, células dendríticas, linfócitos T, citocinas e outros mediadores inflamatórios. A inflamação crônica característica da doença é, principalmente, promovida pela IL‐23, a qual induz a diferenciação de células T naïve em linfócitos Th17 e sua expansão clonal.<a class="elsevierStyleCrossRefs" href="#bib1110">85,86</a>A transdução do sinal da IL‐23 é mediada pela TYK2. As células Th17 ativadas liberam citocinas proinflamatórias como TNFα, IL‐22, IL‐26 e IL‐29, as quais induzem a proliferação dos queratinócitos. Na psoríase, há ainda níveis séricos aumentados de citocinas Th1 (IFN‐γ e IL‐2), bem como níveis diminuídos de IL‐10. A IL‐22, produzida pelas células Th22, é citocina mediada pela via JAK‐STAT e induz a proliferação queratinocítica. A liberação da IL‐22, em associação à IL‐15, é sinalizada pela JAK1 e JAK3. Desse modo, a inibição da JAK/TYK é alvo potencial para seu tratamento. Contudo, face à patogênese da doença, os iJAK de segunda geração, seletivos para JAK2/TYK2, seriam potencialmente mais efetivos do que os que bloqueiam múltiplas isoformas de JAK/TYK.<a class="elsevierStyleCrossRefs" href="#bib0690">1,87</a> A propósito, indivíduos com polimorfismo genético e consequente perda da função da TYK2 apresentam menor risco de desenvolver psoríase e outras doenças imunomediadas.<a class="elsevierStyleCrossRef" href="#bib1125">88</a>De maneira geral, tofacitinibe (2, 5, 10 e 15mg, 2×/dia), solcitinibe (200 e 400mg, 2×/dia), baricitinibe (8 e 10mg, 2×/dia) e deucravacitinibe (3 e 6mg, 2×/dia) apresentaram resposta PASI75 superior ao placebo, tanto na semana 8 quanto na 12, nos ensaios clínicos randomizados de psoríase em placas moderada à grave.<a class="elsevierStyleCrossRefs" href="#bib1130">89,90</a>Uma metanálise concluiu que tofacitinibe (15 e 10mg, 2×/dia) e deucravacitinibe (6mg, 2×/dia e 12mg/dia) apresentaram as melhores respostas de PGA e PASI75 (nas semanas 8 e 12), dentre os iJAK utilizados no tratamento da psoríase em placas. Apesar de a mesma metanálise mostrar perfil satisfatório de segurança dos iJAK no tratamento da psoríase em placa, tofacitinibe não obteve aprovação pela FDA em virtude dos efeitos colaterais apresentados; o medicamento é aprovado apenas na dose de 5mg, 2×/dia, para a terapia da AR. Os iJAK em estudo para o tratamento da psoríase em placas são deucravacitinibe, brepocitinibe e ropsacitinibe, todos inibidores da TKY2.<a class="elsevierStyleCrossRef" href="#bib1130">89</a>No Brasil, tofacitinibe 5mg, 2×/dia, é aprovado para o tratamento da artrite psoriásica em adultos. Contudo, pode ser eficaz no tratamento da psoríase ungueal; 33% dos pacientes atingiram NAPSI50 na semana 16 com tofacitinibe 5mg, 2×/dia, 44% com 10mg, 2×/dia, e 12% com placebo.<a class="elsevierStyleCrossRef" href="#bib1140">91</a>Atualmente, o único iJAK tópico em estudo para o tratamento da psoríase é o brepocitinibe, inibidor ortostérico da JAK1 e JAK2. Em ensaio fase I envolvendo indivíduos sadios e doentes com psoríase em placas moderada a grave, o brepocitinibe confirmou segurança e boa tolerabilidade.<a class="elsevierStyleCrossRef" href="#bib1145">92</a>Em comparação ao apremilaste, único outro medicamento oral aprovado para a terapia da psoríase, os inibidores da JAK2/TYK2 apresentam maior seletividade imunológica, restringindo a possibilidade de efeitos colaterais. O deucravacitinibe foi aprovado pela FDA e pela agência japonesa para o tratamento da psoríase em placa moderada a grave em adultos.<a class="elsevierStyleCrossRef" href="#bib1150">93</a> Estudo randomizado com 332 pacientes usando 6mg/dia revelou resposta PASI75 superior, na semana 16, ao apremilaste oral 30mg, 2×/dia e placebo (58%, 35% e 13%). A taxa de efeitos colaterais foi similar nos três grupos. Entretanto, não se recomenda associar deucravacitinibe com outros imunossupressores.<a class="elsevierStyleCrossRef" href="#bib1155">94</a>Alopecia areataA alopecia areata (AA) tem patogênese autoimune envolvendo o colapso do privilégio imunológico no folículo piloso. Nas áreas de AA, observa‐se infiltrado inflamatório composto por linfócitos CD4+, CD8+ e NK ao redor do bulbo dos folículos em fase anágena, levando à interrupção da melanogênese e da produção da haste.<a class="elsevierStyleCrossRef" href="#bib1160">95</a> A presença dos linfócitos TCD8+NKG2D+ é determinante para o desenvolvimento das lesões de alopecia.<a class="elsevierStyleCrossRef" href="#bib1165">96</a>IFN‐γ e IL‐15 induzem, principalmente, resposta citotóxica do tipo I. Linfócitos T CD8+ produzem IFN‐γ, que contribuem para a quebra do privilégio imunológico, induzindo a produção de IL‐15 pelas células epiteliais, que por sua vez leva à ativação das células efetoras CD8+NKGD2+ com mais produção de IFN‐γ fechando o ciclo que perpetua a doença. Tanto a ação da IFN‐γ na célula epitelial quanto da IL‐15 nas células CD8+NKG2D+ são mediadas pela via JAK‐STAT.<a class="elsevierStyleCrossRef" href="#bib1165">96</a>A partir do relato de repilação de AA com tofacitinibe empregado no tratamento de psoríase,<a class="elsevierStyleCrossRef" href="#bib1170">97</a> múltiplas séries de casos e estudos abertos não comparativos foram publicados mostrando resultados favoráveis com uso dos iJAK sistêmicos para tratamento da AA grave. O medicamento utilizado com mais frequência foi o tofacitinibe, seguido por ruxolitinibe e baricitinibe.<a class="elsevierStyleCrossRefs" href="#bib1175">98,99</a>Em estudo comparativo aberto, 75 pacientes com AA comprometendo mais de 30% do couro cabeludo foram randomizados em dois grupos: tofacitinibe 10mg/dia e ruxolitinibe 40mg/dia. Após seis meses de tratamento, ambos apresentaram melhora, sem diferença entre eles. O escore SALT50 foi atingido por 84% dos pacientes no grupo ruxolitinibe e 78% do grupo tofacitinibe, em seis meses.<a class="elsevierStyleCrossRef" href="#bib1185">100</a>Em dois ensaios duplo‐cegos (BRAVE‐AA1, BRAVE‐AA2), pacientes com AA grave foram randomizados em três grupos: baricitinibe 2mg/dia, 4mg/dia ou placebo. Um total de 1.200 pacientes foi incluído para a análise de fase III desses estudos, na semana 36. O escore SALT20 foi atingido por 20% e 34% nos braços de 2 e 4mg/dia de baricitinibe, em comparação com 4% no placebo.<a class="elsevierStyleCrossRef" href="#bib1190">101</a> A porcentagem de pacientes que descontinuou o tratamento por EA foi semelhante entre os grupos. Em 2022, o baricitinibe recebeu aprovação da FDA para o tratamento da AA.No estudo ALLEGRO, 718 pacientes foram randomizados em seis grupos: ritlecitinibe 200mg/dia por quatro semanas e após 50mg/dia por 20 semanas; ritlecitinibe 200mg/dia por quatro semanas e após 30mg/dia por 20 semanas; ritlecitinibe 50mg/dia por 24 semanas; ritlecitinibe 10mg/dia por 24 semanas, ou placebo. A resposta ao ritlecitinibe foi dose‐dependente e 31% dos que usaram 50mg/dia após dose de ataque atingiram SALT20 na semana 24.<a class="elsevierStyleCrossRef" href="#bib1195">102</a>Em um ensaio fase II, 149 pacientes foram divididos em quatro grupos: deuruxolitinibe 12, 8, 4mg/dia e placebo. Houve resposta dose‐dependente: 42%, 26%, 14% e 7% (placebo) dos pacientes atingiram SALT20 na semana 24.<a class="elsevierStyleCrossRef" href="#bib1200">103</a>Um ensaio duplo‐cego recrutou 16 participantes com AA universal que foram orientados a aplicar tofacitinibe 2% pomada, ruxolitinibe 1% pomada, clobetasol 0,05% pomada e placebo, em diferentes locais do couro cabeludo. Seis pacientes (38%) em uso de tofacitinibe, cinco (31%) do ruxolitinibe e 10 (63%) do clobetasol tiveram repilação parcial nas áreas de tratamento, enquanto nenhum teve crescimento com placebo.<a class="elsevierStyleCrossRef" href="#bib1205">104</a>Em estudo aberto, o ruxolitinibe 1,5% creme não se mostrou eficaz comparado ao placebo.<a class="elsevierStyleCrossRef" href="#bib1210">105</a> Delgocitinibe 3% em pomada também não apresentou melhora no SALT após 12 semanas de tratamento.<a class="elsevierStyleCrossRef" href="#bib1215">106</a> A baixa eficácia dos iJAK tópicos pode ser explicada pela dificuldade de penetração em camadas profundas da pele, não permitindo alcançar a inflamação peribulbar. Veículos que facilitem a penetração cutânea podem trazer perspectivas para os iJAK na AA.O tratamento da AA grave é desafiador. Muitos pacientes não respondem à terapia convencional com imunossupressores sistêmicos ou são limitados pelos EA. Os casos graves apresentam altas taxas de recidiva após a suspensão do tratamento. Em consenso organizado pela Sociedade Brasileira de Dermatologia (2020), orienta‐se o uso dos iJAK sistêmicos como opção para AA extensa nos casos refratários à terapia convencional.<a class="elsevierStyleCrossRef" href="#bib1220">107</a> Deve‐se destacar que, nos estudos que permitiram a aprovação do baricitinibe pela FDA, menos de 40% dos pacientes atingiram SALT20. Além disso, pacientes com mais de oito anos de doença (pior prognóstico) não foram incluídos. Estudos comparando iJAK sistêmicos com outros imunossupressores são essenciais para estabelecer reais benefícios frente às terapias disponíveis.Na maioria dos casos, a manutenção dos resultados alcançados na AA depende da continuidade do tratamento. Estudos com maior período de seguimento são necessários para determinar a eficácia e segurança dos iJAK a longo prazo.VitiligoO vitiligo afeta indivíduos suscetíveis geneticamente, e a autoimunidade é a principal causa da agressão aos melanócitos. As hipo/acromias, localizadas ou generalizadas, são as manifestações da destruição dos melanócitos dirigida pelos linfócitos T citotóxicos.<a class="elsevierStyleCrossRef" href="#bib1225">108</a>As duas principais citocinas envolvidas na patogênese do vitiligo são a IFN‐γ e a IL‐15.<a class="elsevierStyleCrossRef" href="#bib1230">109</a> A primeira é produzida pelos linfócitos T de memória (TRM) presentes na pele despigmentada e se liga ao receptor de IFN‐γ para estimular a expressão de quimiocinas como CXCL9, CXCL10 e CXCL11, que promovem a infiltração de células T autorreativas.<a class="elsevierStyleCrossRef" href="#bib1235">110</a> A IL‐15 é produzida principalmente por queratinócitos, e está envolvida na sinalização para geração e manutenção das TRM na pele lesada.<a class="elsevierStyleCrossRef" href="#bib1240">111</a>Duas iJAK são exploradas para o tratamento do vitiligo: ruxolitinibe 1,5% creme foi aprovado para uso nos EUA,<a class="elsevierStyleCrossRef" href="#bib1245">112</a> e ritlecitinibe 10‐50mg/dia oral encontra‐se em estudo de fase IIb.<a class="elsevierStyleCrossRef" href="#bib1250">113</a> Há relatos anedóticos do uso do tofacitinibe 5‐10mg/dia oral e tópico 2% creme ou pomada no vitiligo;<a class="elsevierStyleCrossRefs" href="#bib1255">114,115</a> entretanto, não foram publicados ensaios clínicos randomizados e controlados com essa substância.O racional do uso de iJAK em vitiligo decorre de estudos farmacológicos pré‐clínicos que demonstraram a inibição da ação citolítica dos linfócitos T CD8+ e células NK quando inibidas enzimas da família das quinases (BTK, BMX, ITK, RLK e TEC) pelo ritlecitinibe, principalmente ITK, no caso dos linfócitos T citotóxicos, e RLK e TEC no caso das células NK. Ritlecitinibe é altamente seletivo para JAK3 e, potencialmente, inibe IL‐2 e IL‐15. Além disso, com base em estudos in vitro e ensaios celulares, ritlecitinibe pode diminuir a produção de IFN‐γ liberada por células T citotóxicas e NK, relacionadas a uma provável inibição de ITK.<a class="elsevierStyleCrossRefs" href="#bib1265">116,117</a>O ruxolitinibe é um inibidor de JAK1 e JAK2, cujo creme 1,5% diminuiu a concentração sérica de CXCL10, além de diminuir a ação pró‐inflamatória de quimiocinas e IL‐15 em cultivo celular de queratinócitos e melanócitos.<a class="elsevierStyleCrossRefs" href="#bib1275">118,119</a>O tofacitinibe é um inibidor de JAK1 e JAK3. Em um estudo com modelo murino de vitiligo‐induzido, o nível sérico de CXCL10 foi menor no grupo tratado com tofacitinibe oral comparado com o grupo placebo.<a class="elsevierStyleCrossRef" href="#bib1285">120</a> Contudo, o ritlecitinibe tem maior efeito inibitório de JAK3, comparado ao tofacitinibe.<a class="elsevierStyleCrossRef" href="#bib1270">117</a>Dois estudos randomizados, duplo‐cegos e controlados por placebo com ruxolitinibe creme a 1,5% envolveram pacientes maiores de 12 anos com vitiligo não segmentar e área afetada de no máximo 10% da superfície corporal. Os pacientes foram randomizados para usar o medicamento ou o veículo (2:1), 2×/dia na face ou no corpo por 24 semanas; depois desse período, todos utilizaram o ativo, totalizando 52 semanas. Os desfechos primários foram a melhora desde o início do tratamento de ao menos 75% do Vitiligo Area Score Index (VASI) facial, ou resposta F‐VASI75 (F‐VASI com escore de 0 a 3) na semana 24.<a class="elsevierStyleCrossRef" href="#bib1245">112</a>No total, 674 pacientes foram incluídos, 330 em um estudo denominado TRue‐V1 e 344 no chamado TRue‐V2. No primeiro estudo, a porcentagem de pacientes que atingiy reposta F‐VASI75 na semana 24 foi de 29,8% no grupo ruxolitinibe e 7,4% no grupo placebo (risco relativo, 4,0; intervalo de confiança [IC] de 95%, 1,9‐8,4); no segundo estudo, 30,9% e 11,4%, respectivamente (risco relativo, 2,7; 95%IC 1,5‐4,9). Os EA mais comuns em cada estudo foram acne (6,3% e 6,6%), nasofaringite (5,4̈% e 6,1%) e prurido no local de aplicação (5,4% e 5,3%), respectivamente.Um importante desfecho secundário foi a diminuição de 50% do T‐VASI (área total afetada), desde o início do tratamento (T‐VASI50). Aproximadamente 20% dos pacientes alcançaram uma resposta T‐VASI50 e 50% dos pacientes atingiram F‐VASI50. Essa desproporção é usual em ensaios de vitiligo em virtude da maior concentração de folículos na face, de onde migram melanoblastos para a repigmentação.<a class="elsevierStyleCrossRefs" href="#bib1290">121,122</a>Até o momento, não existem estudos randomizados e controlados com ruxolitinibe oral no tratamento do vitiligo, tampouco ruxolitinibe tópico comparado ou associado aos tratamentos ativos de escolha (fototerapia, inibidores de calcineurina ou corticosteroides tópicos).Outro estudo randomizado controlado com placebo utilizou ritlecitinibe oral dose‐escalonado, por 24 semanas, com um período de extensão de 24 semanas e mais oito semanas de seguimento, em pacientes com vitiligo não segmentar entre 18 e 65 anos de idade, área corporal afetada entre 4% e 50%, e área facial afetada> 25%.<a class="elsevierStyleCrossRef" href="#bib1250">113</a> Os pacientes foram randomizados em cinco grupos com ritlecitinibe e um com placebo. Dois grupos receberam dose de ataque de 100 ou 200mg/dia por quatro semanas seguidos de 50mg/dia de manutenção, por 20 semanas. Três grupos receberam 50, 30 ou 10mg/dia por 24 semanas, e um grupo recebeu placebo por 24 semanas. Os pacientes foram alocados no período de extensão com base na resposta na semana 16; não respondedores (< 50% T‐VASI) foram alocados para um grupo aberto com brepocitinibe, outro aberto com ritlecitinibe+fototerapia com UVB de banda estreita (NBUVB) ou ritlecitinibe 200mg de dose de ataque+50mg/dia. O desfecho primário foi a mudança desde o início no F‐VASI central na semana 24; o desfecho secundário foi a proporção de pacientes com F‐VASI75 central na semana 24.Um total de 364 pacientes recebeu tratamento, e para fins de comparação com o estudo de ruxolitinibe tópico vamos usar os resultados do desfecho secundário. F‐VASI75 na semana 24 foram alcançados em 12,1%, 8,5%, 7,7%, 2,7%, 2,3% e 0% nos grupos ritlecitinibe 200/50mg, 100/50mg, 50mg, 30mg, 10mg e placebo, respectivamente. Quanto à segurança, 77% dos pacientes apresentaram algum EA, e os três mais comuns foram nasofaringite (15,9%), infecções de trato respiratório superior (11,5%) e cefaleia (8,8%).Apesar dos resultados modestos na semana 24, percebeu‐se a aceleração da repigmentação após a semana 28. A morosidade no processo de repigmentação é bem fundamentado, o que justifica a fototerapia como tratamento adjuvante na aceleração da repigmentação, pelo menos com as medicações antitirosina quinase aqui apresentadas, como no caso do tofacitinibe, ruxolitinibe e mesmo pela alocação de alguns dos não respondedores com ritlecitinibe para um braço de ritlecitinibe associado com NBUVB.<a class="elsevierStyleCrossRefs" href="#bib1300">123,124</a>Se comparados os estudos com ruxolitinibe tópico e ritlecitinibe oral em relação ao F‐VASI75 na semana 24, a resposta do ruxolitinibe foi superior (30% vs. 12,1%).<a class="elsevierStyleCrossRef" href="#bib1310">125</a> É relevante ainda que esse desfecho tenha sido atingido com a maior dose de ritlecitinibe, o F‐VASI tenha sido calculado apenas no centro da face e os pacientes do ruxolitinibe apresentavam fototipos mais baixos que os do estudo do ritlecitinibe, que são mais difíceis de repigmentar.<a class="elsevierStyleCrossRef" href="#bib1250">113</a>Até o momento, não existem estudos randomizados e controlados com ruxolitinibe oral no tratamento do vitiligo, tampouco, ruxolitinibe tópico comparado ou associado aos tratamentos tópicos de escolha (inibidores de calcineurina, ou corticosteroides tópicos). Não obstante, em um estudo com camundongos como modelo, foi administrado oralmente tofacitinibe ou ruxolitinibe. Como resultado, foi observada superioridade do tofacitinibe em relação ao ruxolitinibe na diminuição nos escores de vitiligo dos pacientes afetados.<a class="elsevierStyleCrossRefs" href="#bib1265">116,126</a>Desse modo, os iJAK revelaram‐se potenciais terapêuticas para o vitiligo, com bom perfil de segurança, porém, que devem ser explorados em associação com outras medidas (p. ex., fototerapia) para maximizar sua eficácia.Outras dermatosesA hidradenite supurativa (HS) decorre da desregulação do sistema imune inato e adaptativo, evolvendo diversas citocinas mediadas pela via JAK‐STAT (p. ex., IL‐17, IL‐23, IL‐10) e, em menor quantidade, TNF‐α. Tofacitinibe 5mg, 2×/dia, foi relatado em dois pacientes, com resultados favoráveis.<a class="elsevierStyleCrossRef" href="#bib1320">127</a>Um estudo retrospectivo com 20 pacientes em uso de upadacitinibe demonstrou que 75% dos indivíduos atingiram HiSCR50 em quatro semanas, e 100% em 12 semanas. Todos receberam 15mg/dia, e os que não atingiram HiSCR50 em quatro semanas tiveram a dose aumentada para 30mg/dia.<a class="elsevierStyleCrossRef" href="#bib1325">128</a> Estudos de fase II com INCB054707, 15mg, 30mg, 60mg e 90mg/dia, demonstraram que 43%, 56%, 56% e 88% dos pacientes,respectivamente, atingiram HiSCR na semana 8.<a class="elsevierStyleCrossRef" href="#bib1330">129</a>Pioderma gangrenoso (PG) é dermatose inflamatória neutrofílica com incidência estimada de 3‐10 casos/milhão de pessoas‐ano. Sua patogênese é mal compreendida, mas parece envolver a desregulação tanto da imunidade inata quanto da adaptativa.<a class="elsevierStyleCrossRef" href="#bib1335">130</a> A frequência de comorbidades imunomediadas associadas, superexpressão de citocinas inflamatórias, além da resposta a imunomoduladores (p. ex., corticoides, anti‐TNFα, inibidores de calcineurina) reforçam um mecanismo subjacente imunomediado.<a class="elsevierStyleCrossRef" href="#bib1340">131</a>Não existe abordagem padronizada na estratégia terapêutica imunossupressora do PG, havendo casos resistentes.<a class="elsevierStyleCrossRefs" href="#bib1340">131,132</a> Já foram demonstradas desregulações da via JAK‐STAT no PG, com JAK1, JAK2, JAK3 e STAT1 a STAT6 superexpressas nas lesões. Mutações da via JAK‐STAT também foram implicadas na progressão do PG.<a class="elsevierStyleCrossRef" href="#bib1335">130</a> Apesar de não haver estudos clínicos controlados, diversos relatos demonstraram benefícios do tofacitinibe, ruxolitinibe e baricitinibe em casos de PG.<a class="elsevierStyleCrossRefs" href="#bib1345">132–135</a>Dermatomiosite (DM) é doença multissistêmica em que ocorre ativação do sistema imune inato com secreção de interferonas do tipo I. As atuais opções de tratamento incluem uma combinação de fotoproteção, glicocorticoides (GCs), imunossupressores e imunomoduladores.Tofacitinibe foi relatado com sucesso em casos refratários de DM em doses de 5mg, 2×/dia, em 34 pacientes, 11mg/dia (liberação prolongada) em 10 pacientes e 10mg, 2×/dia, em dois pacientes. Ruxolitinibe foi usado em sete pacientes com dose máxima de até 30mg/dia. Após o início do tratamento, não ocorreu nenhuma recidiva em 3‐15 meses, havendo melhora dos sinais cutâneos, sintomas e testes de força muscular.<a class="elsevierStyleCrossRef" href="#bib1365">136</a> No entanto, a maioria dos estudos incluídos nessa revisão foi de séries de casos, que são suscetíveis a viés de observação, e não houve comparação direta com outro método de tratamento.A doença enxerto versus hospedeiro (DEVH) desenvolve‐se após transplante alogênico de células‐tronco hematopoéticas, quando as células T do doador não apenas reconhecem as células tumorais remanescentes como estranhas, mas também o tecido do receptor, levando a uma condição potencialmente grave. Órgãos‐alvo típicos incluem a pele, o fígado e os do trato digestório. Atualmente, todas as estratégias aprovadas para o tratamento da DEVH são terapias imunossupressoras, como a corticoterapia.Como a DEVH é caracterizada principalmente pelo aumento das citocinas pró‐inflamatórias, esclerose sistêmica e dano de órgãos internos, a inibição da sinalização das tirosina quinases ativadas revelou‐se estratégia promissora para reduzir a gravidade e a progressão da doença. Várias pequenas moléculas estão sendo estudadas (fases I a III), entre elas: ruxolitinibe, itacitinibe, baricitinibe, ibrutinibe (inibidor da tirosina quinase de Bruton) e pacritinibe.O tratamento com ruxolitinibe para DEVH aguda refratária à corticoterapia diminui os níveis de citocinas pró‐inflamatórias no soro dos pacientes e o número de células T ativadas, com taxa de resposta total de 82%. Efeitos similares foram obtidos em pacientes tratados com itacitinibe. Na DEVH crônica refratária, estudo de fase III com ruxolitinibe demonstrou quase o dobro de valores no alcance dos objetivos primários do tratamento em relação ao grupo controle.<a class="elsevierStyleCrossRef" href="#bib1370">137</a>O reconhecimento dos iJAK como opção terapêutica para o tratamento de dermatoses pruriginosas crônicas começou a partir da DA. Porém, recentemente o gusacitinibe oral recebeu a designação de fast track pela FDA para o tratamento de eczema crônico das mãos. Além disso, iniciaram‐se ensaios clínicos do delgocitinibe tópico para tratamento de eczema crônico das mãos em pacientes pediátricos e adultos. Ainda, como a patogênese do prurigo nodularis (PN) envolve inflamação mediada por Th2 e Th17/Th22, que podem ser atenuadas por meio dos iJAK, estudos de fase II estão examinando o papel de abrocitinibe no tratamento do PN e prurido crônico de origem desconhecida.<a class="elsevierStyleCrossRef" href="#bib0990">61</a>Conclusão e pesquisas futurasHá intensa atividade científica ligada ao desenvolvimento de medicamentos que interfiram em diferentes níveis da via JAK‐STAT, assim como a exploração de novas indicações e regimes posológicos.O perfil de segurança da inibição das JAK, especialmente da JAK1 ou JAK3, associada à modulação da resposta imune, deve levar ao progressivo aumento do uso de iJAK em comparação aos imunossupressores (como os corticosteroides orais, azatioprina, micofenolato, metotrexato e ciclosporina) no tratamento de dermatoses inflamatórias e autoimunes. Todavia, apenas os ensaios clínicos com comparadores ativos podem posicionar os iJAK quanto às melhores indicações, regimes posológicos e seus aspectos farmacoeconômicos.Por fim, a maior disponibilidade de moléculas deve levar à redução do custo ao sistema de saúde e aumentar o acesso aos pacientes. Em contrapartida, seu uso de longo prazo deve esclarecer aspectos ligados à manutenção da eficácia terapêutica, o impacto do bloqueio imunológico de vias seletivas de citocinas, além da segurança quanto à emergência de infecções e neoplasias malignas.Suporte financeiroNenhum.Contribuição dos autoresHélio Amante Miot: Idealização do estudo, escrita e aprovação do texto final.Paulo Ricardo Criado: Idealização do estudo, escrita e aprovação do texto final.Caio César Silva de Castro: Idealização do estudo, escrita e aprovação do texto final.Mayra Ianhez: Idealização do estudo, escrita e aprovação do texto final.Carolina Talhari: Idealização do estudo, escrita e aprovação do texto final.Paulo Müller Ramos: Idealização do estudo, escrita e aprovação do texto final.Conflito de interessesDr. Caio Castro: Advisory Board ‐ Sanofi, Aché, Sun‐Pharma, Galderma. Speaker ‐ Abbvie, Jansen, Novartis, Sanofi, Leo‐ Pharma. Pesquisa Clínica ‐ Abbvie, Pfizer, Jansen, Sanofi.Dr. Paulo Criado pesquisa Clínica para Pfizer, Novartis, Sanofi e Lilly; Advisory board Pfizer, Galderma, Takeda, Hypera, Novartis, Sanofi. Palestrantre: Pfizer, Abbvie, Sanofi, Hypera, Takeda, Novartis.Dr. Hélio Miot: Advisory Board – Johnson & Johnson, L’Oréal, Theraskin e Pfizer; pesquisa clínica Abbvie e Merz.Dra. Mayra Ianhez: Speaker e Advisory Board ‐ Abbvie, Sanofi‐Genzyme, Pfizer, Janssen, Galderma, Theraskin.Dr. Paulo Müller Ramos: Advisory Board – Pfizer;Dra. Carolina Talhari: Nenhum conflito de interesses." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1940767" "titulo" => "Resumo" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1672273" "titulo" => "Palavras‐chave" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introdução" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Via JAK‐STAT" ] 4 => array:3 [ "identificador" => "sec0105" "titulo" => "Principais características dos iJAK na dermatologia" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Segurança e tolerabilidade dos iJAK" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Interações medicamentosas" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Infecções e eventos adversos gerais" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Eventos tromboembólicos" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Neoplasias malignas" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Contraindicações aos iJAK" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Avaliação dos pacientes antes e durante o uso dos iJAK" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Manejo de eventos durante o tratamento com os iJAK" ] ] ] 5 => array:3 [ "identificador" => "sec0055" "titulo" => "iJAK nas dermatoses inflamatórias e autoimunes" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Dermatite atópica" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Psoríase" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Alopecia areata" ] 3 => array:2 [ "identificador" => "sec0075" "titulo" => "Vitiligo" ] 4 => array:2 [ "identificador" => "sec0080" "titulo" => "Outras dermatoses" ] ] ] 6 => array:2 [ "identificador" => "sec0085" "titulo" => "Conclusão e pesquisas futuras" ] 7 => array:2 [ "identificador" => "sec0090" "titulo" => "Suporte financeiro" ] 8 => array:2 [ "identificador" => "sec0095" "titulo" => "Contribuição dos autores" ] 9 => array:2 [ "identificador" => "sec0100" "titulo" => "Conflito de interesses" ] 10 => array:1 [ "titulo" => "Referências" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-01-14" "fechaAceptado" => "2023-03-02" "PalabrasClave" => array:1 [ "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras‐chave" "identificador" => "xpalclavsec1672273" "palabras" => array:6 [ 0 => "Alopecia areata" 1 => "Dermatite atópica" 2 => "Inibidores de Janus Quinases" 3 => "Psoríase" 4 => "Tratamento" 5 => "Vitiligo" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "A via de sinalização Janus Quinase (JAK) e transdutor de sinal/ativador da transcrição (STAT) medeia importantes processos celulares, como a resposta imune, carcinogênese, diferenciação, divisão e morte celular. Portanto, medicamentos que interfiram nos diferentes padrões de sinalização JAK‐STAT têm potencial indicação para várias condições médicas. Os principais alvos dermatológicos dos inibidores da via JAK‐STAT são doenças inflamatórias ou autoimunes como psoríase, vitiligo, dermatite atópica e alopecia areata, porém, diversas dermatoses estão em investigação para ampliar esse rol de indicações. Como os inibidores da via JAK‐STAT devem, paulatinamente, ocupar espaço relevante na prescrição dermatológica, esta revisão apresenta os principais medicamentos disponíveis, seus efeitos imunológicos e suas características farmacológicas relacionadas à eficácia clínica e de segurança, a fim de substanciar a melhor prática dermatológica." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Como citar este artigo: Miot HA, Criado PR, Castro CC, Ianhez M, Talhari C, Ramos P. JAK‐STAT pathway inhibitors in dermatology. An Bras Dermatol. 2023;98:656–77." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "Trabalho realizado no Departamento de Dermatologia da Faculdade de Medicina, Universidade Estadual Paulista, Botucatu, SP, Brasil." ] ] "multimedia" => array:9 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1414 "Ancho" => 2508 "Tamanyo" => 274064 ] ] "descripcion" => array:1 [ "pt" => "Representação esquemática da via (canônica) de sinalização JAK‐STAT. (A) Diversas citocinas e fatores de crescimento presentes no meio extracelular dependem de receptores transmembrana para dar início ao processo de sinalização celular e transcrição nuclear dos genes associados a cada via. (B) O acoplamento da citocina com o domínio extracelular do receptor transmembrana leva a mudança em sua conformação e fosforilação dos dímeros de JAK, situados no domínio intracelular do receptor, e que transfosforilam seus resíduos terminais de tirosina. Esse processo induz a dimerização e fosforilação de unidades inativas de STAT, que migram para o núcleo e medeiam a transcrição de genes relacionados à via da citocina específica. (C) Inibidores da via de sinalização JAK‐STAT (iJAK) impedem a fosforilação da JAK, interrompendo a sinalização nuclear da citocina ou fator de crescimento. Fonte: os autores" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1390 "Ancho" => 1675 "Tamanyo" => 135468 ] ] "descripcion" => array:1 [ "pt" => "Diagrama representando os principais iJAK que apresentam resultados favoráveis em estudos clínicos para dermatoses inflamatórias e autoimunes. AA, alopecia areata; DA, dermatite atópica; DM, dermatomiosite; PSO, psoríase; VITI, vitiligo; HS, hidradenite supurativa; DEVH, doença enxerto versus hospedeiro; Abro, abrocitinibe; Upa, upadacitinibe; Bari, baricitinibe; DelgoT, delgocitinibe tópico; Tofa, tofacitinibe; RuxoT, ruxolitinibe tópico; Ruxo, ruxolitinibe; Ritle, ritlecitinibe; Deucra, deucravacitinibe; Solci, solcitinibe; Itaci, itacitinibe; Deuruxo, deuruxolitinibe" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Tabela 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">JAK \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Citocinas e fatores de crescimento \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IFN‐α, IFN‐β, IFN‐γ, IL‐2, IL‐4, IL‐6, IL‐7, IL‐9, IL‐10, IL‐11, IL‐13, IL‐15, IL‐19, IL‐21, IL‐22, IL‐27, IL‐28, IL‐29, IL‐31, IL‐35, fator neurotrófico ciliar (CNTF), oncostatina‐M (OSM), cardiotrofina (CT‐1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IFN‐γ, IL‐3, IL‐5, IL‐6, IL‐10, IL‐11, IL‐13, IL‐12, IL‐19, IL‐22, IL‐23, IL‐27, IL‐35, fator de estimulação de colônias de granulócitos e macrófagos (GM‐CSF), eritropoitina (EPO), tireoide peroxidase (TPO), leptina, oncogene viral mieloproliferativo da leucemia (mpl), prolactina, hormônio do crescimento (GH) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL‐2, IL‐4, IL‐7, IL‐9, IL‐13, IL‐15, IL‐21 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TYK2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IFN‐α, IFN‐β, IL‐10, IL‐11, IL‐12, IL‐19, IL‐22, IL‐23, IL‐27, IL‐28, IL‐29 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3233299.png" ] ] ] ] "descripcion" => array:1 [ "pt" => "Principais citocinas e fatores de crescimento influenciados pela sinalização de diferentes subtipos de JAK, em humanos" ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Tabela 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Medicamento \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Concentração inibitória (IC50) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Metabolismo \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Meia‐vida plasmática \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tofacitinibe</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK1: 2,9 nM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepático CYP3A4> CYP2C19</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 a 8 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK2: 1,2 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK3: 1,1 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TYK2: 42 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baricitinibe</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK1: 4,0 nM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepático CYP3A4</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 a 13 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK2: 6,6 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK3: 787 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TYK2: 61 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ruxolitinibe</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK1: 6,4 nM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepático CYP3A4</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 a 4 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK2: 8,8 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK3: 487,0 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TYK2: 30,0 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ritlecitinibe</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK1: 1.638 nM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepático: CYP450; Sérico: glutationa‐S‐transferase</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 a 3 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK2: 1.507 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK3: 0,3 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TYK2: 3.779 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abrocitinibe</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK1: 29 nM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepático CYP2C19> CYP2C9> CYP3A4> CYP2D6</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 a 5 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK2: 803 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK3:>10.000 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TYK2: 1.259 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Upadacitinibe</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK1: 14 nM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepático CYP3A4> CYP2D6</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 a 15 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK2: 593 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK3: 1.860 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TYK2: 2.715 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Delgocitinibe</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK1: 2,8 nM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA: uso tópico</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA: uso tópico</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK2: 2,6 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK3: 13,0 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TYK2: 58,0 nM \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3233301.png" ] ] ] ] "descripcion" => array:1 [ "pt" => "Características farmacológicas dos principais inibidores da via JAK‐STAT disponíveis no mercado" ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Tabela 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Aumentam os níveis dos iJAK</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reduzem os níveis dos iJAK</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inibidores potentes da OAT3 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inibidores potentes do CYP2C19 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inibidores potentes do CYP3A4 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inibidores moderados do CYP3A4 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Indutores fracos da CYP3A4 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Indutores potentes da CYP3A4 \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colchinina‐probenecide, probenecide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Amitriptilina, cloranfenicol, clomipramina, delavirdina, fluconazol, fluoxetina, fluvoxamina, gemfibrozil, imipramina, isoniazida, lansoprazol, miconazol, stiripentol, ticlopidina, tioconazol, zafirlucaste \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atazanavir, boceprevir, claritromicina, cobicistat, conivaptan, curcumin, danoprevir, darunavir, delavirdine, econazol, efavirenz, elvitegravir, ergotamina, idelaisibe, indinavir, itraconazol, cetoconazol, loperamida, lopinavir, mebefradil, midostaurin, naloxona, nefazadona, nelfinavir, nilotinibe, posaconazol, ribociclibe, ritonavir, saquinavir, stiripentol, sulfametoxazol‐tripetropim, telaprevir, telitromicina, terfenadina, tipranavir, troleandomicina, voriconazol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ácido fusídico, amiodarona, amprenavir, anastrozol, aprepitante, barnidipina, ciclosporina, clobazam, clozapina, crizotinibe, danazol, desvenlafaxina, diltiazem, dimetil sulfóxido (DMSO), dronedarona, eritromicina, fluconazole, fluvoxamina, fosamprenavir, foesnetupitante, haloperidol, imatinibe, idalpina, isavuconazol, isavuconazonio, isoniazida, isradipina, linagliptina, lovastatina, luliconazol, miconazol, mifepristona, milnaciprana, netupitante, nicardapina, nilvadipina, paroxetina, primaquina, risperidona, sertralina, simeprevir, tioconazol, venetoclax, venlafaxina, verapamil, zimeldina, ziprasidona \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clonazepan, colchicina, diazepan, pantoprazol, prednisona, ritonavir \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ácido valproico, atorvastatina, carbamazepina, dexametasona, efavirenz, fenitoína, fenobarbital, rifampicina, sinvastatina \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3233305.png" ] ] ] ] "descripcion" => array:1 [ "pt" => "Medicamentos que potencialmente interferem com os níveis séricos e segurança dos inibidores da via JAK‐STAT" ] ] 5 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Tabela 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "CPK, creatinofosfoquinase; ITRS, infecção do trato respiratório superior; VO, via oral." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dermatose \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Medicamento \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Via de administração/ n de pacientes \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Eventos adversos \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="8" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alopecia areata</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="8" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tofacitinibe</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VO</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nenhum evento adverso grave \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28,9% ITRS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90 pacientes34</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 leucopenia reversível \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 elevação de transaminases que normalizou com a perda ponderal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VO e tópico</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56,8% ITRS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13,2% acne \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">252 pacientes<a class="elsevierStyleCrossRef" href="#bib0860">35</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29,1% cefaleia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7,7% alteração de transaminases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vitiligo</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tofacitinibe e ruxolitinibe</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VO e tópico \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8,9% acne e alteração de transaminases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45 pacientes<a class="elsevierStyleCrossRef" href="#bib0865">36</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,4% ITRS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="13" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dermatite atópica</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baricitinibe (BREEZE AD 1 e 2)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VO</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17,3% nasofaringite (dose 1 mg) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Herpes simples oral, cefaleia, diarreia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.239 pacientes<a class="elsevierStyleCrossRef" href="#bib0890">41</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uma paciente teve tromboembolismo; era tabagista e usava contraceptivo oral (dose 4 mg) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abrocitinibe<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> (JADE MONO 2)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VO</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14,2% náusea \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7,7% nasofaringite e cefaleia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.233 pacientes<a class="elsevierStyleCrossRef" href="#bib0895">42</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5,8% acne \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5,2% vômitos \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3,2% ITRS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Upadacitinibe<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> (Measure Up1)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VO</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7% a 17% acne \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9% a 13% ITRS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">566 pacientes<a class="elsevierStyleCrossRef" href="#bib0900">43</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8% a 12% nasofaringite \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5% a 7% cefaleia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6% aumento CPK \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3233304.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "A dose considerada do estudo JADE MONO‐2 para os eventos adversos foi de 200mg/dia." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Eventos adversos expressos de acordo com as doses utilizadas (15 e 30mg)." ] ] ] "descripcion" => array:1 [ "pt" => "Principais eventos adversos por ordem de frequência das principais dermatoses em que os inibidores da via JAK‐STAT são utilizados" ] ] 6 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Tabela 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "iJAK, inibidor da via JAK‐STAT; PPD, teste tubercuínico intradérmico; IGRA, teste tuberculínico de liberação de interferona." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dados clínicos ou laboratoriais \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Condição especial \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comentário \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Faixa etária</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">> 65 anos \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Risco elevado de eventos adversos \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><15 anos \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baricitinibe não deve ser administrado \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><12 anos \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não utilizar iJAK indivíduos com menos de 12 anos \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peso corporal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><30 kg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Upadacitinibe não deve ser usado em crianças com <30 kg \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Amamentação \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Os iJAK não devem ser utilizados por lactantes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gravidez</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraindicação absoluta \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interromper o iJAK em pessoas sob risco de gravidez \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Em caso de gravidez, interromper o uso e solicitar seguimento rígido com ginecologista/obstetra \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatite B</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HBsAg positivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carga viral ≥ 20 IU/mL (1,3 log IU/mL): não usar iJAK \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carga viral <20 IU/mL: monitorar a cada 1‐3 meses além das transaminases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti‐HBcAg ou anti‐HBsAg positivos \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Verificar a carga viral, como na situação anterior \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Caso apenas o anti‐HBsAg seja positivo e todo o restante negativo (HBsAg, HBeAg, anti‐HBeAg e anti‐HBcAg e carga viral negativa), pode‐se usar iJAK \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatite C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti‐HVC positivo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Consultar hepatologista/infectologista \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pacientes com anti‐HVC positivo foram excluídos dos ensaios clínicos dessas medicações \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vacinação com vírus vivos \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Deve ser administrada 30 dias antes do início do iJAK \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">É contraindicada durante o tratamento \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tuberculose ativa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Deve ser interrompido/contraindicado o uso de iJAK \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tuberculose latente/suspeito assintomático \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PPD, IGRA/quantiferona gold positiva \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Quimioprofilaxia da tuberculose (isoniazida) pelo menos três semanas antes do início do iJAK \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Se estiver em uso de iJAK: quimioprofilaxia por 6 a 9 meses \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Histórico de câncer prévio \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monitorar o surgimento de eventos adversos \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Disfunção renal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clearance de creatinina> 30 mL/min/1,73m2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não ultrapassar 2 mg/dia de baricitinibe \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não ultrapassar 50 mg/d de abrocitininbe \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clearance de creatinina ≤ 30 mL/min/1,73m2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preferir upadacitinibe 15 mg/dia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não ultrapassar 50 mg/d de abrocitininbe \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Risco de tromboembolismo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Uso cauteloso de iJAK: preferência pelos inibidores da JAK1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infecções potencialmente graves \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraindicado o uso dos iJAK orais \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alterações hematológicas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Linfopenia <500/mm3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraindicado o uso dos iJAK orais \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutropenia <1.000/mm3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraindicado o uso do upadacitinibe e do abrocitinibe \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutropenia <500/mm3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraindicado o uso dos iJAK orais \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trombocitopenia <50.000/mm3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraindicado o uso do abrocitinibe \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alteração hepática grave \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Classe C de Child \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraindicado o uso do upadacitinibe e do abrocitinibe \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infecção recorrente por herpesvírus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Considerar o risco de reativação de herpes com iJAK \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infecção pelo HIV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraindicado o uso dos iJAK orais \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3233302.png" ] ] ] ] "descripcion" => array:1 [ "pt" => "Considerações clínicas e laboratoriais sobre o uso dos inibidores da via JAK‐STAT" ] ] 7 => array:8 [ "identificador" => "tbl0030" "etiqueta" => "Tabela 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at6" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "iJAK, inibidor da via JAK‐STAT; AA, alopecia areata; DA, dermatite atópica; DM, dermatomiosite; PSO, psoríase; VITI, vitiligo; HS, hidradenite supurativa; LP, líquen plano e líquen plano pilar; LE, lúpus eritematoso; PG, pioderma gangrenoso; GA, granuloma anular; SARC, sarcoidose; NL, necrobiose lipoídica; VL, vasculopatia livedoide; MOR, morfeia; ECZm, eczema crônico das mãos; DEVH, doença enxerto versus hospedeiro." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">iJAK \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DA \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PSO \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VITI \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AA \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LP \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LE \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DM \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VL \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PG \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">GA \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">NL \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SARC \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MOR \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HS \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DEVH \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ECZm \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tofacitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baricitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abrocitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Upadacitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ruxolitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Delgocitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ritlecitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Elsubritinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Itacitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peficitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Deucravacitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Filotinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Solcitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pacritinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Deuruxolitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gusacitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tópico \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tofacitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ruxolitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Brepocitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Delgocitinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cerdulatinibe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3233303.png" ] ] ] ] "descripcion" => array:1 [ "pt" => "Indicações dermatológicas para os inibidores da via JAK‐STAT, relatadas na literatura" ] ] 8 => array:8 [ "identificador" => "tbl0035" "etiqueta" => "Tabela 7" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at7" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "EASI75 e EASI90, redução de ≥ 75%/ ≥ 90% no índice de área e gravidade do eczema; IGA 0/1, Avaliação Global do Investigador resulta em mínimo eritema e pápulas perceptíveis." "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">iJAK oral \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Estudo (duração) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dose diária \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">EASI75 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">EASI90 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IGA 0/1 (ou ‐2 pontos) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="9" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Upadacitinibe<a class="elsevierStyleCrossRefs" href="#bib0900">43,69</a> (> 12 anos)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Measure Up 1 (16 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8,4% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Measure Up 2 (16 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38,8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,7% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AD Up (+ corticoide tópico 16 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58,6% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39,6% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10,9% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abrocitinibe<a class="elsevierStyleCrossRef" href="#bib0895">42</a> (>12 anos</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JADE MONO‐1 (12 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">200 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43,8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23,7% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7,9% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JADE MONO‐2 (12 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">200 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38,1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28,4% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9,1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="11" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baricitinibe<a class="elsevierStyleCrossRefs" href="#bib0890">41,70</a> (> 18 anos)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BREEZE AD‐1 (16 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BREEZE AD‐2 (16 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BREEZE AD‐7 (+ corticoide tópico 16 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3233300.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">iJAK tópico \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Estudo (duração) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Concentração 2×/dia \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">EASI 75 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">EASI 90 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IGA 0/1 (ou–2 pontos) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ruxolitinibe<a class="elsevierStyleCrossRef" href="#bib1040">71</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TRuE ‐ AD 1 (8 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1,5% creme \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62,1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53,8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0,75% creme \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56,0% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Veículo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24,6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15,1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TRuE ‐ AD 2 (8 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1,5% creme \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61,8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51,3% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0,75% creme \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51,5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Veículo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14,4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7,6% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tofacitinibe<a class="elsevierStyleCrossRef" href="#bib1045">72</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NCT02001181 (4 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2% pomada \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">68,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Veículo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Delgocitinibe<a class="elsevierStyleCrossRefs" href="#bib1050">73,74</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OBA 4‐1 (4 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0,5% creme \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26,4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Corpo – 10,4% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Face – 22,8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Veículo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5,8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Corpo – 3,8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Face – 4,0% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JapicCTI‐184064 (4 semanas)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0,5% creme \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37,7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Veículo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3233306.png" ] ] ] ] "descripcion" => array:1 [ "pt" => "Resultados dos principais estudos clínicos sobre os inibidores da via JAK‐STAT utilizados no tratamento da dermatite atópica" ] ] ] "bibliografia" => array:2 [ "titulo" => "Referências" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:137 [ 0 => array:3 [ "identificador" => "bib0690" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Janus kinase inhibitors in dermatology: Part I. 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Inibidores da via JAK‐STAT na dermatologia

Hélio Amante Miota,

Corresponding author

helio.a.miot@unesp.br

Autor para correspondência.

, Paulo Ricardo Criadob,c, Caio César Silva de Castrod,e, Mayra Ianhezf, Carolina Talharig, Paulo Müller Ramosa

a Departamento de Dermatologia, Faculdade de Medicina, Universidade Estadual Paulista, Botucatu, SP, Brasil

b Centro Universitário Faculdade de Medicina do ABC, Santo André, SP, Brasil

c Faculdade de Ciências Médicas de Santos, Santos, SP, Brasil

d Hospital de Dermatologia Sanitária do Paraná, Curitiba, PR, Brasil

e Escola de Medicina, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brasil

f Departamento de Medicina Tropical e Dermatologia, Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO, Brasil

g Departamento de Dermatologia, Universidade do Estado do Amazonas, Manaus, AM, Brasil

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          "pt" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Representa&#231;&#227;o esquem&#225;tica da via &#40;can&#244;nica&#41; de sinaliza&#231;&#227;o JAK&#8208;STAT&#46; &#40;A&#41; Diversas citocinas e fatores de crescimento presentes no meio extracelular dependem de receptores transmembrana para dar in&#237;cio ao processo de sinaliza&#231;&#227;o celular e transcri&#231;&#227;o nuclear dos genes associados a cada via&#46; &#40;B&#41; O acoplamento da citocina com o dom&#237;nio extracelular do receptor transmembrana leva a mudan&#231;a em sua conforma&#231;&#227;o e fosforila&#231;&#227;o dos d&#237;meros de JAK&#44; situados no dom&#237;nio intracelular do receptor&#44; e que transfosforilam seus res&#237;duos terminais de tirosina&#46; Esse processo induz a dimeriza&#231;&#227;o e fosforila&#231;&#227;o de unidades inativas de STAT&#44; que migram para o n&#250;cleo e medeiam a transcri&#231;&#227;o de genes relacionados &#224; via da citocina espec&#237;fica&#46; &#40;C&#41; Inibidores da via de sinaliza&#231;&#227;o JAK&#8208;STAT &#40;iJAK&#41; impedem a fosforila&#231;&#227;o da JAK&#44; interrompendo a sinaliza&#231;&#227;o nuclear da citocina ou fator de crescimento&#46; Fonte&#58; os autores</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introdu&#231;&#227;o</span><p id="par0005" class="elsevierStylePara elsevierViewall">A via de sinaliza&#231;&#227;o <span class="elsevierStyleItalic">Janus Quinase</span> &#40;JAK&#41; e transdutor de sinal&#47;ativador da transcri&#231;&#227;o &#40;STAT&#41; compreende uma fam&#237;lia de mol&#233;culas ligadas aos dom&#237;nios intracelulares dos receptores de diversas citocinas e fatores de crescimento&#44; que medeiam sua sinaliza&#231;&#227;o at&#233; o n&#250;cleo&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">1</span></a> A denomina&#231;&#227;o dessas quinases como <span class="elsevierStyleItalic">Janus</span> refere&#8208;se ao deus romano que representava o in&#237;cio ou abertura de um processo&#46; Janus tinha duas faces&#44; que est&#227;o associadas aos dois dom&#237;nios das JAK&#58; um catal&#237;tico e um semelhante &#224; quinase&#46; Historicamente&#44; o in&#237;cio do dia&#44; do m&#234;s e do ano era destinado em sacramento a Janus&#59; assim&#44; segundo a lenda&#44; o m&#234;s de janeiro origina&#8208;se de seu nome&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">A via JAK&#8208;STAT pertence a um complexo sistema de prote&#237;na quinases&#44; conservado evolutivamente&#44; em que mediadores extracelulares controlam a express&#227;o de genes espec&#237;ficos envolvidos em diversas fun&#231;&#245;es celulares como mitose&#44; diferencia&#231;&#227;o&#44; apoptose&#44; hematopoese&#44; desenvolvimento do sistema imune &#40;inato e adaptativo&#41; e atividade de gl&#226;ndulas ex&#243;crinas&#46; Al&#233;m disso&#44; participa de respostas celulares a agress&#245;es como hipoxia&#44; irradia&#231;&#227;o ultravioleta&#44; est&#237;mulo por endotoxinas&#44; estresse oxidativo e hiperosmolar&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Desse modo&#44; diversas dermatoses inflamat&#243;rias ou autoimunes s&#227;o alvo de estudo para a indica&#231;&#227;o de inibidores da via JAK&#8208;STAT &#40;iJAK&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">3</span></a> Uma vez que essa classe terap&#234;utica se revelou promissora em substituir o uso cr&#244;nico dos imunossupressores cl&#225;ssicos &#40;p&#46; ex&#46;&#44; ciclosporina&#44; azatioprina&#44; micofenolato&#44; metotrexato&#44; corticosteroides&#41; em virtude de sua seletividade de a&#231;&#227;o&#44; os iJAK devem&#44; paulatinamente&#44; ocupar espa&#231;o na prescri&#231;&#227;o dermatol&#243;gica&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Esta &#233; uma revis&#227;o narrativa que englobou artigos publicados sobre iJAK com direcionamento para as principais doen&#231;as dermatol&#243;gicas nas bases de dados MEDLINE&#44; SciELO e Google Scholar&#44; que avaliou o per&#237;odo de 1992 &#40;dos primeiros fundamentos do processo de sinaliza&#231;&#227;o intracelular&#41; at&#233; os dias atuais&#46; Apresentamos os principais medicamentos dispon&#237;veis&#44; seus efeitos imunol&#243;gicos e suas caracter&#237;sticas farmacol&#243;gicas relacionadas &#224; efic&#225;cia cl&#237;nica e de seguran&#231;a&#44; a fim de substanciar a melhor pr&#225;tica dermatol&#243;gica&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Via JAK&#8208;STAT</span><p id="par0025" class="elsevierStylePara elsevierViewall">As enzimas JAK s&#227;o tirosina quinases agregadas aos dom&#237;nios intracelulares dos receptores transmembrana de certas citocinas e fatores de crescimento&#46; Ap&#243;s o acoplamento das mol&#233;culas nos dom&#237;nios extracelulares de seus receptores ocorre modifica&#231;&#227;o conformacional em sua estrutura&#44; que leva &#224; fosforila&#231;&#227;o de res&#237;duos espec&#237;ficos de tirosina nos d&#237;meros de JAK&#46; Essa fosforila&#231;&#227;o possibilita o recrutamento de prote&#237;nas como os fatores de transcri&#231;&#227;o STAT&#44; que se dimerizam e s&#227;o translocadas para o n&#250;cleo das c&#233;lulas &#40;via <span class="elsevierStyleItalic">Ran</span> de importa&#231;&#227;o nuclear&#41; a fim de regular a transcri&#231;&#227;o de genes espec&#237;ficos &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Cada subtipo de JAK cont&#233;m um res&#237;duo de tirosina espec&#237;fico para a fosforila&#231;&#227;o ATP&#8208;dependente&#46; Essa especificidade as diferencia entre si e entre as mais de 500 tirosinas quinases humanas&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Os principais componentes da via JAK&#8208;STAT constituem quatro enzimas JAK &#40;JAK1&#44; JAK2&#44; JAK3 e tirosina quinase 2 &#91;Tyk2&#93;&#41;&#44; e sete enzimas STAT &#40;STAT1&#44; STAT2&#44; STAT3&#44; STAT4&#44; STAT5A&#44; STAT5B e STAT6&#41;&#46; Elas se distribuem como d&#237;meros cuja composi&#231;&#227;o varia de acordo com o tipo de receptor transmembrana e o tipo celular envolvido&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">1</span></a> Logo&#44; de acordo com o padr&#227;o de inibi&#231;&#227;o para diferentes JAK&#8208;STAT&#44; diferentes perfis de sinaliza&#231;&#227;o de citocina s&#227;o afetados&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">O bloqueio seletivo da sinaliza&#231;&#227;o de grupos de citocinas &#233; uma caracter&#237;stica do efeito imunomodulador dos iJAK em compara&#231;&#227;o com os imunossupressores convencionais &#40;p&#46; ex&#46;&#44; ciclosporina ou corticosteroides&#41;&#44; que suprimem uma vasta gama de mediadores&#59; ou com os imunobiol&#243;gicos&#44; que suprimem&#44; especificamente&#44; uma citocina&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">6</span></a> A <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a> apresenta as principais citocinas e os fatores de crescimento afetados pelo bloqueio dos subtipos de JAK&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Como as unidades JAK est&#227;o acopladas apenas a receptores de citocinas tipos I e II&#44; os iJAK n&#227;o medeiam&#44; diretamente&#44; a sinaliza&#231;&#227;o de TNF &#40;&#945;&#44; &#946;&#41;&#44; TGF &#40;&#945;&#44; &#946;&#41;&#44; EGF&#44; quimiocinas &#40;p&#46; ex&#46;&#44; IL&#8208;8&#44; CXC&#44; CX3C&#41;&#44; PDGF e IL&#8208;1 &#40;&#945;&#44; &#946;&#41;&#44; que s&#227;o patog&#234;nicas em uma s&#233;rie de dermatoses&#46;<a class="elsevierStyleCrossRefs" href="#bib0720"><span class="elsevierStyleSup">7&#44;8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">A via de sinaliza&#231;&#227;o JAK&#8208;STAT constitui prof&#237;cua linha de pesquisa em biologia celular envolvendo aspectos ligados ao comportamento de variantes mutantes de suas enzimas&#44; a regula&#231;&#227;o intracelular por inibidores&#47;ativadores&#44; efeitos da ativa&#231;&#227;o n&#227;o can&#244;nica e intera&#231;&#227;o com outras vias inflamat&#243;rias&#44; apopt&#243;ticas ou de crescimento celular que s&#227;o assuntos clinicamente relevantes&#44; por&#233;m que ultrapassam o escopo deste texto&#46;<a class="elsevierStyleCrossRefs" href="#bib0730"><span class="elsevierStyleSup">9&#8211;16</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Principais caracter&#237;sticas dos iJAK na dermatologia</span><p id="par0055" class="elsevierStylePara elsevierViewall">Os iJAK s&#227;o mol&#233;culas pequenas &#40;&#60; 500&#160;kD&#41;&#44; o que favorece sua absor&#231;&#227;o intestinal e permea&#231;&#227;o cut&#226;nea&#44; apesar de serem pouco lipof&#237;licas &#40;<span class="elsevierStyleItalic">log p</span> entre&#160;1&#44;5&#160;e&#160;2&#41;&#46; Por constitu&#237;rem medicamentos finais e n&#227;o dependerem de metaboliza&#231;&#227;o para o efeito farmacol&#243;gico&#44; sua r&#225;pida absor&#231;&#227;o leva a efeito cl&#237;nico precoce&#59; porquanto&#44; seus picos plasm&#225;ticos e meia&#8208;vidas de elimina&#231;&#227;o tamb&#233;m s&#227;o breves &#40;&#60; 18 horas&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">17</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Nas formula&#231;&#245;es t&#243;picas&#44; iJAK n&#227;o implicam em n&#237;veis s&#233;ricos elevados dos medicamentos&#44; minimizando efeitos adversos &#40;EA&#41; sist&#234;micos e intera&#231;&#245;es medicamentosas&#46;<a class="elsevierStyleCrossRefs" href="#bib0770"><span class="elsevierStyleSup">17&#44;18</span></a> Al&#233;m disso&#44; atingem alta concentra&#231;&#227;o na epiderme e derme superior&#44; o que justifica sua efic&#225;cia em eczemas&#44; psor&#237;ase e vitiligo&#44; conforme discutido adiante&#46; Entretanto&#44; recomenda&#8208;se n&#227;o ultrapassar 20&#37;&#160;da superf&#237;cie cut&#226;nea&#44; utilizar camada fina e n&#227;o prolongar seu uso&#44; com o intuito de reduzir a chance de efeitos sist&#234;micos&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">17</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Quanto &#224; seletividade&#44; os iJAK podem ser classificados como de primeira gera&#231;&#227;o &#40;p&#46; ex&#46;&#44; tofacitinibe&#44; baricitinibe&#41; ou n&#227;o seletivos&#44; ou de segunda gera&#231;&#227;o &#40;p&#46; ex&#46;&#44; upadacitinibe&#44; abrocitinibe&#44; ritlecitinibe&#41;&#44; considerados os mais seletivos para um dos subtipos de JAK&#46; Al&#233;m disso&#44; os iJAK diferem quanto ao bloqueio enzim&#225;tico &#40;revers&#237;vel ou covalente&#41; e o s&#237;tio de liga&#231;&#227;o &#40;tipo I&#44; II e alost&#233;rico&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">19</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Quando consideradas suas estruturas moleculares&#44; os iJAK podem ser agrupados como iJAK&#945; &#40;baricitinibe&#44; delgocitinibe&#44; ruxolitinibe&#44; tofacitinibe&#41; ou iJAK&#946; &#40;abrocitinibe&#44; upadacitinibe&#44; filgotinibe&#44; deucravacitinibe&#41;&#46; Os iJAK&#945; t&#234;m estrutura semelhante &#224; purina e sistema bic&#237;clico condensado formado por heterociclos de pirimidina&#47;pirrol&#46; Todas essas subst&#226;ncias exibem um grupo cianeto nucleof&#237;lico para o s&#237;tio de liga&#231;&#227;o da quinase&#46; Dada a semelhan&#231;a dos segmentos JH1 entre as isoformas JAK&#44; os iJAK&#945; as inibem todas&#44; apesar de diferentes afinidades&#46; Os iJAK&#946; foram especificamente sintetizados por modelagem qu&#237;mica para otimizar as liga&#231;&#245;es&#44; na tentativa de combinar a estrutura dos iJAK&#946; com um respectivo s&#237;tio de liga&#231;&#227;o&#44; gerando maior seletividade&#46; Por&#233;m&#44; os iJAK&#946; s&#227;o menos compar&#225;veis entre si quanto &#224; estrutura qu&#237;mica&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">20</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Em virtude da semelhan&#231;a estrutural das enzimas do grupo JAK&#44; os diferentes iJAK exercem algum efeito inibit&#243;rio em todos os seus quatro subtipos&#44; de acordo com a concentra&#231;&#227;o utilizada&#46; A <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a> resume as caracter&#237;sticas farmacol&#243;gicas dos principais iJAK de uso atual na dermatologia&#46; Entretanto&#44; a maior parte dos indicadores farmacol&#243;gicos e farmacodin&#226;micos &#233; estimada por ensaios em que as concentra&#231;&#245;es inibit&#243;rias s&#227;o realizadas por testes <span class="elsevierStyleItalic">in vitro</span> que empregam diferentes metodologias&#44; sem considerar varia&#231;&#245;es metab&#243;licas ligadas a sexo&#44; faixa et&#225;ria&#44; ascend&#234;ncia &#233;tnica&#44; composi&#231;&#227;o corporal&#44; comorbidades e uso de medicamentos concomitantes&#46; Essas caracter&#237;sticas justificam cautela em sua prescri&#231;&#227;o e seguimento de longo prazo&#44; uma vez que os resultados de farmacovigil&#226;ncia das principais subst&#226;ncias ainda est&#227;o em andamento em virtude da recente aprova&#231;&#227;o &#40;menos de cinco&#160;anos&#41; pelas ag&#234;ncias regulat&#243;rias internacionais&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Seguran&#231;a e tolerabilidade dos iJAK</span><p id="par0080" class="elsevierStylePara elsevierViewall">Tal como ocorre com outras medica&#231;&#245;es&#44; exceto em rea&#231;&#245;es imunologicamente mediadas&#44; os EA e riscos ligados a medicamentos que interferem nas vias de sinaliza&#231;&#227;o e transcri&#231;&#227;o de citocinas&#44; fatores de crescimento celular e indu&#231;&#227;o da apoptose celular s&#227;o diretamente proporcionais aos seguintes condicionantes&#58; &#40;i&#41;&#160;ocorr&#234;ncia de doen&#231;as concomitantes &#40;tuberculose latente&#44; infec&#231;&#227;o por HIV&#44; HTLV&#8208;1&#44; doen&#231;a de Chagas&#44; doen&#231;as autoimunes&#44; doen&#231;a intestinal inflamat&#243;ria &#91;DII&#93;&#44; trombofilias&#44; hepatopatias&#44; nefropatias e hematol&#243;gica&#41;&#59; &#40;ii&#41;&#160;dose da medica&#231;&#227;o&#59; &#40;iii&#41;&#160;longevidade do tratamento&#44; e &#40;iv&#41;&#160;vias metab&#243;licas alteradas por polimorfismo g&#234;nico &#40;defici&#234;ncia da glicose&#8208;6&#8208;fosfato desidrogenase&#44; acetilador lento&#44; HLA de predisposi&#231;&#227;o a rea&#231;&#245;es adversas graves como no caso do abacavir&#44; HLA&#8208;B&#42;5701&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">21</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Mesmo assim&#44; muitos EA podem ser pouco frequentes&#44; ou mesmo n&#227;o estar presentes em estudos de fase III com limitado n&#250;mero de pacientes e curta exposi&#231;&#227;o ao f&#225;rmaco&#44; que somente ser&#227;o identificados pelos relatos de farmacovigil&#226;ncia&#44; j&#225; que a maioria dos iJAK tem menos de cinco anos de comercializa&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">22</span></a> Cabe ao dermatologista estar atento &#224; possibilidade de EA oriundos do uso prolongado desses f&#225;rmacos&#44; assim como identificar subgrupos de pacientes suscet&#237;veis e&#44; principalmente&#44; a possibilidade de intera&#231;&#245;es medicamentosas&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Intera&#231;&#245;es medicamentosas</span><p id="par0090" class="elsevierStylePara elsevierViewall">O envelhecimento populacional e a disponibilidade de novos f&#225;rmacos favorecem o uso concomitante de medicamentos pela popula&#231;&#227;o&#44; o que maximiza a possibilidade de intera&#231;&#245;es medicamentosas&#44; por exemplo&#44; via citocromo P450 &#40;CYP&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">23</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Em pacientes com artrite reumatoide &#40;AR&#41; que receberam iJAK&#44; identificou&#8208;se em mais de&#160;10&#37; deles a prescri&#231;&#227;o concomitante de medicamentos com potencial intera&#231;&#227;o medicamentosa&#44; como inibidores da bomba OAT3 &#40;<span class="elsevierStyleItalic">organic anion transporter</span>&#160;3&#41;&#44; inibidores potentes do CYP3A4 e CYP2C19&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">23</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Enquanto os iJAK s&#227;o primariamente metabolizados no f&#237;gado pelo sistema CYP&#44; via enzimas metabolizadoras do CYP3A4&#44; a extens&#227;o do metabolismo por essas vias e outras enzimas varia de acordo com o iJAK utilizado&#44; bem como seu n&#237;vel de excre&#231;&#227;o renal&#46; A <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a> fornece uma extensa lista de medicamentos que&#44; potencialmente&#44; interferem com CYP3A4&#44; CYP2C19 e bomba OAT3 e que devem ser considerados no uso concomitante de iJAK&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Destaque&#8208;se que fazem parte dessa lista medicamentos de uso corriqueiro&#44; como ansiol&#237;ticos&#44; antidepressivos&#44; antif&#250;ngicos&#44; antilipemiantes e anti&#8208;hipertensivos&#44; e os dermatologistas devem ponderar os riscos dessas intera&#231;&#245;es&#46; Inclusive&#44; subst&#226;ncias de uso recreativo &#40;p&#46; ex&#46;&#44; <span class="elsevierStyleItalic">Cannabis</span> sp&#46;&#41; e extratos vegetais &#40;p&#46; ex&#46;&#44; <span class="elsevierStyleItalic">Echinacea purpurea</span>&#44; <span class="elsevierStyleItalic">Hypericum perforatum</span>&#41;&#44; que s&#227;o frequentemente omitidos pelos pacientes&#44; t&#234;m efeito sobre a metaboliza&#231;&#227;o hep&#225;tica de medicamentos&#46;<a class="elsevierStyleCrossRefs" href="#bib0805"><span class="elsevierStyleSup">24&#44;25</span></a> No entanto&#44; o breve uso concomitante de iJAK com potenciais subst&#226;ncias que promovem intera&#231;&#227;o&#44; como fluconazol para candidose vulvovaginal&#44; n&#227;o implica em preju&#237;zo&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Diferentes iJAK de uso sist&#234;mico t&#234;m particularidades farmacocin&#233;ticas e metab&#243;licas dependentes de sua fra&#231;&#227;o de liga&#231;&#227;o com prote&#237;nas plasm&#225;ticas&#44; taxa de metaboliza&#231;&#227;o hep&#225;tica e atividade dos seus metab&#243;litos &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">O tofacitinibe &#233; rapidamente absorvido por via oral&#44; com pico de concentra&#231;&#227;o plasm&#225;tica em&#160;1 hora&#44; atingindo equil&#237;brio &#40;<span class="elsevierStyleItalic">steady&#8208;state</span>&#41; em at&#233;&#160;48 horas&#46; Sua biodisponibilidade oral &#233; de&#160;74&#37;&#44; independente da ingesta de alimentos&#44; e 40&#37; da subst&#226;ncia se ligam a prote&#237;nas plasm&#225;ticas&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">20</span></a> &#201; eliminado principalmente via hep&#225;tica &#40;70&#37;&#41; e renal &#40;30&#37;&#41;&#44; o que demanda doses menores em hepatopatas e nefropatas&#46; A principal via de metaboliza&#231;&#227;o utiliza o CYP3A4&#44; com pequena contribui&#231;&#227;o do CYP2C19&#44; al&#233;m de ser substrato da glicoprote&#237;na&#8208;P&#46; N&#227;o foram demonstradas intera&#231;&#245;es com midazolam&#44; contraceptivos orais ou metformina&#46;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">26</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">O upadacitinibe &#233; absorvido em ampla faixa de pH &#40;entre&#160;1&#8208;7&#44;5&#41; sem grande interfer&#234;ncia alimentar&#44; e apenas 52&#37; se ligam &#224;s prote&#237;nas plasm&#225;ticas&#59; portanto&#44; n&#227;o s&#227;o esperadas intera&#231;&#245;es relevantes dependentes do deslocamento proteico&#46; Nenhum ajuste de dose &#233; necess&#225;rio para indiv&#237;duos com insufici&#234;ncia renal ou hep&#225;tica leve ou moderada&#46;<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">27</span></a> O upadacitinibe &#233; metabolizado pela CYP3A4&#44; com participa&#231;&#227;o menor de CYP2D6&#46; O uso concomitante com cetoconazol aumenta a concentra&#231;&#227;o m&#225;xima &#40;C<span class="elsevierStyleInf">m&#225;x</span>&#41; do medicamento e a curva de concentra&#231;&#227;o plasm&#225;tica &#40;AUC&#41; no tempo em 70&#37; e 75&#37;&#44; respectivamente&#46; O uso concomitante com rifampicina diminui a C<span class="elsevierStyleInf">m&#225;x</span> e AUC em 50&#37; e 60&#37;&#44; respectivamente&#46; N&#227;o h&#225; intera&#231;&#227;o medicamentosa com varfarina&#44; omeprazol&#44; midazolam e etinilestradiol<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>levonorgestrel&#46;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">26</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">O abrocitinibe&#44; ap&#243;s absor&#231;&#227;o&#44; liga&#8208;se em 37&#37; &#224;s prote&#237;nas plasm&#225;ticas&#59; a excre&#231;&#227;o &#233; principalmente renal &#40;85&#37;&#41; e fecal &#40;9&#44;5&#37;&#41;&#46; Quanto &#224; forma n&#227;o metabolizada&#44; 0&#44;6&#37; s&#227;o excretadas nos rins e 0&#44;3&#37; nas fezes&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">20</span></a> A coadministra&#231;&#227;o deve seguir a seguintes recomenda&#231;&#245;es&#58; &#40;i&#41; uso concomitante com inibidores do CYP2C19 &#8211; a dose do abrocitinibe deve ser reduzida pela metade&#59; &#40;ii&#41; uso concomitante com indutores potentes do CYP2C9&#47;CYP2C19 &#8211; n&#227;o recomendado&#59; &#40;iii&#41; inibidores do OAT3 &#8211; sem necessidade de ajuste&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">28</span></a> Como exemplos&#44; aten&#231;&#227;o especial&#58; &#40;i&#41; fluconazol&#44; fluoxetina&#44; fluvoxamina e ticlopidina &#40;inibidores do CYP2C19&#41;&#59; &#40;ii&#41; apalutamida e rifampicina &#40;uso n&#227;o recomendado&#41;&#59; e &#40;iii&#41; probenecida e teriflunomida &#40;sem necessidade de ajuste de dose&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">28</span></a> Insufici&#234;ncia hep&#225;tica n&#227;o tem efeito clinicamente relevante na farmacocin&#233;tica e seguran&#231;a do abrocitinibe&#44; autorizando seu uso sem ajuste da dose em casos de insufici&#234;ncia hep&#225;tica leve ou moderada&#46;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">29</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">O baricitinibe &#233; rapidamente absorvido por via oral em jejum&#44; com pico plasm&#225;tico em&#160;1 hora e biodisponibilidade de 80&#37;&#46; Alimentos gordurosos e cal&#243;ricos diminuem sua absor&#231;&#227;o em 29&#37;&#44; atrasando o pico plasm&#225;tico para 3 horas&#46; Ocorre liga&#231;&#227;o de 50&#37; &#224;s prote&#237;nas plasm&#225;ticas&#44; e <span class="elsevierStyleItalic">steady&#8208;state</span> &#233; atingido em at&#233; 48 horas&#46; Menos de 10&#37; do baricitinibe ingerido sofrem metabolismo pelo CYP3A4&#44; n&#227;o se detectando metab&#243;litos no plasma&#44; o que dispensa ajuste de dose na insufici&#234;ncia hep&#225;tica leve ou moderada&#46; O baricitinibe &#233; excretado sem altera&#231;&#227;o na urina &#40;69&#37;&#41; e nas fezes &#40;15&#37;&#41;&#44; enquanto 6&#37; da dose s&#227;o excretados como metab&#243;litos&#46; A filtra&#231;&#227;o glomerular &#233; o principal mecanismo de excre&#231;&#227;o e secre&#231;&#227;o ativa pelo OAT3&#44; glicoprote&#237;na&#8208;P&#44; BCRP e pela MATE2&#8208;K&#46; Assim&#44; a concentra&#231;&#227;o plasm&#225;tica do baricitinibe aumenta em pacientes com disfun&#231;&#227;o renal leve &#40;1&#44;4<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#41; e moderada &#40;2&#44;2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#41;&#46; Em pacientes com <span class="elsevierStyleItalic">clearence</span> de creatinina entre 30&#8208;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#44; a dose do baricitinibe deve ser reduzida para 2<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; e n&#227;o &#233; recomendado quando o <span class="elsevierStyleItalic">clearance</span> de creatinina for<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">30</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">O ajuste nas doses do tofacitinibe ou baricitinibe&#44; mas n&#227;o do upadacitinibe&#44; &#233; necess&#225;rio com a progress&#227;o da gravidade da insufici&#234;ncia renal&#46; Embora a dose do tofacitinibe precise ser ajustada para pacientes com insufici&#234;ncia hep&#225;tica moderada&#44; n&#227;o &#233; o caso do baricitinibe ou do upadacitinibe&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">31</span></a> Insufici&#234;ncia renal moderada e grave levaram a maior exposi&#231;&#227;o &#224; por&#231;&#227;o ativa do abrocitinibe&#44; sugerindo que a dose de abrocitinibe deva ser reduzida pela metade nesses casos&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Infec&#231;&#245;es e eventos adversos gerais</span><p id="par0140" class="elsevierStylePara elsevierViewall">Os efeitos farmacol&#243;gicos dos iJAK s&#227;o proporcionais &#224;s doses utilizadas&#44; de modo que sua prescri&#231;&#227;o deve levar em considera&#231;&#227;o a menor dose clinicamente eficaz&#44; a fim de minimizar os riscos associados &#224; imunossupress&#227;o ou &#224; inibi&#231;&#227;o da JAK2&#44; associada aos EA hematol&#243;gicos&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">O uso de iJAK t&#243;picos demonstrou poucos EA sist&#234;micos&#44; por&#233;m acne&#44; j&#225; relatada em pacientes com iJAK orais&#44; foi observada em alguns relatos e s&#233;ries de casos&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">3</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">A maioria dos eventos infecciosos relacionados aos iJAK &#233; relatada pelo uso do tofacitinibe&#44; liberado para comercializa&#231;&#227;o em 2012&#44; de modo que se torna evidente o maior tempo e o grande n&#250;mero de doentes expostos a essa medica&#231;&#227;o e&#44; consequentemente&#44; o maior n&#250;mero de publica&#231;&#245;es na literatura&#46;<a class="elsevierStyleCrossRefs" href="#bib0850"><span class="elsevierStyleSup">33&#8211;36</span></a>O estudo ORALSURV envolveu 4&#46;362 indiv&#237;duos com AR&#44; com mais de 50 anos e pelo menos um fator de risco cardiovascular&#46; Doentes em uso pr&#233;vio de metotrexato foram alocados para receber tofacitinibe 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#59; tofacitinibe 10<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#59; ou anti&#8208;TNF&#945; &#40;etanercepte ou adalimumabe&#41;&#46; Em rela&#231;&#227;o &#224;s infec&#231;&#245;es&#44; o estudo demonstrou que tofacitinibe conferia risco similar de infec&#231;&#245;es em rela&#231;&#227;o aos anti&#8208;TNF&#945;&#44; exceto pela propens&#227;o em reativar v&#237;rus latentes &#40;p&#46; ex&#46;&#44; varicela&#8208;z&#243;ster&#44; herpes <span class="elsevierStyleItalic">simplex</span> e citomegalov&#237;rus&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">33</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Com rela&#231;&#227;o aos eventos infecciosos graves &#40;EIG&#41;&#44; o <span class="elsevierStyleItalic">ORALSURV</span> identificou risco semelhante para a dose de 5<span class="elsevierStyleHsp" style=""></span>mg de tofacitinibe e os anti&#8208;TNF&#945;&#44; mesmo em pacientes com mais de 65 anos&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">33</span></a> Os dados dos EIG no estudo foram consistentes com os dados dos programas de desenvolvimento dos iJAK e agentes biol&#243;gicos modificadores do comportamento da AR &#40;bDMARD&#41; atualmente aprovados&#44; nos quais as taxas de EIG foram semelhantes &#40;3&#8208;4&#160;EIG&#47;100&#160;pacientes&#8208;ano&#41;&#44; com taxas mais elevadas em idosos&#46;<a class="elsevierStyleCrossRefs" href="#bib0850"><span class="elsevierStyleSup">33&#44;37</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Os EAs mais comuns relatados nos estudos de fase III dos iJAK sist&#234;micos foram cefaleia&#44; n&#225;useas e nasofaringite&#46; Infec&#231;&#245;es virais como herpes simples &#40;HSV&#44; <span class="elsevierStyleItalic">herpes simplex virus</span>&#41;&#44; erup&#231;&#227;o variceliforme de Kaposi &#40;eczema herp&#233;tico &#91;EH&#93;&#41; e herpes&#8208;z&#243;ster &#40;HZ&#41; constituem os EA dermatol&#243;gicos mais comuns em pacientes com dermatite at&#243;pica &#40;DA&#41; sob tratamento com iJAK&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">13</span></a> A maioria dos dados sobre infec&#231;&#227;o pelo HSV procede do uso do tofacitinibe na AR&#44; artrite psori&#225;sica e DII&#46; No entanto&#44; h&#225; menor incid&#234;ncia de infec&#231;&#227;o pelo HSV&#44; HZ e EH nos ensaisos cl&#237;nicos de iJAK1 &#40;seletivos&#41; em pacientes com DA&#46;<a class="elsevierStyleCrossRefs" href="#bib0875"><span class="elsevierStyleSup">38&#44;39</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">No estudo JADE REGIMEN foram inclu&#237;dos 1&#46;233 pacientes com DA moderada a grave em</p><p id="par0170" class="elsevierStylePara elsevierViewall">fase aberta &#40;12 semanas&#41; em monoterapia com abrocitinibe 200<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">39</span></a> Ao final de 12 semanas&#44; 798 pacientes &#40;64&#44;7&#37;&#41; foram considerados respondedores ao medicamento e aleatoriamente alocados no estudo cego com abrocitinibe 200<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; 100<span class="elsevierStyleHsp" style=""></span>mg&#47;dia ou placedo &#40;40 semanas&#41;&#46; Considerando a fase de estudo aberto &#40;indu&#231;&#227;o&#41; e cego&#44; os pacientes completaram 52 semanas de seguimento&#46; Na fase de indu&#231;&#227;o &#40;12 semanas&#41;&#44; foram observados EIGs em seis pacientes &#40;0&#44;5&#37;&#41;&#44; com HZ em nove pacientes &#40;0&#44;7&#37;&#41;&#46; Na fase cega &#40;40 semanas&#41;&#44; as taxas de EIG e HZ variaram entre os pacientes alocados nos tr&#234;s diferentes grupos&#58; &#40;i&#41; placebo&#44; 267 pacientes&#44; foram observados EIG em dois casos &#40;0&#44;7&#37;&#41; e em HZ dois casos &#40;0&#44;7&#37;&#41;&#59; &#40;ii&#41; abrocitinibe 100<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; 265 pacientes&#44; EIG em dois casos &#40;0&#44;8&#37;&#41; e HZ em dois casos &#40;0&#44;8&#37;&#41;&#59; &#40;iii&#41; abrocitinibe 200<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; 266 pacientes&#44; foram observados EIG em cinco casos &#40;1&#44;9&#37;&#41;&#44; e HZ em nove casos &#40;3&#44;4&#37;&#41;&#46; Somando&#8208;se os tr&#234;s grupos da fase cega &#40;20 semanas&#59; 798 pacientes&#41;&#44; foram foram nove casos &#40;1&#44;1&#37;&#41; de EIG e 13 &#40;1&#44;6&#37;&#41; de HZ&#46;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">39</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Em metan&#225;lise sobre a efic&#225;cia e seguran&#231;a de abrocitinibe&#44; baricitinibe e upadacitinibe em pacientes com DA moderada a grave&#44; os autores conclu&#237;ram que quando se analisou o n&#250;mero total de EA &#40;TEAE&#59; do ingl&#234;s&#44; <span class="elsevierStyleItalic">treatment&#8208;emergent adverse events</span>&#41;&#44; o upadacitinibe e o abrocitinibe demonstraram maior incid&#234;ncia que o grupo placebo&#44; e o abrocitinibe esteve associado a aumento nos TEAE&#44; quando comparado com o baricitinibe&#46; No entanto&#44; quando se analisaram esses iJAK em rela&#231;&#227;o aos TEAE e dose da medica&#231;&#227;o utilizada&#44; apenas a dose de&#160;30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia do upadacitinibe aumentou a incid&#234;ncia dos TEAE&#58; <span class="elsevierStyleItalic">odds ratio</span> &#40;OR&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#44;64&#46; Ainda na metan&#225;lise de rede&#44; a compara&#231;&#227;o dos eventos adversos de abrocitinibe <span class="elsevierStyleItalic">versus</span> placebo resultou em OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#44;57&#59; baricitinibe <span class="elsevierStyleItalic">versus</span> placebo&#44; OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44;92&#59; abrocitinibe <span class="elsevierStyleItalic">versus</span> baricitinibe&#44; OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;92&#59; abrocitinibe <span class="elsevierStyleItalic">versus</span> upadacitinibe&#44; OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;41&#59; e baricitinibe <span class="elsevierStyleItalic">versus</span> upadacitinibe&#44; OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;21&#46; Os autores da metan&#225;lise ressaltam que a maioria dos estudos de ensaios cl&#237;nicos foi conduzida com avalia&#231;&#245;es de efic&#225;cia e seguran&#231;a em um per&#237;odo curto de avalia&#231;&#227;o&#44; sem compara&#231;&#227;o ainda em estudos entre eles&#44; e que estudos de efic&#225;cia e seguran&#231;a de longo prazo devem ser conduzidos&#46;<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">40</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Como exemplos de estudos de fase III publicados com casu&#237;stica consider&#225;vel&#44; randomizados e placebo&#8208;controlados&#44; <span class="elsevierStyleItalic">Measure Up</span><span class="elsevierStyleItalic">1</span> e <span class="elsevierStyleItalic">Measure Up</span><span class="elsevierStyleItalic">2</span> avaliaram&#44; respectivamente&#44; 847 e 836 pacientes com DA moderada a grave alocados em grupos recebendo 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; 15<span class="elsevierStyleHsp" style=""></span>mg&#47;dia de upadacitinibe ou placebo&#46; Os desfechos prim&#225;rios de efic&#225;cia foram avaliados na semana 16&#44; e os EA foram registrados &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabela 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0185" class="elsevierStylePara elsevierViewall">No que se refere &#224;s complica&#231;&#245;es infectocontagiosas&#44; &#233; importante considerar que as preval&#234;ncias das doen&#231;as variam com a epidemiologia de cada pa&#237;s&#46; A via JAK&#8208;STAT faz a transmiss&#227;o de sinaliza&#231;&#227;o intracelular de mais de 50 citocinas e fatores de crescimento e &#233; considerada a via de comunica&#231;&#227;o central do sistema imune&#44; inclusive na defesa contra pat&#243;genos&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">A altera&#231;&#227;o funcional do sistema JAK&#8208;STAT pode ocorrer n&#227;o apenas por a&#231;&#227;o farmacoter&#225;pica&#44; mas tamb&#233;m por muta&#231;&#245;es germinativas de perda ou ganho de fun&#231;&#227;o&#44; as quais determinam diversos fen&#243;tipos imunes e doen&#231;as mieloproliferativas&#46; Como exemplos&#58; &#40;i&#41;&#160;muta&#231;&#245;es com perda de fun&#231;&#227;o da JAK3 s&#227;o relacionadas com imunodefici&#234;ncia combinada grave &#40;SCID&#59; do ingl&#234;s&#44; <span class="elsevierStyleItalic">severe combined immunodeficiency</span>&#41;&#59; &#40;ii&#41;&#160;perda de fun&#231;&#227;o por muta&#231;&#245;es na STAT1 pode gerar defici&#234;ncia de respostas ligadas &#224;s interferonas &#40;IFN&#41;&#44; tipo&#160;1 &#40;&#945; e &#946;&#41; e IFN&#8208;&#947;&#44; ocasionando aumento na suscetibilidade de infec&#231;&#245;es virais&#59; &#40;iii&#41;&#160;muta&#231;&#245;es com perda da fun&#231;&#227;o da JAK1&#44; TYK2&#44; STAT1 e STAT5B determinam infec&#231;&#245;es bacterianas intracelulares&#44; e a defici&#234;ncia da STATB5 pode ocasionar pneumonias de repeti&#231;&#227;o&#59; e &#40;iv&#41;&#160;muta&#231;&#227;o com ganho de fun&#231;&#227;o da STAT1 pode determinar infec&#231;&#245;es recorrentes por <span class="elsevierStyleItalic">Candida</span> spp<span class="elsevierStyleItalic">&#46;</span>&#44; pois a STAT1 antagoniza os efeitos antif&#250;ngicos mediados pela IL&#8208;17 via STAT3&#44; suprimindo essa sinaliza&#231;&#227;o intracelular&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Pacientes com dermatoses cr&#244;nicas inflamat&#243;rias apresentam maior risco de infec&#231;&#227;o em decorr&#234;ncia tanto de sua pr&#243;pria doen&#231;a &#40;p&#46; ex&#46;&#44; disbiose cut&#226;nea com coloniza&#231;&#227;o de estafilococos na DA&#41; quanto pelo tratamento ao qual s&#227;o submetidos&#44; em particular imunossupressores como ciclosporina&#44; azatioprina&#44; micofenolato e metotrexato&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a> Como exemplo&#44; na AR h&#225; o dobro de risco de esses pacientes apresentarem infec&#231;&#245;es graves&#44; particularmente broncopulmonares e geniturin&#225;rias&#44; que contribuem para maior mortalidade&#46;<a class="elsevierStyleCrossRef" href="#bib0910"><span class="elsevierStyleSup">45</span></a> Assim&#44; ao prescrever iJAK&#44; um dos fatores a se considerar s&#227;o os potenciais EAs dessas subst&#226;ncias&#44; mas tamb&#233;m a idade do paciente &#40;imunossenesc&#234;ncia&#41;&#44; comorbidades associadas e aspectos da patog&#234;nese da doen&#231;a&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Apesar de as infec&#231;&#245;es oportunistas se mostrarem mais frequentes em todas as classes de iJAK&#44; n&#227;o foram observadas diferen&#231;as em rela&#231;&#227;o ao risco de EIGs em uma recente an&#225;lise de rede de ensaios cl&#237;nicos&#46;<a class="elsevierStyleCrossRef" href="#bib0910"><span class="elsevierStyleSup">45</span></a> Contudo&#44; os ensaios cl&#237;nicos individuais n&#227;o foram desenvolvidos para examinar desfechos raros&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Uma an&#225;lise dos estudos de extens&#227;o de longo prazo &#40;EELP&#41; sobre o tofacitinibe encontrou incid&#234;ncia de EIGs de 2&#44;7 casos por 100 pacientes&#8208;ano&#46;<a class="elsevierStyleCrossRef" href="#bib0915"><span class="elsevierStyleSup">46</span></a> Quando os iJAK foram associados a drogas antirreum&#225;ticas modificadoras da doen&#231;a &#40;DMARDs&#59; do ingl&#234;s&#44; <span class="elsevierStyleItalic">disease&#8208;modifying antirheumatic drugs</span>&#41; em um registro nos EUA com 21&#46;832 pacientes com AR&#44; houve maior ocorr&#234;ncia de EIGs com tofacitinibe associado a outro DMARD na taxa de 3&#44;67 <span class="elsevierStyleItalic">vs&#46;</span> 2&#44;01 EIG para cada 100 pacientes&#8208;ano entre os pacientes em uso apenas do DMARD&#46; A incid&#234;ncia de EIG na associa&#231;&#227;o tofacitinibe<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DMARD foi&#44; inclusive&#44; maior que nos pacientes que utilizaram tofacitinibe<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>anti&#8208;TNF&#945;&#58; 3&#44;67 casos&#47;100&#160;pacientes&#8208;ano <span class="elsevierStyleItalic">vs&#46;</span> 2&#44;16 casos&#47;100 pacientes&#8208;ano&#46;<a class="elsevierStyleCrossRefs" href="#bib0920"><span class="elsevierStyleSup">47&#44;48</span></a> Entretanto&#44; esses dados ainda n&#227;o est&#227;o dispon&#237;veis em doen&#231;as dermatol&#243;gicas tratadas com iJAK&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Dados de vida real de pacientes com DA comparando os perfis de seguran&#231;a do baricitinibe e tofacitinibe confirmaram HZ como evento adverso mais frequente &#40;5&#44;6&#37; tofacitinibe<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4&#44;9&#37; baricitinibe&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">40</span></a> O risco &#233; maior em idosos e na coadministra&#231;&#227;o com corticosteroides ou metotrexato&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a> No entanto&#44; s&#227;o poucos os casos de herpes disseminado ou acometendo v&#225;rios derm&#225;tomos&#44; sem evid&#234;ncia de doen&#231;a visceral ou &#243;bito pela infec&#231;&#227;o herp&#233;tica&#46; Os estudos cl&#237;nicos demonstraram que o upadacitinibe apresentou maior risco de HZ comparado a indiv&#237;duos que utilizavam imunobiol&#243;gicos e DMARDS&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a> Tal como nos iJAK de primeira gera&#231;&#227;o&#44; o upadacitinibe em pacientes com AR apresentou risco maior de HZ quando prescrito em doses elevadas&#44; nas quais o HZ &#233; mais prov&#225;vel ocorrer e ser mais grave e de natureza a envolver v&#225;rios derm&#225;tomos&#46;<a class="elsevierStyleCrossRef" href="#bib0930"><span class="elsevierStyleSup">49</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Assim&#44; a vacina&#231;&#227;o contra o v&#237;rus do HZ &#233; um meio importante&#44; embora imperfeito&#44; de reduzir o impacto da infec&#231;&#227;o pelo HZV&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a> Por&#233;m&#44; tanto a vacina contra varicela &#40;Varivax&#174;&#44; para indiv&#237;duos n&#227;o imunes com menos de 50 anos&#41; quanto a vacina contra z&#243;ster &#40;Zostavax&#174; para indiv&#237;duos &#8805; 50 anos&#41; utilizam v&#237;rus vivos &#40;assim como a da febre amarela&#41; e&#44; como tal&#44; recomenda&#8208;se administrar pelo menos tr&#234;s a quatro semanas antes do in&#237;cio dos iJAK&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">No Brasil&#44; j&#225; est&#225; dispon&#237;vel a vacina recombinante contra o HZV&#44; Shingrix&#174;&#44; para pacientes com mais de 50 anos&#44; adultos maiores de 18 anos com imunossupress&#227;o ou que v&#227;o receber imunossupressores&#44; como os iJAK&#46; Essa vacina confere taxas de prote&#231;&#227;o de 91&#44;3&#37; para pessoas com 70 anos ou mais&#44; e de 67&#44;3&#37; em imunocomprometidos com mais de 50 anos&#46; A vacina &#233; composta pelo ant&#237;geno glicoprote&#237;na E &#40;gE&#41; da superf&#237;cie viral e deve ser oferecida em duas doses &#40;0&#8208;2 meses&#41;&#46; Como n&#227;o utiliza part&#237;culas vivas&#44; pode ser administrada em concomit&#226;ncia com o tratamento iJAK&#46;<a class="elsevierStyleCrossRef" href="#bib0935"><span class="elsevierStyleSup">50</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Estudos de efic&#225;cia sobre o uso de Shingrix&#174; em uma popula&#231;&#227;o imunocomprometida &#8805; 65 anos e em indiv&#237;duos tratados para DII com imunossupressores e &#8805; 50 anos mostraram boa prote&#231;&#227;o contra HZ&#46; Como ambos &#40;iJAK e Shingrix&#174;&#41; est&#227;o recentemente dispon&#237;veis&#44; o seguimento de longo prazo dessa associa&#231;&#227;o deve revelar detalhes do perfil de imuniza&#231;&#227;o nesses pacientes&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Os iJAK reduzem as diferentes citocinas e a sinaliza&#231;&#227;o dos receptores do fator de crescimento&#44; dependendo do tipo de inibi&#231;&#227;o de JAK&#46; Tofacitinibe&#44; um inibidor de JAK1&#47;3&#44; tem efeitos importantes no desenvolvimento dos linf&#243;citos B <span class="elsevierStyleItalic">na&#239;ve</span>&#46; Isso sugere perda na capacidade de imuniza&#231;&#227;o contra novos ant&#237;genos&#46; Encontrou&#8208;se resposta imune diminu&#237;da &#224; vacina pneumoc&#243;cica polissacar&#237;dica 23&#8208;valente &#40;PPSV&#8208;23&#41;&#44; especialmente em pacientes recebendo metotrexato concomitantemente&#58; tofacitinibe&#44; 45&#44;1&#37; <span class="elsevierStyleItalic">vs&#46;</span> controles saud&#225;veis 68&#44;4&#37;&#46; A interrup&#231;&#227;o tempor&#225;ria do tofacitinibe por duas semanas &#40;uma semana antes e uma ap&#243;s a vacina&#231;&#227;o&#41; n&#227;o restaurou a efic&#225;cia da vacina pneumoc&#243;cica&#46; J&#225; os resultados para a vacina da influenza n&#227;o foram afetados pelo uso do tofacitinibe&#46;<a class="elsevierStyleCrossRef" href="#bib0940"><span class="elsevierStyleSup">51</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">No entanto&#44; a maioria dos pacientes com psor&#237;ase tratada com tofacitinibe desenvolveu imunidade adequada contra infec&#231;&#227;o pneumoc&#243;cica &#40;vacina pneumoc&#243;cica conjugada&#8208;13&#41; e vacina contra o t&#233;tano&#46; A vacina&#231;&#227;o com a pneumoc&#243;cica conjugada &#40;PCV&#8208;13&#41; foi bem&#8208;sucedida em 68&#37; dos pacientes com AR tratados com o baricitinibe&#44; enquanto apenas 43&#37; alcan&#231;aram aumento &#8805; 4<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>nas concentra&#231;&#245;es da IgG antitet&#226;nica&#46; Contudo&#44; a maioria dos pacientes tamb&#233;m fazia uso de metotrexato &#40;89&#37;&#41; e&#47;ou corticosteroides &#40;30&#37;&#41;&#46; Resultados semelhantes foram encontrados para upadacitinibe&#44; com resposta humoral satisfat&#243;ria &#40;aumento &#8805; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>nos n&#237;veis de anticorpos&#41; para a vacina PCV&#8208;13 em 12 semanas em 65&#37; e 55&#37;&#44;respectivamente&#44; entre os pacientes em uso de 15<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46;<a class="elsevierStyleCrossRef" href="#bib0940"><span class="elsevierStyleSup">51</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Assim&#44; a opini&#227;o dos autores desta revis&#227;o &#233; de que todo o calend&#225;rio vacinal seja atualizado ao menos tr&#234;s a quatro semanas antes do in&#237;cio do uso dos iJAK sist&#234;micos&#44; conforme orienta&#231;&#245;es da autoridade de sa&#250;de local&#44; inclusive aquelas do Minist&#233;rio da Sa&#250;de do Brasil&#46; E&#44; durante o tratamento com iJAK&#44; seja cumprido o calend&#225;rio vacinal &#40;exceto para v&#237;rus vivos&#41;&#44; sem interrup&#231;&#227;o do tratamento&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Tal como ocorre com outros imunossupressores e com imunobiol&#243;gicos anti&#8208;TNF&#945;&#44; h&#225; preocupa&#231;&#227;o de infec&#231;&#227;o por <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> com o uso de iJAK&#44;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">17</span></a> e todos os pacientes que v&#227;o iniciar seu uso devem ser examinados e investigados quanto &#224; tuberculose latente ou ativa&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a> O risco de infec&#231;&#227;o por tuberculose &#233; dependente do risco epidemiol&#243;gico de cada regi&#227;o&#46; A incid&#234;ncia de tuberculose com tofacitinibe foi maior em regi&#245;es end&#234;micas &#40;0&#44;75&#47;100 pacientes&#8208;ano&#41; em rela&#231;&#227;o &#224;s regi&#245;es de menor risco &#40;0&#44;02&#47;100 pacientes&#8208;ano&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0905"><span class="elsevierStyleSup">44&#44;52</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">Como o Brasil apresenta taxas end&#234;micas de tuberculose&#44; que pode permanecer latente por d&#233;cadas&#44; a vigil&#226;ncia deve ocorrer previamente e durante o uso de imunossupressores como iJAK por meio do teste PPD &#40;prova da tuberculina&#47;<span class="elsevierStyleItalic">Mantoux</span>&#41; ou dos ensaios de libera&#231;&#227;o da IFN &#40;IGRA&#58; ELISPOT&#44; <span class="elsevierStyleItalic">Quantiferon gold&#44; Quantiferon gold plus</span>&#41;&#44; que apresentam performance discretamente superior&#46;<a class="elsevierStyleCrossRefs" href="#bib0950"><span class="elsevierStyleSup">53&#44;54</span></a> Testes de rastreio de tuberculose positivos devem ser referenciados ao infectologista a fim de considerar o tratamento da tuberculose latente com isoniazida&#44; por nove meses&#44; j&#225; que 5&#37;&#8208;10&#37; apresentam ativa&#231;&#227;o&#44; especialmente em pacientes sob imunossupress&#227;o&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">No &#226;mbito do uso de iJAK&#44; essas medica&#231;&#245;es conferem maior risco de infec&#231;&#245;es gerais&#44; risco de infec&#231;&#245;es oportunistas como pneumonia por <span class="elsevierStyleItalic">Pneumocystis jirovecii</span>&#44; HZ&#44; tuberculose&#44; citomegalovirose e infec&#231;&#245;es por Epstein&#8208;Barr v&#237;rus&#46; Recomenda&#8208;se&#58; 1&#41; rastreamento de infec&#231;&#227;o pelo v&#237;rus da hepatite B previamente ao tratamento&#59; 2&#41; profilaxia para <span class="elsevierStyleItalic">P&#46; jirovecii</span> em pacientes com fatores de risco adicionais&#44; como uso de corticosteroides&#59; 3&#41; rastreamento de tuberculose latente&#59; 4&#41; monitoriza&#231;&#227;o da carga viral em pacientes HBsAg negativos por&#233;m anti&#8208;HBcAg positivos em virtude do risco de reativa&#231;&#227;o de infec&#231;&#227;o oculta pelo v&#237;rus da hepatite C&#59; 5&#41; ao longo do uso cr&#244;nico de iJAK&#44; os m&#233;dicos devem estar atentos para o aumento de outras infec&#231;&#245;es oportunistas&#44; como infec&#231;&#245;es f&#250;ngicas invasivas&#44; especialmente em pacientes que j&#225; apresentam risco adicional por fatores como uso pr&#233;vio ou concomitante de corticosteroides&#44; baixa contagem de linf&#243;citos no hemograma ou terapia dependente de altas doses de iJAK&#46;<a class="elsevierStyleCrossRef" href="#bib0960"><span class="elsevierStyleSup">55</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">Infec&#231;&#245;es f&#250;ngicas invasivas foram detectadas em EELP e nos ensaios com tofacitinibe em 15 casos entre 9&#46;291 pacientes&#59; infec&#231;&#227;o por <span class="elsevierStyleItalic">Candida</span> spp&#46; foi a mais comum&#44; seguida por critptococose&#44; histplasmose e <span class="elsevierStyleItalic">P&#46; jirovecii</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Eventos tromboemb&#243;licos</span><p id="par0265" class="elsevierStylePara elsevierViewall">Baricitinibe&#44; tofacitinibe&#44; ruxolitinibe e upadacitinibe incluem advert&#234;ncias para potencial eventos de trombose venosa profunda&#44; embolia pulmonar e trombose arterial&#46;<a class="elsevierStyleCrossRef" href="#bib0965"><span class="elsevierStyleSup">56</span></a> Embora esses riscos pare&#231;am ser baixos e dependentes da dose&#44; estudos adicionais s&#227;o necess&#225;rios para determinar o mecanismo exato por tr&#225;s de seus efeitos tromb&#243;ticos&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">A descoberta pelo estudo ORALSURV de risco aumentado de tromboembolismo venoso &#40;TEV&#41; com dose de 10<span class="elsevierStyleHsp" style=""></span>mg&#47;dia do tofacitinibe em rela&#231;&#227;o aos anti&#8208;TNF&#945; corrobora esse fato&#44; observado pela primeira vez em ensaios cl&#237;nicos com pacientes com AR na dose de 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dia de baricitinibe&#44; o que fortalece o conceito de que o TEV pode ser um verdadeiro evento adverso relacionado ao uso de iJAK em pacientes com AR&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">Embora ainda falte plausibilidade biol&#243;gica&#44; &#233; razo&#225;vel especular que maior modula&#231;&#227;o de JAK2&#44; observada com doses mais altas de tofacitinibe e baricitinibe&#44; mediaria os efeitos tromb&#243;ticos&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a> Contudo&#44; de modo tranquilizador&#44; os iJAK usados na AR&#44; em suas doses atualmente aprovadas&#44; ainda n&#227;o parecem apresentar risco excessivo de eventos tromboemb&#243;licos&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">O estudo ORALSURV relatou que 5<span class="elsevierStyleHsp" style=""></span>mg&#47;dia de tofacitinibe e o uso de anti&#8208;TNF&#945; est&#227;o associados a risco semelhante de TEV&#44; e isso &#233; consistente com dados do mundo real&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a> Al&#233;m disso&#44; as taxas de incid&#234;ncia de TEV observadas nos estudos principais de tofacitinibe e upadacitinibe foram semelhantes &#40;e foram menores nos estudos de filgotinibe&#41;&#44; e as taxas nos grupos de comparadores ativos desses programas &#40;metotrexato ou adalimumabe&#41; n&#227;o foram superiores&#46; Mesmo para o baricitinibe&#44; para o qual o desequil&#237;brio inicial no risco de TEV entre as doses de 2<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dia nas primeiras 12 semanas dos ensaios de fase III levantou suspeitas&#44; taxas de incid&#234;ncia de longo prazo semelhantes foram relatadas para ambas as doses&#44; de 0&#44;5&#47;100 pacientes&#8208;ano&#44; em linha com estudos de base populacional de AR&#46;<a class="elsevierStyleCrossRefs" href="#bib0905"><span class="elsevierStyleSup">44&#44;57</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">Por fim&#44; baricitinibe 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dia administrado por duas semanas n&#227;o aumentou o risco de TEV no tratamento da COVID&#8208;19&#44; uma condi&#231;&#227;o <span class="elsevierStyleItalic">per se</span> com risco aumentado de TEV no in&#237;cio do estudo&#46;<a class="elsevierStyleCrossRef" href="#bib0975"><span class="elsevierStyleSup">58</span></a> Como as descobertas do ORALSURV sugerem haver risco dose&#8208;dependente com tofacitinibe em rela&#231;&#227;o aos anti&#8208;TNF&#945;&#44; at&#233; que pesquisas mais fundamentadas sejam realizadas com cada um desses compostos&#44; &#233; prudente evitar os iJAK em pacientes com risco elevado de TEV&#44; particularmente aqueles com hist&#243;ria de TEV que n&#227;o estejam atualmente anticoagulados&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">44</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">Em 2021&#44; a Food and Drug Administration &#40;FDA&#41; emitiu uma comunica&#231;&#227;o de seguran&#231;a e exigiu revis&#245;es de preucau&#231;&#227;o na embalagem para os iJAK tofacitinibe&#44; baricitinibe e upadacitinibe&#44; que inclu&#237;a informa&#231;&#245;es sobre o risco de eventos card&#237;acos graves&#44; c&#226;ncer&#44; trombose e &#243;bito&#46;<a class="elsevierStyleCrossRef" href="#bib0960"><span class="elsevierStyleSup">55</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Neoplasias malignas</span><p id="par0295" class="elsevierStylePara elsevierViewall">A taxa geral de ocorr&#234;ncia de neoplasias malignas com o uso dos iJAK em ensaios cl&#237;nicos randomizados envolvendo pacientes com AR e estudos de extens&#227;o de longo prazo foi semelhante &#224; observada com bDMARD&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">33</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall">No estudo ORALSURV&#44; a taxa de incid&#234;ncia de malignidade &#40;por 100 pacientes&#8208;ano&#41; foi de 1&#44;13 para pacientes tratados com tofacitinibe 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia e 1&#44;13 com tofacitinibe 10<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#44; em compara&#231;&#227;o com 0&#44;77 para os anti&#8208;TNF&#945;&#46;<a class="elsevierStyleCrossRefs" href="#bib0850"><span class="elsevierStyleSup">33&#44;44</span></a></p><p id="par0305" class="elsevierStylePara elsevierViewall">O maior risco de malignidades foi impulsionado por taxas diferenciais de v&#225;rios tipos de c&#226;ncer &#40;particularmente c&#226;ncer de pulm&#227;o e linfoma&#41;&#44; observados principalmente nos grupos norte&#8208;americanos do estudo &#40;em compara&#231;&#227;o com o restante do mundo&#41;&#44; entre indiv&#237;duos mais idosos e com hist&#243;rico de tabagismo&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">33</span></a> Tamb&#233;m foi notado risco aumentado de c&#226;ncer de pele n&#227;o melanoma&#44; observado anteriormente com o uso da dose de 10<span class="elsevierStyleHsp" style=""></span>mg&#47;dia de tofacitinibe na colite ulcerativa&#46;<a class="elsevierStyleCrossRef" href="#bib0980"><span class="elsevierStyleSup">59</span></a> Entretanto&#44; taxas mais altas de melanoma foram observadas em pacientes usando anti&#8208;TNF&#945; 0&#44;09 <span class="elsevierStyleItalic">vs&#46;</span> 0&#44;02 para qualquer dose do tofacitinibe&#46;<a class="elsevierStyleCrossRef" href="#bib0980"><span class="elsevierStyleSup">59</span></a></p><p id="par0310" class="elsevierStylePara elsevierViewall">O mecanismo pelo qual os iJAK podem estar associados a alguns tipos de c&#226;ncer &#233; desconhecido&#44; mas especula&#8208;se que alguns iJAK&#44; dependendo de sua seletividade e efeito nas c&#233;lulas <span class="elsevierStyleItalic">natural killer</span> &#40;NK&#41;&#44; poderiam diminuir a imunovigil&#226;ncia do hospedeiro&#44; tornando um c&#226;ncer existente ou <span class="elsevierStyleItalic">de novo</span> com maior possibilidade de evolu&#231;&#227;o&#44; como ocorre com os outros imunossupressores<a class="elsevierStyleCrossRef" href="#bib0985"><span class="elsevierStyleSup">60</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">Em resumo&#44; quando os iJAK orais s&#227;o avaliados de modo geral&#44; as taxas de TEV relatadas variaram de nenhum evento a 0&#44;1&#37;&#8208;0&#44;5&#37; em ensaios cl&#237;nicos espec&#237;ficos de dermatologia de fase III em compara&#231;&#227;o com nenhum evento no placebo&#46; As taxas de eventos cardiovasculares variaram de nenhum evento a 0&#44;4&#37;&#8208;1&#44;2&#37; em compara&#231;&#227;o com nenhum evento a 0&#44;5&#37;&#8208;1&#44;2&#37; no placebo&#46; As taxas de infec&#231;&#245;es graves foram de 0&#44;4&#37;&#8208;4&#44;8&#37; em compara&#231;&#227;o com nenhum evento a 0&#44;5&#37;&#8208;1&#44;3&#37; no placebo&#46; As taxas de c&#226;ncer de pele n&#227;o melanoma variaram de nenhum evento a 0&#44;6&#37;&#8208;0&#44;9&#37; em compara&#231;&#227;o com nenhum evento no placebo&#46; As taxas de c&#226;ncer de pele n&#227;o melanoma variaram de nenhum evento a 0&#44;2&#37;&#8208;0&#44;7&#37; em compara&#231;&#227;o com nenhum evento a 0&#44;6&#37; no placebo&#46; A maioria dos pacientes que desenvolveram esses eventos adversos tinha fatores de risco para o evento espec&#237;fico&#46; Os EA mais habituais foram infec&#231;&#245;es das vias a&#233;reas superiores&#44; n&#225;useas&#44; cefaleia&#44; acne e dislipidemia&#46;<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">61</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Contraindica&#231;&#245;es aos iJAK</span><p id="par0320" class="elsevierStylePara elsevierViewall">A principal contraindica&#231;&#227;o aos iJAK &#233; a incerteza no diagn&#243;stico da doen&#231;a inflamat&#243;ria que se deseja tratar&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">62</span></a> V&#225;rias dermatoses inflamat&#243;rias podem simular linfoma cut&#226;neo de c&#233;lulas T&#44; como DA e psor&#237;ase&#59; alopecias podem se relacionar a s&#237;filis&#59; hidradenite supurativa&#44; a processos infecciosos como tuberculose&#44; actinomicose&#44; paracoccidioidomicose e doen&#231;a de Crohn metast&#225;tica&#46; O uso inadvertido dos iJAK nessas condi&#231;&#245;es pode desencadear desfechos graves&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">Outras contraindica&#231;&#245;es dos iJAK incluem&#58; &#40;i&#41; hipersensibilidade aos componentes das medica&#231;&#245;es &#40;p&#46; ex&#46;&#44; Tween 80&#41;&#59; &#40;ii&#41; tuberculose&#59; &#40;iii&#41; fun&#231;&#227;o renal alterada &#40;baricitinibe&#41;&#59; &#40;iv&#41; altera&#231;&#227;o grave da fun&#231;&#227;o hep&#225;tica &#40;upadacitinibe e abrocitinibe&#41;&#59; &#40;v&#41; neutropenia &#60;<span class="elsevierStyleHsp" style=""></span>500 c&#233;lulas&#47;mm<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">3</span></a> &#40;baricitinibe&#41; ou &#60;<span class="elsevierStyleHsp" style=""></span>1&#46;000 c&#233;lulas&#47;mm<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">3</span></a> &#40;upadacitinibe e abrocitinibe&#41;&#59; &#40;vi&#41; anemia &#40;hemoglobina &#8804; 9<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41;&#59; &#40;vii&#41; processos infecciosos ativos&#59; &#40;viii&#41; gestantes&#44; mulheres com desejo de engravidar ou com vida sexual ativa sem uso de m&#233;todo contraconceptivo&#59; &#40;ix&#41; plaquetopenia &#60;<span class="elsevierStyleHsp" style=""></span>50&#46;000<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">3</span> &#40;abrocitinibe&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">62</span></a></p><p id="par0330" class="elsevierStylePara elsevierViewall">A prescri&#231;&#227;o tamb&#233;m dever&#225; ser reconsiderada caso o paciente se mostre impossibilitado de realizar exames de rastreamento infeccioso antes do in&#237;cio do tratamento ou acompanhamento regular durante o tratamento&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Avalia&#231;&#227;o dos pacientes antes e durante o uso dos iJAK</span><p id="par0335" class="elsevierStylePara elsevierViewall">Anamnese e exame cl&#237;nico geral&#44; al&#233;m do dermatol&#243;gico&#44; devem ser realizados em virtude das potenciais complica&#231;&#245;es com doen&#231;as infecciosas virais&#44; bacterianas e f&#250;ngicas&#44; al&#233;m de neoplasias&#46;</p><p id="par0340" class="elsevierStylePara elsevierViewall">Avaliar hist&#243;rico de perda ponderal de causa n&#227;o esclarecida&#44; contatos profissionais ou familiares com doen&#231;as infectocontagiosas &#40;tuberculose&#44; doen&#231;a de Chagas&#44; hansen&#237;ase&#41;&#44; n&#227;o realiza&#231;&#227;o de exames peri&#243;dicos de preven&#231;&#227;o de c&#226;ncer indicados para a faixa et&#225;ria do paciente e antecedentes familiares de c&#226;ncer ou de erros inatos da imunidade &#40;imunodefici&#234;ncias&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">62</span></a></p><p id="par0345" class="elsevierStylePara elsevierViewall">A palpa&#231;&#227;o das cadeias linfonodais&#44; f&#237;gado&#44; ba&#231;o&#44; ausculta pulmonar e card&#237;aca&#44; sinal de Giordano s&#227;o essenciais a cada consulta&#46; Outros dados a serem verificados antes do tratamento est&#227;o inclu&#237;dos na <a class="elsevierStyleCrossRef" href="#tbl0025">tabela 5</a>&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0350" class="elsevierStylePara elsevierViewall">Antes do tratamento e periodicamente&#44; a cada dois meses&#44; os pacientes em uso de iJAK sist&#234;micos devem realizar exames de sangue &#40;hemograma&#44; lipidograma&#44; fun&#231;&#227;o hep&#225;tica e renal&#41;&#44; radiografia do t&#243;rax antes do tratamento&#44; repetindo&#8208;se quando indicado&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Manejo de eventos durante o tratamento com os iJAK</span><p id="par0355" class="elsevierStylePara elsevierViewall">Os iJAK podem promover aumento dos l&#237;pides s&#233;ricos&#44; com aumento do colesterol total&#44; LDL&#44; HDL e triglic&#233;rides&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">62</span></a> Os n&#237;veis do colesterol e triglic&#233;rides devem ser monitorados durante o tratamento&#44; de modo que&#44; quando necess&#225;rio&#44; antilipemiantes orais sejam utilizados&#44; de acordo com os protocolos cl&#237;nicos&#46;<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">63</span></a></p><p id="par0360" class="elsevierStylePara elsevierViewall">&#201; comum a eleva&#231;&#227;o da creatinofosfoquinase &#40;CPK&#41; durante o tratamento&#44; geralmente n&#227;o relacionado &#224; miopatia&#44; o que demanda aten&#231;&#227;o quanto aos resultados no seguimento laboratorial&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">62</span></a> Postula&#8208;se que o aumento nos n&#237;veis da CPK durante o uso do updacitinibe ocorra porque o iJAK1 inibe a a&#231;&#227;o fisiol&#243;gica da oncostatina M &#40;OSM&#41;&#44; que bloqueia a diferencia&#231;&#227;o dos mioblastos a mi&#243;citos&#44; onde se produz mais CPK&#46; Uma vez que se perca essa via inibidora&#44; mais mioblastos se diferenciam em mi&#243;citos e aumenta a s&#237;ntese da CPK&#44; sem rabdomi&#243;lise&#44; apenas pela diferencia&#231;&#227;o celular&#46; Acredita&#8208;se que inclusive a OSM em n&#237;veis elevados determine a sarcopenia nos pacientes com AR&#46; A suspeita de rabdomi&#243;lise decorrente do iJAK deve seguir mialgia&#44; c&#226;imbras e escurecimento da urina&#44; configurando urg&#234;ncia cl&#237;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">62</span></a></p><p id="par0365" class="elsevierStylePara elsevierViewall">Pacientes recebendo iJAK devem ser monitorados quanto &#224; eleva&#231;&#227;o das transaminases e orientados a procurar atendimento m&#233;dico caso apresentem sintomas sist&#234;micos&#58; n&#225;usea&#47;v&#244;mitos&#47;anorexia&#44; como sintomas digestivos&#44; e erup&#231;&#227;o cut&#226;nea&#47;prurido&#47;icter&#237;cia&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">62</span></a></p><p id="par0370" class="elsevierStylePara elsevierViewall">O risco de citopenias &#233; maior entre pacientes<span class="elsevierStyleHsp" style=""></span>&#62; 65 anos&#46; O iJAK deve ser interrompido em casos de neutropenia &#40;&#60; 1&#46;000 neutr&#243;filos&#47;mm<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">3</span></a>&#41;&#44; linfopenia &#40;&#60; 500 linf&#243;citos&#47;mm<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">3</span></a>&#41;&#44; anemia &#40;hemoglobina &#60;<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41; ou plaquetopenia &#40;&#60; 50&#46;000<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">3</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">62</span></a> Neutropenia e linfopenia aumentam os riscos de infec&#231;&#227;o&#44; e o paciente deve ser orientado a procurar atendimento m&#233;dico em caso de febre&#44; calafrios ou dor de garganta ou tosse&#46; Caso ocorram sintomas de fadiga&#44; mal&#8208;estar&#44; palpita&#231;&#245;es&#44; tonturas ou dispneia&#44; dor abdominal de in&#237;cio abrupto&#44; n&#225;useas&#44; v&#244;mitos ou anorexia&#44; o paciente tamb&#233;m deve buscar atendimento m&#233;dico&#44; pelo risco de perfura&#231;&#227;o intestinal&#46; Em pacientes com doen&#231;a diverticular do c&#243;lon&#44; a perfura&#231;&#227;o gastrintestinal pode suceder uma diverticulite&#59; esses pacientes devem ser instru&#237;dos e cautelosamente acompanhados&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">62</span></a></p><p id="par0375" class="elsevierStylePara elsevierViewall">Sintomas como tosse seca&#44; dispneia ao exerc&#237;cio e febre devem alertar o paciente a procurar atendimento m&#233;dico&#44; sob risco de pneumopatia intersticial&#46; Nesse caso&#44; exames de sangue devem ser solicitados&#58; PCR&#44; DHL&#44; Krebs von den Lungen&#8208;6 &#40;KL&#8208;6&#41; e SP&#8208;D &#40;<span class="elsevierStyleItalic">surfactante protein D</span>&#41; &#8211; os n&#237;veis s&#233;ricos dessas duas &#250;ltimas s&#227;o muito sens&#237;veis no diagn&#243;stico de pneumonite de hipersensibilidade medicamentosa&#46;<a class="elsevierStyleCrossRef" href="#bib1005"><span class="elsevierStyleSup">64</span></a> Al&#233;m disso&#44; radiografia ou tomografia computadorizada do t&#243;rax e gasometria devem ser solicitados&#44; devendo ser descontinuado o iJAK at&#233; o diagn&#243;stico&#46;</p><p id="par0380" class="elsevierStylePara elsevierViewall">Pneumonia por <span class="elsevierStyleItalic">P&#46; jirovecci</span> pode ocorrer&#44; e a dosagem dos n&#237;veis de &#946;&#8208;D&#8208;glucana podem auxiliar o diagn&#243;stico&#46; Al&#233;m disso&#44; deve&#8208;se afastar influenza&#44; COVID&#8208;19&#44; infec&#231;&#245;es por <span class="elsevierStyleItalic">Mycoplasma</span>&#44; <span class="elsevierStyleItalic">Chlamydia</span> e <span class="elsevierStyleItalic">Legionella</span> em pacientes com imagens radiol&#243;gicas de padr&#227;o parenquimatoso intersticial&#44; o que pode configurar pneumonia at&#237;pica n&#227;o pneumoc&#237;stica&#46; Exclu&#237;das causas infecciosas&#44; pneumonia de doen&#231;a pulmonar reum&#225;tica induzida por medicamento deve ser considerada&#46; Imagens radiol&#243;gicas exsudativas no pulm&#227;o podem indicar pneumonia bacteriana ou tuberculose&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">62</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">iJAK nas dermatoses inflamat&#243;rias e autoimunes</span><p id="par0385" class="elsevierStylePara elsevierViewall">A maior parte das dermatoses inflamat&#243;rias ou autoimunes n&#227;o decorre do efeito de uma &#250;nica citocina&#44; por&#233;m&#44; segue perfis inflamat&#243;rios que podem ser inibidos pela modula&#231;&#227;o da via JAK&#8208;STAT&#46; A base imunol&#243;gica e os resultados cl&#237;nicos dos principais iJAK&#44; na dermatologia&#44; s&#227;o apresentadas adiante&#46; A <a class="elsevierStyleCrossRef" href="#tbl0030">tabela 6</a> apresenta os iJAK com indica&#231;&#245;es dermatol&#243;gicas descritas na literatura&#44; e a <a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a> resume as principais subst&#226;ncias com ensaios cl&#237;nicos para uso na dermatologia&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Dermatite at&#243;pica</span><p id="par0390" class="elsevierStylePara elsevierViewall">A DA apresenta alta preval&#234;ncia&#44; especialmente em crian&#231;as e adultos jovens&#46; Seu curso cr&#244;nico e redicivante&#44; associado a comorbidades al&#233;rgicas e psicol&#243;gicas&#44; infligem importante impacto na qualidade de vida&#46;<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">65</span></a> Sua patog&#234;nese &#233; complexa e depende da intera&#231;&#227;o de v&#225;rios elementos&#46; Em cerca de 80&#37; dos pacientes ocorrem falha da barreira cut&#226;nea&#44; especialmente por perda de fun&#231;&#227;o do gene da filagrina&#46; Perda transepid&#233;rmica de &#225;gua&#44; altera&#231;&#245;es no microbioma cut&#226;neo&#44; em conjunto com permeabilidade a ant&#237;genos e hiper&#8208;reatividade neural favorecem a exacerba&#231;&#227;o da resposta inflamat&#243;ria local&#44; manifesta especialmente como eczema e prurido&#46;<a class="elsevierStyleCrossRefs" href="#bib1015"><span class="elsevierStyleSup">66&#44;67</span></a></p><p id="par0395" class="elsevierStylePara elsevierViewall">Apesar de ser considerada doen&#231;a inflamat&#243;ria com predomin&#226;ncia do padr&#227;o Th2&#44; diversas citocinas atuam conjuntamente para formar e manter um ambiente de hiper&#8208;reatividade cut&#226;nea e que variam tamb&#233;m entre as fases da doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">3</span></a> O envolvimento no microambiente cut&#226;neo&#44; especialmente de IL&#8208;4&#44; IL&#8208;5&#44; IL&#8208;10&#44; IL&#8208;13&#44; IL&#8208;31&#44; IFN&#8208;&#947;&#44; IL&#8208;17&#44; IL&#8208;22 e IL&#8208;33&#44; &#233; ind&#237;cio do potencial dos iJAK&#44; &#40;principalmente JAK1&#41; em seu tratamento&#46;<a class="elsevierStyleCrossRefs" href="#bib1020"><span class="elsevierStyleSup">67&#44;68</span></a></p><p id="par0400" class="elsevierStylePara elsevierViewall">Modelos experimentais demonstraram que o tratamento da DA com iJAK levou &#224; r&#225;pida supress&#227;o do prurido&#44; melhora da barreira cut&#226;nea&#44; das fibras nervosas cut&#226;neas&#44; redu&#231;&#227;o do infiltrado linfocit&#225;rio e das citocinas inflamat&#243;rias &#40;p&#46; ex&#46;&#44; IL&#8208;4 e IL&#8208;13&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1030"><span class="elsevierStyleSup">69</span></a></p><p id="par0405" class="elsevierStylePara elsevierViewall">No Brasil&#44; baricitinibe&#44; abrocitinibe e upadacitinibe s&#227;o aprovados para uso oral na DA moderada a grave&#59; ruxolitinibe 1&#44;5&#37; creme est&#225; dispon&#237;vel no mercado dos EUA&#44; e delgocitinibe 0&#44;5&#37; creme deve ser aprovado em 2023&#46; Apesar de eficaz no tratamento da DA&#44; n&#227;o foram desenvolvidos ensaios cl&#237;nicos com tofacitinibe oral &#8211; a maioria dos estudos &#233; de relatos e s&#233;ries de casos&#46;<a class="elsevierStyleCrossRef" href="#bib1020"><span class="elsevierStyleSup">67</span></a> A <a class="elsevierStyleCrossRef" href="#tbl0035">tabela 7</a> resume os resultados de ensaios cl&#237;nicos pivotais dos principais iJAK na DA&#46;</p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><p id="par0410" class="elsevierStylePara elsevierViewall">Nos estudos cl&#237;nicos&#44; todos os iJAK sist&#234;micos tiveram desempenho superior ao placebo&#44; com r&#225;pido controle do prurido&#44; melhora da qualidade de vida e do sono e redu&#231;&#227;o da &#225;rea de eczema&#46; Doses mais altas e associa&#231;&#227;o dos iJAK com corticosteroides t&#243;picos promoveram melhor desempenho dos tratamentos&#44; por&#233;m maior taxa de EA&#46;</p><p id="par0415" class="elsevierStylePara elsevierViewall">Na compara&#231;&#227;o dos estudos individuais&#44; abrocitinibe e upadacitinibe orais apresentaram maior propor&#231;&#227;o de redu&#231;&#227;o de escores cl&#237;nicos que baricitinibe&#46;<a class="elsevierStyleCrossRefs" href="#bib0885"><span class="elsevierStyleSup">40&#44;76</span></a> Apesar das diferen&#231;as entre os estudos nas faixas et&#225;rias e etnias dos pacientes&#44; na dura&#231;&#227;o e nas diferentes estrat&#233;gias de resgate&#44; espera&#8208;se que &#8805; 60&#37; daqueles em uso de upadacitinibe nas doses de 15<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e &#8805; 70&#37; na dose de 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia atinjam a redu&#231;&#227;o &#8805; 75&#37; do &#205;ndice de &#193;rea e Gravidade do Eczema &#40;EASI75&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0885"><span class="elsevierStyleSup">40&#44;43</span></a> J&#225; no abrocitinibe 100<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e 200<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; espera&#8208;se que esses valores sejam &#8805; 40&#37; e &#8805; 60&#37;&#46; E&#44; no baricitinibe 2<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; que sejam &#8805; 18&#37; e &#8805; 21&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">40</span></a></p><p id="par0420" class="elsevierStylePara elsevierViewall">A extens&#227;o por 52 semanas do estudo <span class="elsevierStyleItalic">AD UP</span> incluiu 901 pacientes entre 12 e 75 anos&#44; com DA moderada ou grave&#44; randomizados em tr&#234;s grupos&#58; upadacitinibe 15<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e placebo &#40;primeiras 16 semanas&#41;&#44; todos associados a corticosteroide t&#243;pico de baixa pot&#234;ncia ou inibidor de calcineurina&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#46; Na semana 52&#44; a propor&#231;&#227;o de pacientes que atingiu EASI75 foi de 50&#44;8&#37; para o grupo upadacitinibe 15<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e 69&#44;0&#37; para o grupo de 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#59; 7&#44;4&#37; dos pacientes do grupo upadacitinibe 15<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e 2&#44;5&#37; do grupo de 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia abandonaram o estudo por falta de efic&#225;cia&#46;<a class="elsevierStyleCrossRef" href="#bib1035"><span class="elsevierStyleSup">70</span></a></p><p id="par0425" class="elsevierStylePara elsevierViewall">No estudo BREEZE&#8208;AD3&#44; que faz o seguimento por 52 semanas de 292 pacientes do estudo BREEZE&#8208;AD7 &#40;16 semanas&#41; em uso de baricitinibe 2 ou 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e corticosteroides t&#243;picos&#44; observou&#8208;se uma leve perda de efic&#225;cia&#58; EASI75 51&#37; na semana 16 para 43&#37; na semana 68&#46; At&#233; 17&#44;8&#37; dos pacientes tratados com baricitinibe 2<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e 28&#44;4&#37; dos tratados com baricitinibe 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dia abandonaram o seguimento por falta de efic&#225;cia&#46;<a class="elsevierStyleCrossRef" href="#bib1070"><span class="elsevierStyleSup">77</span></a></p><p id="par0430" class="elsevierStylePara elsevierViewall">Em estudo de vida real que incluiu 44 pacientes adultos com DA tratados com baricitinibe&#44; confirmou&#8208;se a efic&#225;cia e perfil de seguran&#231;a do medicamento&#59; entretanto&#44; o seguimento longitudinal revelou que o percentual de pacientes que atingiu EASI75 foi de 53&#37; na semana 4&#44; e 33&#37; na semana 16&#59; 7&#37; dos pacientes abandonaram o estudo por efic&#225;cia insuficiente&#46;<a class="elsevierStyleCrossRef" href="#bib1075"><span class="elsevierStyleSup">78</span></a> Esses dados apontam para a possibilidade de uma leve perda de efic&#225;cia dos tratamentos a partir da quarta semana&#46;</p><p id="par0435" class="elsevierStylePara elsevierViewall">Ainda n&#227;o h&#225; estudos randomizados comparando os iJAK orais a outros imunossupressores &#40;p&#46; ex&#46;&#44; ciclosporina&#44; azatioprina e metotrexato&#41; na DA&#46; Tamb&#233;m n&#227;o s&#227;o dispon&#237;veis dados relativos &#224; associa&#231;&#227;o de iJAK t&#243;pico e sist&#234;mico ou esquemas posol&#243;gicos vari&#225;veis&#44; como a utiliza&#231;&#227;o de doses altas nas primeiras semanas&#44; com posterior redu&#231;&#227;o das doses ou troca de estrat&#233;gia para minimizar custo e EA&#46;</p><p id="par0440" class="elsevierStylePara elsevierViewall">O estudo <span class="elsevierStyleItalic">Heads up</span> comparou 692 adultos com DA&#44; randomizados para usar upadacitinibe oral 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia <span class="elsevierStyleItalic">vs&#46;</span> dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg a cada 14 dias&#44; por 24 semanas&#46; Na semana 16&#44; o EASI75 foi atingido por 71&#37; dos pacientes usando upadacitinibe e por 61&#37; daqueles em uso de dupilumabe&#46; Os demais desfechos cl&#237;nicos seguiram essa superioridade do upadacitinibe&#44; com destaque &#224; maior e mais precoce redu&#231;&#227;o do prurido&#46; Na semana 24&#44; o EASI75 do grupo upadacitinibe reduziu para 64&#37;&#44; enquanto o dupilumabe resultou em 59&#37;&#46; Ambos os grupos demandaram tratamentos de resgate antes da semana 16&#58; upadacitinibe 20&#44;3&#37; e dupilumabe 17&#44;5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib1080"><span class="elsevierStyleSup">79</span></a></p><p id="par0445" class="elsevierStylePara elsevierViewall">Nessas doses&#44; ao fim de 24 semanas&#44; o estudo evidenciou maior frequ&#234;ncia de acne &#40;18&#44;4&#37; <span class="elsevierStyleItalic">vs&#46;</span> 3&#44;2&#37;&#41;&#44; HSV &#40;0&#44;9&#37; <span class="elsevierStyleItalic">vs&#46;</span> 0&#44;0&#37;&#41; e HZ &#40;3&#44;4&#37; <span class="elsevierStyleItalic">vs&#46;</span> 1&#44;2&#37;&#41; no grupo upadacitinibe&#44; enquanto conjuntivite foi mais frequente no grupo dupilumabe &#40;10&#44;2&#37; <span class="elsevierStyleItalic">vs&#46;</span> 1&#44;4&#37;&#41;&#46; Um participante do grupo upadacitinibe faleceu em decorr&#234;ncia de broncopneumonia associada &#224; infec&#231;&#227;o pelo v&#237;rus influenza&#46; No grupo upadacitinibe&#44; houve maior frequ&#234;ncia de altera&#231;&#245;es laboratoriais&#46; Eleva&#231;&#227;o das transaminases ocorreu em 3&#44;4&#37; <span class="elsevierStyleItalic">vs&#46;</span> 1&#44;1&#37;&#44; e dois participantes do grupo upadacitinibe descontinuaram o estudo por esse motivo&#46; Anemia &#40;2&#44;0&#37; <span class="elsevierStyleItalic">vs&#46;</span> 0&#44;3&#37;&#41;&#44; neutropenia &#40;1&#44;7&#37; <span class="elsevierStyleItalic">vs&#46;</span> 0&#44;6&#37;&#41; e eleva&#231;&#227;o da CPK &#40;7&#44;5&#37; <span class="elsevierStyleItalic">vs&#46;</span> 3&#44;2&#37;&#41; tamb&#233;m prevaleceram no upadacitinibe&#46;<a class="elsevierStyleCrossRef" href="#bib1080"><span class="elsevierStyleSup">79</span></a> O perfil de seguran&#231;a de longo prazo do dupilumabe permite recomendar sua administra&#231;&#227;o sem a necessidade de seguimento laboratorial ou risco de intera&#231;&#227;o medicamentosa&#46;<a class="elsevierStyleCrossRefs" href="#bib1020"><span class="elsevierStyleSup">67&#44;76</span></a></p><p id="par0450" class="elsevierStylePara elsevierViewall">O estudo JADE DARE comparou abrocitinibe&#160;200<span class="elsevierStyleHsp" style=""></span>mg&#47;dia <span class="elsevierStyleItalic">vs&#46;</span> dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg a cada 14 dias&#44; em 726 pacientes com DA moderada a grave&#44; por 26 semanas&#46; Ao final do estudo&#44; 73&#37; dos pacientes do grupo abrocitinibe <span class="elsevierStyleItalic">vs&#46;</span> 72&#37; do grupo dupilumabe atingiram o EASI75&#46; Conjuntivite foi mais prevalente no grupo dupilumabe &#40;11&#37; <span class="elsevierStyleItalic">vs&#46;</span> 3&#37;&#41;&#46; No grupo abrocitinibe&#44; foram mais frequentes&#58; acne &#40;13&#37; <span class="elsevierStyleItalic">vs&#46;</span> 3&#37;&#41;&#44; n&#225;useas &#40;19&#37; <span class="elsevierStyleItalic">vs&#46;</span> 2&#37;&#41;&#44; HSV &#40;6&#37; <span class="elsevierStyleItalic">vs&#46;</span> 5&#37;&#41;&#44; HZ &#40;3&#37; <span class="elsevierStyleItalic">vs&#46;</span> 0&#37;&#41; e cefaleia &#40;13&#37; <span class="elsevierStyleItalic">vs&#46;</span> 7&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1085"><span class="elsevierStyleSup">80</span></a></p><p id="par0455" class="elsevierStylePara elsevierViewall">Os iJAK t&#243;picos &#40;ruxolitinibe e delgocitinibe&#41; ratificaram o r&#225;pido in&#237;cio de efeito &#40;&#60; 24 horas para redu&#231;&#227;o do prurido&#41;&#44; com alta taxa de efic&#225;cia&#44; seguran&#231;a e tolerabilidade&#46; At&#233; o momento&#44; iJAK t&#243;picos s&#227;o indicados em quadros com menos de 20&#37; da &#225;rea corporal afetada e uso n&#227;o prolongado&#46;<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">18&#44;75&#44;81</span></a> A efic&#225;cia dos iJAK t&#243;picos aumenta com a concentra&#231;&#227;o do ativo e o n&#250;mero de aplica&#231;&#245;es di&#225;rias&#46; A boa tolerabilidade e o perfil de seguran&#231;a podem revelar&#8208;se oportunos no resgate de pacientes jovens com DA moderada a grave&#44; que geralmente dependem de corticosteroides t&#243;picos para tal&#46; O uso estendido de ruxolitinibe 1&#44;5&#37; creme por at&#233; 44 semanas&#44; com 1&#46;249 adultos orientados a usar nas les&#245;es&#44; se necess&#225;rio&#44; resultou em bom perfil de tolerabilidade e seguran&#231;a&#44; sem evid&#234;ncias de efeito sist&#234;mico&#46; Entre 74&#37; e 78&#37; atingiram o fim do estudo com IGA 0&#47;1&#46;<a class="elsevierStyleCrossRef" href="#bib1095"><span class="elsevierStyleSup">82</span></a></p><p id="par0460" class="elsevierStylePara elsevierViewall">Quando comparados os desempenhos dos iJAK t&#243;picos em estudos cl&#237;nicos individuais&#44; tofacitinibe 2&#37;&#44; delgocitinibe 3&#37; e ruxolitinibe 1&#44;5&#37; apresentaram maior redu&#231;&#227;o de escores de DA que os esperados para os inibidores da PDE4 &#40;p&#46; ex&#46;&#44; crisaborol&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib1075"><span class="elsevierStyleSup">78&#44;83</span></a></p><p id="par0465" class="elsevierStylePara elsevierViewall">Em uma compara&#231;&#227;o duplo&#8208;cega envolvendo 51 pacientes com DA usando triancinolona creme 0&#44;15&#37;&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#44; sob diferentes concentra&#231;&#245;es e regimes de ruxolitinibe creme por oito semanas&#44; tanto a triancinolona quanto as diferentes posologias de ruxolitinibe evidenciaram superioridade em rela&#231;&#227;o ao ve&#237;culo e incremento do efeito em fun&#231;&#227;o do tempo&#46; EASI75 ocorreu em 56&#37; dos pacientes do grupo que utilizou ruxolitinibe 1&#44;5&#37;&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia <span class="elsevierStyleItalic">vs&#46;</span> 47&#37; dos que usaram triancinolona&#46;<a class="elsevierStyleCrossRef" href="#bib1105"><span class="elsevierStyleSup">84</span></a></p><p id="par0470" class="elsevierStylePara elsevierViewall">De modo geral&#44; os iJAK ainda n&#227;o s&#227;o liberados para crian&#231;as menores de 12 anos&#44; exatamente a popula&#231;&#227;o mais afligida pela DA&#44; por&#233;m os estudos de seguran&#231;a t&#234;m avan&#231;ado para ampliar a faixa et&#225;ria de uso&#46;</p><p id="par0475" class="elsevierStylePara elsevierViewall">Por fim&#44; os iJAK orais ou t&#243;picos revelaram&#8208;se op&#231;&#245;es terap&#234;uticas valiosas para a DA&#44; com bom perfil de seguran&#231;a&#44; por&#233;m sua indica&#231;&#227;o em DA precisa ser bem definida frente aos demais imunossupressores&#44; imunobiol&#243;gicos e fototerapia&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Psor&#237;ase</span><p id="par0480" class="elsevierStylePara elsevierViewall">A patog&#234;nese da psor&#237;ase envolve tanto o sistema imune inato quanto o adaptativo&#44; a partir de uma complexa intera&#231;&#227;o entre queratin&#243;citos&#44; c&#233;lulas dendr&#237;ticas&#44; linf&#243;citos T&#44; citocinas e outros mediadores inflamat&#243;rios&#46; A inflama&#231;&#227;o cr&#244;nica caracter&#237;stica da doen&#231;a &#233;&#44; principalmente&#44; promovida pela IL&#8208;23&#44; a qual induz a diferencia&#231;&#227;o de c&#233;lulas T <span class="elsevierStyleItalic">na&#239;ve</span> em linf&#243;citos Th17 e sua expans&#227;o clonal&#46;<a class="elsevierStyleCrossRefs" href="#bib1110"><span class="elsevierStyleSup">85&#44;86</span></a></p><p id="par0485" class="elsevierStylePara elsevierViewall">A transdu&#231;&#227;o do sinal da IL&#8208;23 &#233; mediada pela TYK2&#46; As c&#233;lulas Th17 ativadas liberam citocinas proinflamat&#243;rias como TNF&#945;&#44; IL&#8208;22&#44; IL&#8208;26 e IL&#8208;29&#44; as quais induzem a prolifera&#231;&#227;o dos queratin&#243;citos&#46; Na psor&#237;ase&#44; h&#225; ainda n&#237;veis s&#233;ricos aumentados de citocinas Th1 &#40;IFN&#8208;&#947; e IL&#8208;2&#41;&#44; bem como n&#237;veis diminu&#237;dos de IL&#8208;10&#46; A IL&#8208;22&#44; produzida pelas c&#233;lulas Th22&#44; &#233; citocina mediada pela via JAK&#8208;STAT e induz a prolifera&#231;&#227;o queratinoc&#237;tica&#46; A libera&#231;&#227;o da IL&#8208;22&#44; em associa&#231;&#227;o &#224; IL&#8208;15&#44; &#233; sinalizada pela JAK1 e JAK3&#46; Desse modo&#44; a inibi&#231;&#227;o da JAK&#47;TYK &#233; alvo potencial para seu tratamento&#46; Contudo&#44; face &#224; patog&#234;nese da doen&#231;a&#44; os iJAK de segunda gera&#231;&#227;o&#44; seletivos para JAK2&#47;TYK2&#44; seriam potencialmente mais efetivos do que os que bloqueiam m&#250;ltiplas isoformas de JAK&#47;TYK&#46;<a class="elsevierStyleCrossRefs" href="#bib0690"><span class="elsevierStyleSup">1&#44;87</span></a> A prop&#243;sito&#44; indiv&#237;duos com polimorfismo gen&#233;tico e consequente perda da fun&#231;&#227;o da TYK2 apresentam menor risco de desenvolver psor&#237;ase e outras doen&#231;as imunomediadas&#46;<a class="elsevierStyleCrossRef" href="#bib1125"><span class="elsevierStyleSup">88</span></a></p><p id="par0490" class="elsevierStylePara elsevierViewall">De maneira geral&#44; tofacitinibe &#40;2&#44; 5&#44; 10 e 15<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#41;&#44; solcitinibe &#40;200 e 400<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#41;&#44; baricitinibe &#40;8 e 10<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#41; e deucravacitinibe &#40;3 e 6<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#41; apresentaram resposta PASI75 superior ao placebo&#44; tanto na semana 8 quanto na 12&#44; nos ensaios cl&#237;nicos randomizados de psor&#237;ase em placas moderada &#224; grave&#46;<a class="elsevierStyleCrossRefs" href="#bib1130"><span class="elsevierStyleSup">89&#44;90</span></a></p><p id="par0495" class="elsevierStylePara elsevierViewall">Uma metan&#225;lise concluiu que tofacitinibe &#40;15 e 10<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#41; e deucravacitinibe &#40;6<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia e 12<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#41; apresentaram as melhores respostas de PGA e PASI75 &#40;nas semanas 8 e 12&#41;&#44; dentre os iJAK utilizados no tratamento da psor&#237;ase em placas&#46; Apesar de a mesma metan&#225;lise mostrar perfil satisfat&#243;rio de seguran&#231;a dos iJAK no tratamento da psor&#237;ase em placa&#44; tofacitinibe n&#227;o obteve aprova&#231;&#227;o pela FDA em virtude dos efeitos colaterais apresentados&#59; o medicamento &#233; aprovado apenas na dose de 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#44; para a terapia da AR&#46; Os iJAK em estudo para o tratamento da psor&#237;ase em placas s&#227;o deucravacitinibe&#44; brepocitinibe e ropsacitinibe&#44; todos inibidores da TKY2&#46;<a class="elsevierStyleCrossRef" href="#bib1130"><span class="elsevierStyleSup">89</span></a></p><p id="par0500" class="elsevierStylePara elsevierViewall">No Brasil&#44; tofacitinibe 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#44; &#233; aprovado para o tratamento da artrite psori&#225;sica em adultos&#46; Contudo&#44; pode ser eficaz no tratamento da psor&#237;ase ungueal&#59; 33&#37; dos pacientes atingiram NAPSI50 na semana 16 com tofacitinibe 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#44; 44&#37; com 10<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#44; e 12&#37; com placebo&#46;<a class="elsevierStyleCrossRef" href="#bib1140"><span class="elsevierStyleSup">91</span></a></p><p id="par0505" class="elsevierStylePara elsevierViewall">Atualmente&#44; o &#250;nico iJAK t&#243;pico em estudo para o tratamento da psor&#237;ase &#233; o brepocitinibe&#44; inibidor ortost&#233;rico da JAK1 e JAK2&#46; Em ensaio fase I envolvendo indiv&#237;duos sadios e doentes com psor&#237;ase em placas moderada a grave&#44; o brepocitinibe confirmou seguran&#231;a e boa tolerabilidade&#46;<a class="elsevierStyleCrossRef" href="#bib1145"><span class="elsevierStyleSup">92</span></a></p><p id="par0510" class="elsevierStylePara elsevierViewall">Em compara&#231;&#227;o ao apremilaste&#44; &#250;nico outro medicamento oral aprovado para a terapia da psor&#237;ase&#44; os inibidores da JAK2&#47;TYK2 apresentam maior seletividade imunol&#243;gica&#44; restringindo a possibilidade de efeitos colaterais&#46; O deucravacitinibe foi aprovado pela FDA e pela ag&#234;ncia japonesa para o tratamento da psor&#237;ase em placa moderada a grave em adultos&#46;<a class="elsevierStyleCrossRef" href="#bib1150"><span class="elsevierStyleSup">93</span></a> Estudo randomizado com 332 pacientes usando 6<span class="elsevierStyleHsp" style=""></span>mg&#47;dia revelou resposta PASI75 superior&#44; na semana 16&#44; ao apremilaste oral 30<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia e placebo &#40;58&#37;&#44; 35&#37; e 13&#37;&#41;&#46; A taxa de efeitos colaterais foi similar nos tr&#234;s grupos&#46; Entretanto&#44; n&#227;o se recomenda associar deucravacitinibe com outros imunossupressores&#46;<a class="elsevierStyleCrossRef" href="#bib1155"><span class="elsevierStyleSup">94</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Alopecia areata</span><p id="par0515" class="elsevierStylePara elsevierViewall">A alopecia areata &#40;AA&#41; tem patog&#234;nese autoimune envolvendo o colapso do privil&#233;gio imunol&#243;gico no fol&#237;culo piloso&#46; Nas &#225;reas de AA&#44; observa&#8208;se infiltrado inflamat&#243;rio composto por linf&#243;citos CD4<span class="elsevierStyleSup">&#43;</span>&#44; CD8<span class="elsevierStyleSup">&#43;</span> e NK ao redor do bulbo dos fol&#237;culos em fase an&#225;gena&#44; levando &#224; interrup&#231;&#227;o da melanog&#234;nese e da produ&#231;&#227;o da haste&#46;<a class="elsevierStyleCrossRef" href="#bib1160"><span class="elsevierStyleSup">95</span></a> A presen&#231;a dos linf&#243;citos TCD8<span class="elsevierStyleSup">&#43;</span>NKG2D<span class="elsevierStyleSup">&#43;</span> &#233; determinante para o desenvolvimento das les&#245;es de alopecia&#46;<a class="elsevierStyleCrossRef" href="#bib1165"><span class="elsevierStyleSup">96</span></a></p><p id="par0520" class="elsevierStylePara elsevierViewall">IFN&#8208;&#947; e IL&#8208;15 induzem&#44; principalmente&#44; resposta citot&#243;xica do tipo I&#46; Linf&#243;citos T CD8<span class="elsevierStyleSup">&#43;</span> produzem IFN&#8208;&#947;&#44; que contribuem para a quebra do privil&#233;gio imunol&#243;gico&#44; induzindo a produ&#231;&#227;o de IL&#8208;15 pelas c&#233;lulas epiteliais&#44; que por sua vez leva &#224; ativa&#231;&#227;o das c&#233;lulas efetoras CD8<span class="elsevierStyleSup">&#43;</span>NKGD2<span class="elsevierStyleSup">&#43;</span> com mais produ&#231;&#227;o de IFN&#8208;&#947; fechando o ciclo que perpetua a doen&#231;a&#46; Tanto a a&#231;&#227;o da IFN&#8208;&#947; na c&#233;lula epitelial quanto da IL&#8208;15 nas c&#233;lulas CD8<span class="elsevierStyleSup">&#43;</span>NKG2D<span class="elsevierStyleSup">&#43;</span> s&#227;o mediadas pela via JAK&#8208;STAT&#46;<a class="elsevierStyleCrossRef" href="#bib1165"><span class="elsevierStyleSup">96</span></a></p><p id="par0525" class="elsevierStylePara elsevierViewall">A partir do relato de repila&#231;&#227;o de AA com tofacitinibe empregado no tratamento de psor&#237;ase&#44;<a class="elsevierStyleCrossRef" href="#bib1170"><span class="elsevierStyleSup">97</span></a> m&#250;ltiplas s&#233;ries de casos e estudos abertos n&#227;o comparativos foram publicados mostrando resultados favor&#225;veis com uso dos iJAK sist&#234;micos para tratamento da AA grave&#46; O medicamento utilizado com mais frequ&#234;ncia foi o tofacitinibe&#44; seguido por ruxolitinibe e baricitinibe&#46;<a class="elsevierStyleCrossRefs" href="#bib1175"><span class="elsevierStyleSup">98&#44;99</span></a></p><p id="par0530" class="elsevierStylePara elsevierViewall">Em estudo comparativo aberto&#44; 75 pacientes com AA comprometendo mais de 30&#37; do couro cabeludo foram randomizados em dois grupos&#58; tofacitinibe 10<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e ruxolitinibe 40<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46; Ap&#243;s seis meses de tratamento&#44; ambos apresentaram melhora&#44; sem diferen&#231;a entre eles&#46; O escore SALT50 foi atingido por 84&#37; dos pacientes no grupo ruxolitinibe e 78&#37; do grupo tofacitinibe&#44; em seis meses&#46;<a class="elsevierStyleCrossRef" href="#bib1185"><span class="elsevierStyleSup">100</span></a></p><p id="par0535" class="elsevierStylePara elsevierViewall">Em dois ensaios duplo&#8208;cegos &#40;BRAVE&#8208;AA1&#44; BRAVE&#8208;AA2&#41;&#44; pacientes com AA grave foram randomizados em tr&#234;s grupos&#58; baricitinibe 2<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dia ou placebo&#46; Um total de 1&#46;200 pacientes foi inclu&#237;do para a an&#225;lise de fase III desses estudos&#44; na semana 36&#46; O escore SALT20 foi atingido por 20&#37; e 34&#37; nos bra&#231;os de 2 e 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dia de baricitinibe&#44; em compara&#231;&#227;o com 4&#37; no placebo&#46;<a class="elsevierStyleCrossRef" href="#bib1190"><span class="elsevierStyleSup">101</span></a> A porcentagem de pacientes que descontinuou o tratamento por EA foi semelhante entre os grupos&#46; Em 2022&#44; o baricitinibe recebeu aprova&#231;&#227;o da FDA para o tratamento da AA&#46;</p><p id="par0540" class="elsevierStylePara elsevierViewall">No estudo ALLEGRO&#44; 718 pacientes foram randomizados em seis grupos&#58; ritlecitinibe 200<span class="elsevierStyleHsp" style=""></span>mg&#47;dia por quatro semanas e ap&#243;s 50<span class="elsevierStyleHsp" style=""></span>mg&#47;dia por 20 semanas&#59; ritlecitinibe 200<span class="elsevierStyleHsp" style=""></span>mg&#47;dia por quatro semanas e ap&#243;s 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia por 20 semanas&#59; ritlecitinibe 50<span class="elsevierStyleHsp" style=""></span>mg&#47;dia por 24 semanas&#59; ritlecitinibe 10<span class="elsevierStyleHsp" style=""></span>mg&#47;dia por 24 semanas&#44; ou placebo&#46; A resposta ao ritlecitinibe foi dose&#8208;dependente e 31&#37; dos que usaram 50<span class="elsevierStyleHsp" style=""></span>mg&#47;dia ap&#243;s dose de ataque atingiram SALT20 na semana 24&#46;<a class="elsevierStyleCrossRef" href="#bib1195"><span class="elsevierStyleSup">102</span></a></p><p id="par0545" class="elsevierStylePara elsevierViewall">Em um ensaio fase II&#44; 149 pacientes foram divididos em quatro grupos&#58; deuruxolitinibe 12&#44; 8&#44; 4<span class="elsevierStyleHsp" style=""></span>mg&#47;dia e placebo&#46; Houve resposta dose&#8208;dependente&#58; 42&#37;&#44; 26&#37;&#44; 14&#37; e 7&#37; &#40;placebo&#41; dos pacientes atingiram SALT20 na semana 24&#46;<a class="elsevierStyleCrossRef" href="#bib1200"><span class="elsevierStyleSup">103</span></a></p><p id="par0550" class="elsevierStylePara elsevierViewall">Um ensaio duplo&#8208;cego recrutou 16 participantes com AA universal que foram orientados a aplicar tofacitinibe 2&#37; pomada&#44; ruxolitinibe 1&#37; pomada&#44; clobetasol 0&#44;05&#37; pomada e placebo&#44; em diferentes locais do couro cabeludo&#46; Seis pacientes &#40;38&#37;&#41; em uso de tofacitinibe&#44; cinco &#40;31&#37;&#41; do ruxolitinibe e 10 &#40;63&#37;&#41; do clobetasol tiveram repila&#231;&#227;o parcial nas &#225;reas de tratamento&#44; enquanto nenhum teve crescimento com placebo&#46;<a class="elsevierStyleCrossRef" href="#bib1205"><span class="elsevierStyleSup">104</span></a></p><p id="par0555" class="elsevierStylePara elsevierViewall">Em estudo aberto&#44; o ruxolitinibe 1&#44;5&#37; creme n&#227;o se mostrou eficaz comparado ao placebo&#46;<a class="elsevierStyleCrossRef" href="#bib1210"><span class="elsevierStyleSup">105</span></a> Delgocitinibe 3&#37; em pomada tamb&#233;m n&#227;o apresentou melhora no SALT ap&#243;s 12 semanas de tratamento&#46;<a class="elsevierStyleCrossRef" href="#bib1215"><span class="elsevierStyleSup">106</span></a> A baixa efic&#225;cia dos iJAK t&#243;picos pode ser explicada pela dificuldade de penetra&#231;&#227;o em camadas profundas da pele&#44; n&#227;o permitindo alcan&#231;ar a inflama&#231;&#227;o peribulbar&#46; Ve&#237;culos que facilitem a penetra&#231;&#227;o cut&#226;nea podem trazer perspectivas para os iJAK na AA&#46;</p><p id="par0560" class="elsevierStylePara elsevierViewall">O tratamento da AA grave &#233; desafiador&#46; Muitos pacientes n&#227;o respondem &#224; terapia convencional com imunossupressores sist&#234;micos ou s&#227;o limitados pelos EA&#46; Os casos graves apresentam altas taxas de recidiva ap&#243;s a suspens&#227;o do tratamento&#46; Em consenso organizado pela Sociedade Brasileira de Dermatologia &#40;2020&#41;&#44; orienta&#8208;se o uso dos iJAK sist&#234;micos como op&#231;&#227;o para AA extensa nos casos refrat&#225;rios &#224; terapia convencional&#46;<a class="elsevierStyleCrossRef" href="#bib1220"><span class="elsevierStyleSup">107</span></a> Deve&#8208;se destacar que&#44; nos estudos que permitiram a aprova&#231;&#227;o do baricitinibe pela FDA&#44; menos de 40&#37; dos pacientes atingiram SALT20&#46; Al&#233;m disso&#44; pacientes com mais de oito anos de doen&#231;a &#40;pior progn&#243;stico&#41; n&#227;o foram inclu&#237;dos&#46; Estudos comparando iJAK sist&#234;micos com outros imunossupressores s&#227;o essenciais para estabelecer reais benef&#237;cios frente &#224;s terapias dispon&#237;veis&#46;</p><p id="par0565" class="elsevierStylePara elsevierViewall">Na maioria dos casos&#44; a manuten&#231;&#227;o dos resultados alcan&#231;ados na AA depende da continuidade do tratamento&#46; Estudos com maior per&#237;odo de seguimento s&#227;o necess&#225;rios para determinar a efic&#225;cia e seguran&#231;a dos iJAK a longo prazo&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Vitiligo</span><p id="par0570" class="elsevierStylePara elsevierViewall">O vitiligo afeta indiv&#237;duos suscet&#237;veis geneticamente&#44; e a autoimunidade &#233; a principal causa da agress&#227;o aos melan&#243;citos&#46; As hipo&#47;acromias&#44; localizadas ou generalizadas&#44; s&#227;o as manifesta&#231;&#245;es da destrui&#231;&#227;o dos melan&#243;citos dirigida pelos linf&#243;citos T citot&#243;xicos&#46;<a class="elsevierStyleCrossRef" href="#bib1225"><span class="elsevierStyleSup">108</span></a></p><p id="par0575" class="elsevierStylePara elsevierViewall">As duas principais citocinas envolvidas na patog&#234;nese do vitiligo s&#227;o a IFN&#8208;&#947; e a IL&#8208;15&#46;<a class="elsevierStyleCrossRef" href="#bib1230"><span class="elsevierStyleSup">109</span></a> A primeira &#233; produzida pelos linf&#243;citos T de mem&#243;ria &#40;TRM&#41; presentes na pele despigmentada e se liga ao receptor de IFN&#8208;&#947; para estimular a express&#227;o de quimiocinas como CXCL9&#44; CXCL10 e CXCL11&#44; que promovem a infiltra&#231;&#227;o de c&#233;lulas T autorreativas&#46;<a class="elsevierStyleCrossRef" href="#bib1235"><span class="elsevierStyleSup">110</span></a> A IL&#8208;15 &#233; produzida principalmente por queratin&#243;citos&#44; e est&#225; envolvida na sinaliza&#231;&#227;o para gera&#231;&#227;o e manuten&#231;&#227;o das TRM na pele lesada&#46;<a class="elsevierStyleCrossRef" href="#bib1240"><span class="elsevierStyleSup">111</span></a></p><p id="par0580" class="elsevierStylePara elsevierViewall">Duas iJAK s&#227;o exploradas para o tratamento do vitiligo&#58; ruxolitinibe 1&#44;5&#37; creme foi aprovado para uso nos EUA&#44;<a class="elsevierStyleCrossRef" href="#bib1245"><span class="elsevierStyleSup">112</span></a> e ritlecitinibe 10&#8208;50<span class="elsevierStyleHsp" style=""></span>mg&#47;dia oral encontra&#8208;se em estudo de fase IIb&#46;<a class="elsevierStyleCrossRef" href="#bib1250"><span class="elsevierStyleSup">113</span></a> H&#225; relatos aned&#243;ticos do uso do tofacitinibe 5&#8208;10<span class="elsevierStyleHsp" style=""></span>mg&#47;dia oral e t&#243;pico 2&#37; creme ou pomada no vitiligo&#59;<a class="elsevierStyleCrossRefs" href="#bib1255"><span class="elsevierStyleSup">114&#44;115</span></a> entretanto&#44; n&#227;o foram publicados ensaios cl&#237;nicos randomizados e controlados com essa subst&#226;ncia&#46;</p><p id="par0585" class="elsevierStylePara elsevierViewall">O racional do uso de iJAK em vitiligo decorre de estudos farmacol&#243;gicos pr&#233;&#8208;cl&#237;nicos que demonstraram a inibi&#231;&#227;o da a&#231;&#227;o citol&#237;tica dos linf&#243;citos T CD8<span class="elsevierStyleSup">&#43;</span> e c&#233;lulas NK quando inibidas enzimas da fam&#237;lia das quinases &#40;BTK&#44; BMX&#44; ITK&#44; RLK e TEC&#41; pelo ritlecitinibe&#44; principalmente ITK&#44; no caso dos linf&#243;citos T citot&#243;xicos&#44; e RLK e TEC no caso das c&#233;lulas NK&#46; Ritlecitinibe &#233; altamente seletivo para JAK3 e&#44; potencialmente&#44; inibe IL&#8208;2 e IL&#8208;15&#46; Al&#233;m disso&#44; com base em estudos <span class="elsevierStyleItalic">in vitro</span> e ensaios celulares&#44; ritlecitinibe pode diminuir a produ&#231;&#227;o de IFN&#8208;&#947; liberada por c&#233;lulas T citot&#243;xicas e NK&#44; relacionadas a uma prov&#225;vel inibi&#231;&#227;o de ITK&#46;<a class="elsevierStyleCrossRefs" href="#bib1265"><span class="elsevierStyleSup">116&#44;117</span></a></p><p id="par0590" class="elsevierStylePara elsevierViewall">O ruxolitinibe &#233; um inibidor de JAK1 e JAK2&#44; cujo creme 1&#44;5&#37; diminuiu a concentra&#231;&#227;o s&#233;rica de CXCL10&#44; al&#233;m de diminuir a a&#231;&#227;o pr&#243;&#8208;inflamat&#243;ria de quimiocinas e IL&#8208;15 em cultivo celular de queratin&#243;citos e melan&#243;citos&#46;<a class="elsevierStyleCrossRefs" href="#bib1275"><span class="elsevierStyleSup">118&#44;119</span></a></p><p id="par0595" class="elsevierStylePara elsevierViewall">O tofacitinibe &#233; um inibidor de JAK1 e JAK3&#46; Em um estudo com modelo murino de vitiligo&#8208;induzido&#44; o n&#237;vel s&#233;rico de CXCL10 foi menor no grupo tratado com tofacitinibe oral comparado com o grupo placebo&#46;<a class="elsevierStyleCrossRef" href="#bib1285"><span class="elsevierStyleSup">120</span></a> Contudo&#44; o ritlecitinibe tem maior efeito inibit&#243;rio de JAK3&#44; comparado ao tofacitinibe&#46;<a class="elsevierStyleCrossRef" href="#bib1270"><span class="elsevierStyleSup">117</span></a></p><p id="par0600" class="elsevierStylePara elsevierViewall">Dois estudos randomizados&#44; duplo&#8208;cegos e controlados por placebo com ruxolitinibe creme a 1&#44;5&#37; envolveram pacientes maiores de 12 anos com vitiligo n&#227;o segmentar e &#225;rea afetada de no m&#225;ximo 10&#37; da superf&#237;cie corporal&#46; Os pacientes foram randomizados para usar o medicamento ou o ve&#237;culo &#40;2&#58;1&#41;&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia na face ou no corpo por 24 semanas&#59; depois desse per&#237;odo&#44; todos utilizaram o ativo&#44; totalizando 52 semanas&#46; Os desfechos prim&#225;rios foram a melhora desde o in&#237;cio do tratamento de ao menos 75&#37; do Vitiligo Area Score Index &#40;VASI&#41; facial&#44; ou resposta F&#8208;VASI75 &#40;F&#8208;VASI com escore de 0 a 3&#41; na semana 24&#46;<a class="elsevierStyleCrossRef" href="#bib1245"><span class="elsevierStyleSup">112</span></a></p><p id="par0605" class="elsevierStylePara elsevierViewall">No total&#44; 674 pacientes foram inclu&#237;dos&#44; 330 em um estudo denominado <span class="elsevierStyleItalic">TRue&#8208;V1</span> e 344 no chamado <span class="elsevierStyleItalic">TRue&#8208;V2</span>&#46; No primeiro estudo&#44; a porcentagem de pacientes que atingiy reposta F&#8208;VASI75 na semana 24 foi de 29&#44;8&#37; no grupo ruxolitinibe e 7&#44;4&#37; no grupo placebo &#40;risco relativo&#44; 4&#44;0&#59; intervalo de confian&#231;a &#91;IC&#93; de 95&#37;&#44; 1&#44;9&#8208;8&#44;4&#41;&#59; no segundo estudo&#44; 30&#44;9&#37; e 11&#44;4&#37;&#44; respectivamente &#40;risco relativo&#44; 2&#44;7&#59; 95&#37;IC 1&#44;5&#8208;4&#44;9&#41;&#46; Os EA mais comuns em cada estudo foram acne &#40;6&#44;3&#37; e 6&#44;6&#37;&#41;&#44; nasofaringite &#40;5&#44;4&#776;&#37; e 6&#44;1&#37;&#41; e prurido no local de aplica&#231;&#227;o &#40;5&#44;4&#37; e 5&#44;3&#37;&#41;&#44; respectivamente&#46;</p><p id="par0610" class="elsevierStylePara elsevierViewall">Um importante desfecho secund&#225;rio foi a diminui&#231;&#227;o de 50&#37; do T&#8208;VASI &#40;&#225;rea total afetada&#41;&#44; desde o in&#237;cio do tratamento &#40;T&#8208;VASI50&#41;&#46; Aproximadamente 20&#37; dos pacientes alcan&#231;aram uma resposta T&#8208;VASI50 e 50&#37; dos pacientes atingiram F&#8208;VASI50&#46; Essa despropor&#231;&#227;o &#233; usual em ensaios de vitiligo em virtude da maior concentra&#231;&#227;o de fol&#237;culos na face&#44; de onde migram melanoblastos para a repigmenta&#231;&#227;o&#46;<a class="elsevierStyleCrossRefs" href="#bib1290"><span class="elsevierStyleSup">121&#44;122</span></a></p><p id="par0615" class="elsevierStylePara elsevierViewall">At&#233; o momento&#44; n&#227;o existem estudos randomizados e controlados com ruxolitinibe oral no tratamento do vitiligo&#44; tampouco ruxolitinibe t&#243;pico comparado ou associado aos tratamentos ativos de escolha &#40;fototerapia&#44; inibidores de calcineurina ou corticosteroides t&#243;picos&#41;&#46;</p><p id="par0620" class="elsevierStylePara elsevierViewall">Outro estudo randomizado controlado com placebo utilizou ritlecitinibe oral dose&#8208;escalonado&#44; por 24 semanas&#44; com um per&#237;odo de extens&#227;o de 24 semanas e mais oito semanas de seguimento&#44; em pacientes com vitiligo n&#227;o segmentar entre 18 e 65 anos de idade&#44; &#225;rea corporal afetada entre 4&#37; e 50&#37;&#44; e &#225;rea facial afetada<span class="elsevierStyleHsp" style=""></span>&#62; 25&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib1250"><span class="elsevierStyleSup">113</span></a> Os pacientes foram randomizados em cinco grupos com ritlecitinibe e um com placebo&#46; Dois grupos receberam dose de ataque de 100 ou 200<span class="elsevierStyleHsp" style=""></span>mg&#47;dia por quatro semanas seguidos de 50<span class="elsevierStyleHsp" style=""></span>mg&#47;dia de manuten&#231;&#227;o&#44; por 20 semanas&#46; Tr&#234;s grupos receberam 50&#44; 30 ou 10<span class="elsevierStyleHsp" style=""></span>mg&#47;dia por 24 semanas&#44; e um grupo recebeu placebo por 24 semanas&#46; Os pacientes foram alocados no per&#237;odo de extens&#227;o com base na resposta na semana 16&#59; n&#227;o respondedores &#40;&#60; 50&#37; T&#8208;VASI&#41; foram alocados para um grupo aberto com brepocitinibe&#44; outro aberto com ritlecitinibe<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>fototerapia com UVB de banda estreita &#40;NBUVB&#41; ou ritlecitinibe 200<span class="elsevierStyleHsp" style=""></span>mg de dose de ataque<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46; O desfecho prim&#225;rio foi a mudan&#231;a desde o in&#237;cio no F&#8208;VASI central na semana 24&#59; o desfecho secund&#225;rio foi a propor&#231;&#227;o de pacientes com F&#8208;VASI75 central na semana 24&#46;</p><p id="par0625" class="elsevierStylePara elsevierViewall">Um total de 364 pacientes recebeu tratamento&#44; e para fins de compara&#231;&#227;o com o estudo de ruxolitinibe t&#243;pico vamos usar os resultados do desfecho secund&#225;rio&#46; F&#8208;VASI75 na semana 24 foram alcan&#231;ados em 12&#44;1&#37;&#44; 8&#44;5&#37;&#44; 7&#44;7&#37;&#44; 2&#44;7&#37;&#44; 2&#44;3&#37; e 0&#37; nos grupos ritlecitinibe 200&#47;50<span class="elsevierStyleHsp" style=""></span>mg&#44; 100&#47;50<span class="elsevierStyleHsp" style=""></span>mg&#44; 50<span class="elsevierStyleHsp" style=""></span>mg&#44; 30<span class="elsevierStyleHsp" style=""></span>mg&#44; 10<span class="elsevierStyleHsp" style=""></span>mg e placebo&#44; respectivamente&#46; Quanto &#224; seguran&#231;a&#44; 77&#37; dos pacientes apresentaram algum EA&#44; e os tr&#234;s mais comuns foram nasofaringite &#40;15&#44;9&#37;&#41;&#44; infec&#231;&#245;es de trato respirat&#243;rio superior &#40;11&#44;5&#37;&#41; e cefaleia &#40;8&#44;8&#37;&#41;&#46;</p><p id="par0630" class="elsevierStylePara elsevierViewall">Apesar dos resultados modestos na semana 24&#44; percebeu&#8208;se a acelera&#231;&#227;o da repigmenta&#231;&#227;o ap&#243;s a semana 28&#46; A morosidade no processo de repigmenta&#231;&#227;o &#233; bem fundamentado&#44; o que justifica a fototerapia como tratamento adjuvante na acelera&#231;&#227;o da repigmenta&#231;&#227;o&#44; pelo menos com as medica&#231;&#245;es antitirosina quinase aqui apresentadas&#44; como no caso do tofacitinibe&#44; ruxolitinibe e mesmo pela aloca&#231;&#227;o de alguns dos n&#227;o respondedores com ritlecitinibe para um bra&#231;o de ritlecitinibe associado com NBUVB&#46;<a class="elsevierStyleCrossRefs" href="#bib1300"><span class="elsevierStyleSup">123&#44;124</span></a></p><p id="par0635" class="elsevierStylePara elsevierViewall">Se comparados os estudos com ruxolitinibe t&#243;pico e ritlecitinibe oral em rela&#231;&#227;o ao F&#8208;VASI75 na semana 24&#44; a resposta do ruxolitinibe foi superior &#40;30&#37; <span class="elsevierStyleItalic">vs&#46;</span> 12&#44;1&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1310"><span class="elsevierStyleSup">125</span></a> &#201; relevante ainda que esse desfecho tenha sido atingido com a maior dose de ritlecitinibe&#44; o F&#8208;VASI tenha sido calculado apenas no centro da face e os pacientes do ruxolitinibe apresentavam fototipos mais baixos que os do estudo do ritlecitinibe&#44; que s&#227;o mais dif&#237;ceis de repigmentar&#46;<a class="elsevierStyleCrossRef" href="#bib1250"><span class="elsevierStyleSup">113</span></a></p><p id="par0640" class="elsevierStylePara elsevierViewall">At&#233; o momento&#44; n&#227;o existem estudos randomizados e controlados com ruxolitinibe oral no tratamento do vitiligo&#44; tampouco&#44; ruxolitinibe t&#243;pico comparado ou associado aos tratamentos t&#243;picos de escolha &#40;inibidores de calcineurina&#44; ou corticosteroides t&#243;picos&#41;&#46; N&#227;o obstante&#44; em um estudo com camundongos como modelo&#44; foi administrado oralmente tofacitinibe ou ruxolitinibe&#46; Como resultado&#44; foi observada superioridade do tofacitinibe em rela&#231;&#227;o ao ruxolitinibe na diminui&#231;&#227;o nos escores de vitiligo dos pacientes afetados&#46;<a class="elsevierStyleCrossRefs" href="#bib1265"><span class="elsevierStyleSup">116&#44;126</span></a></p><p id="par0645" class="elsevierStylePara elsevierViewall">Desse modo&#44; os iJAK revelaram&#8208;se potenciais terap&#234;uticas para o vitiligo&#44; com bom perfil de seguran&#231;a&#44; por&#233;m&#44; que devem ser explorados em associa&#231;&#227;o com outras medidas &#40;p&#46; ex&#46;&#44; fototerapia&#41; para maximizar sua efic&#225;cia&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Outras dermatoses</span><p id="par0650" class="elsevierStylePara elsevierViewall">A hidradenite supurativa &#40;HS&#41; decorre da desregula&#231;&#227;o do sistema imune inato e adaptativo&#44; evolvendo diversas citocinas mediadas pela via JAK&#8208;STAT &#40;p&#46; ex&#46;&#44; IL&#8208;17&#44; IL&#8208;23&#44; IL&#8208;10&#41; e&#44; em menor quantidade&#44; TNF&#8208;&#945;&#46; Tofacitinibe 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#44; foi relatado em dois pacientes&#44; com resultados favor&#225;veis&#46;<a class="elsevierStyleCrossRef" href="#bib1320"><span class="elsevierStyleSup">127</span></a></p><p id="par0655" class="elsevierStylePara elsevierViewall">Um estudo retrospectivo com 20 pacientes em uso de upadacitinibe demonstrou que 75&#37; dos indiv&#237;duos atingiram HiSCR50 em quatro semanas&#44; e 100&#37; em 12 semanas&#46; Todos receberam 15<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; e os que n&#227;o atingiram HiSCR50 em quatro semanas tiveram a dose aumentada para 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46;<a class="elsevierStyleCrossRef" href="#bib1325"><span class="elsevierStyleSup">128</span></a> Estudos de fase II com INCB054707&#44; 15<span class="elsevierStyleHsp" style=""></span>mg&#44; 30<span class="elsevierStyleHsp" style=""></span>mg&#44; 60<span class="elsevierStyleHsp" style=""></span>mg e 90<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#44; demonstraram que 43&#37;&#44; 56&#37;&#44; 56&#37; e 88&#37; dos pacientes&#44;respectivamente&#44; atingiram HiSCR na semana 8&#46;<a class="elsevierStyleCrossRef" href="#bib1330"><span class="elsevierStyleSup">129</span></a></p><p id="par0660" class="elsevierStylePara elsevierViewall">Pioderma gangrenoso &#40;PG&#41; &#233; dermatose inflamat&#243;ria neutrof&#237;lica com incid&#234;ncia estimada de 3&#8208;10 casos&#47;milh&#227;o de pessoas&#8208;ano&#46; Sua patog&#234;nese &#233; mal compreendida&#44; mas parece envolver a desregula&#231;&#227;o tanto da imunidade inata quanto da adaptativa&#46;<a class="elsevierStyleCrossRef" href="#bib1335"><span class="elsevierStyleSup">130</span></a> A frequ&#234;ncia de comorbidades imunomediadas associadas&#44; superexpress&#227;o de citocinas inflamat&#243;rias&#44; al&#233;m da resposta a imunomoduladores &#40;p&#46; ex&#46;&#44; corticoides&#44; anti&#8208;TNF&#945;&#44; inibidores de calcineurina&#41; refor&#231;am um mecanismo subjacente imunomediado&#46;<a class="elsevierStyleCrossRef" href="#bib1340"><span class="elsevierStyleSup">131</span></a></p><p id="par0665" class="elsevierStylePara elsevierViewall">N&#227;o existe abordagem padronizada na estrat&#233;gia terap&#234;utica imunossupressora do PG&#44; havendo casos resistentes&#46;<a class="elsevierStyleCrossRefs" href="#bib1340"><span class="elsevierStyleSup">131&#44;132</span></a> J&#225; foram demonstradas desregula&#231;&#245;es da via JAK&#8208;STAT no PG&#44; com JAK1&#44; JAK2&#44; JAK3 e STAT1 a STAT6 superexpressas nas les&#245;es&#46; Muta&#231;&#245;es da via JAK&#8208;STAT tamb&#233;m foram implicadas na progress&#227;o do PG&#46;<a class="elsevierStyleCrossRef" href="#bib1335"><span class="elsevierStyleSup">130</span></a> Apesar de n&#227;o haver estudos cl&#237;nicos controlados&#44; diversos relatos demonstraram benef&#237;cios do tofacitinibe&#44; ruxolitinibe e baricitinibe em casos de PG&#46;<a class="elsevierStyleCrossRefs" href="#bib1345"><span class="elsevierStyleSup">132&#8211;135</span></a>Dermatomiosite &#40;DM&#41; &#233; doen&#231;a multissist&#234;mica em que ocorre ativa&#231;&#227;o do sistema imune inato com secre&#231;&#227;o de interferonas do tipo I&#46; As atuais op&#231;&#245;es de tratamento incluem uma combina&#231;&#227;o de fotoprote&#231;&#227;o&#44; glicocorticoides &#40;GCs&#41;&#44; imunossupressores e imunomoduladores&#46;</p><p id="par0670" class="elsevierStylePara elsevierViewall">Tofacitinibe foi relatado com sucesso em casos refrat&#225;rios de DM em doses de 5<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#44; em 34 pacientes&#44; 11<span class="elsevierStyleHsp" style=""></span>mg&#47;dia &#40;libera&#231;&#227;o prolongada&#41; em 10 pacientes e 10<span class="elsevierStyleHsp" style=""></span>mg&#44; 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&#44; em dois pacientes&#46; Ruxolitinibe foi usado em sete pacientes com dose m&#225;xima de at&#233; 30<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46; Ap&#243;s o in&#237;cio do tratamento&#44; n&#227;o ocorreu nenhuma recidiva em 3&#8208;15 meses&#44; havendo melhora dos sinais cut&#226;neos&#44; sintomas e testes de for&#231;a muscular&#46;<a class="elsevierStyleCrossRef" href="#bib1365"><span class="elsevierStyleSup">136</span></a> No entanto&#44; a maioria dos estudos inclu&#237;dos nessa revis&#227;o foi de s&#233;ries de casos&#44; que s&#227;o suscet&#237;veis a vi&#233;s de observa&#231;&#227;o&#44; e n&#227;o houve compara&#231;&#227;o direta com outro m&#233;todo de tratamento&#46;</p><p id="par0675" class="elsevierStylePara elsevierViewall">A doen&#231;a enxerto <span class="elsevierStyleItalic">versus</span> hospedeiro &#40;DEVH&#41; desenvolve&#8208;se ap&#243;s transplante alog&#234;nico de c&#233;lulas&#8208;tronco hematopo&#233;ticas&#44; quando as c&#233;lulas T do doador n&#227;o apenas reconhecem as c&#233;lulas tumorais remanescentes como estranhas&#44; mas tamb&#233;m o tecido do receptor&#44; levando a uma condi&#231;&#227;o potencialmente grave&#46; &#211;rg&#227;os&#8208;alvo t&#237;picos incluem a pele&#44; o f&#237;gado e os do trato digest&#243;rio&#46; Atualmente&#44; todas as estrat&#233;gias aprovadas para o tratamento da DEVH s&#227;o terapias imunossupressoras&#44; como a corticoterapia&#46;</p><p id="par0680" class="elsevierStylePara elsevierViewall">Como a DEVH &#233; caracterizada principalmente pelo aumento das citocinas pr&#243;&#8208;inflamat&#243;rias&#44; esclerose sist&#234;mica e dano de &#243;rg&#227;os internos&#44; a inibi&#231;&#227;o da sinaliza&#231;&#227;o das tirosina quinases ativadas revelou&#8208;se estrat&#233;gia promissora para reduzir a gravidade e a progress&#227;o da doen&#231;a&#46; V&#225;rias pequenas mol&#233;culas est&#227;o sendo estudadas &#40;fases I a III&#41;&#44; entre elas&#58; ruxolitinibe&#44; itacitinibe&#44; baricitinibe&#44; ibrutinibe &#40;inibidor da tirosina quinase de Bruton&#41; e pacritinibe&#46;</p><p id="par0685" class="elsevierStylePara elsevierViewall">O tratamento com ruxolitinibe para DEVH aguda refrat&#225;ria &#224; corticoterapia diminui os n&#237;veis de citocinas pr&#243;&#8208;inflamat&#243;rias no soro dos pacientes e o n&#250;mero de c&#233;lulas T ativadas&#44; com taxa de resposta total de 82&#37;&#46; Efeitos similares foram obtidos em pacientes tratados com itacitinibe&#46; Na DEVH cr&#244;nica refrat&#225;ria&#44; estudo de fase III com ruxolitinibe demonstrou quase o dobro de valores no alcance dos objetivos prim&#225;rios do tratamento em rela&#231;&#227;o ao grupo controle&#46;<a class="elsevierStyleCrossRef" href="#bib1370"><span class="elsevierStyleSup">137</span></a></p><p id="par0690" class="elsevierStylePara elsevierViewall">O reconhecimento dos iJAK como op&#231;&#227;o terap&#234;utica para o tratamento de dermatoses pruriginosas cr&#244;nicas come&#231;ou a partir da DA&#46; Por&#233;m&#44; recentemente o gusacitinibe oral recebeu a designa&#231;&#227;o de <span class="elsevierStyleItalic">fast track</span> pela FDA para o tratamento de eczema cr&#244;nico das m&#227;os&#46; Al&#233;m disso&#44; iniciaram&#8208;se ensaios cl&#237;nicos do delgocitinibe t&#243;pico para tratamento de eczema cr&#244;nico das m&#227;os em pacientes pedi&#225;tricos e adultos&#46; Ainda&#44; como a patog&#234;nese do prurigo <span class="elsevierStyleItalic">nodularis</span> &#40;PN&#41; envolve inflama&#231;&#227;o mediada por Th2 e Th17&#47;Th22&#44; que podem ser atenuadas por meio dos iJAK&#44; estudos de fase II est&#227;o examinando o papel de abrocitinibe no tratamento do PN e prurido cr&#244;nico de origem desconhecida&#46;<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">61</span></a></p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclus&#227;o e pesquisas futuras</span><p id="par0695" class="elsevierStylePara elsevierViewall">H&#225; intensa atividade cient&#237;fica ligada ao desenvolvimento de medicamentos que interfiram em diferentes n&#237;veis da via JAK&#8208;STAT&#44; assim como a explora&#231;&#227;o de novas indica&#231;&#245;es e regimes posol&#243;gicos&#46;</p><p id="par0700" class="elsevierStylePara elsevierViewall">O perfil de seguran&#231;a da inibi&#231;&#227;o das JAK&#44; especialmente da JAK1 ou JAK3&#44; associada &#224; modula&#231;&#227;o da resposta imune&#44; deve levar ao progressivo aumento do uso de iJAK em compara&#231;&#227;o aos imunossupressores &#40;como os corticosteroides orais&#44; azatioprina&#44; micofenolato&#44; metotrexato e ciclosporina&#41; no tratamento de dermatoses inflamat&#243;rias e autoimunes&#46; Todavia&#44; apenas os ensaios cl&#237;nicos com comparadores ativos podem posicionar os iJAK quanto &#224;s melhores indica&#231;&#245;es&#44; regimes posol&#243;gicos e seus aspectos farmacoecon&#244;micos&#46;</p><p id="par0705" class="elsevierStylePara elsevierViewall">Por fim&#44; a maior disponibilidade de mol&#233;culas deve levar &#224; redu&#231;&#227;o do custo ao sistema de sa&#250;de e aumentar o acesso aos pacientes&#46; Em contrapartida&#44; seu uso de longo prazo deve esclarecer aspectos ligados &#224; manuten&#231;&#227;o da efic&#225;cia terap&#234;utica&#44; o impacto do bloqueio imunol&#243;gico de vias seletivas de citocinas&#44; al&#233;m da seguran&#231;a quanto &#224; emerg&#234;ncia de infec&#231;&#245;es e neoplasias malignas&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Suporte financeiro</span><p id="par0710" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Contribui&#231;&#227;o dos autores</span><p id="par0715" class="elsevierStylePara elsevierViewall">H&#233;lio Amante Miot&#58; Idealiza&#231;&#227;o do estudo&#44; escrita e aprova&#231;&#227;o do texto final&#46;</p><p id="par0720" class="elsevierStylePara elsevierViewall">Paulo Ricardo Criado&#58; Idealiza&#231;&#227;o do estudo&#44; escrita e aprova&#231;&#227;o do texto final&#46;</p><p id="par0725" class="elsevierStylePara elsevierViewall">Caio C&#233;sar Silva de Castro&#58; Idealiza&#231;&#227;o do estudo&#44; escrita e aprova&#231;&#227;o do texto final&#46;</p><p id="par0730" class="elsevierStylePara elsevierViewall">Mayra Ianhez&#58; Idealiza&#231;&#227;o do estudo&#44; escrita e aprova&#231;&#227;o do texto final&#46;</p><p id="par0735" class="elsevierStylePara elsevierViewall">Carolina Talhari&#58; Idealiza&#231;&#227;o do estudo&#44; escrita e aprova&#231;&#227;o do texto final&#46;</p><p id="par0740" class="elsevierStylePara elsevierViewall">Paulo M&#252;ller Ramos&#58; Idealiza&#231;&#227;o do estudo&#44; escrita e aprova&#231;&#227;o do texto final&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflito de interesses</span><p id="par0745" class="elsevierStylePara elsevierViewall">Dr&#46; Caio Castro&#58; <span class="elsevierStyleItalic">Advisory Board</span> &#8208; Sanofi&#44; Ach&#233;&#44; Sun&#8208;Pharma&#44; Galderma&#46; Speaker &#8208; Abbvie&#44; Jansen&#44; Novartis&#44; Sanofi&#44; Leo&#8208; Pharma&#46; Pesquisa Cl&#237;nica &#8208; Abbvie&#44; Pfizer&#44; Jansen&#44; Sanofi&#46;</p><p id="par0750" class="elsevierStylePara elsevierViewall">Dr&#46; Paulo Criado pesquisa Cl&#237;nica para Pfizer&#44; Novartis&#44; Sanofi e Lilly&#59; <span class="elsevierStyleItalic">Advisory board</span> Pfizer&#44; Galderma&#44; Takeda&#44; Hypera&#44; Novartis&#44; Sanofi&#46; Palestrantre&#58; Pfizer&#44; Abbvie&#44; Sanofi&#44; Hypera&#44; Takeda&#44; Novartis&#46;</p><p id="par0755" class="elsevierStylePara elsevierViewall">Dr&#46; H&#233;lio Miot&#58; <span class="elsevierStyleItalic">Advisory Board</span> &#8211; Johnson &#38; Johnson&#44; L&#8217;Or&#233;al&#44; Theraskin e Pfizer&#59; pesquisa cl&#237;nica Abbvie e Merz&#46;</p><p id="par0760" class="elsevierStylePara elsevierViewall">Dra&#46; Mayra Ianhez&#58; Speaker e Advisory Board &#8208; Abbvie&#44; Sanofi&#8208;Genzyme&#44; Pfizer&#44; Janssen&#44; Galderma&#44; Theraskin&#46;</p><p id="par0765" class="elsevierStylePara elsevierViewall">Dr&#46; Paulo M&#252;ller Ramos&#58; Advisory Board &#8211; Pfizer&#59;</p><p id="par0770" class="elsevierStylePara elsevierViewall">Dra&#46; Carolina Talhari&#58; Nenhum conflito de interesses&#46;</p></span></span>"
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          "titulo" => "Via JAK&#8208;STAT"
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              "identificador" => "sec0070"
              "titulo" => "Alopecia areata"
            ]
            3 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Vitiligo"
            ]
            4 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Outras dermatoses"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "Conclus&#227;o e pesquisas futuras"
        ]
        7 => array:2 [
          "identificador" => "sec0090"
          "titulo" => "Suporte financeiro"
        ]
        8 => array:2 [
          "identificador" => "sec0095"
          "titulo" => "Contribui&#231;&#227;o dos autores"
        ]
        9 => array:2 [
          "identificador" => "sec0100"
          "titulo" => "Conflito de interesses"
        ]
        10 => array:1 [
          "titulo" => "Refer&#234;ncias"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2023-01-14"
    "fechaAceptado" => "2023-03-02"
    "PalabrasClave" => array:1 [
      "pt" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras&#8208;chave"
          "identificador" => "xpalclavsec1672273"
          "palabras" => array:6 [
            0 => "Alopecia areata"
            1 => "Dermatite at&#243;pica"
            2 => "Inibidores de Janus Quinases"
            3 => "Psor&#237;ase"
            4 => "Tratamento"
            5 => "Vitiligo"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A via de sinaliza&#231;&#227;o <span class="elsevierStyleItalic">Janus Quinase</span> &#40;JAK&#41; e transdutor de sinal&#47;ativador da transcri&#231;&#227;o &#40;STAT&#41; medeia importantes processos celulares&#44; como a resposta imune&#44; carcinog&#234;nese&#44; diferencia&#231;&#227;o&#44; divis&#227;o e morte celular&#46; Portanto&#44; medicamentos que interfiram nos diferentes padr&#245;es de sinaliza&#231;&#227;o JAK&#8208;STAT t&#234;m potencial indica&#231;&#227;o para v&#225;rias condi&#231;&#245;es m&#233;dicas&#46; Os principais alvos dermatol&#243;gicos dos inibidores da via JAK&#8208;STAT s&#227;o doen&#231;as inflamat&#243;rias ou autoimunes como psor&#237;ase&#44; vitiligo&#44; dermatite at&#243;pica e alopecia areata&#44; por&#233;m&#44; diversas dermatoses est&#227;o em investiga&#231;&#227;o para ampliar esse rol de indica&#231;&#245;es&#46; Como os inibidores da via JAK&#8208;STAT devem&#44; paulatinamente&#44; ocupar espa&#231;o relevante na prescri&#231;&#227;o dermatol&#243;gica&#44; esta revis&#227;o apresenta os principais medicamentos dispon&#237;veis&#44; seus efeitos imunol&#243;gicos e suas caracter&#237;sticas farmacol&#243;gicas relacionadas &#224; efic&#225;cia cl&#237;nica e de seguran&#231;a&#44; a fim de substanciar a melhor pr&#225;tica dermatol&#243;gica&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Como citar este artigo&#58; Miot HA&#44; Criado PR&#44; Castro CC&#44; Ianhez M&#44; Talhari C&#44; Ramos P&#46; JAK&#8208;STAT pathway inhibitors in dermatology&#46; An Bras Dermatol&#46; 2023&#59;98&#58;656&#8211;77&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Trabalho realizado no Departamento de Dermatologia da Faculdade de Medicina&#44; Universidade Estadual Paulista&#44; Botucatu&#44; SP&#44; Brasil&#46;</p>"
      ]
    ]
    "multimedia" => array:9 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figura 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1414
            "Ancho" => 2508
            "Tamanyo" => 274064
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        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Representa&#231;&#227;o esquem&#225;tica da via &#40;can&#244;nica&#41; de sinaliza&#231;&#227;o JAK&#8208;STAT&#46; &#40;A&#41; Diversas citocinas e fatores de crescimento presentes no meio extracelular dependem de receptores transmembrana para dar in&#237;cio ao processo de sinaliza&#231;&#227;o celular e transcri&#231;&#227;o nuclear dos genes associados a cada via&#46; &#40;B&#41; O acoplamento da citocina com o dom&#237;nio extracelular do receptor transmembrana leva a mudan&#231;a em sua conforma&#231;&#227;o e fosforila&#231;&#227;o dos d&#237;meros de JAK&#44; situados no dom&#237;nio intracelular do receptor&#44; e que transfosforilam seus res&#237;duos terminais de tirosina&#46; Esse processo induz a dimeriza&#231;&#227;o e fosforila&#231;&#227;o de unidades inativas de STAT&#44; que migram para o n&#250;cleo e medeiam a transcri&#231;&#227;o de genes relacionados &#224; via da citocina espec&#237;fica&#46; &#40;C&#41; Inibidores da via de sinaliza&#231;&#227;o JAK&#8208;STAT &#40;iJAK&#41; impedem a fosforila&#231;&#227;o da JAK&#44; interrompendo a sinaliza&#231;&#227;o nuclear da citocina ou fator de crescimento&#46; Fonte&#58; os autores</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figura 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1390
            "Ancho" => 1675
            "Tamanyo" => 135468
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Diagrama representando os principais iJAK que apresentam resultados favor&#225;veis em estudos cl&#237;nicos para dermatoses inflamat&#243;rias e autoimunes&#46; AA&#44; alopecia areata&#59; DA&#44; dermatite at&#243;pica&#59; DM&#44; dermatomiosite&#59; PSO&#44; psor&#237;ase&#59; VITI&#44; vitiligo&#59; HS&#44; hidradenite supurativa&#59; DEVH&#44; doen&#231;a enxerto versus hospedeiro&#59; Abro&#44; abrocitinibe&#59; Upa&#44; upadacitinibe&#59; Bari&#44; baricitinibe&#59; DelgoT&#44; delgocitinibe t&#243;pico&#59; Tofa&#44; tofacitinibe&#59; RuxoT&#44; ruxolitinibe t&#243;pico&#59; Ruxo&#44; ruxolitinibe&#59; Ritle&#44; ritlecitinibe&#59; Deucra&#44; deucravacitinibe&#59; Solci&#44; solcitinibe&#59; Itaci&#44; itacitinibe&#59; Deuruxo&#44; deuruxolitinibe</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Tabela 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">JAK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Citocinas e fatores de crescimento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IFN&#8208;&#945;&#44; IFN&#8208;&#946;&#44; IFN&#8208;&#947;&#44; IL&#8208;2&#44; IL&#8208;4&#44; IL&#8208;6&#44; IL&#8208;7&#44; IL&#8208;9&#44; IL&#8208;10&#44; IL&#8208;11&#44; IL&#8208;13&#44; IL&#8208;15&#44; IL&#8208;19&#44; IL&#8208;21&#44; IL&#8208;22&#44; IL&#8208;27&#44; IL&#8208;28&#44; IL&#8208;29&#44; IL&#8208;31&#44; IL&#8208;35&#44; fator neurotr&#243;fico ciliar &#40;CNTF&#41;&#44; oncostatina&#8208;M &#40;OSM&#41;&#44; cardiotrofina &#40;CT&#8208;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IFN&#8208;&#947;&#44; IL&#8208;3&#44; IL&#8208;5&#44; IL&#8208;6&#44; IL&#8208;10&#44; IL&#8208;11&#44; IL&#8208;13&#44; IL&#8208;12&#44; IL&#8208;19&#44; IL&#8208;22&#44; IL&#8208;23&#44; IL&#8208;27&#44; IL&#8208;35&#44; fator de estimula&#231;&#227;o de col&#244;nias de granul&#243;citos e macr&#243;fagos &#40;GM&#8208;CSF&#41;&#44; eritropoitina &#40;EPO&#41;&#44; tireoide peroxidase &#40;TPO&#41;&#44; leptina&#44; oncogene viral mieloproliferativo da leucemia &#40;mpl&#41;&#44; prolactina&#44; horm&#244;nio do crescimento &#40;GH&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL&#8208;2&#44; IL&#8208;4&#44; IL&#8208;7&#44; IL&#8208;9&#44; IL&#8208;13&#44; IL&#8208;15&#44; IL&#8208;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TYK2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IFN&#8208;&#945;&#44; IFN&#8208;&#946;&#44; IL&#8208;10&#44; IL&#8208;11&#44; IL&#8208;12&#44; IL&#8208;19&#44; IL&#8208;22&#44; IL&#8208;23&#44; IL&#8208;27&#44; IL&#8208;28&#44; IL&#8208;29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3233299.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Principais citocinas e fatores de crescimento influenciados pela sinaliza&#231;&#227;o de diferentes subtipos de JAK&#44; em humanos</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Tabela 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Medicamento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Concentra&#231;&#227;o inibit&#243;ria &#40;IC<span class="elsevierStyleInf">50</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Metabolismo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Meia&#8208;vida plasm&#225;tica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tofacitinibe</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK1&#58; 2&#44;9 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hep&#225;tico CYP3A4<span class="elsevierStyleHsp" style=""></span>&#62; CYP2C19</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 a 8 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK2&#58; 1&#44;2 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK3&#58; 1&#44;1 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TYK2&#58; 42 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baricitinibe</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK1&#58; 4&#44;0 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hep&#225;tico CYP3A4</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 a 13 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK2&#58; 6&#44;6 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK3&#58; 787 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TYK2&#58; 61 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ruxolitinibe</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK1&#58; 6&#44;4 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hep&#225;tico CYP3A4</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 a 4 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK2&#58; 8&#44;8 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK3&#58; 487&#44;0 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TYK2&#58; 30&#44;0 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ritlecitinibe</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK1&#58; 1&#46;638 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hep&#225;tico&#58; CYP450&#59; S&#233;rico&#58; glutationa&#8208;S&#8208;transferase</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 a 3 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK2&#58; 1&#46;507 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK3&#58; 0&#44;3 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TYK2&#58; 3&#46;779 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abrocitinibe</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK1&#58; 29 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hep&#225;tico CYP2C19<span class="elsevierStyleHsp" style=""></span>&#62; CYP2C9<span class="elsevierStyleHsp" style=""></span>&#62; CYP3A4<span class="elsevierStyleHsp" style=""></span>&#62; CYP2D6</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 a 5 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK2&#58; 803 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK3&#58;<span class="elsevierStyleHsp" style=""></span>&#62;10&#46;000 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TYK2&#58; 1&#46;259 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Upadacitinibe</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK1&#58; 14 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hep&#225;tico CYP3A4<span class="elsevierStyleHsp" style=""></span>&#62; CYP2D6</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 a 15 horas</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK2&#58; 593 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK3&#58; 1&#46;860 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TYK2&#58; 2&#46;715 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Delgocitinibe</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK1&#58; 2&#44;8 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&#58; uso t&#243;pico</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&#58; uso t&#243;pico</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK2&#58; 2&#44;6 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK3&#58; 13&#44;0 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TYK2&#58; 58&#44;0 nM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3233301.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Caracter&#237;sticas farmacol&#243;gicas dos principais inibidores da via JAK&#8208;STAT dispon&#237;veis no mercado</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Tabela 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Aumentam os n&#237;veis dos iJAK</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reduzem os n&#237;veis dos iJAK</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inibidores potentes da OAT3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inibidores potentes do CYP2C19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inibidores potentes do CYP3A4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inibidores moderados do CYP3A4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Indutores fracos da CYP3A4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Indutores potentes da CYP3A4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colchinina&#8208;probenecide&#44; probenecide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amitriptilina&#44; cloranfenicol&#44; clomipramina&#44; delavirdina&#44; fluconazol&#44; fluoxetina&#44; fluvoxamina&#44; gemfibrozil&#44; imipramina&#44; isoniazida&#44; lansoprazol&#44; miconazol&#44; stiripentol&#44; ticlopidina&#44; tioconazol&#44; zafirlucaste&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Atazanavir&#44; boceprevir&#44; claritromicina&#44; cobicistat&#44; conivaptan&#44; curcumin&#44; danoprevir&#44; darunavir&#44; delavirdine&#44; econazol&#44; efavirenz&#44; elvitegravir&#44; ergotamina&#44; idelaisibe&#44; indinavir&#44; itraconazol&#44; cetoconazol&#44; loperamida&#44; lopinavir&#44; mebefradil&#44; midostaurin&#44; naloxona&#44; nefazadona&#44; nelfinavir&#44; nilotinibe&#44; posaconazol&#44; ribociclibe&#44; ritonavir&#44; saquinavir&#44; stiripentol&#44; sulfametoxazol&#8208;tripetropim&#44; telaprevir&#44; telitromicina&#44; terfenadina&#44; tipranavir&#44; troleandomicina&#44; voriconazol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#193;cido fus&#237;dico&#44; amiodarona&#44; amprenavir&#44; anastrozol&#44; aprepitante&#44; barnidipina&#44; ciclosporina&#44; clobazam&#44; clozapina&#44; crizotinibe&#44; danazol&#44; desvenlafaxina&#44; diltiazem&#44; dimetil sulf&#243;xido &#40;DMSO&#41;&#44; dronedarona&#44; eritromicina&#44; fluconazole&#44; fluvoxamina&#44; fosamprenavir&#44; foesnetupitante&#44; haloperidol&#44; imatinibe&#44; idalpina&#44; isavuconazol&#44; isavuconazonio&#44; isoniazida&#44; isradipina&#44; linagliptina&#44; lovastatina&#44; luliconazol&#44; miconazol&#44; mifepristona&#44; milnaciprana&#44; netupitante&#44; nicardapina&#44; nilvadipina&#44; paroxetina&#44; primaquina&#44; risperidona&#44; sertralina&#44; simeprevir&#44; tioconazol&#44; venetoclax&#44; venlafaxina&#44; verapamil&#44; zimeldina&#44; ziprasidona&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clonazepan&#44; colchicina&#44; diazepan&#44; pantoprazol&#44; prednisona&#44; ritonavir&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#193;cido valproico&#44; atorvastatina&#44; carbamazepina&#44; dexametasona&#44; efavirenz&#44; fenito&#237;na&#44; fenobarbital&#44; rifampicina&#44; sinvastatina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3233305.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Medicamentos que potencialmente interferem com os n&#237;veis s&#233;ricos e seguran&#231;a dos inibidores da via JAK&#8208;STAT</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Tabela 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CPK&#44; creatinofosfoquinase&#59; ITRS&#44; infec&#231;&#227;o do trato respirat&#243;rio superior&#59; VO&#44; via oral&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dermatose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Medicamento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Via de administra&#231;&#227;o&#47; n de pacientes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Eventos adversos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alopecia areata</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="8" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tofacitinibe</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VO</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nenhum evento adverso grave&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&#44;9&#37; ITRS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">90 pacientes<span class="elsevierStyleSup">34</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 leucopenia revers&#237;vel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 eleva&#231;&#227;o de transaminases que normalizou com a perda ponderal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VO e t&#243;pico</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&#44;8&#37; ITRS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#44;2&#37; acne&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">252 pacientes<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">35</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#44;1&#37; cefaleia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#44;7&#37; altera&#231;&#227;o de transaminases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vitiligo</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tofacitinibe e ruxolitinibe</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VO e t&#243;pico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#44;9&#37; acne e altera&#231;&#227;o de transaminases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45 pacientes<a class="elsevierStyleCrossRef" href="#bib0865"><span class="elsevierStyleSup">36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#44;4&#37; ITRS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="13" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dermatite at&#243;pica</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baricitinibe &#40;<span class="elsevierStyleItalic">BREEZE AD 1</span> e <span class="elsevierStyleItalic">2</span>&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VO</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#44;3&#37; nasofaringite &#40;dose 1&#160;mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Herpes simples oral&#44; cefaleia&#44; diarreia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;239 pacientes<a class="elsevierStyleCrossRef" href="#bib0890"><span class="elsevierStyleSup">41</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uma paciente teve tromboembolismo&#59; era tabagista e usava contraceptivo oral &#40;dose 4 mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abrocitinibe<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;<span class="elsevierStyleItalic">JADE MONO</span> 2&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VO</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#44;2&#37; n&#225;usea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#44;7&#37; nasofaringite e cefaleia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;233 pacientes<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">42</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#44;8&#37; acne&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#44;2&#37; v&#244;mitos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#44;2&#37; ITRS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Upadacitinibe<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> &#40;<span class="elsevierStyleItalic">Measure Up</span><span class="elsevierStyleItalic">1</span>&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VO</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#37; a 17&#37; acne&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#37; a 13&#37; ITRS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">566 pacientes<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">43</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#37; a 12&#37; nasofaringite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#37; a 7&#37; cefaleia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#37; aumento CPK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab3233304.png"
              ]
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          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">A dose considerada do estudo JADE MONO&#8208;2 para os eventos adversos foi de 200<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Eventos adversos expressos de acordo com as doses utilizadas &#40;15 e 30<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Principais eventos adversos por ordem de frequ&#234;ncia das principais dermatoses em que os inibidores da via JAK&#8208;STAT s&#227;o utilizados</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0025"
        "etiqueta" => "Tabela 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at5"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">iJAK&#44; inibidor da via JAK&#8208;STAT&#59; PPD&#44; teste tubercu&#237;nico intrad&#233;rmico&#59; IGRA&#44; teste tubercul&#237;nico de libera&#231;&#227;o de interferona&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dados cl&#237;nicos ou laboratoriais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Condi&#231;&#227;o especial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Coment&#225;rio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Faixa et&#225;ria</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62; 65 anos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Risco elevado de eventos adversos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>15 anos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baricitinibe n&#227;o deve ser administrado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>12 anos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o utilizar iJAK indiv&#237;duos com menos de 12 anos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Peso corporal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>30 kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Upadacitinibe n&#227;o deve ser usado em crian&#231;as com &#60;<span class="elsevierStyleHsp" style=""></span>30 kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amamenta&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Os iJAK n&#227;o devem ser utilizados por lactantes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gravidez</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindica&#231;&#227;o absoluta&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interromper o iJAK em pessoas sob risco de gravidez&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Em caso de gravidez&#44; interromper o uso e solicitar seguimento r&#237;gido com ginecologista&#47;obstetra&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatite B</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HBsAg positivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carga viral &#8805; 20 IU&#47;mL &#40;1&#44;3 log IU&#47;mL&#41;&#58; n&#227;o usar iJAK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carga viral &#60;<span class="elsevierStyleHsp" style=""></span>20 IU&#47;mL&#58; monitorar a cada 1&#8208;3 meses al&#233;m das transaminases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;HBcAg ou anti&#8208;HBsAg positivos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Verificar a carga viral&#44; como na situa&#231;&#227;o anterior&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Caso apenas o anti&#8208;HBsAg seja positivo e todo o restante negativo &#40;HBsAg&#44; HBeAg&#44; anti&#8208;HBeAg e anti&#8208;HBcAg e carga viral negativa&#41;&#44; pode&#8208;se usar iJAK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatite C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;HVC positivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Consultar hepatologista&#47;infectologista&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pacientes com anti&#8208;HVC positivo foram exclu&#237;dos dos ensaios cl&#237;nicos dessas medica&#231;&#245;es&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vacina&#231;&#227;o com v&#237;rus vivos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Deve ser administrada 30 dias antes do in&#237;cio do iJAK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#201; contraindicada durante o tratamento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tuberculose ativa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Deve ser interrompido&#47;contraindicado o uso de iJAK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tuberculose latente&#47;suspeito assintom&#225;tico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PPD&#44; IGRA&#47;quantiferona <span class="elsevierStyleItalic">gold</span> positiva&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Quimioprofilaxia da tuberculose &#40;isoniazida&#41; pelo menos tr&#234;s semanas antes do in&#237;cio do iJAK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Se estiver em uso de iJAK&#58; quimioprofilaxia por 6 a 9 meses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hist&#243;rico de c&#226;ncer pr&#233;vio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monitorar o surgimento de eventos adversos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Clearance</span> de creatinina<span class="elsevierStyleHsp" style=""></span>&#62; 30 mL&#47;min&#47;1&#44;73m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o ultrapassar 2 mg&#47;dia de baricitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o ultrapassar 50 mg&#47;d de abrocitininbe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Clearance</span> de creatinina &#8804; 30 mL&#47;min&#47;1&#44;73m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Preferir upadacitinibe 15 mg&#47;dia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o ultrapassar 50 mg&#47;d de abrocitininbe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Risco de tromboembolismo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uso cauteloso de iJAK&#58; prefer&#234;ncia pelos inibidores da JAK1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infec&#231;&#245;es potencialmente graves&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicado o uso dos iJAK orais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Altera&#231;&#245;es hematol&#243;gicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Linfopenia &#60;<span class="elsevierStyleHsp" style=""></span>500&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicado o uso dos iJAK orais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neutropenia &#60;<span class="elsevierStyleHsp" style=""></span>1&#46;000&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicado o uso do upadacitinibe e do abrocitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neutropenia &#60;<span class="elsevierStyleHsp" style=""></span>500&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicado o uso dos iJAK orais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trombocitopenia &#60;<span class="elsevierStyleHsp" style=""></span>50&#46;000&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicado o uso do abrocitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Altera&#231;&#227;o hep&#225;tica grave&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Classe C de Child&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicado o uso do upadacitinibe e do abrocitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infec&#231;&#227;o recorrente por herpesv&#237;rus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Considerar o risco de reativa&#231;&#227;o de herpes com iJAK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infec&#231;&#227;o pelo HIV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicado o uso dos iJAK orais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3233302.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Considera&#231;&#245;es cl&#237;nicas e laboratoriais sobre o uso dos inibidores da via JAK&#8208;STAT</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0030"
        "etiqueta" => "Tabela 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at6"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">iJAK&#44; inibidor da via JAK&#8208;STAT&#59; AA&#44; alopecia areata&#59; DA&#44; dermatite at&#243;pica&#59; DM&#44; dermatomiosite&#59; PSO&#44; psor&#237;ase&#59; VITI&#44; vitiligo&#59; HS&#44; hidradenite supurativa&#59; LP&#44; l&#237;quen plano e l&#237;quen plano pilar&#59; LE&#44; l&#250;pus eritematoso&#59; PG&#44; pioderma gangrenoso&#59; GA&#44; granuloma anular&#59; SARC&#44; sarcoidose&#59; NL&#44; necrobiose lipo&#237;dica&#59; VL&#44; vasculopatia livedoide&#59; MOR&#44; morfeia&#59; ECZm&#44; eczema cr&#244;nico das m&#227;os&#59; DEVH&#44; doen&#231;a enxerto v<span class="elsevierStyleItalic">ersus</span> hospedeiro&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">iJAK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PSO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VITI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">GA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">NL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SARC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MOR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DEVH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ECZm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tofacitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baricitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abrocitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Upadacitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ruxolitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Delgocitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ritlecitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elsubritinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Itacitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Peficitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Deucravacitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Filotinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Solcitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pacritinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Deuruxolitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gusacitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T&#243;pico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tofacitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ruxolitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Brepocitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Delgocitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">EASI75 e EASI90&#44; redu&#231;&#227;o de &#8805; 75&#37;&#47; &#8805; 90&#37; no &#237;ndice de &#225;rea e gravidade do eczema&#59; IGA 0&#47;1&#44; Avalia&#231;&#227;o Global do Investigador resulta em m&#237;nimo eritema e p&#225;pulas percept&#237;veis&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">iJAK oral&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Estudo &#40;dura&#231;&#227;o&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dose di&#225;ria&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">EASI75&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">EASI90&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IGA 0&#47;1 &#40;ou &#8208;2 pontos&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="9" align="left" valign="\n
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                  \t\t\t\t">Upadacitinibe<a class="elsevierStyleCrossRefs" href="#bib0900"><span class="elsevierStyleSup">43&#44;69</span></a> &#40;&#62; 12 anos&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Measure Up 1</span> &#40;16 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Measure Up 2</span> &#40;16 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">AD Up</span> &#40;&#43; corticoide t&#243;pico 16 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">77&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abrocitinibe<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">42</span></a> &#40;&#62;12 anos</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">JADE MONO&#8208;1</span> &#40;12 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">200 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#44;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">JADE MONO&#8208;2</span> &#40;12 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">200 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="11" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baricitinibe<a class="elsevierStyleCrossRefs" href="#bib0890"><span class="elsevierStyleSup">41&#44;70</span></a> &#40;&#62; 18 anos&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BREEZE AD&#8208;1</span> &#40;16 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BREEZE AD&#8208;2</span> &#40;16 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BREEZE AD&#8208;</span>7 &#40;&#43; corticoide t&#243;pico 16 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3233300.png"
              ]
            ]
            1 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">iJAK t&#243;pico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Estudo &#40;dura&#231;&#227;o&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Concentra&#231;&#227;o 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#47;dia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">EASI 75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">EASI 90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IGA 0&#47;1 &#40;ou<span class="elsevierStyleHsp" style=""></span>&#8211;<span class="elsevierStyleHsp" style=""></span>2 pontos&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ruxolitinibe<a class="elsevierStyleCrossRef" href="#bib1040"><span class="elsevierStyleSup">71</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TRuE &#8208; AD 1</span> &#40;8 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;5&#37; creme&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;75&#37; creme&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ve&#237;culo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#44;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TRuE &#8208; AD 2</span> &#40;8 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;5&#37; creme&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#44;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;75&#37; creme&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#44;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ve&#237;culo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#44;6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tofacitinibe<a class="elsevierStyleCrossRef" href="#bib1045"><span class="elsevierStyleSup">72</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NCT02001181 &#40;4 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#37; pomada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ve&#237;culo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Delgocitinibe<a class="elsevierStyleCrossRefs" href="#bib1050"><span class="elsevierStyleSup">73&#44;74</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">OBA</span> 4&#8208;1 &#40;4 semanas&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;5&#37; creme&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Corpo &#8211; 10&#44;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Face &#8211; 22&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ve&#237;culo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Corpo &#8211; 3&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Face &#8211; 4&#44;0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">JapicCTI&#8208;184064</span> &#40;4 semanas&#41;</td><td class="td" title="\n
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                  \t\t\t\t">37&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 26662752
Original language: Portuguese

DOI:10.1016/j.abdp.2023.05.018

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