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n&#227;o h&#225; tratamentos aprovados pela <span class="elsevierStyleItalic">Food and Drug Administration</span> &#40;FDA&#41;&#44; criando ainda mais desafios frente ao diagn&#243;stico de PN&#44; resultando em grande necessidade n&#227;o atendida de pacientes cujos sintomas s&#227;o inadequadamente controlados com as terapias tradicionais&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Pesquisas recentes sugerem que citocinas T&#8208;<span class="elsevierStyleItalic">helper</span> 2 &#40;Th2&#41;&#44; como interleucina&#8208;4 &#40;IL&#8208;4&#41; e interleucina&#8208;13 &#40;IL&#8208;13&#41;&#44; podem participar da patog&#234;nese do PN&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> O presente estudo avalia a efic&#225;cia e a seguran&#231;a do dupilumabe&#44; um antagonista do receptor&#8208;&#945; da IL&#8208;4 &#40;IL&#8208;4R&#945;&#41;&#44; como tratamento <span class="elsevierStyleItalic">off&#8208;label</span> para pacientes adultos com PN refrat&#225;rio&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><p id="par0015" class="elsevierStylePara elsevierViewall">Este &#233; um estudo observacional que recruta pacientes adultos no Departamento de Dermatologia em um ambiente de pr&#225;tica cl&#237;nica hospitalar&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Pacientes e desenho do estudo</span><p id="par0020" class="elsevierStylePara elsevierViewall">O presente estudo incluiu consecutivamente pacientes que foram diagnosticados com PN por pelo menos seis meses e que n&#227;o responderam &#224;s terapias tradicionais&#46; Todos os pacientes inclu&#237;dos foram avaliados por dermatologista credenciado com classifica&#231;&#227;o na escala de Avalia&#231;&#227;o Global do Investigador &#40;IGA&#44; <span class="elsevierStyleItalic">Investigator Global Assessment</span>&#41; &#8805; 3 e classifica&#231;&#227;o NRSI &#8805; 7&#46; Pacientes que receberam imunossupressores sist&#234;micos ou fototerapia tr&#234;s meses antes da inscri&#231;&#227;o no estudo foram exclu&#237;dos&#46; Os pacientes inclu&#237;dos neste estudo receberam inje&#231;&#227;o subcut&#226;nea de dupilumabe seguindo o esquema posol&#243;gico padr&#227;o &#40;dose de indu&#231;&#227;o de 600<span class="elsevierStyleHsp" style=""></span>mg seguida de 300<span class="elsevierStyleHsp" style=""></span>mg a cada duas semanas&#41; por pelo menos 16 semanas&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Durante o per&#237;odo de tratamento com dupilumabe&#44; os pacientes foram autorizados a usar glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; pomadas antibi&#243;ticas t&#243;picas e medicamentos tradicionais chineses como tratamentos de resgate&#46; Informa&#231;&#245;es demogr&#225;ficas dos pacientes&#44; hist&#243;rico m&#233;dico e hist&#243;rico familiar de dist&#250;rbios al&#233;rgicos foram relatados na semana 0 &#40;linha basal&#41;&#46; Resposta cl&#237;nica&#44; resultados dos exames de sangue e eventos adversos &#40;EAs&#41; foram monitorados de perto durante o per&#237;odo de tratamento para auxiliar na avalia&#231;&#227;o da efic&#225;cia da terapia com dupilumabe&#46; Especificamente&#44; o exame de sangue foi solicitado na semana 0 e na semana 16 do tratamento com dupilumabe a fim de avaliar a contagem de gl&#243;bulos brancos &#40;CGB&#41;&#44; a contagem absoluta de eosin&#243;filos &#40;CAE&#41; s&#233;rica e os n&#237;veis s&#233;ricos totais de IgE &#40;IgET&#41;&#46; Al&#233;m disso&#44; os escores da IGA&#44; do &#205;ndice Dermatol&#243;gico de Qualidade de Vida &#40;<span class="elsevierStyleItalic">Dermatology Life Quality Index</span> &#8208; DLQI&#41;&#44; e da Escala Hospitalar de Depress&#227;o e Ansiedade &#40;<span class="elsevierStyleItalic">Hospital Anxiety and Depression Scale</span> &#8208; HADS&#41; foram relatados na semana 0 e na semana 16 do tratamento com dupilumabe&#46; O consentimento informado por escrito foi obtido de todos os pacientes antes da inclus&#227;o no estudo que foi realizado ap&#243;s aprova&#231;&#227;o do Comit&#234; de &#201;tica em Pesquisa Cl&#237;nica do hospital&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Coleta de amostras de pele de pacientes com PN</span><p id="par0030" class="elsevierStylePara elsevierViewall">Bi&#243;psias de pele foram coletadas de dois pacientes diagnosticados com PN apresentando n&#243;dulos pruriginosos nas extremidades inferiores&#44; e uma amostra de pele saud&#225;vel foi obtida no mesmo local&#46; Os experimentos em amostras humanas foram conduzidos ap&#243;s obten&#231;&#227;o do consentimento informado por escrito e aprova&#231;&#227;o do Comit&#234; de &#201;tica em Pesquisa Cl&#237;nica do hospital&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Imunofluoresc&#234;ncia</span><p id="par0035" class="elsevierStylePara elsevierViewall">O anticorpo prim&#225;rio utilizado para imunomarca&#231;&#227;o foi o anticorpo antirreceptor da IL&#8208;17A &#40;ab180904&#44; Abcam&#41; dilu&#237;do a 1&#58;50&#46; Essa etapa foi seguida por um anticorpo secund&#225;rio conjugado com FITC &#40;ZF&#8208;0311&#44; ZSGB&#8208;BIO&#41; dilu&#237;do a 1&#58;250&#46; As amostras foram examinadas por microscopia fluorescente &#40;Leica&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Estat&#237;sticas</span><p id="par0040" class="elsevierStylePara elsevierViewall">As an&#225;lises estat&#237;sticas foram realizadas com o programa GraphPad PRISM &#40;vers&#227;o 9&#46;2&#46;0&#41; com o teste <span class="elsevierStyleItalic">t</span> de Student como indicado &#40;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#44; &#42;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#44; &#42;&#42;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0005&#44; &#42;&#42;&#42;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#59; ns&#44; n&#227;o significante&#41;&#46; Os resultados num&#233;ricos foram apresentados como m&#233;dia<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>erro padr&#227;o da m&#233;dia &#40;E&#46;P&#46;M&#46;&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Resultados</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Pacientes</span><p id="par0045" class="elsevierStylePara elsevierViewall">Oito pacientes &#40;62&#44;5&#37; do sexo feminino&#41; diagnosticados com PN moderado a grave por pelo menos seis meses &#40;dura&#231;&#227;o m&#233;dia de 5&#44;525 anos &#91;desvio padr&#227;o&#58; 6&#44;6 anos&#93;&#41; foram inclu&#237;dos no estudo&#46; Todos os pacientes tinham sido tratados anteriormente com terapias tradicionais multimodais&#44; mas n&#227;o apresentaram resposta&#46; O tratamento com imunossupressores sist&#234;micos foi descontinuado em todos os pacientes inclu&#237;dos tr&#234;s meses antes da dose de indu&#231;&#227;o de dupilumabe&#46; Nenhum EA foi relatado durante o per&#237;odo do estudo&#44; e nenhum paciente desistiu em decorr&#234;ncia de EAs causados pelo tratamento com dupilumabe&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Os dados demogr&#225;ficos basais e as caracter&#237;sticas da doen&#231;a s&#227;o apresentados na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46; Poucos pacientes &#40;37&#44;5&#37;&#41; tinham hist&#243;rico familiar de dist&#250;rbios al&#233;rgicos&#47;at&#243;picos&#46; Tr&#234;s pacientes &#40;37&#44;5&#37;&#41; tinham hist&#243;rico pessoal de alergia&#47;atopia&#46; Mais da metade da popula&#231;&#227;o total &#40;62&#44;5&#37;&#41; tinha comorbidades &#40;hepatite B&#44; 12&#44;5&#37;&#59; diabetes&#44; 25&#44;0&#37;&#59; hipertens&#227;o&#44; 50&#44;0&#37;&#41;&#46; Em todos os pacientes &#40;100&#37;&#41;&#44; o in&#237;cio do PN ocorreu na idade adulta &#40;&#8805; 18 anos&#41;&#44; e todos eles &#40;100&#37;&#41; relataram respostas ineficazes &#224;s terapias anteriores antes do uso de dupilumabe &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Efic&#225;cia do tratamento com dupilumabe</span><p id="par0055" class="elsevierStylePara elsevierViewall">Na semana 0&#44; todos os pacientes inclu&#237;dos apresentavam n&#243;dulos eritematosos generalizados e placas distribu&#237;das simetricamente nas extremidades&#44; m&#227;os e tronco &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>A&#41;&#46; Ap&#243;s 16 semanas de administra&#231;&#227;o de dupilumabe&#44; as les&#245;es cut&#226;neas diminu&#237;ram na maioria dos casos &#40;87&#44;5&#37;&#41;&#44; indicado pela redu&#231;&#227;o do tamanho e n&#250;mero de n&#243;dulos &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>B&#41;&#46; Um paciente &#40;12&#44;5&#37;&#41; apresentou resposta deficiente&#44; com prurido e n&#250;mero de n&#243;dulos persistentes&#46; O n&#250;mero de n&#243;dulos em seu corpo n&#227;o foi significantemente reduzido&#44; enquanto apenas as erup&#231;&#245;es cut&#226;neas na face extensora dos membros inferiores diminu&#237;ram ligeiramente de tamanho&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Em geral&#44; na 16&#170; semana de tratamento com dupilumabe&#44; alguns pacientes &#40;25&#44;0&#37;&#41; tiveram resposta completa ao tratamento com diminui&#231;&#227;o de 3 graus na IGA&#59; metade da popula&#231;&#227;o &#40;50&#44;0&#37;&#41; relatou resposta parcial ao tratamento com diminui&#231;&#227;o de 2 graus na IGA&#59; um paciente &#40;12&#44;5&#37;&#41; relatou resposta deficiente ao tratamento com dupilumabe com diminui&#231;&#227;o de menos de 2 graus na IGA &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>A&#41;&#46; O tratamento com dupilumabe levou &#224; redu&#231;&#227;o significante nas classifica&#231;&#245;es m&#233;dias da escala IGA em toda a popula&#231;&#227;o de pacientes com PN da semana 0 &#224; semana 16 &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#59; <a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>B&#41;&#44; enquanto n&#227;o foram observadas diferen&#231;as estatisticamente significantes para os resultados laboratoriais de CGB &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;4137&#41; e CAE &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;2438&#59; <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#46; A m&#233;dia da IGA na semana 0 &#40;3&#44;75&#41; diminuiu para 1&#44;50 na semana 16 na popula&#231;&#227;o total&#44; enquanto cinco pacientes &#40;62&#44;5&#37;&#41; receberam valor de IGA igual a 1 ap&#243;s 16 semanas de tratamento com dupilumabe&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Depois de 16 semanas&#44; todos os pacientes relataram melhora subjetiva no prurido&#44; qualidade de vida e n&#237;veis de ansiedade&#46; Foi observada diminui&#231;&#227;o estatisticamente significante nas classifica&#231;&#245;es m&#233;dias semanais de NRSI &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#44; DLQI &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; e HADS &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41; na semana 16 do tratamento com dupilumabe &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>&#41;&#46; Os valores basais m&#233;dios &#40;semana 0&#41; dos escores m&#233;dios semanais de NRSI &#40;8&#44;625&#41;&#44; DLQI &#40;15&#44;13&#41; e HADS &#40;14&#44;50&#41; diminu&#237;ram para 1&#44;563&#44; 4&#44;625 e 1&#44;000&#44; respectivamente&#44; ap&#243;s 16 semanas de tratamento com dupilumabe&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">A maioria dos pacientes &#40;75&#44;0&#37;&#41; experimentou redu&#231;&#227;o no n&#237;vel de IgET durante as 16 semanas de tratamento com dupilumabe &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#41;&#46; Enquanto isso&#44; 4&#47;8 pacientes apresentaram n&#237;veis de IgET significantemente mais baixos &#40;&#37; de varia&#231;&#227;o m&#233;dia<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>52&#44;58&#37;&#41; da semana 0 &#224; semana 16&#44; enquanto os outros pacientes n&#227;o exibiram altera&#231;&#227;o significante&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Imunofluoresc&#234;ncia da biopsia de pele lesional de PN</span><p id="par0075" class="elsevierStylePara elsevierViewall">A imunofluoresc&#234;ncia das amostras de pele lesional de PN de dois pacientes mostrou grande n&#250;mero de queratin&#243;citos positivos para o receptor de IL&#8208;17A &#40;IL&#8208;17RA&#41; na camada granulosa e na camada espinhosa da epiderme&#44; enquanto o controle saud&#225;vel mostrou apenas poucos queratin&#243;citos positivos para IL&#8208;17RA na camada basal da epiderme &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discuss&#227;o</span><p id="par0080" class="elsevierStylePara elsevierViewall">PN &#233; doen&#231;a inflamat&#243;ria da pele caracterizada por prurido intenso&#44; presen&#231;a de m&#250;ltiplas p&#225;pulas hipercerat&#243;ticas&#44; les&#245;es nodulares&#44; hiperpigmenta&#231;&#227;o e ansiedade associada ao prurido&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5&#44;6</span></a> Por falta de tratamento aprovado pela FDA para PN&#44; as terapias usualmente prescritas geralmente incluem o uso t&#243;pico e sist&#234;mico de anti&#8208;histam&#237;nicos&#44; esteroides&#44; gabapentinoides&#44; imunossupressores&#44; antidepressivos e outros agentes neuromoduladores que frequentemente colocam os pacientes em risco de efeitos colaterais graves&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">7&#44;8</span></a> Portanto&#44; muitos pacientes t&#234;m necessidade duradoura e n&#227;o alcan&#231;ada de tratamento seguro e eficaz para PN&#46; Neste estudo observacional da pr&#225;tica cl&#237;nica&#44; s&#227;o apresentados dados sobre efic&#225;cia e seguran&#231;a do tratamento com dupilumabe em pacientes com PN&#46; Em pacientes adultos com PN refrat&#225;rio que n&#227;o responderam &#224;s terapias tradicionais&#44; 16 semanas de tratamento com dupilumabe resultaram em melhora estat&#237;stica e clinicamente significante nos sinais&#44; sintomas&#44; intensidade do prurido&#44; n&#237;veis de ansiedade&#44; n&#237;veis de depress&#227;o e qualidade de vida&#44; com nenhum caso de EAs&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Em termos de efic&#225;cia geral do dupilumabe para PN&#44; Calugareanu et al&#46; obtiveram como resultado que 50&#37; dos pacientes com PN tiveram resposta completa&#44; 41&#44;7&#37; dos pacientes tiveram resposta parcial e 1&#47;16 pacientes n&#227;o apresentaram resposta ap&#243;s seis meses de tratamento com dupilumabe&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> Relatamos resultados igualmente not&#225;veis&#44; com 37&#44;5&#37; dos pacientes com PN apresentando resposta completa&#44; 50&#37; com resposta parcial e apenas 1&#47;8 pacientes com resposta deficiente ao dupilumabe&#46; No presente estudo&#44; a melhora dos sintomas ap&#243;s o in&#237;cio do tratamento com dupilumabe foi r&#225;pida e significante&#46; Melhora nas les&#245;es e n&#243;dulos cut&#226;neos podem ser observadas em est&#225;gio inicial ap&#243;s quatro semanas de tratamento com dupilumabe&#46; Ap&#243;s 16 semanas&#44; o escore IGA m&#233;dio dos pacientes diminuiu de 3&#44;75 para 1&#44;50&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Do mesmo modo&#44; Chiricozzi et al&#46; relataram redu&#231;&#227;o no escore IGA de pelo menos 2 graus em 82&#44;6&#37; dos pacientes ap&#243;s 16 semanas de tratamento com dupilumabe&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> Essas observa&#231;&#245;es provaram a tend&#234;ncia do dupilumabe em provocar respostas r&#225;pidas e not&#225;veis de redu&#231;&#227;o dos sintomas em pacientes com PN&#46; Al&#233;m disso&#44; a melhora subjetiva relatada pelos pacientes na intensidade do prurido ap&#243;s a inje&#231;&#227;o de dupilumabe foi ainda mais r&#225;pida&#46; Na presente coorte&#44; alguns pacientes relataram resposta ao dupilumabe em termos de redu&#231;&#227;o do prurido j&#225; durante a segunda semana de tratamento&#46; Na 16&#170; semana do tratamento com dupilumabe&#44; uma redu&#231;&#227;o m&#233;dia de NRSI de 7&#44;063 foi obtida no presente estudo&#46; Com base em estudos anteriores&#44; Zhai et al&#46; observaram redu&#231;&#227;o m&#233;dia do escore NRSI de 7&#44;89 em duas semanas de tratamento com dupilumabe&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> Beck et al&#46; relataram melhora do prurido para quase zero em termos do escore NRSI para todos os tr&#234;s pacientes em 12 semanas de tratamento com dupilumabe&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> Esses resultados confirmam a efic&#225;cia do dupilumabe no al&#237;vio do prurido em pacientes com PN&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">N&#227;o apenas os sintomas cl&#237;nicos melhoraram significantemente ap&#243;s o tratamento com dupilumabe&#44; mas a sa&#250;de mental e a qualidade de vida dos pacientes tamb&#233;m apresentaram melhoras subjetivas&#46; A m&#233;dia do escore HADS dos pacientes diminuiu de 14&#44;50 na semana 0 para 1&#44;00 na semana 16&#44; mostrando melhora significante na sa&#250;de mental&#46; Al&#233;m disso&#44; a m&#233;dia do escore DLQI dos pacientes diminuiu de 15&#44;13 para 4&#44;625 ap&#243;s 16 semanas de tratamento com dupilumabe&#46; Giovannini et al&#46; relataram resultado semelhante de redu&#231;&#227;o do escore DLQI de 16 para 1 ap&#243;s 12 semanas de tratamento com dupilumabe em um paciente com PN&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> A redu&#231;&#227;o mais not&#225;vel e precoce no escore DLQI do caso relatado pode ser decorrente da idade do paciente&#44; que era adolescente&#44; enquanto a presente coorte era composta por pacientes adultos&#46; &#201; poss&#237;vel que o tratamento com dupilumabe seja mais eficaz em pacientes adolescentes com PN&#46; No entanto&#44; ainda n&#227;o existem evid&#234;ncias suficientes em raz&#227;o do pequeno n&#250;mero de estudos dispon&#237;veis publicamente&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">O tratamento com dupilumabe provou ser seguro na presente coorte de pacientes adultos com PN&#44; pois nenhum EA foi relatado no presente estudo&#46; Sua seguran&#231;a tamb&#233;m foi comprovada por in&#250;meros casos anteriores de uso de dupilumabe em pacientes com PN&#44; com nenhum EA detectado&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">10&#8211;16</span></a> Os resultados do presente estudo sugerem que o tratamento com dupilumabe &#233; op&#231;&#227;o de tratamento eficaz e toler&#225;vel para pacientes adultos com PN intrat&#225;vel&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Dupilumabe &#233; anticorpo monoclonal totalmente humano que atua como antagonista de IL&#8208;4R&#945; para bloquear os efeitos biol&#243;gicos ativos de IL&#8208;4 e IL&#8208;13 na realiza&#231;&#227;o de respostas imunes tipo 2&#44; incluindo alguns sintomas de PN&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4&#44;14&#44;15&#44;17</span></a> Entretanto&#44; a patog&#234;nese exata do PN permanece amb&#237;gua&#46; Alguns autores argumentam que o PN &#233; o resultado em longo prazo do ciclo cr&#244;nico de prurido&#8208;ato de co&#231;ar de pacientes com prurido cr&#244;nico&#44; enquanto outros acreditam que o PN &#233; uma doen&#231;a distinta que existe por conta pr&#243;pria&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">18&#44;19</span></a> Evid&#234;ncias sugerem que o PN pode constituir doen&#231;a multifatorial decorrente de origens neurol&#243;gica&#44; dermatol&#243;gica e sist&#234;mica&#44; com a possibilidade de causas desconhecidas em muitos casos&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Os mecanismos espec&#237;ficos do dupilumabe como tratamento eficaz para PN ainda n&#227;o est&#227;o estabelecidos&#46; Talvez a efic&#225;cia do dupilumabe no tratamento do PN possa ser explicada pela interrup&#231;&#227;o do ciclo prurido&#8208;ato de co&#231;ar por meio da inibi&#231;&#227;o da IL&#8208;4R&#945; neuronal&#44; que &#233; necess&#225;ria para a transdu&#231;&#227;o da sinaliza&#231;&#227;o do prurido cr&#244;nico e resulta na atenua&#231;&#227;o do prurido e da inflama&#231;&#227;o da pele&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> Al&#233;m disso&#44; os dados do presente estudo mostraram que 37&#44;5&#37; dos pacientes inclu&#237;dos tinham hist&#243;rico m&#233;dico de dist&#250;rbios al&#233;rgicos que mostraram diminui&#231;&#227;o significante da IgET s&#233;rica ap&#243;s o tratamento com dupilumabe&#46; Al&#233;m disso&#44; estudo conduzido por Fukushi et al&#46; observou a express&#227;o de IL&#8208;4 e IL&#8208;13 em biopsias cut&#226;neas de les&#245;es de PN&#44; indicando o papel patog&#234;nico das citocinas Th2 no PN&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> Esses achados sugerem que uma resposta al&#233;rgica Th2 excessiva pode atuar como fator contribuinte na patog&#234;nese do PN&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Recentemente&#44; Belzberg et al&#46; observaram um aumento na express&#227;o de genes associados a c&#233;lulas Th17 &#40;p&#46; ex&#46;&#44; S100&#44; LOR&#44; K6&#44; K17 etc&#46;&#41; em amostras de pele de les&#245;es de PN&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> Portanto&#44; foi realizada a imunofluoresc&#234;ncia para IL&#8208;17RA em dois pacientes com PN e um controle saud&#225;vel&#46; O resultado revelou maior n&#250;mero de queratin&#243;citos positivos para IL&#8208;17RA nas amostras de pele lesional de PN quando comparadas &#224; amostra do controle saud&#225;vel&#46; Com base nesse achado&#44; foi levantada a hip&#243;tese de que a regula&#231;&#227;o positiva observada em IL&#8208;17RA pode ser outro fator subjacente que contribui para o desenvolvimento de PN&#46; Tamb&#233;m &#233; poss&#237;vel que o PN esteja clinicamente correlacionado com a dermatite at&#243;pica &#40;DA&#41;&#44; pois as citocinas relacionadas &#224; Th17 foram consideradas contribuintes potenciais na patog&#234;nese da DA nos &#250;ltimos anos&#44; enquanto o dupilumabe tem n&#250;mero razo&#225;vel de casos relatados de sucesso no tratamento de pacientes com DA grave e intrat&#225;vel&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">24&#8211;30</span></a> Essas descobertas apresentam a possibilidade de que as terapias moduladoras de inflama&#231;&#227;o Th17&#47;IL&#8208;17 se tornem um alvo de tratamento ben&#233;fico para pacientes com PN no futuro&#46; Entretanto&#44; os pap&#233;is patog&#234;nicos espec&#237;ficos e as vias de sinaliza&#231;&#227;o de citocinas relacionadas a Th2&#44; citocinas relacionadas a Th17 e DA no PN precisam de investiga&#231;&#245;es adicionais&#44; com mais modelos de doen&#231;a&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Alguns casos cl&#237;nicos avaliaram a resposta ao dupilumabe em pacientes com PN anteriormente&#44; mas o presente estudo tem seus pr&#243;prios pontos fortes&#46; Primeiro&#44; foram utilizados escalas e question&#225;rios de medidas padronizados e abrangentes que cobrem todos os aspectos da avalia&#231;&#227;o dos sintomas da doen&#231;a&#44; sa&#250;de mental e qualidade de vida na coorte&#44; o que resultou em resultados detalhados e precisos&#46; Em segundo lugar&#44; o presente estudo foi estritamente desenvolvido na pr&#225;tica cl&#237;nica&#44; que por sua vez aumentaram a viabilidade e a generaliza&#231;&#227;o da aplica&#231;&#227;o do tratamento com dupilumabe em pacientes com PN na pr&#225;tica di&#225;ria&#46; Entretanto&#44; o presente estudo tamb&#233;m tem algumas limita&#231;&#245;es&#46; Primeiro&#44; o tamanho da amostra foi relativamente pequeno&#44; com apenas oito pacientes inclu&#237;dos&#46; Em segundo lugar&#44; a coorte foi limitada a pacientes adultos com PN &#8211; portanto&#44; os desfechos pedi&#225;tricos n&#227;o s&#227;o claros&#46; Em terceiro lugar&#44; este estudo foi limitado pelo curto per&#237;odo de tratamento de 16 semanas&#44; o que significa que faltam avalia&#231;&#245;es de efic&#225;cia e seguran&#231;a em longo prazo&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclus&#227;o</span><p id="par0125" class="elsevierStylePara elsevierViewall">O tratamento com dupilumabe provou ser eficaz na melhora de les&#245;es cut&#226;neas&#44; redu&#231;&#227;o do prurido e melhora da qualidade de vida dos pacientes&#46; Al&#233;m disso&#44; n&#227;o foram detectados EAs&#44; demonstrando que o tratamento com dupilumabe &#233; op&#231;&#227;o segura e toler&#225;vel para pacientes adultos com PN&#46; &#201; evidente que o IL&#8208;4R constitui alvo importante no tratamento do PN&#44; enquanto outras abordagens potenciais tendo como alvo as citocinas Th17 e seus receptores podem se tornar op&#231;&#245;es de tratamento futuras para pacientes com PN&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Status de aprova&#231;&#227;o do CEP</span><p id="par0130" class="elsevierStylePara elsevierViewall">Revisado e aprovado pelo Comit&#234; de &#201;tica em Pesquisa Cl&#237;nica do <span class="elsevierStyleItalic">Peking University First Hospital</span>&#44; ID&#58; 2021&#47;223&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Suporte financeiro</span><p id="par0135" class="elsevierStylePara elsevierViewall">O presente estudo recebeu apoio financeiro da National Natural Science Foundation of China &#40;concess&#227;o n&#176; 81903213 para J&#46; Zhao&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Contribui&#231;&#227;o dos autores</span><p id="par0140" class="elsevierStylePara elsevierViewall">Zhixin Zhang&#58; Revis&#227;o cr&#237;tica da literatura&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; an&#225;lise estat&#237;stica&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Siyuan Li&#58; Revis&#227;o cr&#237;tica da literatura&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Yang Wang&#58; Revis&#227;o cr&#237;tica da literatura&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; manejo dos casos estudados&#59; revis&#227;o cr&#237;tica do manuscrito&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Jiahui Zhao&#58; Revis&#227;o cr&#237;tica da literatura&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; manejo dos casos estudados&#59; revis&#227;o cr&#237;tica do manuscrito&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; concep&#231;&#227;o e planejamento do estudo&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflito de interesses</span><p id="par0160" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Fundamentos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Prurigo nodular &#40;PN&#41; &#233; dermatose inflamat&#243;ria cr&#244;nica que tem lacunas de op&#231;&#245;es de tratamento eficazes&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Avaliar a efic&#225;cia e a seguran&#231;a do dupilumabe em pacientes adultos com PN refrat&#225;rio &#224;s terapias tradicionais&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">M&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Este estudo cont&#237;nuo da pr&#225;tica cl&#237;nica avaliou o tratamento com dupilumabe em oito pacientes adultos diagnosticados com PN por pelo menos seis meses&#46; Os pacientes inclu&#237;dos receberam prescri&#231;&#227;o de 300<span class="elsevierStyleHsp" style=""></span>mg de dupilumabe quinzenalmente por pelo menos 16 semanas&#46; A efic&#225;cia foi o desfecho prim&#225;rio por meio de m&#250;ltiplas medidas de escala padronizadas&#59; a seguran&#231;a tamb&#233;m foi relatada&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Os pacientes com PN tratados com dupilumabe apresentaram melhoras cl&#237;nicas not&#225;veis&#46; Ap&#243;s 16 semanas de tratamento&#44; o escore m&#233;dio da Avalia&#231;&#227;o Global do Investigador &#40;<span class="elsevierStyleItalic">Investigator&#39;s Global Assessment</span> &#8208; IGA&#41; reduziu de 3&#44;75 para 1&#44;50&#46; Os escores m&#233;dios da Escala Num&#233;rica de Avalia&#231;&#227;o da Intensidade do Prurido &#40;<span class="elsevierStyleItalic">Numerical Rating Scale Itch Intensity</span> &#8208; NRSI&#41;&#44; do &#205;ndice Dermatol&#243;gico de Qualidade de Vida &#40;<span class="elsevierStyleItalic">Dermatology Life Quality Index</span> &#8208; DLQI&#41; e Escala Hospitalar de Depress&#227;o e Ansiedade &#40;<span class="elsevierStyleItalic">Hospital Anxiety and Depression Scale</span> &#8208; HADS&#41; diminu&#237;ram de 8&#44;625&#44; 15&#44;13 e 14&#44;50 para 1&#44;563&#44; 4&#44;625 e 1&#44;000&#44; respectivamente&#46; A maioria dos pacientes &#40;87&#44;5&#37;&#41; relatou dupilumabe como eficaz&#44; enquanto nenhum evento adverso foi relatado&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Limita&#231;&#245;es do estudo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Este estudo foi limitado a pequena coorte de pacientes adultos com PN e curto per&#237;odo de observa&#231;&#227;o&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclus&#245;es</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">O dupilumabe &#233; eficaz e toler&#225;vel em pacientes adultos com PN&#44; com melhora significativa das les&#245;es cut&#226;neas&#44; do prurido e da qualidade de vida&#46;</p></span>"
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          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Imunofluoresc&#234;ncia para IL&#8208;17RA &#40;verde&#41; em bi&#243;psias de pele lesional de dois pacientes antes do in&#237;cio do dupilumabe&#46; &#40;A&#41; Imunofluoresc&#234;ncia para IL&#8208;17RA no Paciente 1 com PN mostrando hiperqueratiniza&#231;&#227;o&#44; acantose irregular e hipergranulose&#46; Os queratin&#243;citos positivos para IL&#8208;17RA podem ser observados em partes das camadas granulosa e espinhosa da epiderme&#46; &#40;B&#41; Imunofluoresc&#234;ncia para IL&#8208;17RA no Paciente 2 com PN mostrando hiperqueratiniza&#231;&#227;o&#44; acantose irregular e hipergranulose&#46; Os queratin&#243;citos positivos para IL&#8208;17RA podem ser observados em grandes &#225;reas das camadas granulosa e espinhosa da epiderme&#46; &#40;C&#41; Imunofluoresc&#234;ncia para IL&#8208;17RA em amostra de controle mostrando alguns queratin&#243;citos positivos para IL&#8208;17RA na camada basal da epiderme&#46; Barra<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#46; IL&#8208;17RA&#44; receptor de interleucina&#8208;17A&#59; PN&#44; prurigo nodular&#46;</p>"
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                  \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">Idade &#40;anos&#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">Sexo&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">Hist&#243;rico de dist&#250;rbios al&#233;rgicos&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">Hist&#243;rico familiar de doen&#231;as al&#233;rgicas&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">Hist&#243;rico de PN&#44; anos&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">Terapias anteriores&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">Resposta cl&#237;nica a terapias anteriores&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">Terapias atuais&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">Outras complica&#231;&#245;es concomitantes &#40;comorbidades&#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">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  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;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">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; pomada antibi&#243;tica t&#243;pica&#44; glicos&#237;deos tripter&#237;gios&#44; talidomida&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&#44; pomada antibi&#243;tica t&#243;pica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;A&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">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rinite al&#233;rgica&#44; urtic&#225;ria cr&#244;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Eczema&#44; rinite al&#233;rgica&#44; asma&#44; urtic&#225;ria cr&#244;nica&#44; prurigo nodular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; medicina tradicional Chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;A&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">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;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">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; pomadas antibi&#243;ticas t&#243;picas&#44; glicos&#237;deos de tripter&#237;gios&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;A&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">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asma&#44; rinite al&#233;rgica&#44; urtic&#225;ria cr&#244;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Eczema&#44; rinite al&#233;rgica&#44; asma&#44; urtic&#225;ria cr&#244;nica&#44; prurigo nodular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; medicina tradicional Chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatite B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;A&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">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;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">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diabetes&#44; hipertens&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&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">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;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">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; azatioprina&#44; talidomida&#44; glicirrizina&#44; gabapentina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipertens&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&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">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">Rinite al&#233;rgica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; pomadas antibi&#243;ticas t&#243;picas&#44; anti&#8208;histam&#237;nicos orais&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipertens&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&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">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asma&#44; rinite al&#233;rgica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">0&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diabetes&#44; hipertens&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&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"><span class="elsevierStyleBold">Valor&#44; n &#40;&#37;&#41;</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">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&#233;dia<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>desvio&#8208;padr&#227;o&#58; 64<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino&#58; 3 &#40;37&#44;5&#41;&#59; Feminino&#58; 5 &#40;62&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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 &#40;37&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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 &#40;37&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&#233;dia<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>desvio&#8208;padr&#227;o&#58; 5&#44;525<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">&#58; 0 &#40;0&#41;&#59; Ineficaz&#58; 8 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">Hepatite B&#58; 1 &#40;12&#44;5&#41;&#59; Diabetes&#58; 2 &#40;25&#44;0&#41;&#59; Hipertens&#227;o&#58; 4 &#40;50&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "pt" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Dados demogr&#225;ficos basais e caracter&#237;sticas da doen&#231;a de pacientes com PN &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">CAE&#44; contagem absoluta de eosin&#243;filos no soro&#59; CGB&#44; contagem de gl&#243;bulos brancos&#46;</p>"
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                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="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CGB dos pacientes &#40;c&#233;ls&#46;&#42;10<span class="elsevierStyleSup">9</span>&#47;L&#41;</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">CAE dos pacientes &#40;c&#233;ls&#46;&#42;10<span class="elsevierStyleSup">9</span>&#47;L&#41;</th></tr><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" style="border-bottom: 2px solid black">&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">Semana 0&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">Semana 16&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">Semana 0&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">Semana 16&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">Paciente 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;15&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">Paciente 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#44;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;46&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">Paciente 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;13&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">Paciente 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#44;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;14&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">Paciente 5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;89&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;14&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">Paciente 6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;31&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">Paciente 7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;16&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">Paciente 8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#44;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3211258.png"
              ]
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          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Contagem de gl&#243;bulos brancos e contagem absoluta de eosin&#243;filos no soro da semana 0 &#224; semana 16 nos oito pacientes tratados</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Tabela 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">kU&#47;L&#44; quilo unidade por litro&#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="" 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="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IgE total s&#233;rica dos pacientes &#40;kU&#47;L&#41;</th></tr><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" style="border-bottom: 2px solid black">&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">Semana 0&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">Semana 16&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">Paciente 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">196&#44;&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">180&#44;0&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">Paciente 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1093&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">711&#44;0&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">Paciente 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1438&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1592&#44;0&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">Paciente 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5000&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1175&#44;0&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">Paciente 5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;8&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">Paciente 6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&#44;0&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">Paciente 7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">515&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">268&#44;0&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">Paciente 8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">273&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3211257.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">IgE total s&#233;rica &#40;kU&#47;L&#41; desde a linha basal at&#233; a semana 16 nos oito pacientes tratados</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Refer&#234;ncias"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:30 [
            0 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prurigo nodularis&#58; Epidemiology and clinical features"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46;H&#46; Huang"
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Artigo original
Estudo observacional da prática clínica do tratamento com dupilumabe em pacientes adultos com prurigo nodular
Zhixin Zhang, Siyuan Li, Yang Wang, Jiahui Zhao
Corresponding author
zzjh_2007@163.com

Autor para correspondência.
Departamento de Dermatologia, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Disease, NMPA Key Laboratory for Quality Control and Evaluation of Cosmetics, Beijing, China
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n&#227;o h&#225; tratamentos aprovados pela <span class="elsevierStyleItalic">Food and Drug Administration</span> &#40;FDA&#41;&#44; criando ainda mais desafios frente ao diagn&#243;stico de PN&#44; resultando em grande necessidade n&#227;o atendida de pacientes cujos sintomas s&#227;o inadequadamente controlados com as terapias tradicionais&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Pesquisas recentes sugerem que citocinas T&#8208;<span class="elsevierStyleItalic">helper</span> 2 &#40;Th2&#41;&#44; como interleucina&#8208;4 &#40;IL&#8208;4&#41; e interleucina&#8208;13 &#40;IL&#8208;13&#41;&#44; podem participar da patog&#234;nese do PN&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> O presente estudo avalia a efic&#225;cia e a seguran&#231;a do dupilumabe&#44; um antagonista do receptor&#8208;&#945; da IL&#8208;4 &#40;IL&#8208;4R&#945;&#41;&#44; como tratamento <span class="elsevierStyleItalic">off&#8208;label</span> para pacientes adultos com PN refrat&#225;rio&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><p id="par0015" class="elsevierStylePara elsevierViewall">Este &#233; um estudo observacional que recruta pacientes adultos no Departamento de Dermatologia em um ambiente de pr&#225;tica cl&#237;nica hospitalar&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Pacientes e desenho do estudo</span><p id="par0020" class="elsevierStylePara elsevierViewall">O presente estudo incluiu consecutivamente pacientes que foram diagnosticados com PN por pelo menos seis meses e que n&#227;o responderam &#224;s terapias tradicionais&#46; Todos os pacientes inclu&#237;dos foram avaliados por dermatologista credenciado com classifica&#231;&#227;o na escala de Avalia&#231;&#227;o Global do Investigador &#40;IGA&#44; <span class="elsevierStyleItalic">Investigator Global Assessment</span>&#41; &#8805; 3 e classifica&#231;&#227;o NRSI &#8805; 7&#46; Pacientes que receberam imunossupressores sist&#234;micos ou fototerapia tr&#234;s meses antes da inscri&#231;&#227;o no estudo foram exclu&#237;dos&#46; Os pacientes inclu&#237;dos neste estudo receberam inje&#231;&#227;o subcut&#226;nea de dupilumabe seguindo o esquema posol&#243;gico padr&#227;o &#40;dose de indu&#231;&#227;o de 600<span class="elsevierStyleHsp" style=""></span>mg seguida de 300<span class="elsevierStyleHsp" style=""></span>mg a cada duas semanas&#41; por pelo menos 16 semanas&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Durante o per&#237;odo de tratamento com dupilumabe&#44; os pacientes foram autorizados a usar glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; pomadas antibi&#243;ticas t&#243;picas e medicamentos tradicionais chineses como tratamentos de resgate&#46; Informa&#231;&#245;es demogr&#225;ficas dos pacientes&#44; hist&#243;rico m&#233;dico e hist&#243;rico familiar de dist&#250;rbios al&#233;rgicos foram relatados na semana 0 &#40;linha basal&#41;&#46; Resposta cl&#237;nica&#44; resultados dos exames de sangue e eventos adversos &#40;EAs&#41; foram monitorados de perto durante o per&#237;odo de tratamento para auxiliar na avalia&#231;&#227;o da efic&#225;cia da terapia com dupilumabe&#46; Especificamente&#44; o exame de sangue foi solicitado na semana 0 e na semana 16 do tratamento com dupilumabe a fim de avaliar a contagem de gl&#243;bulos brancos &#40;CGB&#41;&#44; a contagem absoluta de eosin&#243;filos &#40;CAE&#41; s&#233;rica e os n&#237;veis s&#233;ricos totais de IgE &#40;IgET&#41;&#46; Al&#233;m disso&#44; os escores da IGA&#44; do &#205;ndice Dermatol&#243;gico de Qualidade de Vida &#40;<span class="elsevierStyleItalic">Dermatology Life Quality Index</span> &#8208; DLQI&#41;&#44; e da Escala Hospitalar de Depress&#227;o e Ansiedade &#40;<span class="elsevierStyleItalic">Hospital Anxiety and Depression Scale</span> &#8208; HADS&#41; foram relatados na semana 0 e na semana 16 do tratamento com dupilumabe&#46; O consentimento informado por escrito foi obtido de todos os pacientes antes da inclus&#227;o no estudo que foi realizado ap&#243;s aprova&#231;&#227;o do Comit&#234; de &#201;tica em Pesquisa Cl&#237;nica do hospital&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Coleta de amostras de pele de pacientes com PN</span><p id="par0030" class="elsevierStylePara elsevierViewall">Bi&#243;psias de pele foram coletadas de dois pacientes diagnosticados com PN apresentando n&#243;dulos pruriginosos nas extremidades inferiores&#44; e uma amostra de pele saud&#225;vel foi obtida no mesmo local&#46; Os experimentos em amostras humanas foram conduzidos ap&#243;s obten&#231;&#227;o do consentimento informado por escrito e aprova&#231;&#227;o do Comit&#234; de &#201;tica em Pesquisa Cl&#237;nica do hospital&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Imunofluoresc&#234;ncia</span><p id="par0035" class="elsevierStylePara elsevierViewall">O anticorpo prim&#225;rio utilizado para imunomarca&#231;&#227;o foi o anticorpo antirreceptor da IL&#8208;17A &#40;ab180904&#44; Abcam&#41; dilu&#237;do a 1&#58;50&#46; Essa etapa foi seguida por um anticorpo secund&#225;rio conjugado com FITC &#40;ZF&#8208;0311&#44; ZSGB&#8208;BIO&#41; dilu&#237;do a 1&#58;250&#46; As amostras foram examinadas por microscopia fluorescente &#40;Leica&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Estat&#237;sticas</span><p id="par0040" class="elsevierStylePara elsevierViewall">As an&#225;lises estat&#237;sticas foram realizadas com o programa GraphPad PRISM &#40;vers&#227;o 9&#46;2&#46;0&#41; com o teste <span class="elsevierStyleItalic">t</span> de Student como indicado &#40;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#44; &#42;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#44; &#42;&#42;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0005&#44; &#42;&#42;&#42;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#59; ns&#44; n&#227;o significante&#41;&#46; Os resultados num&#233;ricos foram apresentados como m&#233;dia<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>erro padr&#227;o da m&#233;dia &#40;E&#46;P&#46;M&#46;&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Resultados</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Pacientes</span><p id="par0045" class="elsevierStylePara elsevierViewall">Oito pacientes &#40;62&#44;5&#37; do sexo feminino&#41; diagnosticados com PN moderado a grave por pelo menos seis meses &#40;dura&#231;&#227;o m&#233;dia de 5&#44;525 anos &#91;desvio padr&#227;o&#58; 6&#44;6 anos&#93;&#41; foram inclu&#237;dos no estudo&#46; Todos os pacientes tinham sido tratados anteriormente com terapias tradicionais multimodais&#44; mas n&#227;o apresentaram resposta&#46; O tratamento com imunossupressores sist&#234;micos foi descontinuado em todos os pacientes inclu&#237;dos tr&#234;s meses antes da dose de indu&#231;&#227;o de dupilumabe&#46; Nenhum EA foi relatado durante o per&#237;odo do estudo&#44; e nenhum paciente desistiu em decorr&#234;ncia de EAs causados pelo tratamento com dupilumabe&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Os dados demogr&#225;ficos basais e as caracter&#237;sticas da doen&#231;a s&#227;o apresentados na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46; Poucos pacientes &#40;37&#44;5&#37;&#41; tinham hist&#243;rico familiar de dist&#250;rbios al&#233;rgicos&#47;at&#243;picos&#46; Tr&#234;s pacientes &#40;37&#44;5&#37;&#41; tinham hist&#243;rico pessoal de alergia&#47;atopia&#46; Mais da metade da popula&#231;&#227;o total &#40;62&#44;5&#37;&#41; tinha comorbidades &#40;hepatite B&#44; 12&#44;5&#37;&#59; diabetes&#44; 25&#44;0&#37;&#59; hipertens&#227;o&#44; 50&#44;0&#37;&#41;&#46; Em todos os pacientes &#40;100&#37;&#41;&#44; o in&#237;cio do PN ocorreu na idade adulta &#40;&#8805; 18 anos&#41;&#44; e todos eles &#40;100&#37;&#41; relataram respostas ineficazes &#224;s terapias anteriores antes do uso de dupilumabe &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Efic&#225;cia do tratamento com dupilumabe</span><p id="par0055" class="elsevierStylePara elsevierViewall">Na semana 0&#44; todos os pacientes inclu&#237;dos apresentavam n&#243;dulos eritematosos generalizados e placas distribu&#237;das simetricamente nas extremidades&#44; m&#227;os e tronco &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>A&#41;&#46; Ap&#243;s 16 semanas de administra&#231;&#227;o de dupilumabe&#44; as les&#245;es cut&#226;neas diminu&#237;ram na maioria dos casos &#40;87&#44;5&#37;&#41;&#44; indicado pela redu&#231;&#227;o do tamanho e n&#250;mero de n&#243;dulos &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>B&#41;&#46; Um paciente &#40;12&#44;5&#37;&#41; apresentou resposta deficiente&#44; com prurido e n&#250;mero de n&#243;dulos persistentes&#46; O n&#250;mero de n&#243;dulos em seu corpo n&#227;o foi significantemente reduzido&#44; enquanto apenas as erup&#231;&#245;es cut&#226;neas na face extensora dos membros inferiores diminu&#237;ram ligeiramente de tamanho&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Em geral&#44; na 16&#170; semana de tratamento com dupilumabe&#44; alguns pacientes &#40;25&#44;0&#37;&#41; tiveram resposta completa ao tratamento com diminui&#231;&#227;o de 3 graus na IGA&#59; metade da popula&#231;&#227;o &#40;50&#44;0&#37;&#41; relatou resposta parcial ao tratamento com diminui&#231;&#227;o de 2 graus na IGA&#59; um paciente &#40;12&#44;5&#37;&#41; relatou resposta deficiente ao tratamento com dupilumabe com diminui&#231;&#227;o de menos de 2 graus na IGA &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>A&#41;&#46; O tratamento com dupilumabe levou &#224; redu&#231;&#227;o significante nas classifica&#231;&#245;es m&#233;dias da escala IGA em toda a popula&#231;&#227;o de pacientes com PN da semana 0 &#224; semana 16 &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#59; <a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>B&#41;&#44; enquanto n&#227;o foram observadas diferen&#231;as estatisticamente significantes para os resultados laboratoriais de CGB &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;4137&#41; e CAE &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;2438&#59; <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#46; A m&#233;dia da IGA na semana 0 &#40;3&#44;75&#41; diminuiu para 1&#44;50 na semana 16 na popula&#231;&#227;o total&#44; enquanto cinco pacientes &#40;62&#44;5&#37;&#41; receberam valor de IGA igual a 1 ap&#243;s 16 semanas de tratamento com dupilumabe&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Depois de 16 semanas&#44; todos os pacientes relataram melhora subjetiva no prurido&#44; qualidade de vida e n&#237;veis de ansiedade&#46; Foi observada diminui&#231;&#227;o estatisticamente significante nas classifica&#231;&#245;es m&#233;dias semanais de NRSI &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#44; DLQI &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; e HADS &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41; na semana 16 do tratamento com dupilumabe &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>&#41;&#46; Os valores basais m&#233;dios &#40;semana 0&#41; dos escores m&#233;dios semanais de NRSI &#40;8&#44;625&#41;&#44; DLQI &#40;15&#44;13&#41; e HADS &#40;14&#44;50&#41; diminu&#237;ram para 1&#44;563&#44; 4&#44;625 e 1&#44;000&#44; respectivamente&#44; ap&#243;s 16 semanas de tratamento com dupilumabe&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">A maioria dos pacientes &#40;75&#44;0&#37;&#41; experimentou redu&#231;&#227;o no n&#237;vel de IgET durante as 16 semanas de tratamento com dupilumabe &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#41;&#46; Enquanto isso&#44; 4&#47;8 pacientes apresentaram n&#237;veis de IgET significantemente mais baixos &#40;&#37; de varia&#231;&#227;o m&#233;dia<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>52&#44;58&#37;&#41; da semana 0 &#224; semana 16&#44; enquanto os outros pacientes n&#227;o exibiram altera&#231;&#227;o significante&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Imunofluoresc&#234;ncia da biopsia de pele lesional de PN</span><p id="par0075" class="elsevierStylePara elsevierViewall">A imunofluoresc&#234;ncia das amostras de pele lesional de PN de dois pacientes mostrou grande n&#250;mero de queratin&#243;citos positivos para o receptor de IL&#8208;17A &#40;IL&#8208;17RA&#41; na camada granulosa e na camada espinhosa da epiderme&#44; enquanto o controle saud&#225;vel mostrou apenas poucos queratin&#243;citos positivos para IL&#8208;17RA na camada basal da epiderme &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discuss&#227;o</span><p id="par0080" class="elsevierStylePara elsevierViewall">PN &#233; doen&#231;a inflamat&#243;ria da pele caracterizada por prurido intenso&#44; presen&#231;a de m&#250;ltiplas p&#225;pulas hipercerat&#243;ticas&#44; les&#245;es nodulares&#44; hiperpigmenta&#231;&#227;o e ansiedade associada ao prurido&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5&#44;6</span></a> Por falta de tratamento aprovado pela FDA para PN&#44; as terapias usualmente prescritas geralmente incluem o uso t&#243;pico e sist&#234;mico de anti&#8208;histam&#237;nicos&#44; esteroides&#44; gabapentinoides&#44; imunossupressores&#44; antidepressivos e outros agentes neuromoduladores que frequentemente colocam os pacientes em risco de efeitos colaterais graves&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">7&#44;8</span></a> Portanto&#44; muitos pacientes t&#234;m necessidade duradoura e n&#227;o alcan&#231;ada de tratamento seguro e eficaz para PN&#46; Neste estudo observacional da pr&#225;tica cl&#237;nica&#44; s&#227;o apresentados dados sobre efic&#225;cia e seguran&#231;a do tratamento com dupilumabe em pacientes com PN&#46; Em pacientes adultos com PN refrat&#225;rio que n&#227;o responderam &#224;s terapias tradicionais&#44; 16 semanas de tratamento com dupilumabe resultaram em melhora estat&#237;stica e clinicamente significante nos sinais&#44; sintomas&#44; intensidade do prurido&#44; n&#237;veis de ansiedade&#44; n&#237;veis de depress&#227;o e qualidade de vida&#44; com nenhum caso de EAs&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Em termos de efic&#225;cia geral do dupilumabe para PN&#44; Calugareanu et al&#46; obtiveram como resultado que 50&#37; dos pacientes com PN tiveram resposta completa&#44; 41&#44;7&#37; dos pacientes tiveram resposta parcial e 1&#47;16 pacientes n&#227;o apresentaram resposta ap&#243;s seis meses de tratamento com dupilumabe&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> Relatamos resultados igualmente not&#225;veis&#44; com 37&#44;5&#37; dos pacientes com PN apresentando resposta completa&#44; 50&#37; com resposta parcial e apenas 1&#47;8 pacientes com resposta deficiente ao dupilumabe&#46; No presente estudo&#44; a melhora dos sintomas ap&#243;s o in&#237;cio do tratamento com dupilumabe foi r&#225;pida e significante&#46; Melhora nas les&#245;es e n&#243;dulos cut&#226;neos podem ser observadas em est&#225;gio inicial ap&#243;s quatro semanas de tratamento com dupilumabe&#46; Ap&#243;s 16 semanas&#44; o escore IGA m&#233;dio dos pacientes diminuiu de 3&#44;75 para 1&#44;50&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Do mesmo modo&#44; Chiricozzi et al&#46; relataram redu&#231;&#227;o no escore IGA de pelo menos 2 graus em 82&#44;6&#37; dos pacientes ap&#243;s 16 semanas de tratamento com dupilumabe&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> Essas observa&#231;&#245;es provaram a tend&#234;ncia do dupilumabe em provocar respostas r&#225;pidas e not&#225;veis de redu&#231;&#227;o dos sintomas em pacientes com PN&#46; Al&#233;m disso&#44; a melhora subjetiva relatada pelos pacientes na intensidade do prurido ap&#243;s a inje&#231;&#227;o de dupilumabe foi ainda mais r&#225;pida&#46; Na presente coorte&#44; alguns pacientes relataram resposta ao dupilumabe em termos de redu&#231;&#227;o do prurido j&#225; durante a segunda semana de tratamento&#46; Na 16&#170; semana do tratamento com dupilumabe&#44; uma redu&#231;&#227;o m&#233;dia de NRSI de 7&#44;063 foi obtida no presente estudo&#46; Com base em estudos anteriores&#44; Zhai et al&#46; observaram redu&#231;&#227;o m&#233;dia do escore NRSI de 7&#44;89 em duas semanas de tratamento com dupilumabe&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> Beck et al&#46; relataram melhora do prurido para quase zero em termos do escore NRSI para todos os tr&#234;s pacientes em 12 semanas de tratamento com dupilumabe&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> Esses resultados confirmam a efic&#225;cia do dupilumabe no al&#237;vio do prurido em pacientes com PN&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">N&#227;o apenas os sintomas cl&#237;nicos melhoraram significantemente ap&#243;s o tratamento com dupilumabe&#44; mas a sa&#250;de mental e a qualidade de vida dos pacientes tamb&#233;m apresentaram melhoras subjetivas&#46; A m&#233;dia do escore HADS dos pacientes diminuiu de 14&#44;50 na semana 0 para 1&#44;00 na semana 16&#44; mostrando melhora significante na sa&#250;de mental&#46; Al&#233;m disso&#44; a m&#233;dia do escore DLQI dos pacientes diminuiu de 15&#44;13 para 4&#44;625 ap&#243;s 16 semanas de tratamento com dupilumabe&#46; Giovannini et al&#46; relataram resultado semelhante de redu&#231;&#227;o do escore DLQI de 16 para 1 ap&#243;s 12 semanas de tratamento com dupilumabe em um paciente com PN&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> A redu&#231;&#227;o mais not&#225;vel e precoce no escore DLQI do caso relatado pode ser decorrente da idade do paciente&#44; que era adolescente&#44; enquanto a presente coorte era composta por pacientes adultos&#46; &#201; poss&#237;vel que o tratamento com dupilumabe seja mais eficaz em pacientes adolescentes com PN&#46; No entanto&#44; ainda n&#227;o existem evid&#234;ncias suficientes em raz&#227;o do pequeno n&#250;mero de estudos dispon&#237;veis publicamente&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">O tratamento com dupilumabe provou ser seguro na presente coorte de pacientes adultos com PN&#44; pois nenhum EA foi relatado no presente estudo&#46; Sua seguran&#231;a tamb&#233;m foi comprovada por in&#250;meros casos anteriores de uso de dupilumabe em pacientes com PN&#44; com nenhum EA detectado&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">10&#8211;16</span></a> Os resultados do presente estudo sugerem que o tratamento com dupilumabe &#233; op&#231;&#227;o de tratamento eficaz e toler&#225;vel para pacientes adultos com PN intrat&#225;vel&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Dupilumabe &#233; anticorpo monoclonal totalmente humano que atua como antagonista de IL&#8208;4R&#945; para bloquear os efeitos biol&#243;gicos ativos de IL&#8208;4 e IL&#8208;13 na realiza&#231;&#227;o de respostas imunes tipo 2&#44; incluindo alguns sintomas de PN&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4&#44;14&#44;15&#44;17</span></a> Entretanto&#44; a patog&#234;nese exata do PN permanece amb&#237;gua&#46; Alguns autores argumentam que o PN &#233; o resultado em longo prazo do ciclo cr&#244;nico de prurido&#8208;ato de co&#231;ar de pacientes com prurido cr&#244;nico&#44; enquanto outros acreditam que o PN &#233; uma doen&#231;a distinta que existe por conta pr&#243;pria&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">18&#44;19</span></a> Evid&#234;ncias sugerem que o PN pode constituir doen&#231;a multifatorial decorrente de origens neurol&#243;gica&#44; dermatol&#243;gica e sist&#234;mica&#44; com a possibilidade de causas desconhecidas em muitos casos&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Os mecanismos espec&#237;ficos do dupilumabe como tratamento eficaz para PN ainda n&#227;o est&#227;o estabelecidos&#46; Talvez a efic&#225;cia do dupilumabe no tratamento do PN possa ser explicada pela interrup&#231;&#227;o do ciclo prurido&#8208;ato de co&#231;ar por meio da inibi&#231;&#227;o da IL&#8208;4R&#945; neuronal&#44; que &#233; necess&#225;ria para a transdu&#231;&#227;o da sinaliza&#231;&#227;o do prurido cr&#244;nico e resulta na atenua&#231;&#227;o do prurido e da inflama&#231;&#227;o da pele&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> Al&#233;m disso&#44; os dados do presente estudo mostraram que 37&#44;5&#37; dos pacientes inclu&#237;dos tinham hist&#243;rico m&#233;dico de dist&#250;rbios al&#233;rgicos que mostraram diminui&#231;&#227;o significante da IgET s&#233;rica ap&#243;s o tratamento com dupilumabe&#46; Al&#233;m disso&#44; estudo conduzido por Fukushi et al&#46; observou a express&#227;o de IL&#8208;4 e IL&#8208;13 em biopsias cut&#226;neas de les&#245;es de PN&#44; indicando o papel patog&#234;nico das citocinas Th2 no PN&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> Esses achados sugerem que uma resposta al&#233;rgica Th2 excessiva pode atuar como fator contribuinte na patog&#234;nese do PN&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Recentemente&#44; Belzberg et al&#46; observaram um aumento na express&#227;o de genes associados a c&#233;lulas Th17 &#40;p&#46; ex&#46;&#44; S100&#44; LOR&#44; K6&#44; K17 etc&#46;&#41; em amostras de pele de les&#245;es de PN&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> Portanto&#44; foi realizada a imunofluoresc&#234;ncia para IL&#8208;17RA em dois pacientes com PN e um controle saud&#225;vel&#46; O resultado revelou maior n&#250;mero de queratin&#243;citos positivos para IL&#8208;17RA nas amostras de pele lesional de PN quando comparadas &#224; amostra do controle saud&#225;vel&#46; Com base nesse achado&#44; foi levantada a hip&#243;tese de que a regula&#231;&#227;o positiva observada em IL&#8208;17RA pode ser outro fator subjacente que contribui para o desenvolvimento de PN&#46; Tamb&#233;m &#233; poss&#237;vel que o PN esteja clinicamente correlacionado com a dermatite at&#243;pica &#40;DA&#41;&#44; pois as citocinas relacionadas &#224; Th17 foram consideradas contribuintes potenciais na patog&#234;nese da DA nos &#250;ltimos anos&#44; enquanto o dupilumabe tem n&#250;mero razo&#225;vel de casos relatados de sucesso no tratamento de pacientes com DA grave e intrat&#225;vel&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">24&#8211;30</span></a> Essas descobertas apresentam a possibilidade de que as terapias moduladoras de inflama&#231;&#227;o Th17&#47;IL&#8208;17 se tornem um alvo de tratamento ben&#233;fico para pacientes com PN no futuro&#46; Entretanto&#44; os pap&#233;is patog&#234;nicos espec&#237;ficos e as vias de sinaliza&#231;&#227;o de citocinas relacionadas a Th2&#44; citocinas relacionadas a Th17 e DA no PN precisam de investiga&#231;&#245;es adicionais&#44; com mais modelos de doen&#231;a&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Alguns casos cl&#237;nicos avaliaram a resposta ao dupilumabe em pacientes com PN anteriormente&#44; mas o presente estudo tem seus pr&#243;prios pontos fortes&#46; Primeiro&#44; foram utilizados escalas e question&#225;rios de medidas padronizados e abrangentes que cobrem todos os aspectos da avalia&#231;&#227;o dos sintomas da doen&#231;a&#44; sa&#250;de mental e qualidade de vida na coorte&#44; o que resultou em resultados detalhados e precisos&#46; Em segundo lugar&#44; o presente estudo foi estritamente desenvolvido na pr&#225;tica cl&#237;nica&#44; que por sua vez aumentaram a viabilidade e a generaliza&#231;&#227;o da aplica&#231;&#227;o do tratamento com dupilumabe em pacientes com PN na pr&#225;tica di&#225;ria&#46; Entretanto&#44; o presente estudo tamb&#233;m tem algumas limita&#231;&#245;es&#46; Primeiro&#44; o tamanho da amostra foi relativamente pequeno&#44; com apenas oito pacientes inclu&#237;dos&#46; Em segundo lugar&#44; a coorte foi limitada a pacientes adultos com PN &#8211; portanto&#44; os desfechos pedi&#225;tricos n&#227;o s&#227;o claros&#46; Em terceiro lugar&#44; este estudo foi limitado pelo curto per&#237;odo de tratamento de 16 semanas&#44; o que significa que faltam avalia&#231;&#245;es de efic&#225;cia e seguran&#231;a em longo prazo&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclus&#227;o</span><p id="par0125" class="elsevierStylePara elsevierViewall">O tratamento com dupilumabe provou ser eficaz na melhora de les&#245;es cut&#226;neas&#44; redu&#231;&#227;o do prurido e melhora da qualidade de vida dos pacientes&#46; Al&#233;m disso&#44; n&#227;o foram detectados EAs&#44; demonstrando que o tratamento com dupilumabe &#233; op&#231;&#227;o segura e toler&#225;vel para pacientes adultos com PN&#46; &#201; evidente que o IL&#8208;4R constitui alvo importante no tratamento do PN&#44; enquanto outras abordagens potenciais tendo como alvo as citocinas Th17 e seus receptores podem se tornar op&#231;&#245;es de tratamento futuras para pacientes com PN&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Status de aprova&#231;&#227;o do CEP</span><p id="par0130" class="elsevierStylePara elsevierViewall">Revisado e aprovado pelo Comit&#234; de &#201;tica em Pesquisa Cl&#237;nica do <span class="elsevierStyleItalic">Peking University First Hospital</span>&#44; ID&#58; 2021&#47;223&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Suporte financeiro</span><p id="par0135" class="elsevierStylePara elsevierViewall">O presente estudo recebeu apoio financeiro da National Natural Science Foundation of China &#40;concess&#227;o n&#176; 81903213 para J&#46; Zhao&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Contribui&#231;&#227;o dos autores</span><p id="par0140" class="elsevierStylePara elsevierViewall">Zhixin Zhang&#58; Revis&#227;o cr&#237;tica da literatura&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; an&#225;lise estat&#237;stica&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Siyuan Li&#58; Revis&#227;o cr&#237;tica da literatura&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Yang Wang&#58; Revis&#227;o cr&#237;tica da literatura&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; manejo dos casos estudados&#59; revis&#227;o cr&#237;tica do manuscrito&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Jiahui Zhao&#58; Revis&#227;o cr&#237;tica da literatura&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; manejo dos casos estudados&#59; revis&#227;o cr&#237;tica do manuscrito&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; concep&#231;&#227;o e planejamento do estudo&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflito de interesses</span><p id="par0160" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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              "titulo" => "Efic&#225;cia do tratamento com dupilumabe"
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              "titulo" => "Imunofluoresc&#234;ncia da biopsia de pele lesional de PN"
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          "titulo" => "Status de aprova&#231;&#227;o do CEP"
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          "titulo" => "Suporte financeiro"
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          "titulo" => "Contribui&#231;&#227;o dos autores"
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    "fechaRecibido" => "2022-08-25"
    "fechaAceptado" => "2022-09-30"
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            0 => "Dupilumabe"
            1 => "Prurigo"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Fundamentos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Prurigo nodular &#40;PN&#41; &#233; dermatose inflamat&#243;ria cr&#244;nica que tem lacunas de op&#231;&#245;es de tratamento eficazes&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Avaliar a efic&#225;cia e a seguran&#231;a do dupilumabe em pacientes adultos com PN refrat&#225;rio &#224;s terapias tradicionais&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">M&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Este estudo cont&#237;nuo da pr&#225;tica cl&#237;nica avaliou o tratamento com dupilumabe em oito pacientes adultos diagnosticados com PN por pelo menos seis meses&#46; Os pacientes inclu&#237;dos receberam prescri&#231;&#227;o de 300<span class="elsevierStyleHsp" style=""></span>mg de dupilumabe quinzenalmente por pelo menos 16 semanas&#46; A efic&#225;cia foi o desfecho prim&#225;rio por meio de m&#250;ltiplas medidas de escala padronizadas&#59; a seguran&#231;a tamb&#233;m foi relatada&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Os pacientes com PN tratados com dupilumabe apresentaram melhoras cl&#237;nicas not&#225;veis&#46; Ap&#243;s 16 semanas de tratamento&#44; o escore m&#233;dio da Avalia&#231;&#227;o Global do Investigador &#40;<span class="elsevierStyleItalic">Investigator&#39;s Global Assessment</span> &#8208; IGA&#41; reduziu de 3&#44;75 para 1&#44;50&#46; Os escores m&#233;dios da Escala Num&#233;rica de Avalia&#231;&#227;o da Intensidade do Prurido &#40;<span class="elsevierStyleItalic">Numerical Rating Scale Itch Intensity</span> &#8208; NRSI&#41;&#44; do &#205;ndice Dermatol&#243;gico de Qualidade de Vida &#40;<span class="elsevierStyleItalic">Dermatology Life Quality Index</span> &#8208; DLQI&#41; e Escala Hospitalar de Depress&#227;o e Ansiedade &#40;<span class="elsevierStyleItalic">Hospital Anxiety and Depression Scale</span> &#8208; HADS&#41; diminu&#237;ram de 8&#44;625&#44; 15&#44;13 e 14&#44;50 para 1&#44;563&#44; 4&#44;625 e 1&#44;000&#44; respectivamente&#46; A maioria dos pacientes &#40;87&#44;5&#37;&#41; relatou dupilumabe como eficaz&#44; enquanto nenhum evento adverso foi relatado&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Limita&#231;&#245;es do estudo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Este estudo foi limitado a pequena coorte de pacientes adultos com PN e curto per&#237;odo de observa&#231;&#227;o&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclus&#245;es</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">O dupilumabe &#233; eficaz e toler&#225;vel em pacientes adultos com PN&#44; com melhora significativa das les&#245;es cut&#226;neas&#44; do prurido e da qualidade de vida&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Como citar este artigo&#58; Zhang Z&#44; Li S&#44; Wang Y&#44; Zhao J&#46; A real&#8208;world observational study of dupilumab treatment in adult patients with prurigo nodularis&#46; An Bras Dermatol&#46; 2023&#59;98&#58;440&#8211;8&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Trabalho realizado no Departamento de Dermatologia e Venereologia&#44; Peking University First Hospital&#44; Beijing&#44; China&#46;</p>"
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          "pt" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Resposta cl&#237;nica do prurigo nodular ao tratamento com dupilumabe&#46; &#40;A&#41; M&#250;ltiplos n&#243;dulos cut&#226;neos marrom&#8208;avermelhados&#44; firmes e hipercerat&#243;ticos&#44; amplamente distribu&#237;dos na parte superior da regi&#227;o dorsal na semana 0 &#40;linha basal&#41; antes do tratamento com dupilumabe&#46; &#40;B&#41; Os n&#243;dulos de prurigo mostraram regress&#227;o significante acompanhada de hiperpigmenta&#231;&#227;o p&#243;s&#8208;inflamat&#243;ria e aus&#234;ncia de eros&#227;o ou escoria&#231;&#227;o na 16&#170; semana de tratamento com dupilumabe&#46;</p>"
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          "pt" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">An&#225;lise estat&#237;stica dos par&#226;metros cl&#237;nicos do prurigo nodular&#46; &#40;A&#41; Resposta geral do tratamento com dupilumabe em oito pacientes com prurigo nodular na semana 16 do tratamento&#46; &#40;B&#41; Avalia&#231;&#227;o Global do Investigador &#40;<span class="elsevierStyleItalic">Investigator Global Assessment</span> &#8208; IGA&#41; dos pacientes na semana 0 e na semana 16 do tratamento com dupilumabe&#46; A signific&#226;ncia estat&#237;stica foi avaliada por testes <span class="elsevierStyleItalic">t</span> pareados&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8 pacientes&#59; &#42;&#42;&#42;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#46;</p>"
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">An&#225;lise estat&#237;stica das classifica&#231;&#245;es de gravidade do prurigo nodular&#46; Resultados relatados pelos pacientes da m&#233;dia semanal da Escala Num&#233;rica de Avalia&#231;&#227;o da Intensidade do Prurido &#40;<span class="elsevierStyleItalic">Numerical Rating Scale Itch Intensity</span> &#8208; NRSI&#41;&#44; do &#205;ndice Dermatol&#243;gico de Qualidade de Vida &#40;<span class="elsevierStyleItalic">Dermatology Life Quality Index</span> &#8208; DLQI&#41; e da Escala Hospitalar de Depress&#227;o e Ansiedade &#40;<span class="elsevierStyleItalic">Hospital Anxiety and Depression Scale</span> &#8208; HADS&#41; na semana 0 e na semana 16 do tratamento com dupilumabe&#46; A signific&#226;ncia estat&#237;stica foi avaliada por testes <span class="elsevierStyleItalic">t</span> pareados&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8 pacientes&#59; &#42;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#44; &#42;&#42;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0005&#44; &#42;&#42;&#42;&#42;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#46;</p>"
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Imunofluoresc&#234;ncia para IL&#8208;17RA &#40;verde&#41; em bi&#243;psias de pele lesional de dois pacientes antes do in&#237;cio do dupilumabe&#46; &#40;A&#41; Imunofluoresc&#234;ncia para IL&#8208;17RA no Paciente 1 com PN mostrando hiperqueratiniza&#231;&#227;o&#44; acantose irregular e hipergranulose&#46; Os queratin&#243;citos positivos para IL&#8208;17RA podem ser observados em partes das camadas granulosa e espinhosa da epiderme&#46; &#40;B&#41; Imunofluoresc&#234;ncia para IL&#8208;17RA no Paciente 2 com PN mostrando hiperqueratiniza&#231;&#227;o&#44; acantose irregular e hipergranulose&#46; Os queratin&#243;citos positivos para IL&#8208;17RA podem ser observados em grandes &#225;reas das camadas granulosa e espinhosa da epiderme&#46; &#40;C&#41; Imunofluoresc&#234;ncia para IL&#8208;17RA em amostra de controle mostrando alguns queratin&#243;citos positivos para IL&#8208;17RA na camada basal da epiderme&#46; Barra<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#46; IL&#8208;17RA&#44; receptor de interleucina&#8208;17A&#59; PN&#44; prurigo nodular&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">N&#47;A&#44; N&#227;o aplic&#225;vel&#59; n&#44; n&#250;mero de indiv&#237;duos que preenchem os crit&#233;rios&#59; PN&#44; Prurigo nodular&#59; cqd&#44; a cada quinze dias&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sexo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Hist&#243;rico de dist&#250;rbios al&#233;rgicos&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Hist&#243;rico familiar de doen&#231;as al&#233;rgicas&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Hist&#243;rico de PN&#44; anos&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Terapias anteriores&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Resposta cl&#237;nica a terapias anteriores&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Terapias atuais&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Outras complica&#231;&#245;es concomitantes &#40;comorbidades&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">N&#47;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
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                  \t\t\t\t">N&#47;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
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; pomada antibi&#243;tica t&#243;pica&#44; glicos&#237;deos tripter&#237;gios&#44; talidomida&#44; medicina tradicional chinesa&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">Ineficaz&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&#44; pomada antibi&#243;tica t&#243;pica&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rinite al&#233;rgica&#44; urtic&#225;ria cr&#244;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Eczema&#44; rinite al&#233;rgica&#44; asma&#44; urtic&#225;ria cr&#244;nica&#44; prurigo nodular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; medicina tradicional Chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;A&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">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;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">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; pomadas antibi&#243;ticas t&#243;picas&#44; glicos&#237;deos de tripter&#237;gios&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;A&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">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asma&#44; rinite al&#233;rgica&#44; urtic&#225;ria cr&#244;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Eczema&#44; rinite al&#233;rgica&#44; asma&#44; urtic&#225;ria cr&#244;nica&#44; prurigo nodular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; medicina tradicional Chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatite B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;A&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">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;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">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diabetes&#44; hipertens&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&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">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">N&#47;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">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; azatioprina&#44; talidomida&#44; glicirrizina&#44; gabapentina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipertens&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&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">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">Rinite al&#233;rgica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; pomadas antibi&#243;ticas t&#243;picas&#44; anti&#8208;histam&#237;nicos orais&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipertens&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&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">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asma&#44; rinite al&#233;rgica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">0&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glicocorticoides t&#243;picos&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ineficaz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dupilumabe 300<span class="elsevierStyleHsp" style=""></span>mg cqd&#44; glicocorticoides t&#243;picos&#44; anti&#8208;histam&#237;nicos orais&#44; medicina tradicional chinesa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diabetes&#44; hipertens&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&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"><span class="elsevierStyleBold">Valor&#44; n &#40;&#37;&#41;</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">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&#233;dia<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>desvio&#8208;padr&#227;o&#58; 64<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masculino&#58; 3 &#40;37&#44;5&#41;&#59; Feminino&#58; 5 &#40;62&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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 &#40;37&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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 &#40;37&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&#233;dia<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>desvio&#8208;padr&#227;o&#58; 5&#44;525<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">&#58; 0 &#40;0&#41;&#59; Ineficaz&#58; 8 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#47;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">Hepatite B&#58; 1 &#40;12&#44;5&#41;&#59; Diabetes&#58; 2 &#40;25&#44;0&#41;&#59; Hipertens&#227;o&#58; 4 &#40;50&#44;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "pt" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Dados demogr&#225;ficos basais e caracter&#237;sticas da doen&#231;a de pacientes com PN &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">CAE&#44; contagem absoluta de eosin&#243;filos no soro&#59; CGB&#44; contagem de gl&#243;bulos brancos&#46;</p>"
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                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="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CGB dos pacientes &#40;c&#233;ls&#46;&#42;10<span class="elsevierStyleSup">9</span>&#47;L&#41;</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">CAE dos pacientes &#40;c&#233;ls&#46;&#42;10<span class="elsevierStyleSup">9</span>&#47;L&#41;</th></tr><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" style="border-bottom: 2px solid black">&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">Semana 0&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">Semana 16&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">Semana 0&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">Semana 16&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">Paciente 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;15&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">Paciente 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#44;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;46&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">Paciente 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;13&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">Paciente 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#44;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;14&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">Paciente 5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;89&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;14&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">Paciente 6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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;31&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">Paciente 7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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Article information
ISSN: 26662752
Original language: Portuguese
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