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por&#233;m mais tardiamente nos homens&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Ainda que tamb&#233;m acometa crian&#231;as e idosos&#44; o LEC exclusivo &#233; mais comum entre&#160;20&#160;e&#160;40&#160;anos&#44; com idade m&#233;dia de instala&#231;&#227;o aos&#160;43&#160;anos&#44; por&#233;m com varia&#231;&#227;o conforme o subtipo&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">As les&#245;es cut&#226;neas do LE constituem consider&#225;vel morbidade&#44; sobretudo devido &#224; natureza cr&#244;nica&#44; ao acometimento preferencial das partes expostas do corpo e car&#225;ter desfigurante de suas sequelas&#44; que resultam em significante preju&#237;zo da qualidade de vida dos pacientes&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Classifica&#231;&#227;o</span><p id="par0035" class="elsevierStylePara elsevierViewall">Os crit&#233;rios diagn&#243;sticos para classifica&#231;&#227;o do LES n&#227;o s&#227;o uniformes e universalmente aceitos&#59; s&#227;o precursores aqueles propostos em&#160;1971 pelo American College of Rheumatology &#40;ACR&#41;&#44; revistos em&#160;1997 &#40;ACR 1997&#41;&#59; posteriormente&#44; surgiram mais dois sistemas de classifica&#231;&#227;o &#8211; o da Systemic Lupus International Collaborating Clinics &#40;SLICC&#160;2012&#41; e o conjunto entre a European League Against Rheumatism e o ACR &#40;EULAR&#47;ACR&#160;2019&#41;&#44; que est&#227;o discriminados e podem ser comparados na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;8&#44;9</span></a> Cada um desses tr&#234;s sistemas contempla quatro achados dermatol&#243;gicos como crit&#233;rios diagn&#243;sticos do LES&#46; Estudo australiano atual&#44; que avaliou a performance dos diferentes crit&#233;rios de classifica&#231;&#227;o do LES&#44; concluiu que o ACR&#160;1997 detinha a maior especificidade&#44; por&#233;m o SLICC&#160;2012 era o que proporcionava a maior acur&#225;cia diagn&#243;stica global &#40;94&#44;4&#37;&#41;&#44; com desempenho similar entre os pacientes com doen&#231;a inicial&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">10</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Foi pioneira a classifica&#231;&#227;o proposta por Gilliam &#38; Sontheimer&#44; em&#160;1981&#44; que discrimina as les&#245;es cut&#226;neas do LE entre espec&#237;ficas e inespec&#237;ficas&#46; As espec&#237;ficas&#44; definidas pela presen&#231;a da dermatite de interface dermoepid&#233;rmica&#44; s&#227;o exclusivas do LE&#44; com ou sem doen&#231;a sist&#234;mica&#46; S&#227;o subdivididas em tr&#234;s categorias&#44; com base nas caracter&#237;sticas cl&#237;nicas&#58; LECA&#44; LECS e LECC&#46; As les&#245;es inespec&#237;ficas incluem as demais manifesta&#231;&#245;es cut&#226;neas associadas ao LES&#46; Em&#160;2004&#44; a classifica&#231;&#227;o de D&#252;sseldorf acrescentou outro subtipo&#44; o LEC intermitente &#40;LECI&#41;&#44; que corresponde ao LE t&#250;mido&#44; anteriormente considerado variante de LECC&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Algumas limita&#231;&#245;es das classifica&#231;&#245;es anteriormente citadas podem ser destacadas&#58; a&#41;&#160;nem sempre as les&#245;es de LEC podem ser classificadas como agudas&#44; subagudas ou cr&#244;nicas&#44; com base na histologia&#59; b&#41;&#160;a dermatite de interface&#44; utilizada como crit&#233;rio para definir as les&#245;es espec&#237;ficas do LEC&#44; na realidade&#44; carece de especificidade&#44; j&#225; que pode estar presente em outras condi&#231;&#245;es&#44; como dermatomiosite&#44; doen&#231;a do enxerto&#8208;<span class="elsevierStyleItalic">versus</span>&#8208;hospedeiro e rea&#231;&#245;es medicamentosas&#59; c&#41;&#160;alguns subtipos inclu&#237;dos como espec&#237;ficos&#44; como o LE t&#250;mido e a paniculite l&#250;pica&#44; nem sempre apresentam dermatite de interface&#59; d&#41;&#160;termos como agudo&#44; subagudo ou cr&#244;nico&#44; de natureza cronol&#243;gica&#44; s&#227;o utilizados para definir varia&#231;&#245;es morfol&#243;gicas&#44; al&#233;m de serem associados a graus de extens&#227;o mal definidos&#44; como localizado ou disseminado&#44; referindo&#8208;se &#224; topografia&#46; Por essas raz&#245;es&#44; em&#160;2010&#44; Lipsker prop&#244;s uma nova classifica&#231;&#227;o das les&#245;es cut&#226;neas do LE&#44; com base nas caracter&#237;sticas cl&#237;nicas e nos achados histol&#243;gicos&#46; As les&#245;es cut&#226;neas espec&#237;ficas&#44; sem a presen&#231;a obrigat&#243;ria da dermatite de interface&#44; s&#227;o subdivididas em dermoepid&#233;rmicas&#44; d&#233;rmicas e hipod&#233;rmicas&#46; As les&#245;es inespec&#237;ficas s&#227;o subdivididas em tromb&#243;ticas&#44; neutrof&#237;licas ou de natureza patogen&#233;tica incerta&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">11</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Na falta de classifica&#231;&#227;o universalmente aceita&#44; em&#160;2013 foi constitu&#237;da uma for&#231;a&#8208;tarefa&#44; composta de especialistas no tema para propor uniformidade de crit&#233;rios diagn&#243;sticos e classifica&#231;&#227;o do LEC&#44; por meio do m&#233;todo Delphi&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">12</span></a> Recentemente&#44; foi apresentada a valida&#231;&#227;o dos crit&#233;rios de classifica&#231;&#227;o do LED&#44; forma mais comum de LEC&#44; com base exclusivamente cl&#237;nica&#46; Foram inclu&#237;dos os seguintes par&#226;metros&#44; com pontua&#231;&#245;es distintas&#44; referentes &#224;s les&#245;es cut&#226;neas&#58; cicatriz atr&#243;fica &#40;3&#160;pontos&#41;&#44; localiza&#231;&#227;o na concha auricular &#40;2&#160;pontos&#41;&#44; prefer&#234;ncia por cabe&#231;a e pesco&#231;o &#40;2&#160;pontos&#41;&#44; discromia &#40;1&#160;ponto&#41;&#44; ceratose folicular e tamp&#245;es c&#243;rneos &#40;1&#160;ponto&#41;&#44; colora&#231;&#227;o eritematosa a viol&#225;cea &#40;1&#160;ponto&#41;&#46; Escore &#8805; 5&#160;garante sensibilidade de&#160;84&#37; e especificidade de&#160;76&#37; para classifica&#231;&#227;o como LED&#44; com maior especificidade quanto maior for a pontua&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Etiopatog&#234;nese</span><p id="par0055" class="elsevierStylePara elsevierViewall">LES e LEC s&#227;o doen&#231;as multifatoriais&#44; em que est&#225; envolvida uma complexa intera&#231;&#227;o entre carga gen&#233;tica e exposi&#231;&#245;es ambientais&#44; como radia&#231;&#227;o ultravioleta &#40;RUV&#41;&#44; f&#225;rmacos&#44; defensivos agr&#237;colas e tabaco&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">14&#44;15</span></a> Varia&#231;&#245;es epigen&#233;ticas&#44; como desregula&#231;&#227;o da express&#227;o g&#234;nica&#44; via metila&#231;&#227;o do DNA&#44; ou modifica&#231;&#245;es de histonas&#44; causadas por esses fatores externos&#44; podem ser o gatilho para a ativa&#231;&#227;o das imunidades inata e adaptativa&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;14</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Os estudos sobre os fatores gen&#233;ticos envolvidos no LEC ainda s&#227;o incipientes&#44; se comparados aos descritos no LES&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Apesar disso&#44; polimorfismos gen&#233;ticos&#44; muta&#231;&#245;es e alelos de risco j&#225; foram identificados em diferentes popula&#231;&#245;es de LEC&#44; a maioria deles associados &#224;s vias das imunidades inata e adaptativa&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;14&#44;17</span></a> Genes que atuam na apoptose&#44; migra&#231;&#227;o leucocit&#225;ria&#44; via do IFN tipo&#160;I&#44; cascata do complemento&#44; apresenta&#231;&#227;o de ant&#237;genos e produ&#231;&#227;o de anticorpos est&#227;o entre os mais frequentemente afetados&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">14&#44;17</span></a> Os genes que codificam a produ&#231;&#227;o de citocinas pr&#243;&#8208;inflamat&#243;rias s&#227;o os mais associados &#224;s vias da imunidade inata nas les&#245;es de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> Como exemplos de associa&#231;&#245;es descritas entre genes e manifesta&#231;&#245;es cut&#226;neas&#44; podem ser citados o <span class="elsevierStyleItalic">FCGR2A</span> &#40;risco para LECA&#41;&#44; <span class="elsevierStyleItalic">TYK2</span>&#44; <span class="elsevierStyleItalic">IRF5</span>&#44; <span class="elsevierStyleItalic">TNF</span>&#8208;&#945; &#40;risco para LECS&#41; e <span class="elsevierStyleItalic">ITGAM</span> &#40;risco para LED&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">15&#44;17</span></a> Variantes de HLA tamb&#233;m j&#225; foram correlacionadas &#224; progress&#227;o da doen&#231;a cut&#226;nea&#44; dentre as quais se destacam o HLA&#8208;B8&#44; HLA&#8208;DR e HLA&#8208;DQ&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> At&#233; o presente momento&#44; apenas uma variante monogen&#233;tica de LEC foi identificada&#44; uma forma rara de LE perni&#243;tico familiar associada a muta&#231;&#245;es no gene <span class="elsevierStyleItalic">TREX1</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;14&#44;17&#44;18</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Dentre os fatores ambientais&#44; a RUV &#233; o mais bem estabelecido desencadeador do LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> A irradia&#231;&#227;o da pele altera a morfologia e a fun&#231;&#227;o dos ceratin&#243;citos&#44; induzindo diretamente a produ&#231;&#227;o de citocinas pr&#243;&#8208;inflamat&#243;rias &#40;IL&#8208;1&#945;&#44; IL&#8208;1&#946;&#44; IL&#8208;6&#44; TNF&#8208;&#945; e IFN&#8208;&#945;&#44; k e ¿&#41; e apoptose&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;14&#44;17</span></a> O aumento de citocinas inflamat&#243;rias e a exposi&#231;&#227;o a res&#237;duos celulares&#44; liberados pela morte celular&#44; desencadeiam o recrutamento de linf&#243;citos e c&#233;lulas dendr&#237;ticas plasmocitoides &#40;CDP&#41;&#44; que acionar&#227;o a ativa&#231;&#227;o do sistema imune&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;18</span></a> As CDP s&#227;o raras na pele normal e abundantes nas les&#245;es de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">18</span></a> Res&#237;duos celulares&#44; especialmente nucleares&#44; s&#227;o capturados pelas CDP&#44; que tamb&#233;m podem servir como reservat&#243;rio de autoant&#237;genos frente a linf&#243;citos&#160;B&#160;e&#160;T autorreativos&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">14</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">J&#225; foi demonstrado que a apoptose dos ceratin&#243;citos&#44; como a mediada pela via do Fas&#47;FasL&#44; apresenta forte correla&#231;&#227;o com a atividade da doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> O papel dos ceratin&#243;citos no surgimento e desenvolvimento das les&#245;es de LEC tamb&#233;m envolve retroalimenta&#231;&#227;o positiva na produ&#231;&#227;o de IFN&#44; especialmente dos tipos&#160;I&#160;e&#160;III&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> O IFN produzido &#233; capaz de ativar tanto o sistema imune inato quanto adaptativo&#44; exercendo papel central na patog&#234;nese do LE&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">14&#44;19</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">A ativa&#231;&#227;o do sistema imune inato promove a inflama&#231;&#227;o tecidual&#44; especialmente mediada pelas CDP e neutr&#243;filos &#40;incluindo as redes extracelulares de neutr&#243;filos &#8211; NET&#59; do ingl&#234;s&#44; <span class="elsevierStyleItalic">neutrophil extracellular traps</span>&#41;&#44; e o aumento da express&#227;o de autoant&#237;genos&#44; inclusive o Ro&#47;SS&#8208;A &#40;prote&#237;na induz&#237;vel pelo IFN&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">18&#44;19</span></a> Esse aumento estimula o sistema imune adaptativo&#44; como os linf&#243;citos&#160;T&#160;citot&#243;xicos e os plasm&#243;citos&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> O aumento do IFN tamb&#233;m perpetua a express&#227;o de citocinas e quimiocinas&#44; intimamente relacionadas &#224; produ&#231;&#227;o de anticorpos&#44; os quais se depositam preferencialmente na jun&#231;&#227;o dermoepid&#233;rmica e resultam em agress&#227;o citot&#243;xica mediada principalmente por linf&#243;citos T CD8&#43;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">4</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">A eleva&#231;&#227;o dos n&#237;veis de IFN&#44; especialmente do tipo&#160;I&#44; tamb&#233;m leva diretamente &#224; infiltra&#231;&#227;o de linf&#243;citos Th1&#44; acelerando a inflama&#231;&#227;o tecidual e a produ&#231;&#227;o de IFN&#8208; &#947; e IL&#8208;2&#44; dentre outras citocinas&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">4</span></a> O aumento dessas citocinas estimula as vias de sinaliza&#231;&#227;o intracelulares&#44; como a via JAK&#47;STAT&#44; e altera a transcri&#231;&#227;o g&#234;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">14</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Por fim&#44; a eleva&#231;&#227;o dos n&#237;veis de citocinas&#44; o aumento da exposi&#231;&#227;o de ant&#237;genos e a atividade das c&#233;lulas Th1 estimulam a produ&#231;&#227;o de anticorpos autorreativos&#44; que se depositam principalmente na zona da membrana basal e estimulam a agress&#227;o por c&#233;lulas&#160;T CD8&#43; e c&#233;lulas <span class="elsevierStyleItalic">natural killer</span> &#40;NK&#41;<span class="elsevierStyleItalic">&#44;</span> por meio de enzimas&#44; como a granzima&#160;B&#44; que induzem apoptose pela ativa&#231;&#227;o das caspases e d&#227;o continuidade ao ciclo inflamat&#243;rio&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;19</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">O papel dos autoanticorpos permanece incerto no LEC&#46; Pacientes com LECC apresentam ocorr&#234;ncia muito menor de autoanticorpos s&#233;ricos&#44; como os antinucleares&#44; anti&#8208;DNAn&#44; anti&#8208;Sm&#44; anti&#8208;Ro&#47;SS&#8208;A e anti&#8208;La&#47;SS&#8208;B&#44; se comparados aos pacientes com LES e LECS&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">19</span></a> Por outro lado&#44; as imunoglobulinas est&#227;o fortemente envolvidas na patog&#234;nese local das les&#245;es de LEC&#46; As IgM s&#227;o as primeiras a serem recrutadas para a pele&#44; atraindo&#44; em seguida&#44; o C3 e outras imunoglobulinas&#46; Diferentemente do LES&#44; em que a IgM isolada ou em combina&#231;&#227;o com C3 &#233; a forma mais frequente de forma&#231;&#227;o de imunocomplexos&#44; no LED&#44; a IgG &#233; a respons&#225;vel pela maioria dos dep&#243;sitos de imunocomplexos&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Apesar do aumento dos n&#237;veis s&#233;ricos de IL&#8208;17 e aumento da express&#227;o cut&#226;nea da IL&#8208;17A nos pacientes com LES&#44; poucos linf&#243;citos&#160;T&#160;produtores de IL&#8208;17 s&#227;o encontrados nas les&#245;es de LED&#44; sugerindo um papel menos importante nesta manifesta&#231;&#227;o cl&#237;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Foi descrita tamb&#233;m uma redu&#231;&#227;o na porcentagem de linf&#243;citos&#160;T&#160;reguladores na pele afetada pelo LEC&#46; Outro relato recente &#233; uma rela&#231;&#227;o inversamente proporcional entre a porcentagem de linf&#243;citos Th22 nas les&#245;es e escores de gravidade cl&#237;nica&#44; indicando que a IL&#8208;22 pode ser bom indicador da repara&#231;&#227;o cut&#226;nea&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">19</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Os f&#225;rmacos s&#227;o descritos como outro poss&#237;vel gatilho para o LEC&#44; especialmente para o subtipo subagudo&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">17</span></a> F&#225;rmacos classicamente reconhecidos como indutores de LEC&#44; como anti&#8208;hipertensivos&#44; antif&#250;ngicos e inibidores da bomba de pr&#243;tons&#44; dentre outros mais de cem medicamentos&#44; t&#234;m dividido import&#226;ncia com novas terapias&#8208;alvo&#44; como imunobiol&#243;gicos&#44; imunoter&#225;picos e quimioter&#225;picos&#44; em decorr&#234;ncia da crescente ocorr&#234;ncia de casos relacionados a esses medicamentos&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;17</span></a> Acredita&#8208;se que os f&#225;rmacos causadores de LEC podem ativar diretamente o sistema imune inato ou&#44; indiretamente&#44; ao reduzir a remo&#231;&#227;o de autoant&#237;genos&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> O tabagismo &#233; outro importante fator de risco associado ao LEC&#44; por estimular citocinas pr&#243;&#8208;inflamat&#243;rias&#44; a ativa&#231;&#227;o neutrof&#237;lica&#44; aumentar o estresse celular&#44; a forma&#231;&#227;o de radicais livres e a apoptose&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;14&#44;18</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Os horm&#244;nios sexuais parecem ser pe&#231;a fundamental na patog&#234;nese do LES&#46; Por outro lado&#44; sua import&#226;ncia no LEC parece ser menor&#44; especialmente no LED&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Apesar disso&#44; a incid&#234;ncia de LEC ainda &#233; maior no sexo feminino&#46; Como esse aumento ocorre mesmo fora da per&#237;odo f&#233;rtil&#44; postula&#8208;se que possa haver outras explica&#231;&#245;es para a maior incid&#234;ncia nas mulheres&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> A aus&#234;ncia de piora significante do LEC durante a gesta&#231;&#227;o ou o uso de anticoncepcionais orais tamb&#233;m corroboram esse achado&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Uma poss&#237;vel hip&#243;tese alternativa &#224; influ&#234;ncia hormonal seria um efeito de dose ligado ao cromossomo&#160;X&#44; que poderia explicar&#44; por exemplo&#44; o aumento da incid&#234;ncia de LES em pacientes do sexo masculino portadores da s&#237;ndrome de Klinefelter &#40;gen&#243;tipo&#160;XXY&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Outra hip&#243;tese seria a reativa&#231;&#227;o do cromossomo&#160;X inativado por um processo de demetila&#231;&#227;o nos linf&#243;citos&#160;T CD4&#43;&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">O papel da microbiota cut&#226;nea na patog&#234;nese do LEC ainda &#233; pouco compreendido e tem atra&#237;do maior aten&#231;&#227;o por parte dos pesquisadores&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Aumento significante de <span class="elsevierStyleItalic">Staphylococcus</span> e <span class="elsevierStyleItalic">Corynebacterium</span>&#44; assim como redu&#231;&#227;o de <span class="elsevierStyleItalic">Cutibacterium</span>&#44; foram descritos nas les&#245;es cut&#226;neas de LES&#44; por&#233;m ainda sem evid&#234;ncias que suportem uma rela&#231;&#227;o direta&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">16&#44;17</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Apresenta&#231;&#227;o cl&#237;nica e diagn&#243;stico diferencial</span><p id="par0115" class="elsevierStylePara elsevierViewall">A <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a> relaciona os subtipos cl&#237;nicos de LEC e suas variantes&#44; assim como as manifesta&#231;&#245;es cut&#226;neas inespec&#237;ficas que podem estar associadas ao LE&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">L&#250;pus eritematoso cut&#226;neo agudo</span><p id="par0120" class="elsevierStylePara elsevierViewall">Representa&#160;15&#37; dos casos de LEC e sempre est&#225; associado ao LES&#44; geralmente correlacionando com a atividade da doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a> Presente no momento do diagn&#243;stico em cerca de&#160;50&#37; dos casos de LES&#44; pode ser desencadeado ou exacerbado pela exposi&#231;&#227;o solar aguda&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">2</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">A forma localizada &#233; a predominante &#40;90&#37;&#8208;95&#37;&#41; e corresponde &#224; t&#237;pica erup&#231;&#227;o em vespert&#237;lio ou em asa de borboleta&#44; que se manifesta como les&#227;o eritematosa e finamente escamosa&#44; acometendo de maneira sim&#233;trica as regi&#245;es malares e o dorso nasal&#44; geralmente poupando os sulcos nasolabiais &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>A&#41;&#46; Edema facial tamb&#233;m pode estar presente&#46; O eritema costuma ser ef&#234;mero&#44; resolvendo&#8208;se em alguns dias ou semanas&#46; Eventualmente&#44; afeta a fronte&#44; o mento&#44; os pavilh&#245;es auriculares e a regi&#227;o cervical anterior&#46; Seus principais diagn&#243;sticos diferenciais s&#227;o dermatomiosite e ros&#225;cea&#44; mas ainda devem ser consideradas dermatite seborreica&#44; dermatite perioral e dermatite de contato fotoal&#233;rgica&#46; O acometimento das dobras nasolabiais e das p&#225;lpebras&#44; assim como fraqueza muscular proximal&#44; favorecem a dermatomiosite&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">A forma disseminada&#44; menos comum &#40;5&#37;&#8208;10&#37;&#41;&#44; manifesta&#8208;se como erup&#231;&#227;o exantem&#225;tica urticariforme ou maculopapular predominante nas &#225;reas fotoexpostas &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>B&#41;&#46; Al&#233;m de face e pesco&#231;o&#44; afeta simetricamente o V do decote e a superf&#237;cie extensora dos membros&#44; sobretudo os superiores&#44; mas pode estender&#8208;se ao tronco e at&#233; mesmo palmas e plantas&#46; Quando atinge o dorso de m&#227;os e dedos&#44; tende a poupar as articula&#231;&#245;es&#44; ao contr&#225;rio da dermatomiosite&#46; Deve ser diferenciada de rea&#231;&#245;es de hipersensibilidade a f&#225;rmacos&#44; exantemas virais e dermatites fotot&#243;xicas ou fotoal&#233;rgicas medicamentosas&#44; al&#233;m da dermatomiosite&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">O acometimento mucoso &#233; frequente em ambas as formas&#46; A mucosa oral &#233; a mais afetada&#44; em&#160;8&#37;&#8208;45&#37; dos casos&#44; atingindo principalmente as mucosas jugal&#44; palatina e labial&#44; na forma de placas enantematosas ou purp&#250;ricas&#44; vesicobolhas&#44; eros&#245;es e &#250;lceras&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">20</span></a> Ulcera&#231;&#227;o nasal &#233; menos comum e outras mucosas s&#227;o raramente afetadas&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Uma apresenta&#231;&#227;o rara de LECA&#44; que se assemelha &#224; necr&#243;lise epid&#233;rmica t&#243;xica &#40;NET&#41;&#44; por isso conhecida como variante NET&#8208;s&#237;mile&#44; deve&#8208;se &#224; intensa dermatite de interface com necrose dos ceratin&#243;citos&#44; que resulta em descolamento epitelial de extensas &#225;reas da pele&#46; Pode haver comprometimento mucoso&#44; que costuma ser mais limitado e poupar a conjuntiva ocular&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">21</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Ap&#243;s resolu&#231;&#227;o&#44; as les&#245;es de LECA podem deixar hipercromia residual&#44; mas n&#227;o costumam resultar em cicatrizes&#44; exceto na forma NET&#8208;s&#237;mile&#44; ou quando complicadas por infec&#231;&#227;o secund&#225;ria&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">L&#250;pus eritematoso cut&#226;neo subagudo</span><p id="par0150" class="elsevierStylePara elsevierViewall">Responde por cerca de&#160;8&#37; de todos os casos de LEC&#44; tem dura&#231;&#227;o mais prolongada que o LECA e apresenta extrema fotossensibilidade&#46; Distribui&#8208;se de maneira sim&#233;trica&#44; preferencialmente nas &#225;reas expostas do pesco&#231;o&#44; tronco superior e membros superiores&#44; por&#233;m costuma poupar a regi&#227;o central da face&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a> Manifesta&#8208;se sob duas formas&#44; ambas com placas eritematosas&#44; uma anular polic&#237;clica e outra papuloescamosa psoriasiforme &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>A&#41;&#44; que eventualmente podem coexistir no mesmo paciente&#46; Atrofia e ceratose n&#227;o s&#227;o clinicamente evidentes nas les&#245;es do LECS&#46; Tamb&#233;m tendem a ser menos edematosas que as les&#245;es do LECA e menos infiltradas e discr&#244;micas que aquelas do LED&#46; Em ambas as formas&#44; surgem ocasionalmente les&#245;es vesicobolhosas e crostas na periferia das placas&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Habitualmente&#44; resolvem sem deixar cicatrizes&#44; mas pode haver hipocromia residual&#44; geralmente tempor&#225;ria&#44; por&#233;m permanente em formas mais graves&#46; Eventualmente&#44; pode haver concomit&#226;ncia de les&#245;es de LECA ou LED com les&#245;es de LECS&#44; mas nem sempre &#233; poss&#237;vel uma distin&#231;&#227;o exata dessas les&#245;es&#46; &#201; raro o acometimento da mucosa oral&#44; com placas enantematosas circulares levemente atr&#243;ficas&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">22</span></a> Deve ser diferenciado de granuloma anular&#44; eritema anular centr&#237;fugo&#44; <span class="elsevierStyleItalic">erithema gyratum repens</span>&#44; psor&#237;ase&#44; tinha do corpo&#44; entre outros&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Cerca de 1&#47;3 dos casos de LECS &#233; desencadeado por f&#225;rmacos&#46; Em geral&#44; o LECS medicamentoso &#233; indistingu&#237;vel do LECS idiop&#225;tico&#44; por&#233;m algumas particularidades devem levar &#224; suspei&#231;&#227;o da etiologia medicamentosa &#8211; idade mais avan&#231;ada&#44; quadros mais disseminados e presen&#231;a de les&#245;es bolhosas ou do tipo alvo&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">23</span></a> O quadro costuma ser revers&#237;vel&#44; resolvendo em alguns meses ap&#243;s a suspens&#227;o da medica&#231;&#227;o respons&#225;vel&#46; Os f&#225;rmacos mais frequentemente incriminados s&#227;o hidroclorotiazida&#44; inibidores do canal de c&#225;lcio&#44; inibidores da enzima conversora da angiotensina&#44; inibidores da bomba de pr&#243;tons&#44; terbinafina&#44; agentes anti&#8208;TNF e anticonvulsivantes&#44; por&#233;m a incid&#234;ncia tende a variar com o desenvolvimento de novos medicamentos e a mudan&#231;a na prescri&#231;&#227;o&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">23&#8211;25</span></a> Recente revis&#227;o da literatura&#44; com foco na d&#233;cada passada &#40;2010&#8208;2020&#41;&#44; revelou que os agentes anti&#8208;TNF&#44; os inibidores da bomba de pr&#243;tons e os antineopl&#225;sicos&#44; em particular os inibidores de <span class="elsevierStyleItalic">checkpoint</span> imune&#44; destacam&#8208;se como f&#225;rmacos emergentes desencadeantes de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">26</span></a> A lista de medicamentos respons&#225;veis &#233; extensa&#44; como pode ser observado na <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">O primeiro caso de LECS associado a doen&#231;a maligna foi descrito em&#160;1982&#44; como l&#250;pus eritematoso <span class="elsevierStyleItalic">gyratum repens</span> em paciente com c&#226;ncer de pulm&#227;o&#46; Desde ent&#227;o&#44; surgiram in&#250;meros relatos sugerindo uma rela&#231;&#227;o entre LECS e v&#225;rias neoplasias s&#243;lidas e n&#227;o s&#243;lidas&#44; com maior frequ&#234;ncia de carcinoma de pulm&#227;o e adenocarcinoma da mama&#46; Na maioria dos casos&#44; o paralelismo entre o desenvolvimento tumoral e a atividade da dermatose possibilitou caracterizar a associa&#231;&#227;o como s&#237;ndrome paraneopl&#225;sica&#46; Ainda que rara&#44; &#233; importante considerar essa possibilidade no LECS de in&#237;cio em idade avan&#231;ada&#44; em pacientes com maior risco de neoplasia e nos casos refrat&#225;rios ao tratamento convencional&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">27</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">A s&#237;ndrome de <span class="elsevierStyleItalic">Rowell</span> foi originalmente descrita em&#160;1963 como uma entidade distinta&#44; pela associa&#231;&#227;o de achados cl&#237;nicos de LE e eritema multiforme&#44; al&#233;m da presen&#231;a de algumas altera&#231;&#245;es imunol&#243;gicas&#44; como FAN salpicado&#44; anticorpo anti&#8208;SjT e fator reumatoide&#46; &#192; luz dos conhecimentos cl&#237;nicos e imunol&#243;gicos modernos&#44; essa s&#237;ndrome n&#227;o deve ser vista com identidade nosol&#243;gica&#44; mas como variante rara do LECS&#44; caracterizada por les&#245;es cut&#226;neas do tipo alvo e presen&#231;a de anticorpos anti&#8208;Ro&#47;SS&#8208;A&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">28</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">O LE neonatal tamb&#233;m &#233; considerado variante do LECS&#46; Resulta da passagem transplacent&#225;ria de autoanticorpos maternos contra ant&#237;genos Ro&#47;SS&#8208;A&#44; La&#47;SS&#8208;B e&#44; mais raramente&#44; U1&#8208;RNP&#46; Em grande parte dos casos&#44; a m&#227;e &#233; assintom&#225;tica&#44; mas pode ter s&#237;ndrome de Sj&#246;gren&#44; LECS&#44; LES ou outras doen&#231;as do tecido conjuntivo&#46; O risco &#233; pequeno na primeira gesta&#231;&#227;o ou na aus&#234;ncia da doen&#231;a em gesta&#231;&#245;es anteriores &#40;2&#37;&#41;&#44; mas aumenta substancialmente &#40;10&#160;vezes&#41; se tiver havido diagn&#243;stico em gesta&#231;&#227;o pr&#233;via&#46; As les&#245;es cut&#226;neas ocorrem em at&#233;&#160;40&#37; dos casos de LE neonatal e podem estar presentes ao nascimento&#44; mas geralmente surgem nos primeiros&#160;tr&#234;s&#160;meses de vida&#44; ap&#243;s a exposi&#231;&#227;o solar&#44; resolvendo espontaneamente em 6&#8208;12 meses&#46; S&#227;o eritematosas ou eritemato&#8208;escamosas&#44; circulares&#44; anulares ou polic&#237;clicas e afetam principalmente a face&#44; nas regi&#245;es frontal e periorbit&#225;ria &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>B&#41;&#44; podendo estender&#8208;se ao couro cabeludo&#44; mas raramente atingem tronco e membros&#46; Dermatite seborreica e tinha da face s&#227;o os principais diagn&#243;sticos diferenciais&#46; Outras manifesta&#231;&#245;es poss&#237;veis&#44; tamb&#233;m revers&#237;veis&#44; s&#227;o as citopenias &#40;trombocitopenia&#44; anemia hemol&#237;tica&#41;&#44; doen&#231;a hepatobiliar&#44; esplenomegalia e&#44; mais raras&#44; as altera&#231;&#245;es neurol&#243;gicas e pulmonares&#46; Mais graves e irrevers&#237;veis s&#227;o as altera&#231;&#245;es card&#237;acas&#44; principalmente os dist&#250;rbios de condu&#231;&#227;o&#44; inclusive bloqueio atrioventricular total&#44; miocardiopatia e valvulopatia&#44; que podem ocorrer em 25&#37; dos casos e ser detectadas antes do nascimento&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;29</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">L&#250;pus eritematoso cut&#226;neo cr&#244;nico</span><p id="par0175" class="elsevierStylePara elsevierViewall">O LECC responde por mais de&#160;70&#37; dos casos de LEC e compreende diversas variantes&#44; algumas mais comuns e outras mais raras&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">O LED &#233; a forma cl&#225;ssica e mais comum de LECC&#44; tamb&#233;m presente em&#160;20&#37;&#160;dos casos de LES&#46; Localiza&#8208;se predominantemente na cabe&#231;a e pesco&#231;o&#44; mas&#44; em cerca de&#160;30&#37;&#160;dos casos&#44; pode ser disseminado e acometer tronco e membros&#44; com prefer&#234;ncia pelas &#225;reas fotoexpostas&#44; como face&#44; pavilh&#245;es auriculares&#44; V do decote&#44; lateral do pesco&#231;o&#44; couro cabeludo e dorsal dos membros superiores&#46; As les&#245;es se iniciam como placas eritemato&#8208;infiltradas&#44; induradas &#224; palpa&#231;&#227;o&#44; evoluindo com ceratose&#44; principalmente folicular&#44; atrofia e discromia&#44; com hipocromia no centro e hipercromia na periferia&#46; Costumam ser dolorosas &#224; palpa&#231;&#227;o&#46; Podem deixar les&#245;es vitiligoides&#44; assim como resolver com cicatrizes&#44; muitas vezes mutilantes&#44; sobretudo quando acometem nariz&#44; pavilh&#245;es auriculares e p&#225;lpebras&#46; Les&#245;es em diferentes est&#225;gios costumam ser concomitantes&#46; Quando situadas nas &#225;reas pilosas&#44; como couro cabeludo&#44; barba&#44; c&#237;lios e superc&#237;lios&#44; tendem a destruir os fol&#237;culos&#44; resultando em alopecia cicatricial &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>A&#41;&#46; Les&#245;es palmoplantares s&#227;o raras&#44; costumam ser muito dolorosas e podem ulcerar&#8208;se&#46; Excepcionalmente&#44; observam&#8208;se les&#245;es ungueais e periungueais&#46; Al&#233;m da radia&#231;&#227;o solar&#44; as les&#245;es de LED podem ser provocadas por traumatismos&#44; configurando o fen&#244;meno de Koebner&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;3&#44;30</span></a> LED medicamentoso &#233; muito raro&#44; com relatos espor&#225;dicos associados a leflunomida&#44; 5&#8208;fluoruracil&#44; capecitabina&#44; palbociclibe&#44; pembrolizumabe e mais comumente aos agentes anti&#8208;TNF&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">31</span></a> As les&#245;es recentes de LED devem ser diferenciadas da erup&#231;&#227;o polimorfa &#224; luz&#44; sarcoidose&#44; pseudolinfomas&#44; granuloma facial e LE t&#250;mido&#46; As les&#245;es cr&#244;nicas merecem diferencia&#231;&#227;o com l&#250;pus vulgar&#44; ceratose act&#237;nica hipertr&#243;fica&#44; carcinoma espinocelular e ceratoacantoma&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0185" class="elsevierStylePara elsevierViewall">O LED mucoso &#233; relatado em&#160;3&#37;&#8208;25&#37; dos pacientes com LED e costuma ser assintom&#225;tico em 1&#47;4 dos casos&#46; Apresenta&#8208;se classicamente como placas de enantema&#44; com p&#225;pulas cerat&#243;sicas&#44; atrofia ou eros&#227;o central e ceratose radiada ou reticulada na periferia&#46; Pode ainda se manifestar como placas brancas estriadas ou homog&#234;neas&#44; eros&#245;es e ulcera&#231;&#245;es&#46; &#201; mais comum na mucosa oral&#44; principalmente jugal &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>B&#41;&#44; palatina e labial&#44; mas pode acometer a gengiva e a l&#237;ngua&#46; As mucosas nasal&#44; genital e anal tamb&#233;m podem ser afetadas por les&#245;es discoides&#46; &#201; caracter&#237;stica a les&#227;o da conjuntiva ocular&#44; mais comum na margem palpebral inferior&#44; que pode resultar em cicatriz&#44; perda dos c&#237;lios e ectr&#243;pio&#46; H&#225; risco de transforma&#231;&#227;o maligna em carcinoma escamocelular&#44; com maior frequ&#234;ncia nos l&#225;bios&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;22&#44;32</span></a> Seu principal diagn&#243;stico diferencial &#233; o l&#237;quen plano oral&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">O LE hipertr&#243;fico&#44; tamb&#233;m conhecido como LE verrucoso&#44; &#233; variante bastante rara do LECC que se manifesta com les&#245;es eritematosas&#44; papulosas ou nodulares&#44; de superf&#237;cie cerat&#243;sica e algo verrucosa&#44; localizadas principalmente nas regi&#245;es extensoras dos membros superiores &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>A&#41; e eventualmente na face e tronco superior&#46; Costuma haver coexist&#234;ncia de les&#245;es discoides t&#237;picas&#44; que facilitam o diagn&#243;stico&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">2</span></a> Deve ser diferenciado do l&#237;quen plano hipertr&#243;fico&#44; do ceratoacantoma e das verrugas vulgares&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">O LE l&#237;quen plano&#8208;s&#237;mile ou s&#237;ndrome de superposi&#231;&#227;o l&#250;pus eritematoso&#8208;l&#237;quen plano refere&#8208;se &#224; combina&#231;&#227;o de achados cl&#237;nicos&#44; histol&#243;gicos e imunopatol&#243;gicos de ambas as dermatoses&#46; Trata&#8208;se de condi&#231;&#227;o muito rara&#44; de evolu&#231;&#227;o cr&#244;nica e predominante em mulheres&#44; que apresenta placas dolorosas vermelho&#8208;azuladas&#44; escamosas&#44; com centro atr&#243;fico&#44; localizadas nas extremidades superiores e menos frequentemente nas pernas&#44; face e tronco&#59; o acometimento palmoplantar &#233; caracter&#237;stico&#46; Les&#245;es hipertr&#243;ficas tamb&#233;m podem ocorrer&#46; H&#225; ainda relatos de acometimento mucoso&#44; distrofia ungueal e alopecia cicatricial&#44; assim como de casos desencadeados por medicamentos&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;33&#44;34</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">O LE profundo ou paniculite l&#250;pica responde apenas por&#160;2&#37;&#8208;3&#37; dos casos de LECC&#44; &#233; mais frequente em adultos e mulheres e se manifesta com placas e n&#243;dulos subcut&#226;neos&#44; endurecidos&#44; aderidos &#224; pele sobrejacente&#44; geralmente dolorosos&#44; que se localizam principalmente na face&#44; ombros&#44; bra&#231;os&#44; coxas&#44; gl&#250;teos e mamas &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>B&#41;&#46; A pele da superf&#237;cie pode ou n&#227;o apresentar les&#245;es de LED&#46; Costumam causar intensa atrofia do subcut&#226;neo&#44; deixando &#225;reas deprimidas&#44; com desfigura&#231;&#227;o est&#233;tica&#44; sobretudo quando localizadas na face&#46; Eventualmente&#44; evoluem com calcifica&#231;&#227;o e ulcera&#231;&#227;o&#46; A doen&#231;a tem curso cr&#244;nico&#44; entrecortado por per&#237;odos de exacerba&#231;&#227;o e de remiss&#227;o&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;30</span></a> Deve ser diferenciado principalmente de outros tipos de paniculite&#44; do linfoma subcut&#226;neo de c&#233;lulas&#160;T&#160;paniculite&#8208;s&#237;mile e da sarcoidose subcut&#226;nea&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">O LE perni&#243;tico &#233; forma rara de LECC&#44; que se assemelha &#224; perniose e se manifesta por les&#245;es dolorosas&#44; papulosas&#44; nodulares ou edematosas&#44; de tonalidade eritemato&#8208;viol&#225;cea&#46; Podem evoluir com eros&#227;o ou ulcera&#231;&#227;o&#46; S&#227;o desencadeadas pela exposi&#231;&#227;o ao frio e usualmente acometem quirod&#225;tilos e dorso das m&#227;os&#46; Podod&#225;ctilos&#44; regi&#245;es plantares e calcanhares tamb&#233;m podem ser acometidos&#46; Nariz e pavilh&#245;es auriculares s&#227;o menos afetados&#46; Fen&#244;meno de Raynaud pode estar presente em alguns casos&#46; O quadro pode coexistir com les&#245;es de LED ou ocorrer no contexto de LES&#46; Estima&#8208;se que&#160;20&#37; dos pacientes com LE perni&#243;tico venham a desenvolver doen&#231;a sist&#234;mica&#46; Algumas altera&#231;&#245;es imunol&#243;gicas podem ser observadas&#44; como hipergamaglobulinemia&#44; fator reumatoide e FAN positivos&#44; assim como anticorpos antifosfol&#237;pides e antinucleares espec&#237;ficos&#44; principalmente anti&#8208;Ro&#47;SS&#8208;A&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">35</span></a> H&#225; uma forma familiar da doen&#231;a&#44; que se manifesta na inf&#226;ncia&#44; de heran&#231;a autoss&#244;mica dominante&#44; relacionada a muta&#231;&#245;es no gene TREX1 e menos frequentemente nos genes SAMHD1 ou TMEM173&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;36</span></a> O principal diagn&#243;stico diferencial &#233; a perniose idiop&#225;tica&#44; mas ainda devem ser considerados o l&#250;pus p&#233;rnio&#44; uma forma acral de sarcoidose&#44; assim como as vasculites e vasculopatias acrais&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">O LE comedoniano &#233; outra variante rara do LECC&#44; que se manifesta por comedos&#44; p&#225;pulas&#44; placas eritemato&#8208;infiltradas e cistos em &#225;reas seborreicas e fotoexpostas&#44; deixando cicatrizes acneiformes deprimidas&#46; Acomete preferencialmente mulheres jovens e de meia idade&#59; o tabagismo &#233; importante fator de risco&#44; como em outras formas de LECC&#46; Pode ser acompanhado de les&#245;es t&#237;picas de LED&#44; assim como associado ao LES&#46; Costuma ser confundido com acne vulgar&#44; nevo comedoniano e elastoidose nodular com cistos e comed&#245;es&#44; o que geralmente retarda o diagn&#243;stico e o tratamento&#44; resultando em cicatrizes inest&#233;ticas&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">37&#8211;39</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">L&#250;pus eritematoso cut&#226;neo intermitente</span><p id="par0215" class="elsevierStylePara elsevierViewall">Anteriormente categorizado entre as variantes de LECC&#44; o LE t&#250;mido foi reclassificado como LECI em raz&#227;o de seu curso cl&#237;nico&#44; em que se alternam per&#237;odos de remiss&#227;o e de recorr&#234;ncia&#46; &#201; variante rara do LEC&#44; que acomete mais as mulheres &#40;60&#37;&#160;dos casos&#41;&#44; mas a preponder&#226;ncia sobre os homens &#233; menos evidente que nas outras formas de LEC&#46; Uma caracter&#237;stica marcante do LE t&#250;mido &#233; a fotossensibilidade exacerbada&#44; talvez a mais intensa entre todas as formas de LEC&#46; Manifesta&#8208;se por placas &#250;nicas ou m&#250;ltiplas&#44; eritemato&#8208;edematosas&#44; de superf&#237;cie lisa&#44; que podem assumir configura&#231;&#227;o anular ou arciforme &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>A&#41;&#46; Localizam&#8208;se em &#225;reas fotoexpostas&#44; principalmente na face&#44; pesco&#231;o&#44; tronco superior e membros superiores&#46; &#201; usual a resolu&#231;&#227;o espont&#226;nea das les&#245;es em algumas semanas&#44; sem deixar discromia ou cicatriz&#44; mas sobrev&#234;m epis&#243;dios com novas les&#245;es&#46; &#201; mais comum a ocorr&#234;ncia na forma isolada&#44; mas pode estar associado a outras formas de LEC&#44; principalmente LED&#44; e raramente ao LES&#46; Altera&#231;&#245;es imunol&#243;gicas tamb&#233;m s&#227;o incomuns&#44; como FAN e anticorpos antinucleares espec&#237;ficos&#46; Deve ser diferenciado da erup&#231;&#227;o polimorfa &#224; luz&#44; LED inicial&#44; mucinose reticular eritematosa e pseudolinfomas cut&#226;neos&#44; como a infiltra&#231;&#227;o linfocit&#225;ria de Jessner&#44; considerada por muitos autores como o pr&#243;prio LE t&#250;mido&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;40&#44;41</span></a></p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">L&#250;pus eritematoso bolhoso</span><p id="par0220" class="elsevierStylePara elsevierViewall">O LE bolhoso &#233; dermatose bolhosa autoimune&#44; subepid&#233;rmica&#44; sempre associada ao LES&#44; mediada por autoanticorpos contra o col&#225;geno&#160;VII&#46; Manifesta&#8208;se por ves&#237;culas e bolhas tensas &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>B&#41; que surgem subitamente sobre pele s&#227; ou sobre placas eritematosas e infiltradas&#44; eventualmente assumindo configura&#231;&#227;o anular&#46; Preferem face&#44; tronco superior&#44; pesco&#231;o&#44; regi&#245;es supraclaviculares e flexuras axilares&#44; mas podem disseminar&#8208;se para outras &#225;reas n&#227;o expostas&#46; N&#227;o costumam ser acompanhadas de les&#245;es espec&#237;ficas de LEC&#44; a n&#227;o ser eritema malar&#44; que pode surgir posteriormente&#44; ao longo da evolu&#231;&#227;o da doen&#231;a&#46; As mucosas oral e genital podem ser acometidas&#59; s&#227;o t&#237;picas as les&#245;es labiais e periorais&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">42</span></a> &#201; mais comum em mulheres negras&#44; entre a segunda e quarta d&#233;cadas de vida&#46; O LE bolhoso se instala antes&#44; concomitantemente e&#44; menos frequentemente&#44; ap&#243;s o diagn&#243;stico do LES&#44; podendo ser marcador de intensa atividade sist&#234;mica&#44; com maior risco de nefrite l&#250;pica e manifesta&#231;&#245;es neuropsiqui&#225;tricas&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">43</span></a> As les&#245;es evoluem com eros&#227;o e crostas&#44; regredindo sem cicatrizes e m&#237;lios&#44; mas podem deixar discromia residual&#46; &#201; incomum a recorr&#234;ncia&#44; mesmo com a persist&#234;ncia de doen&#231;a sist&#234;mica ativa&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">44</span></a> Deve ser diferenciado da epiderm&#243;lise bolhosa adquirida&#44; dermatose bolhosa por IgA linear&#44; dermatite herpetiforme e penfigoide bolhoso&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Manifesta&#231;&#245;es cut&#226;neas inespec&#237;ficas do l&#250;pus eritematoso</span><p id="par0225" class="elsevierStylePara elsevierViewall">Exclu&#237;dos os subtipos cl&#237;nicos e respectivas variantes anteriormente expostos&#44; todas as demais manifesta&#231;&#245;es cut&#226;neas associadas ao LE devem ser consideradas inespec&#237;ficas&#46; Est&#227;o associadas ao LES e geralmente guardam rela&#231;&#227;o com a atividade da doen&#231;a&#46; No entanto&#44; n&#227;o s&#227;o exclusivas do LES&#44; podendo ocorrer em outras condi&#231;&#245;es&#44; geralmente de natureza autoimune ou autoinflamat&#243;ria&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">45&#8211;47</span></a> O LE bolhoso&#44; embora classificado como manifesta&#231;&#227;o inespec&#237;fica&#44; neutrof&#237;lica&#44; associada ao LE&#44; deveria ser considerado subtipo cl&#237;nico espec&#237;fico de LEC&#44; pelo fato de sempre estar associado ao LES&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">11</span></a> As manifesta&#231;&#245;es inespec&#237;ficas mais comuns est&#227;o listadas na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Diagn&#243;stico</span><p id="par0230" class="elsevierStylePara elsevierViewall">O diagn&#243;stico do LEC se fundamenta nos dados colhidos na anamnese e no exame f&#237;sico&#44; em combina&#231;&#227;o com os achados da histopatologia e&#44; eventualmente&#44; da imuno&#8208;histologia das les&#245;es cut&#226;neas&#44; para defini&#231;&#227;o do subtipo cl&#237;nico&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">O tipo e a abrang&#234;ncia da investiga&#231;&#227;o laboratorial devem ser adequados a cada paciente&#44; individualmente&#44; a depender do subtipo de LEC definido com base nos achados cl&#237;nicos e histopatol&#243;gicos&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Devem ser realizados exames bioqu&#237;micos de rotina que auxiliem na identifica&#231;&#227;o de poss&#237;vel doen&#231;a sist&#234;mica&#44; al&#233;m de exames espec&#237;ficos&#44; conforme o tratamento proposto&#44; antes de iniciar a medica&#231;&#227;o e para monitorar seus potenciais efeitos adversos&#46; Exames adicionais podem ser necess&#225;rios ap&#243;s a confirma&#231;&#227;o do diagn&#243;stico e defini&#231;&#227;o do subtipo de LEC&#44; que incluem testes sorol&#243;gicos para caracterizar o perfil de autoanticorpos e testes para avaliar a atividade sist&#234;mica da doen&#231;a&#44; assim como exames complementares para investigar acometimento de &#243;rg&#227;os espec&#237;ficos&#44; que podem auxiliar na determina&#231;&#227;o do progn&#243;stico&#46; Os principais exames laboratoriais recomendados no LEC est&#227;o listados na <a class="elsevierStyleCrossRef" href="#tbl0020">tabela 4</a>&#46; Nos casos de LES&#44; faz&#8208;se necess&#225;ria a interven&#231;&#227;o do reumatologista e eventualmente de outros especialistas&#44; que devem orientar a proped&#234;utica complementar individualizada para cada paciente&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">48</span></a></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0245" class="elsevierStylePara elsevierViewall">&#201; importante que a defini&#231;&#227;o de doen&#231;a sist&#234;mica n&#227;o fique estritamente condicionada aos crit&#233;rios diagn&#243;sticos inclu&#237;dos nos sistemas de classifica&#231;&#227;o&#44; como o SLICC&#160;2012 e o EULAR&#47;ACR&#160;2019&#44; que foram primordialmente desenvolvidos com objetivo de se obter uniformidade diagn&#243;stica na sele&#231;&#227;o de pacientes para ensaios cl&#237;nicos&#44; mas n&#227;o s&#227;o capazes de abranger todas as manifesta&#231;&#245;es que podem ocorrer no LES&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">30</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">O uso de escores de atividade da doen&#231;a&#44; originalmente criados para mensura&#231;&#227;o de desfechos em ensaios cl&#237;nicos&#44; &#233; recomend&#225;vel na pr&#225;tica cl&#237;nica&#44; por permitir an&#225;lise mais objetiva da evolu&#231;&#227;o da doen&#231;a no seguimento dos pacientes com LEC&#44; podendo servir de par&#226;metro na avalia&#231;&#227;o da resposta ao tratamento indicado&#46;</p><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Histopatologia</span><p id="par0255" class="elsevierStylePara elsevierViewall">As diferentes formas de LEC&#44; com exce&#231;&#227;o do LE profundo e do LE t&#250;mido&#44; compartilham os achados histopatol&#243;gicos&#44; tornando indispens&#225;vel uma estreita correla&#231;&#227;o cl&#237;nico&#8208;patol&#243;gica para defini&#231;&#227;o do subtipo&#46; A diferencia&#231;&#227;o histopatol&#243;gica depende da evolu&#231;&#227;o e do est&#225;gio das les&#245;es&#46; Assim&#44; do ponto de vista histol&#243;gico&#44; o LE poderia ser classificado em recente &#40;LECA&#44; LECS e LED inicial&#41;&#44; completamente desenvolvido &#40;LED&#41; e tardio &#40;LED atr&#243;fico&#8208;cicatricial&#41;&#46; As altera&#231;&#245;es tendem a ser mais sutis nas les&#245;es recentes e bastante evidentes nas les&#245;es totalmente desenvolvidas&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;49</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">Os principais achados s&#227;o o infiltrado inflamat&#243;rio linfoc&#237;tico perivascular e perianexial na derme superficial e profunda&#44; assim como a dermatite de interface&#44; caracterizada pela agress&#227;o de linf&#243;citos &#224; jun&#231;&#227;o dermoepid&#233;rmica&#46; Como consequ&#234;ncia&#44; outras altera&#231;&#245;es ocorrem&#44; como a degenera&#231;&#227;o vacuolar da camada basal e a necrose de ceratin&#243;citos nas camadas inferiores da epiderme&#44; seguidas por espessamento da membrana basal&#46; A epiderme torna&#8208;se atr&#243;fica e as cristas epiteliais&#44; achatadas&#46; A deposi&#231;&#227;o de mucina na derme &#233; um achado t&#237;pico do LE&#44; embora inespec&#237;fico&#44; variando em intensidade conforme o tipo de les&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">47</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">No LED&#44; prot&#243;tipo das les&#245;es completamente desenvolvidas&#44; al&#233;m das altera&#231;&#245;es j&#225; descritas&#44; bastante proeminentes&#44; s&#227;o muito evidentes os achados de hiperceratose&#44; tamp&#245;es c&#243;rneos foliculares e atrofia epid&#233;rmica&#46; O est&#225;gio tardio e cicatricial do LED mostra incontin&#234;ncia pigmentar&#44; ectasia vascular&#44; fibrose d&#233;rmica e perda dos anexos&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;47</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">No LECA&#44; as altera&#231;&#245;es costumam ser mais discretas&#44; podendo haver edema e hemorragia na derme superficial&#46; O infiltrado linfoc&#237;tico &#233; discreto&#44; apenas perivascular e superficial&#44; com presen&#231;a de neutr&#243;filos nas les&#245;es mais recentes&#46; A variante NET&#8208;s&#237;mile de LECA mostra intensa degenera&#231;&#227;o hidr&#243;pica da basal&#44; que resulta em disceratose&#44; clivagem subepid&#233;rmica e necrose completa da epiderme&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;47</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">No LECS&#44; a dermatite de interface costuma ser intensa&#44; havendo muitos corpos citoides&#46; O infiltrado linfoc&#237;tico &#233; superficial e predominantemente perivascular&#46; A atrofia da epiderme&#44; a hiperceratose&#44; os tamp&#245;es foliculares&#44; a deposi&#231;&#227;o de mucina e o espessamento da membrana basal s&#227;o menos proeminentes que no LED&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;47</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">O LE hipertr&#243;fico&#44; al&#233;m das altera&#231;&#245;es observadas no LED&#44; mostra acantose e acentuada hiperplasia pseudoepiteliomatosa&#44; al&#233;m de intensa hiperceratose&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">47&#44;49</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">O LE profundo apresenta&#8208;se como paniculite linfoc&#237;tica lobular&#44; com n&#243;dulos linfoides parasseptais e necrose hialina dos adip&#243;citos&#44; presen&#231;a de plasm&#243;citos&#44; al&#233;m de deposi&#231;&#227;o de mucina na derme reticular e ocasionalmente na hipoderme&#46; Fibrose e calcifica&#231;&#227;o podem ser observadas nos est&#225;gios finais das les&#245;es&#46; As altera&#231;&#245;es epid&#233;rmicas e d&#233;rmicas caracter&#237;sticas do LE podem estar presentes em metade dos casos&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">47&#44;49</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">O LE t&#250;mido caracteriza&#8208;se por intenso infiltrado linfoc&#237;tico perivascular na derme superficial e profunda&#44; al&#233;m de abundante deposi&#231;&#227;o de mucina&#44; sem a presen&#231;a das altera&#231;&#245;es epid&#233;rmicas e da dermatite de interface&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">47&#44;49</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">Nas les&#245;es de LE perni&#243;tico&#44; al&#233;m dos achados caracter&#237;sticos de LE&#44; em menor intensidade que no LED&#44; destacam&#8208;se a presen&#231;a de vasculite linfoc&#237;tica&#44; eventualmente com necrose fibrinoide e trombose&#44; edema da derme papilar e infiltrado linfoc&#237;tico peri&#233;crino&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">47&#44;49</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall">O LE bolhoso mostra infiltrado inflamat&#243;rio predominante de neutr&#243;filos&#44; que costuma estar alinhado &#224; jun&#231;&#227;o dermoepid&#233;rmica e formar microabscessos nas papilas d&#233;rmicas&#44; al&#233;m de clivagem subepid&#233;rmica e bolha com neutr&#243;filos no interior&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">47&#44;49</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Imuno&#8208;histologia</span><p id="par0305" class="elsevierStylePara elsevierViewall">O teste da imunofluoresc&#234;ncia direta &#40;IFD&#41;&#44; realizado em cortes de tecido obtido por bi&#243;psia da les&#227;o cut&#226;nea&#44; visa identificar imunodep&#243;sitos na jun&#231;&#227;o dermoepid&#233;rmica&#44; conhecido como teste da banda l&#250;pica &#40;TBL&#41;&#46; Geralmente&#44; faz&#8208;se a pesquisa de imunodep&#243;sitos de IgG&#44; IgM&#44; IgA e C3&#46; O TBL &#233; considerado positivo quando identificada a deposi&#231;&#227;o de material granular em faixa junto &#224; zona da membrana basal&#46; &#201; recurso que pode auxiliar no diagn&#243;stico&#44; se a histologia n&#227;o &#233; decisiva frente a les&#245;es sugestivas de LE&#44; por&#233;m n&#227;o &#233; espec&#237;fico para a doen&#231;a&#44; podendo ser observado em outras condi&#231;&#245;es dermatol&#243;gicas&#44; como dermatomiosite&#44; e mesmo na pele normal ou fotodanificada&#44; principalmente da face&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">48&#44;50</span></a> O tipo de dep&#243;sito varia conforme a cronologia e a topografia da les&#227;o&#44; assim como o local biopsiado&#44; se no centro ou periferia da les&#227;o&#46; IgM e IgG s&#227;o os imunodep&#243;sitos mais detectados&#44; em associa&#231;&#227;o ou n&#227;o com C3&#59; IgA &#233; menos comum&#46; O TBL costuma ser positivo na pele lesada de quase&#160;100&#37; dos casos de LECA&#44; em cerca de&#160;60&#37; dos casos de LECS e de&#160;90&#37; dos casos de LED&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">11&#44;19&#44;47</span></a></p><p id="par0310" class="elsevierStylePara elsevierViewall">Estudo recente que avaliou 2&#46;050 bi&#243;psias cut&#226;neas submetidas &#224; histologia e imunofluoresc&#234;ncia direta&#44; com hip&#243;teses diagn&#243;sticas de diferentes dermatoses&#44; concluiu que o valor da IFD no aux&#237;lio diagn&#243;stico do LE &#233; question&#225;vel e seu uso n&#227;o &#233; recomendado como rotina&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">50</span></a> Embora o TBL positivo na pele n&#227;o lesada e n&#227;o exposta seja altamente espec&#237;fico para LES&#44; ele acrescenta pouca informa&#231;&#227;o aos achados obtidos conjuntamente pelo exame cl&#237;nico&#44; histopatologia e sorologia&#46; Al&#233;m disso&#44; foi demonstrada sua associa&#231;&#227;o com a presen&#231;a de anticorpos anti&#8208;DNAn no soro&#44; por&#233;m com taxas de sensibilidade e especificidade similares&#44; sugerindo ser redundante a utiliza&#231;&#227;o de ambos os testes&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">50</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">No LE bolhoso&#44; a IFD da pele perilesional demonstra dep&#243;sito cont&#237;nuo&#44; de padr&#227;o linear ou granular&#44; ao longo da zona da membrana basal&#44; principalmente de IgG&#44; al&#233;m de IgM&#44; IgA e C3&#46; A imunofluoresc&#234;ncia indireta&#44; pela t&#233;cnica de <span class="elsevierStyleItalic">salt&#8208;split skin</span>&#44; revela dep&#243;sito do lado d&#233;rmico da clivagem&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">42&#44;47</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Anticorpos antinucleares</span><p id="par0320" class="elsevierStylePara elsevierViewall">Os autoanticorpos antinucleares s&#227;o marcadores imunol&#243;gicos empregados tanto no diagn&#243;stico quanto na monitora&#231;&#227;o da doen&#231;a no LE&#46; O teste de triagem mais usado &#233; o fator antin&#250;cleo &#40;FAN&#41;&#44; que utiliza a t&#233;cnica da imunofluoresc&#234;ncia indireta&#44; tendo as c&#233;lulas HEp&#8208;2 como substrato&#46; O FAN tem maior relev&#226;ncia no LECA&#47;LES&#44; em que &#233; demonstrado em quase todos os pacientes &#40;94&#37;&#8208;100&#37;&#41;&#44; geralmente em t&#237;tulos elevados&#44; superiores a&#160;1&#47;160&#46; No entanto&#44; mesmo em altos t&#237;tulos&#44; n&#227;o s&#227;o espec&#237;ficos para LES&#44; j&#225; que podem ser detectados em v&#225;rias condi&#231;&#245;es&#44; como outras doen&#231;as do tecido conjuntivo&#44; doen&#231;as hematol&#243;gicas e hep&#225;ticas&#44; infec&#231;&#245;es virais&#44; uso de v&#225;rios medicamentos e at&#233; em indiv&#237;duos saud&#225;veis&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">51</span></a> O FAN &#233; demonstrado em menor propor&#231;&#227;o nas outras formas de LEC&#44; em&#160;52&#37;&#8208;80&#37; dos pacientes de LECS e em&#160;5&#37;&#8208;17&#37; dos pacientes de LED&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0325" class="elsevierStylePara elsevierViewall">Por n&#227;o ser um teste espec&#237;fico para LE&#44; &#233; fundamental que&#44; frente a FAN positivo&#44; a especificidade do anticorpo antinuclear seja determinada por meio de testes adicionais&#46;</p><p id="par0330" class="elsevierStylePara elsevierViewall">Os anticorpos anti&#8208;DNAn e anti&#8208;Sm s&#227;o os mais relevantes por serem espec&#237;ficos para LES&#44; embora apresentem menor sensibilidade&#44; de&#160;56&#37;&#8208;70&#37; e 19&#37;&#8208;25&#37;&#44; respectivamente&#46; Al&#233;m do valor diagn&#243;stico&#44; o anticorpo anti&#8208;DNAn pode ser usado para monitora&#231;&#227;o da doen&#231;a&#44; j&#225; que seus n&#237;veis s&#233;ricos tendem a refletir a atividade da doen&#231;a&#44; em especial a nefropatia&#44; sobretudo quando h&#225; concomit&#226;ncia com o anticorpo anti&#8208;Sm&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;51</span></a> &#201; baixa a preval&#234;ncia dos anticorpos anti&#8208;DNAn e anti&#8208;Sm nos pacientes de LECS&#44; e praticamente nula nos pacientes de LECC&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;25</span></a></p><p id="par0335" class="elsevierStylePara elsevierViewall">Os anticorpos anti&#8208;Ro&#47;SS&#8208;A e anti&#8208;La&#47;SS&#8208;B n&#227;o s&#227;o espec&#237;ficos do LE e est&#227;o frequentemente associados &#224; s&#237;ndrome de Sj&#246;gren&#46; Ocorrem&#44; respectivamente&#44; em 36&#37;&#8208;64&#37; e 8&#37;&#8208;33&#37; dos pacientes de LES e guardam rela&#231;&#227;o com as manifesta&#231;&#245;es cut&#226;neas e hematol&#243;gicas&#44; como as citopenias&#46; Os anticorpos anti&#8208;Ro&#47;SS&#8208;A e anti&#8208;La&#47;SS&#8208;B est&#227;o presentes entre 70&#37;&#8208;90&#37; e&#160;30&#37;&#8208;40&#37;&#44; respectivamente&#44; dos casos de LECS&#44; e em at&#233;&#160;25&#37;&#160;e&#160;5&#37;&#44; respectivamente&#44; dos casos de LED&#46; Particularmente&#44; os anticorpos anti&#8208;Ro&#47;SS&#8208;A s&#227;o considerados marcadores do LECS e est&#227;o relacionados com a extrema fotossensibilidade deste subtipo de LEC&#46; Al&#233;m disso&#44; quando presentes na gestante&#44; esses anticorpos atravessam a barreira placent&#225;ria e podem causar LE neonatal&#46; Os anticorpos especificamente dirigidos contra a subunidase&#160;52&#160;kD do ant&#237;geno Ro&#47;SS&#8208;A est&#227;o associados a maior risco de bloqueio card&#237;aco cong&#234;nito&#46; Adultos com esses anticorpos tamb&#233;m podem apresentar prolongamento do intervalo QT&#44; com maior risco de desenvolver arritmias ventriculares&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">51</span></a></p><p id="par0340" class="elsevierStylePara elsevierViewall">Anticorpos anti&#8208;RNP s&#227;o caracter&#237;sticos da doen&#231;a mista do tecido conjuntivo&#44; mas podem estar presentes em&#160;23&#37;&#8208;49&#37; dos pacientes de LES e n&#227;o mostram correla&#231;&#227;o com quaisquer manifesta&#231;&#245;es da doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">51</span></a> Podem ocorrer entre&#160;8&#37;&#8208;10&#37; dos casos de LECS e muito raramente no LECC&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Avalia&#231;&#227;o da atividade e dano cut&#226;neos</span><p id="par0345" class="elsevierStylePara elsevierViewall">Pacientes diagnosticados com LEC devem ser submetidos a exame dermatol&#243;gico completo&#44; n&#227;o apenas durante epis&#243;dios de exacerba&#231;&#227;o da doen&#231;a&#44; mas tamb&#233;m a intervalos regulares&#44; com o objetivo de se avaliar a atividade e a progress&#227;o da doen&#231;a&#44; assim como identificar poss&#237;veis danos decorrentes do acometimento cut&#226;neo&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">V&#225;rios escores de atividade da doen&#231;a est&#227;o bem estabelecidos na avalia&#231;&#227;o de pacientes com LES&#44; para uso em ensaios cl&#237;nicos e na pr&#225;tica cotidiana&#44; como o SLEDAI &#40;<span class="elsevierStyleItalic">Systemic Lupus Erythematosus Disease Activity Index</span>&#41;&#46; Apesar de inclu&#237;rem alguns crit&#233;rios dermatol&#243;gicos&#44; esses escores carecem de sensibilidade para avaliar a atividade cut&#226;nea nos diferentes subtipos de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">12</span></a></p><p id="par0355" class="elsevierStylePara elsevierViewall">Por essa raz&#227;o&#44; foi criado o CLASI &#40;<span class="elsevierStyleItalic">Cutaneous Lupus Area and Severity Index</span>&#41;&#44; um instrumento desenvolvido especificamente para quantificar o acometimento cut&#226;neo no LE&#44; com escores de atividade &#40;CLASI&#8208;A&#41; e de dano &#40;CLASI&#8208;D&#41;&#46; Esse instrumento avalia a morfologia &#40;eritema&#44; descama&#231;&#227;o&#47;ceratose&#44; discromia e cicatriz&#47;atrofia&#41; e a localiza&#231;&#227;o anat&#244;mica &#40;13&#160;s&#237;tios&#41; das les&#245;es cut&#226;neas&#44; assim como o acometimento de mucosas e couro cabeludo&#46; Foi originalmente estabelecido como recurso para mensurar desfechos em ensaios cl&#237;nicos e validado por dermatologistas e reumatologistas&#46; O CLASI ainda demonstrou boa correla&#231;&#227;o com indicadores da qualidade de vida dos pacientes e revelou&#8208;se instrumento &#250;til e de f&#225;cil aplica&#231;&#227;o na pr&#225;tica cl&#237;nica&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">11&#44;12&#44;53</span></a></p><p id="par0360" class="elsevierStylePara elsevierViewall">Posteriormente&#44; surgiu o CLASI revisado &#40;RCLASI&#41;&#44; que acrescentou novos par&#226;metros &#8211; edema&#47;infiltra&#231;&#227;o e placas&#47;n&#243;dulos subcut&#226;neos &#8211; com o intuito de melhorar a acur&#225;cia na avalia&#231;&#227;o da atividade da doen&#231;a cut&#226;nea&#44; sendo capaz de abranger aspectos importantes de alguns subtipos de LEC&#44; como o LE t&#250;mido e o LE profundo&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">48</span></a></p><p id="par0365" class="elsevierStylePara elsevierViewall">Entretanto&#44; uma recente revis&#227;o sistem&#225;tica constatou que&#44; dentre os ensaios que utilizaram o CLASI como medida de desfecho de interven&#231;&#245;es terap&#234;uticas&#44; s&#227;o poucos com alta qualidade de evid&#234;ncia&#46; Esse estudo concluiu que &#233; necess&#225;ria valida&#231;&#227;o adicional para averiguar a efetividade do CLASI na avalia&#231;&#227;o dos diferentes subtipos de LEC&#46; Os autores sugerem que o uso de medidas de desfecho padronizadas&#44; referidas por paciente e m&#233;dico&#44; poderiam reduzir a heterogeneidade e permitir compara&#231;&#245;es entre pacientes inclu&#237;dos em diferentes ensaios cl&#237;nicos&#46; Tamb&#233;m recomendam que o CLASI&#8208;50 &#40;redu&#231;&#227;o de&#160;50&#37; na pontua&#231;&#227;o do CLASI&#8208;A&#41; poderia ser mais efetivo como medida de resposta terap&#234;utica que o CLASI&#8208;20 &#40;redu&#231;&#227;o de&#160;20&#37; no CLASI&#8208;A&#41;&#44; usualmente utilizado como crit&#233;rio de boa resposta nos ensaios cl&#237;nicos&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">54</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Progress&#227;o de l&#250;pus cut&#226;neo a l&#250;pus eritematoso sist&#234;mico</span><p id="par0370" class="elsevierStylePara elsevierViewall">De&#160;5&#37;&#8208;25&#37; dos casos de LEC isolado&#44; independentemente do subtipo&#44; podem progredir para LES durante sua evolu&#231;&#227;o&#44; com tempo m&#233;dio de&#160;oito&#160;anos entre o diagn&#243;stico da doen&#231;a cut&#226;nea e o desenvolvimento da doen&#231;a sist&#234;mica&#46; Estudo de base populacional desenvolvido na Su&#233;cia mostrou que a maior possibilidade de desenvolver LES ocorre at&#233;&#160;tr&#234;s&#160;anos ap&#243;s o diagn&#243;stico da doen&#231;a cut&#226;nea&#44; al&#233;m de ser mais prov&#225;vel nas mulheres&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0375" class="elsevierStylePara elsevierViewall">Por outro lado&#44; aproximadamente&#160;50&#37;&#8208;60&#37; dos pacientes de LECS experimentam transi&#231;&#227;o ou j&#225; podem ser classificados como LES quando do diagn&#243;stico da doen&#231;a cut&#226;nea&#44; geralmente preenchendo crit&#233;rios cut&#226;neos&#44; musculoesquel&#233;ticos e sorol&#243;gicos&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0380" class="elsevierStylePara elsevierViewall">Entretanto&#44; os pacientes de LEC que progridem para LES tendem a apresentar sintomas sist&#234;micos mais leves&#59; s&#227;o raras as manifesta&#231;&#245;es cardiopulmonares e neurol&#243;gicas&#44; assim como outras complica&#231;&#245;es graves da doen&#231;a&#46; Crit&#233;rios relacionados &#224; nefropatia s&#227;o indicadores relevantes de diferencia&#231;&#227;o entre doen&#231;a cut&#226;nea isolada e doen&#231;a sist&#234;mica&#46; Quando presente&#44; o acometimento renal tende a ser menos grave naqueles que evoluem de LEC a LES&#44; por&#233;m faltam estudos mais consistentes para permitir essa conclus&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0385" class="elsevierStylePara elsevierViewall">H&#225; evid&#234;ncia de que LED e LECS com les&#245;es disseminadas exibem maior probabilidade de evolu&#237;rem com manifesta&#231;&#245;es sist&#234;micas que aqueles com les&#245;es localizadas&#46; Estudo retrospectivo&#44; que comparou pacientes de LED com doen&#231;a localizada e pacientes de LED e LECS com doen&#231;a disseminada&#44; mostrou que&#160;30&#37; dos casos com les&#245;es disseminadas apresentaram manifesta&#231;&#245;es extracut&#226;neas&#44; como nefrite&#44; pleurite e poliartrite&#44; enquanto aqueles com doen&#231;a localizada n&#227;o tiveram manifesta&#231;&#245;es sist&#234;micas&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0390" class="elsevierStylePara elsevierViewall">As les&#245;es cut&#226;neas inespec&#237;ficas prevalecem no LES&#44; principalmente com doen&#231;a em atividade&#46; Por isso&#44; quando presentes&#44; implica maior probabilidade de doen&#231;a sist&#234;mica&#44; em particular a ocorr&#234;ncia de telangiectasias periungueais&#46; A presen&#231;a dessas les&#245;es foi verificada em&#160;76&#37; dos pacientes de LES com LED concomitante e em nenhum paciente com LED exclusivo&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0395" class="elsevierStylePara elsevierViewall">Pacientes de LEC com potencial de desenvolver LES t&#234;m maior probabilidade de apresentar FAN com t&#237;tulos elevados em compara&#231;&#227;o com aqueles de LEC exclusivo&#46; Al&#233;m de marcadores de acometimento sist&#234;mico importante nos pacientes de LES&#44; t&#237;tulos elevados do FAN e a presen&#231;a dos anticorpos espec&#237;ficos anti&#8208;DNAn ou anti&#8208;Sm tamb&#233;m s&#227;o indicativos de evolu&#231;&#227;o para doen&#231;a sist&#234;mica nos pacientes com LEC&#46;</p><p id="par0400" class="elsevierStylePara elsevierViewall">Outras altera&#231;&#245;es laboratoriais persistentes&#44; como anemia&#44; leucopenia&#44; trombocitopenia e eleva&#231;&#227;o da velocidade de hemossedimenta&#231;&#227;o&#44; tamb&#233;m s&#227;o consideradas importantes marcadores de progress&#227;o para LES&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0405" class="elsevierStylePara elsevierViewall">Tamb&#233;m &#233; mat&#233;ria de discuss&#227;o se a administra&#231;&#227;o precoce de antimal&#225;ricos em pacientes de LEC&#44; com potencial de desenvolver doen&#231;a sist&#234;mica&#44; poderia prevenir a progress&#227;o a LES ou atenuar danos a &#243;rg&#227;os vitais&#44; uma vez instalada a doen&#231;a sist&#234;mica&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0410" class="elsevierStylePara elsevierViewall">Recomenda&#8208;se seguimento peri&#243;dico&#44; a intervalos mais curtos&#44; de pacientes com LEC que apresentam fatores de risco para progress&#227;o a LES&#44; com exame cl&#237;nico minucioso e adequada revis&#227;o laboratorial&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Tratamento</span><p id="par0415" class="elsevierStylePara elsevierViewall">O tratamento do LEC envolve medidas farmacol&#243;gicas e n&#227;o farmacol&#243;gicas&#46; Escolher a terapia mais eficaz para cada caso pode ser desafiador e exige aten&#231;&#227;o &#224;s manifesta&#231;&#245;es cl&#237;nicas e familiaridade com as terapias dispon&#237;veis&#46; &#201; importante avaliar a ades&#227;o do paciente ao tratamento em cada consulta&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Embora existam apenas tr&#234;s f&#225;rmacos aprovados pela ag&#234;ncia norte&#8208;americana Food and Drug Administration &#40;FDA&#41; para uso no LES &#8211; corticosteroides&#44; hidroxicloroquina e belimumabe &#8211; e nenhuma aprovada especificamente para LEC&#44; &#233; poss&#237;vel encontrar dados na literatura que permitem racionalizar a abordagem terap&#234;utica&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">56</span></a></p><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Medidas gerais</span><p id="par0420" class="elsevierStylePara elsevierViewall">A fotoprote&#231;&#227;o &#233; pilar fundamental do tratamento do LEC&#46; Os fotoprotetores podem prevenir o surgimento de les&#245;es nos pacientes com LEC&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;55&#8211;58</span></a> Entretanto&#44; outras medidas de cuidado tamb&#233;m se somam a seu uso&#44; como mudan&#231;as comportamentais&#44; uso de chap&#233;us e vestes longas&#44; preferencialmente com tecnologia para prote&#231;&#227;o &#224; RUV&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;58&#44;59</span></a></p><p id="par0425" class="elsevierStylePara elsevierViewall">A cessa&#231;&#227;o do tabagismo deve ser averiguada e encorajada a cada consulta&#44; de prefer&#234;ncia com referenciamento do paciente a programas e terapias de apoio&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;57</span></a> A suplementa&#231;&#227;o de vitamina D nos pacientes com defici&#234;ncia pode ser ben&#233;fica para o controle da doen&#231;a&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">56&#44;57&#44;60</span></a> Em caso de LEC induzido por f&#225;rmacos&#44; a medica&#231;&#227;o suspeita deve ser prontamente suspensa&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a></p><p id="par0430" class="elsevierStylePara elsevierViewall">Contracep&#231;&#227;o pode ser necess&#225;ria quando do uso de f&#225;rmacos teratog&#234;nicos&#46; Mulheres com LEC podem utilizar contraceptivos orais combinados&#44; se n&#227;o houver hist&#243;ria de tromboembolismo ou altos n&#237;veis de anticorpos antifosfol&#237;pides&#59; caso contr&#225;rio&#44; deve&#8208;se optar por dispositivo intrauterino ou uso de progest&#225;genos isolados&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">45&#44;61</span></a></p><p id="par0435" class="elsevierStylePara elsevierViewall">O uso de camuflagem cosm&#233;tica e pr&#243;teses de cabelos podem ocultar cicatrizes e alopecia&#44; melhorando a qualidade de vida e a autoestima dos pacientes&#46;<a class="elsevierStyleCrossRefs" href="#bib0645"><span class="elsevierStyleSup">59&#44;62</span></a> &#201; importante que pacientes com LEC sejam orientados a evitar interven&#231;&#245;es que traumatizem a pele&#44; pelo risco de koebneriza&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">62</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Tratamento t&#243;pico</span><p id="par0440" class="elsevierStylePara elsevierViewall">Os corticosteroides s&#227;o considerados a primeira linha de tratamento t&#243;pico&#44; por seu efeito anti&#8208;inflamat&#243;rio&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;6</span></a> Podem ser utilizados nos casos de les&#245;es localizadas ou como terapia adjuvante nos pacientes em tratamento sist&#234;mico&#46; Corticosteroides potentes&#44; como o clobetasol&#44; s&#227;o mais eficazes para o controle da doen&#231;a que os de baixa pot&#234;ncia&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">56&#44;61</span></a> Entretanto&#44; essas medica&#231;&#245;es est&#227;o associadas a maior risco de efeitos colaterais&#44; como estrias e telangiectasias&#44; por seu efeito nos fibroblastos e vasos sangu&#237;neos&#44; respectivamente&#44; al&#233;m de dermatite perioral rosaceiforme&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;60</span></a> Por isso&#44; a terapia com corticosteroides t&#243;picos potentes deve ser usada pelo menor tempo poss&#237;vel&#46; A inje&#231;&#227;o intralesional de corticoide pode ser aplicada em les&#245;es hipertr&#243;ficas localizadas&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;55</span></a></p><p id="par0445" class="elsevierStylePara elsevierViewall">Os inibidores t&#243;picos da calcineurina &#8211; tacrolimo&#160;0&#44;03&#37;&#160;ou&#160;0&#44;1&#37; em pomada e pimecrolimo&#160;1&#37; em creme &#8211; podem ser utilizados como substitutos dos corticosteroides nos casos que exijam tratamento prolongado ou com maior risco de efeitos colaterais&#44; como les&#245;es na face de crian&#231;as&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;61</span></a> S&#227;o menos eficazes que os corticoides t&#243;picos potentes&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> Os efeitos colaterais relacionados ao uso dessas medica&#231;&#245;es incluem sensa&#231;&#227;o de ard&#234;ncia&#44; prurido e eritema no local da aplica&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">57</span></a> Alguns estudos mostraram bons resultados com a aplica&#231;&#227;o combinada de clobetasol&#160;0&#44;05&#37; e tacrolimo&#160;0&#44;03&#37;&#46;</p><p id="par0450" class="elsevierStylePara elsevierViewall">O R&#8208;salbutamol &#233; um agonista do receptor &#946;2&#8208;adren&#233;rgico que inibe a produ&#231;&#227;o de IL&#8208;2 e IFN&#8208;&#947;&#44; podendo melhorar les&#245;es de LEC&#44; quando utilizado a&#160;0&#44;5&#37; em creme&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;60</span></a> Entretanto&#44; n&#227;o &#233; comercialmente dispon&#237;vel para uso t&#243;pico&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a> Os retinoides t&#243;picos j&#225; foram utilizados com sucesso em algumas pequenas s&#233;ries de casos&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Tratamento sist&#234;mico</span><p id="par0455" class="elsevierStylePara elsevierViewall">Pacientes com les&#245;es localizadas refrat&#225;rias ao tratamento t&#243;pico ou com les&#245;es disseminadas geralmente necessitam de tratamento sist&#234;mico&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> A <a class="elsevierStyleCrossRef" href="#tbl0025">tabela 5</a> mostra o n&#237;vel de evid&#234;ncia e o grau de recomenda&#231;&#227;o dos principais medicamentos de uso sist&#234;mico no tratamento do LEC&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Antimal&#225;ricos</span><p id="par0460" class="elsevierStylePara elsevierViewall">Os antimal&#225;ricos &#40;AM&#41; constituem a primeira linha de tratamento sist&#234;mico&#59; &#233; prov&#225;vel que previnam a progress&#227;o do LEC para doen&#231;a sist&#234;mica&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;59&#44;61&#44;63</span></a> S&#227;o capazes de inibir a apresenta&#231;&#227;o de ant&#237;genos pelas CDP&#44; a forma&#231;&#227;o de complexos ant&#237;geno&#8208;anticorpo e a sinaliza&#231;&#227;o via receptores <span class="elsevierStyleItalic">Toll&#8208;like&#44;</span> reduzindo a produ&#231;&#227;o de IFN tipo&#160;I&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">14&#44;55&#44;59</span></a> A hidroxicloroquina &#40;HCQ&#41; &#233; o AM mais utilizado pelo melhor perfil de seguran&#231;a quanto &#224; toxicidade ocular em rela&#231;&#227;o &#224; cloroquina &#40;CQ&#41;&#46; A dose recomendada de HCQ&#44; em parte da literatura&#44; &#233; de&#160;6&#44;5&#160;mg&#47;kg&#47;dia&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Contudo&#44; em&#160;2016&#44; a American Academy of Ophthalmology recomendou que doses maiores que&#160;5&#160;mg&#47;kg&#47;dia de HCQ e 2&#44;3&#160;mg&#47;kg&#47;dia de CQ sejam evitadas&#44; por risco aumentado de retinopatia&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">58</span></a></p><p id="par0465" class="elsevierStylePara elsevierViewall">O &#237;ndice de resposta dos AM &#233; de cerca de&#160;63&#37; dentre os diversos subtipos de LEC e pode ser um pouco maior para a CQ em rela&#231;&#227;o &#224; HCQ&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">64</span></a> A taxa m&#233;dia de resposta foi de&#160;91&#37; nos casos de LECA&#44; 57&#37;&#160;no LED e apenas&#160;31&#37; no LE perni&#243;tico&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">64</span></a> Pacientes de LECC tendem a responder mais lentamente aos AM que aqueles de LECA&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">56</span></a></p><p id="par0470" class="elsevierStylePara elsevierViewall">Em casos refrat&#225;rios&#44; um AM pode ser substitu&#237;do por outro &#8211; HCQ por CQ ou CQ por HCQ&#59; nesses casos&#44; a taxa de resposta ao segundo AM pode chegar a&#160;56&#37;&#44; mas cair para&#160;42&#37; ap&#243;s&#160;um&#160;ano e 22&#37; ap&#243;s&#160;dois&#160;anos&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;6&#44;45&#44;60&#44;64</span></a> A adi&#231;&#227;o de quinacrina&#44; f&#225;rmaco n&#227;o dispon&#237;vel no Brasil&#44; na dose de&#160;100&#8208;200&#160;mg&#47;dia&#44; nos casos refrat&#225;rios aos AM em monoterapia&#44; pode aumentar a taxa de resposta para&#160;66&#37;&#44; sem aumentar o risco de retinopatia&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">45&#44;57&#44;58&#44;61&#44;64</span></a> O uso de AM durante a gesta&#231;&#227;o e lacta&#231;&#227;o &#233; recomendado&#44; especialmente nas pacientes com les&#245;es cut&#226;neas e LES&#44; podendo reduzir o risco de acometimento card&#237;aco pelo LE neonatal&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">65</span></a></p><p id="par0475" class="elsevierStylePara elsevierViewall">Os efeitos colaterais dos AM incluem n&#225;useas&#44; v&#244;mitos&#44; pigmenta&#231;&#227;o cut&#226;nea&#44; tonteira&#44; cefaleia&#44; ototoxicidade e neuropatia perif&#233;rica&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> A retinopatia &#233; o efeito colateral mais relevante e ocorre em at&#233;&#160;1&#37; dos casos&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Os pacientes devem ser avaliados no in&#237;cio do tratamento e&#44; caso n&#227;o tenham nenhum fator de risco adicional&#44; anualmente&#44; ap&#243;s o quinto ano de uso do medicamento&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> Pacientes com doses acima de&#160;5&#44;0&#160;mg&#47;kg&#47;dia&#44; insufici&#234;ncia renal&#44; uso concomitante de tamoxifeno e maculopatia retiniana preexistente est&#227;o sob maior risco de retinopatia e devem ser monitorados com maior frequ&#234;ncia&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">56</span></a> A campimetria e o exame de fundo de olho podem n&#227;o detectar altera&#231;&#245;es iniciais&#59; a tomografia de coer&#234;ncia &#243;ptica &#233; recomendada para auxiliar no diagn&#243;stico precoce&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">65</span></a> Existem raros relatos de toxicidade card&#237;aca&#44; com prolongamento do intervalo QT&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">65</span></a></p><p id="par0480" class="elsevierStylePara elsevierViewall">Quando dispon&#237;vel&#44; a dosagem s&#233;rica de HCQ pode ser utilizada para avalia&#231;&#227;o do tratamento ap&#243;s&#160;seis&#160;meses de uso sem resposta&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">45&#44;60</span></a> Valores inferiores a&#160;200&#160;ng&#47;mL indicam m&#225;&#8208;ades&#227;o ao tratamento&#44; enquanto valores acima de&#160;750&#160;ng&#47;mL est&#227;o correlacionados a melhores taxas de controle da atividade da doen&#231;a&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">45&#44;56</span></a> Pacientes com contraindica&#231;&#227;o aos AM ou com dose otimizada de AM&#44; mas sem resposta ou com resposta parcial&#44; t&#234;m indica&#231;&#227;o de f&#225;rmacos de segunda linha de tratamento&#46; Tabagistas s&#227;o mais propensos a n&#227;o responderem aos AM&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">57</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Metotrexato</span><p id="par0485" class="elsevierStylePara elsevierViewall">O metotrexato &#40;MTX&#41; &#233; a primeira escolha dentre os f&#225;rmacos de segunda linha para pacientes refrat&#225;rios ou com contraindica&#231;&#227;o ao uso dos AM&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;66</span></a> &#201; um inibidor da diidrofolato&#8208;redutase&#44; que afeta a replica&#231;&#227;o celular e suprime a produ&#231;&#227;o de anticorpos&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">59</span></a> A dose recomendada pode variar de&#160;7&#44;5&#8208;25&#160;mg&#47;semana&#44; via oral ou subcut&#226;nea&#46; Os efeitos colaterais s&#227;o n&#225;useas&#44; v&#244;mitos&#44; dor abdominal&#44; hepatotoxidade&#44; ulcera&#231;&#227;o de mucosas&#44; supress&#227;o medular&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;55&#44;60</span></a> A aplica&#231;&#227;o subcut&#226;nea e a administra&#231;&#227;o de &#225;cido f&#243;lico nos dias posteriores ao uso da medica&#231;&#227;o podem reduzir significantemente os efeitos colaterais gastrintestinais&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">58&#44;61</span></a> Os pacientes devem ser monitorados laboratorialmente nas primeiras semanas de uso&#44; ap&#243;s aumento das doses e&#44; trimestralmente&#44; no acompanhamento regular&#46;</p><p id="par0490" class="elsevierStylePara elsevierViewall">O uso de MTX deve ser evitado em pacientes etilistas&#44; naqueles em uso concomitante de f&#225;rmacos hepatot&#243;xicos&#44; com esteatose hep&#225;tica grave&#44; insufici&#234;ncia renal ou doen&#231;a hep&#225;tica de base&#44; incluindo hepatites virais&#44; condi&#231;&#245;es que devem ser pesquisadas antes do in&#237;cio do tratamento com MTX&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">58&#44;61</span></a> O risco de hepatoxicidade fora dessas condi&#231;&#245;es &#233; baixo&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> Pneumonite intersticial &#233; complica&#231;&#227;o rara e potencialmente fatal&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;55</span></a> MTX &#233; teratog&#234;nico e deve ser recomendada contracep&#231;&#227;o adequada&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Retinoides sist&#234;micos</span><p id="par0495" class="elsevierStylePara elsevierViewall">Os retinoides s&#227;o utilizados com sucesso no tratamento de LEC refrat&#225;rio&#44; especialmente nas formas verrucosas&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;55&#44;61</span></a> Eles inibem a produ&#231;&#227;o de citocinas pr&#243;&#8208;inflamat&#243;rias&#44; como a IL&#8208;6 e o IFN&#8208;&#947;&#44; al&#233;m de regular e normalizar a diferencia&#231;&#227;o dos ceratin&#243;citos&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Dados da literatura n&#227;o mostram diferen&#231;a significante de efic&#225;cia entre HCQ e acitretina em pacientes com diferentes subtipos de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">57</span></a> A isotretino&#237;na tamb&#233;m j&#225; foi utilizada em pequenas s&#233;ries de casos&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a></p><p id="par0500" class="elsevierStylePara elsevierViewall">A dose de acitretina e isotretino&#237;na &#233; de&#160;0&#44;2&#8208;1&#44;0&#160;mg&#47;kg&#47;dia&#46; A resposta&#44; em geral&#44; &#233; r&#225;pida e ocorre em duas a seis semanas&#46; A recidiva tamb&#233;m costuma sobrevir logo ap&#243;s a interrup&#231;&#227;o da medica&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a></p><p id="par0505" class="elsevierStylePara elsevierViewall">Pacientes em uso de retinoides devem ser monitorados regularmente pelo risco de hepatotoxicidade e aumento dos n&#237;veis s&#233;ricos de triglic&#233;rides&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Outros efeitos colaterais incluem xerose mucocut&#226;nea e altera&#231;&#245;es &#243;sseas&#44; como a hiperostose&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">67</span></a> O uso de fotoprotetores deve ser intensificado&#44; pelo risco de agravamento da fotossensibilidade&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">67</span></a> Em decorr&#234;ncia do risco de teratogenicidade&#44; mulheres em idade f&#233;rtil devem ser submetidas a contracep&#231;&#227;o adequada durante e ap&#243;s o t&#233;rmino do tratamento &#40;isotretino&#237;na&#44; at&#233;&#160;um&#160;m&#234;s&#44; e acitretina&#44; at&#233;&#160;dois a tr&#234;s&#160;anos&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;55</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Dapsona</span><p id="par0510" class="elsevierStylePara elsevierViewall">A dapsona &#233; agente imunomodulador e antimicrobiano que inibe a mieloperoxidase presente em neutr&#243;filos e mon&#243;citos&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;59&#44;68</span></a> Pode ser usada isoladamente ou em combina&#231;&#227;o com os AM&#46; Mais de&#160;50&#37; dos pacientes com LEC respondem favoravelmente ao uso da dapsona&#44; inclusive aqueles com LED&#44; subtipo classicamente mais resistente&#44; em que a taxa de resposta se aproxima de&#160;60&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;68</span></a> A dapsona &#233; considerada f&#225;rmaco de primeira escolha no tratamento do LE bolhoso e de outras manifesta&#231;&#245;es neutrof&#237;licas no LE&#44; como a urtic&#225;ria vasculite&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">56&#44;61</span></a> As variantes hipercerat&#243;sicas usualmente n&#227;o respondem bem &#224; dapsona&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a></p><p id="par0515" class="elsevierStylePara elsevierViewall">A dose inicial &#233; de&#160;50&#160;mg&#47;dia e pode ser aumentada at&#233;&#160;200&#160;mg&#47;dia&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;61</span></a> Os pacientes devem ser avaliados quanto &#224; defici&#234;ncia de glicose&#8208;6&#8208;fosfatodesidrogenase antes do in&#237;cio do tratamento&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">58</span></a></p><p id="par0520" class="elsevierStylePara elsevierViewall">Os efeitos colaterais podem ser graves&#44; como erup&#231;&#227;o ao f&#225;rmaco com eosinofilia e sintomas sist&#234;micos&#44; a s&#237;ndrome DRESS &#40;do ingl&#234;s&#44; <span class="elsevierStyleItalic">drug reaction with eosinophilia and systemic symptoms</span>&#41;&#44; meta&#8208;hemoglobinemia e agranulocitose&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;57</span></a> Anemia hemol&#237;tica pode ocorrer em at&#233;&#160;50&#37; dos pacientes&#46;<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">57&#44;68</span></a> Os n&#237;veis de hemoglobina devem ser monitorados durante o primeiro m&#234;s de tratamento e&#44; ent&#227;o&#44; a cada tr&#234;s meses&#46; Os n&#237;veis de meta&#8208;hemoglobina podem ser avaliados entre o&#160;8&#176;&#160;e&#160;14&#176;&#160;dia ap&#243;s a introdu&#231;&#227;o da medica&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a> A dapsona &#233; o &#250;nico f&#225;rmaco de segunda linha que pode ser utilizado durante a gesta&#231;&#227;o e a amamenta&#231;&#227;o&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">60&#44;61</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Micofenolato de mofetila</span><p id="par0525" class="elsevierStylePara elsevierViewall">O micofenolato de mofetila &#40;MFM&#41; &#233; considerado agente de terceira linha para o tratamento do LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> O MFM causa deple&#231;&#227;o do trifosfato de guanosina&#44; necess&#225;rio para ades&#227;o de linf&#243;citos e mon&#243;citos ao endot&#233;lio durante o processo de inflama&#231;&#227;o&#44; al&#233;m de induzir apoptose de linf&#243;citos&#160;T e reduzir a ativa&#231;&#227;o dos linf&#243;citos&#160;B&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Foi relatada uma taxa de resposta completa ou significante em&#160;62&#37; dos pacientes de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> MFM pode ser usado isoladamente ou em combina&#231;&#227;o com AM&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">4</span></a> A dose inicial &#233; de&#160;500&#160;mg&#47;dia e pode ser aumentada at&#233;&#160;3&#160;g&#47;dia&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a></p><p id="par0530" class="elsevierStylePara elsevierViewall">Os efeitos colaterais mais frequentes s&#227;o gastrintestinais&#44; citopenias&#44; hepatotoxicidade e infec&#231;&#245;es virais e urin&#225;rias&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Os pacientes devem realizar revis&#245;es laboratoriais mensalmente&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> O f&#225;rmaco &#233; da categoria&#160;X e n&#227;o pode ser utilizado durante a gesta&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a></p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Azatioprina</span><p id="par0535" class="elsevierStylePara elsevierViewall">A azatioprina &#233; um an&#225;logo da purina que deprime a fun&#231;&#227;o dos linf&#243;citos&#160;T&#160;e&#160;B e reduz a apresenta&#231;&#227;o de ant&#237;genos&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">59</span></a> Pode ser indicada no LEC em caso de insucesso dos tratamentos descritos anteriormente&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> S&#233;ries de caso t&#234;m mostrado sucesso no tratamento do LEC&#44; embora n&#227;o existam grandes estudos que suportem essa recomenda&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Pode ser usada nas gestantes com LES&#44; mas sua rela&#231;&#227;o risco&#8208;benef&#237;cio deve ser ponderada&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> A dose recomendada &#233; de&#160;1&#8208;3&#160;mg&#47;kg&#47;dia&#46; Os efeitos adversos s&#227;o gastrintestinais&#44; infec&#231;&#245;es oportunistas e citopenias&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Talidomida</span><p id="par0540" class="elsevierStylePara elsevierViewall">A talidomida &#233; um f&#225;rmaco utilizado como terapia de resgate nos casos graves&#44; refrat&#225;rios e com alto risco de forma&#231;&#227;o de cicatrizes&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">66</span></a> Atua inibindo a s&#237;ntese de TNF&#8208;&#945;&#44; a angiog&#234;nese e a apoptose de ceratin&#243;citos induzida pela RUV&#44; reduzindo a produ&#231;&#227;o de IFN&#8208;&#947; e a fagocitose por polimorfonucleares&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;69</span></a> A taxa de resposta &#233; superior a&#160;90&#37; nos diferentes subtipos de LEC&#44; a mais alta dentre todos os tratamentos dispon&#237;veis&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;57&#44;70</span></a> Por&#233;m&#44; com alto risco de reca&#237;das&#44; de at&#233;&#160;70&#37;&#44; ap&#243;s a suspens&#227;o da medica&#231;&#227;o&#44; especialmente no LED&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;56&#44;70</span></a> A dose inicial recomendada &#233; de&#160;100&#160;mg&#47;dia&#44; que deve ser reduzida assim que a resposta cl&#237;nica for alcan&#231;ada&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a></p><p id="par0545" class="elsevierStylePara elsevierViewall">A alta frequ&#234;ncia de eventos adversos pode limitar seu uso&#44; afetando&#160;24&#37; dos pacientes &#40;16&#37;&#160;com neuropatia perif&#233;rica e 2&#37;&#160;com eventos tromboemb&#243;licos&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">56&#44;70</span></a> A polineuropatia &#233; classicamente sim&#233;trica&#44; dolorosa e afeta m&#227;os e p&#233;s&#46; &#201; usualmente acompanhada de perda sensorial e preserva&#231;&#227;o da for&#231;a muscular&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">69</span></a> Deve ser realizada eletroneuromiografia no in&#237;cio do tratamento e&#44; como controle&#44; a cada&#160;seis&#160;meses&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">69</span></a> Outros efeitos colaterais s&#227;o seda&#231;&#227;o&#44; hipotens&#227;o ortost&#225;tica&#44; erup&#231;&#227;o maculopapular&#44; constipa&#231;&#227;o e xerostomia&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">67&#44;69</span></a></p><p id="par0550" class="elsevierStylePara elsevierViewall">A teratogenicidade &#233; um dos efeitos colaterais mais tem&#237;veis relacionados ao uso da talidomida&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">69</span></a> Seu uso em mulheres em idade f&#233;rtil deve ser excepcional e apenas ap&#243;s falha de todos os tratamentos dispon&#237;veis&#46; Nesses casos&#44; recomenda&#8208;se a ado&#231;&#227;o de dois m&#233;todos contraceptivos&#44; um de alta efetividade e o outro de barreira&#46; Deve ser realizado teste de gravidez&#160;24&#160;horas antes do in&#237;cio do tratamento&#44; repetido semanalmente no primeiro m&#234;s e&#44; posteriormente&#44; a cada duas a quatro semanas&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">69</span></a></p><p id="par0555" class="elsevierStylePara elsevierViewall">&#193;cido acetilsalic&#237;lico&#44; em baixas doses&#44; pode ser associado &#224; talidomida em pacientes com alto risco cardiovascular ou presen&#231;a de anticorpos antifosfol&#237;pides&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">60&#44;69</span></a></p><p id="par0560" class="elsevierStylePara elsevierViewall">A lenalidomida&#44; um derivado da talidomida&#44; exibe melhor perfil de seguran&#231;a quanto ao risco de neuropatia&#44; por&#233;m ainda existem poucos dados na literatura sobre seu uso em pacientes com LEC&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;61</span></a> Alguns autores contraindicam seu uso no LEC devido ao risco de induzir LES&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a></p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Corticosteroides sist&#234;micos</span><p id="par0565" class="elsevierStylePara elsevierViewall">Os corticosteroides sist&#234;micos podem ser utilizados no in&#237;cio do tratamento das formas agressivas e disseminadas de LEC&#44; at&#233; que as outras medica&#231;&#245;es iniciem sua a&#231;&#227;o terap&#234;utica&#46; Devem ser reduzidos e suspensos o mais brevemente poss&#237;vel&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;6</span></a> Apresentam maior taxa de resposta no LECA&#44; provavelmente pela associa&#231;&#227;o com LES&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> A dose usual &#233; de&#160;0&#44;5&#8208;1&#160;mg&#47;kg&#47;dia de prednisona e deve ser reduzida&#44; logo que poss&#237;vel&#44; at&#233; atingir doses di&#225;rias inferiores a&#160;7&#44;5&#160;mg&#46; A terapia de longo prazo com corticosteroides sist&#234;micos n&#227;o &#233; indicada no LEC&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">60&#44;61</span></a></p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Outros tratamentos</span><p id="par0570" class="elsevierStylePara elsevierViewall">A clofazimina apresenta propriedades antimicrobianas&#44; anti&#8208;inflamat&#243;rias e imunossupressoras&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">59</span></a> A dose &#233; de&#160;100&#8208;200&#160;mg&#47;dia e pode ser utilizada como tratamento adjuvante&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Os principais efeitos colaterais s&#227;o hiperpigmenta&#231;&#227;o cinza&#8208;acastanhada&#44; xerose cut&#226;nea&#44; n&#225;useas e v&#244;mitos&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Os &#233;steres do &#225;cido fum&#225;rico j&#225; foram usados com sucesso no LED&#44; por&#233;m os dados ainda s&#227;o limitados na literatura&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;57</span></a></p><p id="par0575" class="elsevierStylePara elsevierViewall">O uso de antiagregantes plaquet&#225;rios &#233; recomendado nos pacientes com livedo racemoso&#44; les&#245;es do tipo papulose maligna atr&#243;fica &#40;doen&#231;a de Degos&#41;&#44; ulcera&#231;&#227;o&#44; tromboflebite e anetodermia&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">45</span></a></p><p id="par0580" class="elsevierStylePara elsevierViewall">O uso de <span class="elsevierStyleItalic">pulsed&#8208;dye&#8208;laser</span> &#40;<span class="elsevierStyleItalic">laser</span> pulsado de corante&#41; &#233; descrito como tratamento de cicatrizes&#46; Entretanto&#44; dado o risco de fotossensibilidade&#44; seu uso n&#227;o &#233; recomendado na presen&#231;a de les&#245;es cut&#226;neas ativas&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;7&#44;61</span></a></p><p id="par0585" class="elsevierStylePara elsevierViewall">Ciclosporina&#44; ciclofosfamida e imunoglobulina endovenosa n&#227;o s&#227;o indicadas no tratamento do LEC sem acometimento sist&#234;mico&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;61</span></a></p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Terapias&#8208;alvo</span><p id="par0590" class="elsevierStylePara elsevierViewall">Os avan&#231;os na compreens&#227;o da patog&#234;nese&#44; especialmente das vias de ativa&#231;&#227;o dos sistemas imunes inato e adaptativo&#44; abriram um novo campo de pesquisa para uma nova gera&#231;&#227;o de f&#225;rmacos&#44; os chamados imunobiol&#243;gicos&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">56</span></a> Os principais alvos terap&#234;uticos s&#227;o as vias de ativa&#231;&#227;o das c&#233;lulas&#160;B&#44; c&#233;lulas&#160;T e CDP&#44; al&#233;m das citocinas pr&#243;&#8208;inflamat&#243;rias&#44; seus receptores e vias de sinaliza&#231;&#227;o intracelular&#44; como IL&#8208;6&#44; IL&#8208;12&#44; IL&#8208;23&#44; IFN e via de sinaliza&#231;&#227;o JAK&#47;STAT&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;14&#44;60</span></a></p><p id="par0595" class="elsevierStylePara elsevierViewall">Alvo nas c&#233;lulas&#160;B&#58; o belimumabe &#233; um anticorpo monoclonal contra o fator de ativa&#231;&#227;o de c&#233;lulas&#160;B &#40;<span class="elsevierStyleItalic">Blys</span>&#41;&#44; aprovado pelo FDA para uso no LES&#46; Os estudos originais n&#227;o inclu&#237;ram an&#225;lise espec&#237;fica do desfecho das les&#245;es cut&#226;neas&#44; embora an&#225;lises posteriores tenham demonstrado melhora do quadro cut&#226;neo&#46; A efic&#225;cia no LEC est&#225; em investiga&#231;&#227;o em estudos de fase&#160;III&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> Tr&#234;s estudos observacionais&#44; com uso do rituximabe&#44; anticorpo monoclonal anti&#8208;CD20&#44; nas manifesta&#231;&#245;es mucocut&#226;neas do LE&#44; apresentaram taxas de resposta variando entre&#160;35&#37;&#160;e&#160;76&#37;&#46; Resposta mais favor&#225;vel foi verificada no LECA &#8211; no entanto&#44; sem evid&#234;ncia de efeito ben&#233;fico nos subtipos subagudo e cr&#244;nico do LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">57</span></a></p><p id="par0600" class="elsevierStylePara elsevierViewall">Alvo nas vias do interferon&#58; as tentativas de inibi&#231;&#227;o espec&#237;fica dos IFN n&#227;o apresentaram resultados satisfat&#243;rios nos ensaios cl&#237;nicos&#44; provavelmente pela grande redund&#226;ncia entre os diferentes tipos de IFN&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> O bloqueio do receptor de IFN apresenta uma perspectiva mais animadora&#46; O anifrolumabe&#44; um anticorpo monoclonal contra o receptor do IFN tipo&#160;I&#44; reduziu os escores de atividade das les&#245;es cut&#226;neas em pacientes com LES em ensaio cl&#237;nico de fase&#160;IIb&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a></p><p id="par0605" class="elsevierStylePara elsevierViewall">Alvo na via JAK&#47;STAT&#58; essa via &#233; importante para o mecanismo de retroalimenta&#231;&#227;o positiva do IFN&#46; A primeira gera&#231;&#227;o de inibidores &#8211; baricitinibe e ruxolitinibe &#8211; mostrou efic&#225;cia em pequeno n&#250;mero de pacientes com LE perni&#243;tico&#46; A segunda gera&#231;&#227;o de inibidores est&#225; sendo testada em ensaios cl&#237;nicos&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">14</span></a></p></span></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Considera&#231;&#245;es finais</span><p id="par0610" class="elsevierStylePara elsevierViewall">LEC &#233; doen&#231;a autoimune multifatorial&#44; resultante da intera&#231;&#227;o de fatores ambientais&#44; gen&#233;ticos e imunol&#243;gicos&#44; que se apresenta com variada manifesta&#231;&#227;o dermatol&#243;gica&#46; O reconhecimento do subtipo cl&#237;nico &#233; importante na abordagem diagn&#243;stica&#44; na decis&#227;o terap&#234;utica e na determina&#231;&#227;o do progn&#243;stico&#44; tanto na doen&#231;a exclusivamente cut&#226;nea quanto no contexto do LES&#46;</p><p id="par0615" class="elsevierStylePara elsevierViewall">Crit&#233;rios diagn&#243;sticos para defini&#231;&#227;o dos diferentes subtipos de LEC ainda s&#227;o incipientes&#46; Aguardam&#8208;se crit&#233;rios mais assertivos que possam ser futuramente incorporados na pr&#225;tica cl&#237;nica e nos ensaios terap&#234;uticos&#44; auxiliando na avalia&#231;&#227;o das manifesta&#231;&#245;es cut&#226;neas do LE&#46;</p><p id="par0620" class="elsevierStylePara elsevierViewall">Fotoprote&#231;&#227;o&#44; corticosteroides t&#243;picos e antimal&#225;ricos ainda permanecem como primeira linha no tratamento do LEC&#46; Medica&#231;&#245;es alternativas de uso sist&#234;mico incluem MTX&#44; retinoides orais&#44; dapsona e talidomida&#44; entre outros&#46; Com o avan&#231;o no conhecimento da patog&#234;nese da doen&#231;a&#44; novas estrat&#233;gias terap&#234;uticas v&#234;m sendo desenvolvidas&#44; tendo como alvos as diferentes vias de ativa&#231;&#227;o imune que t&#234;m sido identificadas&#46;</p></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Suporte financeiro</span><p id="par0625" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Contribui&#231;&#227;o dos autores</span><p id="par0630" class="elsevierStylePara elsevierViewall">Everton Carlos Siviero do Vale&#58; Concep&#231;&#227;o e desenho do estudo&#59; Revis&#227;o cr&#237;tica da literatura&#59; Elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; Revis&#227;o cr&#237;tica do manuscrito&#59; Aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0635" class="elsevierStylePara elsevierViewall">Lucas Campos Garcia&#58; Revis&#227;o cr&#237;tica da literatura&#59; Elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; Aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Conflito de interesses</span><p id="par0640" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">O l&#250;pus eritematoso cut&#226;neo &#233; doen&#231;a autoimune de express&#227;o cl&#237;nica variada&#44; que pode apresentar&#8208;se como doen&#231;a exclusivamente cut&#226;nea ou ser uma das m&#250;ltiplas manifesta&#231;&#245;es do l&#250;pus eritematoso sist&#234;mico&#46; Sua classifica&#231;&#227;o engloba os subtipos agudo&#44; subagudo&#44; intermitente&#44; cr&#244;nico e bolhoso&#44; que s&#227;o usualmente identificados com base nas caracter&#237;sticas cl&#237;nicas e nos achados histopatol&#243;gicos e laboratoriais&#46; Outras manifesta&#231;&#245;es cut&#226;neas n&#227;o espec&#237;ficas podem estar associadas ao l&#250;pus eritematoso sist&#234;mico e geralmente guardam rela&#231;&#227;o com a atividade da doen&#231;a&#46; Fatores ambientais&#44; gen&#233;ticos e imunol&#243;gicos participam da patog&#234;nese das les&#245;es cut&#226;neas do l&#250;pus eritematoso&#46; Recentemente&#44; tem havido consider&#225;vel progresso na elucida&#231;&#227;o dos mecanismos envolvidos no seu desenvolvimento&#44; o que possibilita antever futuros alvos de tratamentos mais efetivos&#46; Esta revis&#227;o se prop&#245;e a discutir os principais aspectos etiopatog&#234;nicos&#44; cl&#237;nicos&#44; diagn&#243;sticos e terap&#234;uticos do l&#250;pus eritematoso cut&#226;neo&#44; visando &#224; atualiza&#231;&#227;o de internistas e de especialistas de diferentes &#225;reas&#46;</p></span>"
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          "pt" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; L&#250;pus eritematoso cut&#226;neo subagudo&#58; placas eritemato&#8208;papuloescamosas anulares confluentes no t&#243;rax e nos membros superiores&#46; &#40;B&#41; L&#250;pus eritematoso neonatal&#58; placas eritematosas circulares e polic&#237;clicas na face&#46;</p>"
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          "pt" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">L&#250;pus eritematoso cut&#226;neo cr&#244;nico&#46; &#40;A&#41; Forma discoide localizada no couro cabeludo&#44; com alopecia cicatricial&#46; &#40;B&#41; Forma discoide afetando a mucosa jugal&#46;</p>"
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          "pt" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">L&#250;pus eritematoso cut&#226;neo cr&#244;nico&#46; &#40;A&#41; Variante verrucosa localizada no membro superior&#46; &#40;B&#41; Paniculite l&#250;pica acometendo o bra&#231;o e evoluindo com lipoatrofia&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">ACR&#44; American College of Rheumatology&#59; EULAR&#44; European League Against Rheumatism&#59; SLICC&#44; Systemic Lupus International Collaborating Clinics&#59; FAN&#44; fator antin&#250;cleo&#59; LEC&#44; l&#250;pus eritematoso cut&#226;neo&#59; LES&#44; l&#250;pus eritematoso sist&#234;mico&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">ACR 1997&#58; LES &#8805; 4&#160;crit&#233;rios&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">SLICC 2012&#58; LES &#8805;&#160;4&#160;crit&#233;rios&#44; ao menos um cl&#237;nico e um imunol&#243;gico&#59; quadro de nefrite l&#250;pica comprovada por bi&#243;psia&#44; com FAN ou anti&#8208;DNAn&#44; tamb&#233;m pode ser classificado como LES&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">EULAR&#47;ACR 2019&#58; LES &#61; escore &#8805; 10&#160;pontos&#44; ao menos um cl&#237;nico &#40;considera&#8208;se somente o crit&#233;rio com a pontua&#231;&#227;o mais alta em cada dom&#237;nio&#41;&#46;</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Os crit&#233;rios dermatol&#243;gicos est&#227;o destacados em negrito nos tr&#234;s sistemas de classifica&#231;&#227;o&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ACR 1997<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">4</span></a>&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">SLICC 2012<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">8</span></a>&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">EULAR&#47;ACR 2019<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">9</span></a>&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"><span class="elsevierStyleBold">Crit&#233;rio de entrada&#58;</span> nenhum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Crit&#233;rio de entrada&#58;</span> nenhum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Crit&#233;rio de entrada&#58;</span> FAN&#160;&#8805;&#160;1&#58;80&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="elsevierStyleItalic">Crit&#233;rios cl&#237;nicos &#40;&#61; 9&#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"><span class="elsevierStyleItalic">Crit&#233;rios cl&#237;nicos &#40;&#61; 11&#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"><span class="elsevierStyleItalic">Crit&#233;rios cl&#237;nicos &#40;pontos&#41;</span>&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">Erup&#231;&#227;o malar</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"><span class="elsevierStyleBold">LEC agudo&#44; subagudo ou LE bolhoso</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">Constitucional&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">Erup&#231;&#227;o discoide</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"><span class="elsevierStyleBold">LEC cr&#244;nico &#40;inclui LEC t&#250;mido&#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"><span class="elsevierStyleHsp" style=""></span>Febre &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Fotossensibilidade</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"><span class="elsevierStyleBold">&#218;lceras orais ou nasais</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">Hematol&#243;gicos&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">&#218;lceras orais</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"><span class="elsevierStyleBold">Alopecia n&#227;o cicatricial</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"><span class="elsevierStyleHsp" style=""></span>Leucopenia &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Artrite n&#227;o erosiva &#40;&#8805; 2&#160;articula&#231;&#245;es&#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">Sinovite &#40;&#8805; 2&#160;articula&#231;&#245;es&#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"><span class="elsevierStyleHsp" style=""></span>Trombocitopenia &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serosite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serosite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hem&#243;lise autoimune &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pleurite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pleurite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neuropsiqui&#225;tricos&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="elsevierStyleHsp" style=""></span>Pericardite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pericardite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Del&#237;rio &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Derrame pleural ou peric&#225;rdico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Derrame pleural ou peric&#225;rdico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Psicose &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acometimento renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Convuls&#227;o &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Protein&#250;ria<span class="elsevierStyleHsp" style=""></span>&#62; 0&#44;5 g&#47;24 horas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Protein&#250;ria<span class="elsevierStyleHsp" style=""></span>&#62; 0&#44;5 g&#47;24 horas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucocut&#226;neos&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="elsevierStyleHsp" style=""></span>Cilindros celulares&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cilindros hem&#225;ticos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">Alopecia n&#227;o cicatricial &#40;2&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Altera&#231;&#245;es neurol&#243;gicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a neurol&#243;gica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#218;lceras orais &#40;2&#41;</span>&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="elsevierStyleHsp" style=""></span>Convuls&#245;es&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Convuls&#245;es&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">LEC subagudo ou LE &#40;4&#41;</span>&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="elsevierStyleHsp" style=""></span>Psicose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Psicose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">LEC agudo &#40;6&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Altera&#231;&#245;es hematol&#243;gicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mononeurite m&#250;ltipla&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serosite&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="elsevierStyleHsp" style=""></span>Anemia hemol&#237;tica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mielite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Derrame pleural ou peric&#225;rdico &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Leucopenia &#40;&#60; 4&#46;000&#160;mm<span class="elsevierStyleSup">3</span>&#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"><span class="elsevierStyleHsp" style=""></span>Neuropatia craniana ou perif&#233;rica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pericardite aguda &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Linfopenia &#40;&#60; 1&#46;500&#160;mm<span class="elsevierStyleSup">3</span>&#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"><span class="elsevierStyleHsp" style=""></span>Estado confusional agudo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Musculoesquel&#233;tico&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="elsevierStyleHsp" style=""></span>Trombocitopenia &#40;&#60; 100&#46;000&#47;mm<span class="elsevierStyleSup">3</span>&#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">Altera&#231;&#245;es hematol&#243;gicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Acometimento articular &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anemia hemol&#237;tica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucopenia &#40;&#60; 4&#46;000&#160;mm<span class="elsevierStyleSup">3</span>&#41; ou linfopenia &#40;&#60; 1&#46;000 mm<span class="elsevierStyleSup">3</span>&#41;Trombocitopenia &#40;&#60; 100&#46;000&#47;mm<span class="elsevierStyleSup">3</span>&#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">Renais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Protein&#250;ria<span class="elsevierStyleHsp" style=""></span>&#62; 0&#44;5&#160;g&#47;24 horas &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Bi&#243;psia renal &#8211; nefrite l&#250;pica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Classe II ou V &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Bi&#243;psia renal &#8211; nefrite l&#250;pica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Classe III ou IV &#40;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Crit&#233;rios imunol&#243;gicos &#40;&#61; 2&#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"><span class="elsevierStyleItalic">Crit&#233;rios imunol&#243;gicos &#40;&#61; 6&#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"><span class="elsevierStyleItalic">Crit&#233;rios imunol&#243;gicos &#40;pontos&#41;</span>&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">FAN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FAN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpos antifosfol&#237;pides&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">Autoanticorpos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;DNAn&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anticardiolipina &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Anti&#8208;DNAn&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;Sm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti&#8208;&#946;2&#8208;glicoprote&#237;na 1 &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Anti&#8208;Sm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpo antifosfol&#237;pide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anticoagulante l&#250;pico &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Anticorpo antifosfol&#237;pide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anticoagulante l&#250;pico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complemento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Teste n&#227;o trepon&#234;mico falso&#8208;positivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>C3 ou C4 baixo &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anticardiolipina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>C3 e C4 baixos &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti&#8208;&#946;2&#8208;glicoprote&#237;na 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">Anticorpos LES&#8208;espec&#237;ficos&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">Complemento baixo &#40;C3&#44; C4 ou CH50&#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"><span class="elsevierStyleHsp" style=""></span>Anti&#8208;DNAn &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Coombs direto &#40;na aus&#234;ncia de anemia hemol&#237;tica&#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"><span class="elsevierStyleHsp" style=""></span>Anti&#8208;Sm &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab3171299.png"
              ]
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          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Crit&#233;rios de classifica&#231;&#227;o do l&#250;pus eritematoso sist&#234;mico &#8211; ACR 1997&#44; SLICC 2012 e EULAR&#47;ACR 2019</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Tabela 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">LE&#44; l&#250;pus eritematoso&#59; NET&#44; necr&#243;lise epid&#233;rmica t&#243;xica&#46;</p>"
          "tablatextoimagen" => array:2 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Subtipos de LE cut&#226;neo&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">Variantes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE cut&#226;neo agudo</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Localizado&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">Disseminado&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">NET&#8208;s&#237;mile&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE cut&#226;neo subagudo</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anular polic&#237;clico&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">Papuloescamoso psoriasiforme&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">S&#237;ndrome de Rowell&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">LE neonatal&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">LE cut&#226;neo intermitente&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE t&#250;mido&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE cut&#226;neo cr&#244;nico</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE discoide&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">LE discoide mucoso&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">LE hipertr&#243;fico&#47;verrucoso&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">LE profundo&#47;paniculite l&#250;pica&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">LE perni&#243;tico&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">LE l&#237;quen plano&#8208;s&#237;mile&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">LE comedoniano&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">LE bolhoso&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab3171298.png"
              ]
            ]
            1 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Natureza da altera&#231;&#227;o&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">Manifesta&#231;&#245;es inespec&#237;ficas&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">Vascular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fen&#244;meno de Raynaud&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">Livedo reticular&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">Livedo racemoso&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">Vasculites&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">Vasculopatia livedoide&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">Papulose do tipo doen&#231;a de Degos&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">Necrose cut&#226;nea&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">Hemorragia em estilha&#231;o&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">Tromboflebite&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Neutrof&#237;lica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE bolhoso&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">Urtic&#225;ria vasculite&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">Dermatose urticariana neutrof&#237;lica&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">Pustulose amicrobiana das dobras&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">S&#237;ndrome de Sweet&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">Pioderma gangrenoso&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">N&#227;o definida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alopecia n&#227;o cicatricial difusa&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">&#218;lceras mucosas&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">N&#243;dulos reumatoides&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">Dermatite granulomatosa intersticial&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">Dermatofibroma eruptivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Classe&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">Subclasse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Medicamento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></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">Anti&#8208;hipertensivos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diur&#233;ticos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hidroclorotiazida&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  " rowspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidores da enzima conversora da angiotensina</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Captopril&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">Cilazapril&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">Enalapril&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">Lisinopril&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">Ramipril&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">Betabloqueadores&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acebutolol&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">Bloqueadores do canal de c&#225;lcio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diltiazem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nifedipina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nitrendipina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Verapamil&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Inibidores da bomba de pr&#243;tons&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Esomeprazol<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lasanoprazol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Omeprazol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pantoprazol&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Antif&#250;ngicos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Griseofulvina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Terbinafina&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Anticonvulsivantes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carbamazepina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fenito&#237;na&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Estatinas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pravastatina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sinvastatina&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;histam&#237;nicos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bromofeniramina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cinarizina &#43; tietilperazina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ranitidina&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Antibi&#243;ticos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amoxicilina &#43; clavulanato&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ciprofloxacina&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;inflamat&#243;rios n&#227;o esteroides&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Naproxeno&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Piroxicam&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Quimioter&#225;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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#8208;fluoruracil<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Capecitabina<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doxorubicina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gencitabina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mitotane&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nivolumabe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Paclitaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Palbociclibe<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pembrolizumabe<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tamoxifeno&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tegafur&#47;uracil<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Biol&#243;gicos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;TNF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Adalimumabe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Etanercepte&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Golimumabe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infliximabe<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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">Anti&#8208;CD80&#47;86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abatacepte&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">Anti&#8208;CD11a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Efalizumabe&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">Anti&#8208;IL12&#47;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ustekinumabe&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">Anti&#8208;IL17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Secukinumabe&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Antidepressivos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bupropiona&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Outras&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alopurinol<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anastrazol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interferon&#8208;&#945; e &#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Imuglobulina intravenosa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leflunomida<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leuprorrelina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ticlopidina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tiotr&#243;pio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Tamb&#233;m desencadeantes de l&#250;pus eritematoso cut&#226;neo cr&#244;nico&#46;</p>"
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Medicamentos referidos como desencadeantes de l&#250;pus eritematoso cut&#226;neo subagudo</p>"
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            "identificador" => "at4"
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Adaptado de Kuhn et al&#46;&#44; 2014&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">48</span></a>&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Exames de rotina</span> &#40;suspeita de LEC&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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">Hemograma&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">Velocidade de hemossedimenta&#231;&#227;o eritrocit&#225;ria&nbsp;\t\t\t\t\t\t\n
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                  \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">Prote&#237;na C reativa&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">FAN &#40;HEp&#8208;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Enzimas hep&#225;ticas &#40;TGO&#44; TGP&#44; FA&#44; GGT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fun&#231;&#227;o renal &#40;ureia&#44; creatinina&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Urina &#40;EAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Exames especiais</span> &#40;LEC confirmado&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpos espec&#237;ficos &#40;anti&#8208;DNAn&#44; &#8208;Sm&#44; &#8208;Ro&#47;SS&#8208;A&#44; &#8208;La&#47;SS&#8208;B&#44; &#8208;RNPn&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complemento s&#233;rico &#40;C3&#44; C4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpos antifosfol&#237;pides &#40;anticardiolipinas IgG e IgM&#59;&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">anticoagulante l&#250;pico&#59; &#946;2&#8208;glicoprote&#237;na I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fator reumatoide&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">Imunoglobulinas &#40;imunoeletroforese&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TSH&#44; T4&#44; anticorpos antitireoidianos&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">Prote&#237;nas urin&#225;rias 24 horas&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="elsevierStyleItalic">Clearance</span> da creatinina&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">Glicose&#8208;6&#8208;fosfato desidrogenase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "pt" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Avalia&#231;&#227;o laboratorial recomendada no l&#250;pus eritematoso cut&#226;neo &#40;LEC&#41;</p>"
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            "rol" => "short"
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          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Adaptado de Yan et al&#46;&#44; 2020&#46;&#91;58&#93;&#46;</p>"
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            0 => array:2 [
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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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Medica&#231;&#227;o&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">N&#237;vel de evid&#234;ncia<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&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">Grau de recomenda&#231;&#227;o<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a>&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">Hidroxicloroquina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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">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">Acitretina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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">B&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">Isotretino&#237;na&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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">B&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">Metotrexato&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dapsona&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Talidomida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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">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">Micofenolato de mofetila&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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">B&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">Azatioprina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Belimumabe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">N&#237;vel de evid&#234;ncia&#58; 1 &#8211; Ensaio cl&#237;nico randomizado &#40;ECR&#41;&#44; revis&#245;es sistem&#225;ticas &#40;RS&#41;&#47;metan&#225;lise de ECR&#59; 2 &#8211; RS de estudos de coorte&#44; coortes&#59; 3 &#8211; RS de estudos caso&#8208;controle&#44; estudos de caso&#8208;controle&#59; 4 &#8211; S&#233;rie de casos&#44; coorte e caso&#8208;controle de baixa qualidade&#59; 5 &#8211; Opini&#227;o de especialistas&#46;</p>"
            ]
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              "identificador" => "tblfn0015"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Grau de recomenda&#231;&#227;o&#58; A &#8211; Estudos observacionais ou experimentais de maior consist&#234;ncia &#40;metan&#225;lises ou ECR&#41;&#59; B &#8211; Estudos observacionais de menor consist&#234;ncia &#40;outros ensaios cl&#237;nicos n&#227;o randomizados ou observacionais ou caso&#8208;controle&#41;&#59; C &#8211; Relatos ou s&#233;ries de casos &#40;estudos n&#227;o controlados&#41;&#59; D &#8211; Opini&#227;o desprovida de avalia&#231;&#227;o cr&#237;tica&#44; baseadas em consensos&#44; estudos fisiol&#243;gicos ou modelos animais&#46;</p>"
            ]
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Lúpus eritematoso cutâneo: revisão dos aspectos etiopatogênicos, clínicos, diagnósticos e terapêuticos
Everton Carlos Siviero do Valea,
Autor para correspondência
everton.siviero@gmail.com

Autor para correspondência.
, Lucas Campos Garciaa,b
a Serviço de Dermatologia, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
b Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
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    "titulo" => "L&#250;pus eritematoso cut&#226;neo&#58; revis&#227;o dos aspectos etiopatog&#234;nicos&#44; cl&#237;nicos&#44; diagn&#243;sticos e terap&#234;uticos"
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          "pt" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; L&#250;pus eritematoso t&#250;mido&#58; les&#245;es eritemato&#8208;edematosas arciformes e anulares na face e regi&#227;o cervical&#46; &#40;B&#41; L&#250;pus eritematoso bolhoso&#58; les&#245;es bolhosas&#44; ulcerocrostosas hem&#225;ticas e les&#245;es residuais hipocr&#244;micas&#44; localizadas na regi&#227;o cervical&#44; tronco&#44; axilas e membros superiores&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introdu&#231;&#227;o</span><p id="par0005" class="elsevierStylePara elsevierViewall">O l&#250;pus eritematoso &#40;LE&#41; &#233; doen&#231;a autoimune com amplo espectro de express&#227;o cl&#237;nica&#44; que varia desde doen&#231;a cut&#226;nea limitada at&#233; doen&#231;a sist&#234;mica grave e potencialmente fatal&#44; por comprometimento de &#243;rg&#227;os vitais&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> O LE cut&#226;neo &#40;LEC&#41; apresenta&#8208;se como doen&#231;a cut&#226;nea exclusiva ou comp&#245;e uma das m&#250;ltiplas manifesta&#231;&#245;es do LE sist&#234;mico &#40;LES&#41;&#46; Les&#245;es cut&#226;neas est&#227;o presentes em&#160;70&#37;&#8208;80&#37; dos casos de LES&#44; em algum momento de sua evolu&#231;&#227;o&#44; e podem ser a manifesta&#231;&#227;o inicial da doen&#231;a em at&#233;&#160;25&#37; dos pacientes&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Com base em caracter&#237;sticas cl&#237;nicas&#44; achados histopatol&#243;gicos&#44; altera&#231;&#245;es laboratoriais e dura&#231;&#227;o&#44; as les&#245;es cut&#226;neas espec&#237;ficas do LE s&#227;o subdivididas em tr&#234;s subtipos principais&#58; o LEC agudo &#40;LECA&#41;&#44; o LEC subagudo &#40;LECS&#41; e o LEC cr&#244;nico &#40;LECC&#41;&#46; A identifica&#231;&#227;o desses subtipos &#233; fundamental&#44; porque eles costumam ocorrer em contextos cl&#237;nicos distintos&#44; com implica&#231;&#245;es diagn&#243;sticas&#44; progn&#243;sticas e terap&#234;uticas&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">O LEC exclusivo &#233; 2&#8208;3 vezes mais frequente que o LES&#44; com incid&#234;ncia anual de&#160;4&#44;3&#47;100&#46;000&#160;indiv&#237;duos na Europa e nos EUA&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#8211;3</span></a> H&#225; predomin&#226;ncia de LE em mulheres&#44; em que a incid&#234;ncia de LES adulto &#233;&#160;7&#8208;15&#160;vezes maior e de LES infantil&#44; 3&#8208;4&#160;vezes maior&#46; Essa preponder&#226;ncia feminina &#233; menos evidente nas formas cut&#226;neas isoladas de LE&#44; com rela&#231;&#227;o de&#160;4&#58;1&#44; e &#233; ainda menos expressiva&#44; com rela&#231;&#227;o de&#160;3&#58;1&#44; no LE discoide &#40;LED&#41;&#44; forma mais comum de LECC&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">H&#225; ainda diferen&#231;as raciais na ocorr&#234;ncia do LEC&#44; com risco&#160;5&#44;4&#160;vezes maior de LECC nos afro&#8208;americanos em rela&#231;&#227;o aos caucasianos&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">4</span></a> Na Nova Zel&#226;ndia&#44; quando comparados &#224; popula&#231;&#227;o de origem europeia&#44; os ind&#237;genas Maori mostram risco relativo de&#160;2&#44;47&#160;para desenvolver todos os subtipos de LEC e&#160;5&#44;96&#160;para LECC&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">O pico de incid&#234;ncia do LES acontece na meia&#8208;idade adulta&#44; por&#233;m mais tardiamente nos homens&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Ainda que tamb&#233;m acometa crian&#231;as e idosos&#44; o LEC exclusivo &#233; mais comum entre&#160;20&#160;e&#160;40&#160;anos&#44; com idade m&#233;dia de instala&#231;&#227;o aos&#160;43&#160;anos&#44; por&#233;m com varia&#231;&#227;o conforme o subtipo&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">As les&#245;es cut&#226;neas do LE constituem consider&#225;vel morbidade&#44; sobretudo devido &#224; natureza cr&#244;nica&#44; ao acometimento preferencial das partes expostas do corpo e car&#225;ter desfigurante de suas sequelas&#44; que resultam em significante preju&#237;zo da qualidade de vida dos pacientes&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Classifica&#231;&#227;o</span><p id="par0035" class="elsevierStylePara elsevierViewall">Os crit&#233;rios diagn&#243;sticos para classifica&#231;&#227;o do LES n&#227;o s&#227;o uniformes e universalmente aceitos&#59; s&#227;o precursores aqueles propostos em&#160;1971 pelo American College of Rheumatology &#40;ACR&#41;&#44; revistos em&#160;1997 &#40;ACR 1997&#41;&#59; posteriormente&#44; surgiram mais dois sistemas de classifica&#231;&#227;o &#8211; o da Systemic Lupus International Collaborating Clinics &#40;SLICC&#160;2012&#41; e o conjunto entre a European League Against Rheumatism e o ACR &#40;EULAR&#47;ACR&#160;2019&#41;&#44; que est&#227;o discriminados e podem ser comparados na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;8&#44;9</span></a> Cada um desses tr&#234;s sistemas contempla quatro achados dermatol&#243;gicos como crit&#233;rios diagn&#243;sticos do LES&#46; Estudo australiano atual&#44; que avaliou a performance dos diferentes crit&#233;rios de classifica&#231;&#227;o do LES&#44; concluiu que o ACR&#160;1997 detinha a maior especificidade&#44; por&#233;m o SLICC&#160;2012 era o que proporcionava a maior acur&#225;cia diagn&#243;stica global &#40;94&#44;4&#37;&#41;&#44; com desempenho similar entre os pacientes com doen&#231;a inicial&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">10</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Foi pioneira a classifica&#231;&#227;o proposta por Gilliam &#38; Sontheimer&#44; em&#160;1981&#44; que discrimina as les&#245;es cut&#226;neas do LE entre espec&#237;ficas e inespec&#237;ficas&#46; As espec&#237;ficas&#44; definidas pela presen&#231;a da dermatite de interface dermoepid&#233;rmica&#44; s&#227;o exclusivas do LE&#44; com ou sem doen&#231;a sist&#234;mica&#46; S&#227;o subdivididas em tr&#234;s categorias&#44; com base nas caracter&#237;sticas cl&#237;nicas&#58; LECA&#44; LECS e LECC&#46; As les&#245;es inespec&#237;ficas incluem as demais manifesta&#231;&#245;es cut&#226;neas associadas ao LES&#46; Em&#160;2004&#44; a classifica&#231;&#227;o de D&#252;sseldorf acrescentou outro subtipo&#44; o LEC intermitente &#40;LECI&#41;&#44; que corresponde ao LE t&#250;mido&#44; anteriormente considerado variante de LECC&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Algumas limita&#231;&#245;es das classifica&#231;&#245;es anteriormente citadas podem ser destacadas&#58; a&#41;&#160;nem sempre as les&#245;es de LEC podem ser classificadas como agudas&#44; subagudas ou cr&#244;nicas&#44; com base na histologia&#59; b&#41;&#160;a dermatite de interface&#44; utilizada como crit&#233;rio para definir as les&#245;es espec&#237;ficas do LEC&#44; na realidade&#44; carece de especificidade&#44; j&#225; que pode estar presente em outras condi&#231;&#245;es&#44; como dermatomiosite&#44; doen&#231;a do enxerto&#8208;<span class="elsevierStyleItalic">versus</span>&#8208;hospedeiro e rea&#231;&#245;es medicamentosas&#59; c&#41;&#160;alguns subtipos inclu&#237;dos como espec&#237;ficos&#44; como o LE t&#250;mido e a paniculite l&#250;pica&#44; nem sempre apresentam dermatite de interface&#59; d&#41;&#160;termos como agudo&#44; subagudo ou cr&#244;nico&#44; de natureza cronol&#243;gica&#44; s&#227;o utilizados para definir varia&#231;&#245;es morfol&#243;gicas&#44; al&#233;m de serem associados a graus de extens&#227;o mal definidos&#44; como localizado ou disseminado&#44; referindo&#8208;se &#224; topografia&#46; Por essas raz&#245;es&#44; em&#160;2010&#44; Lipsker prop&#244;s uma nova classifica&#231;&#227;o das les&#245;es cut&#226;neas do LE&#44; com base nas caracter&#237;sticas cl&#237;nicas e nos achados histol&#243;gicos&#46; As les&#245;es cut&#226;neas espec&#237;ficas&#44; sem a presen&#231;a obrigat&#243;ria da dermatite de interface&#44; s&#227;o subdivididas em dermoepid&#233;rmicas&#44; d&#233;rmicas e hipod&#233;rmicas&#46; As les&#245;es inespec&#237;ficas s&#227;o subdivididas em tromb&#243;ticas&#44; neutrof&#237;licas ou de natureza patogen&#233;tica incerta&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">11</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Na falta de classifica&#231;&#227;o universalmente aceita&#44; em&#160;2013 foi constitu&#237;da uma for&#231;a&#8208;tarefa&#44; composta de especialistas no tema para propor uniformidade de crit&#233;rios diagn&#243;sticos e classifica&#231;&#227;o do LEC&#44; por meio do m&#233;todo Delphi&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">12</span></a> Recentemente&#44; foi apresentada a valida&#231;&#227;o dos crit&#233;rios de classifica&#231;&#227;o do LED&#44; forma mais comum de LEC&#44; com base exclusivamente cl&#237;nica&#46; Foram inclu&#237;dos os seguintes par&#226;metros&#44; com pontua&#231;&#245;es distintas&#44; referentes &#224;s les&#245;es cut&#226;neas&#58; cicatriz atr&#243;fica &#40;3&#160;pontos&#41;&#44; localiza&#231;&#227;o na concha auricular &#40;2&#160;pontos&#41;&#44; prefer&#234;ncia por cabe&#231;a e pesco&#231;o &#40;2&#160;pontos&#41;&#44; discromia &#40;1&#160;ponto&#41;&#44; ceratose folicular e tamp&#245;es c&#243;rneos &#40;1&#160;ponto&#41;&#44; colora&#231;&#227;o eritematosa a viol&#225;cea &#40;1&#160;ponto&#41;&#46; Escore &#8805; 5&#160;garante sensibilidade de&#160;84&#37; e especificidade de&#160;76&#37; para classifica&#231;&#227;o como LED&#44; com maior especificidade quanto maior for a pontua&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Etiopatog&#234;nese</span><p id="par0055" class="elsevierStylePara elsevierViewall">LES e LEC s&#227;o doen&#231;as multifatoriais&#44; em que est&#225; envolvida uma complexa intera&#231;&#227;o entre carga gen&#233;tica e exposi&#231;&#245;es ambientais&#44; como radia&#231;&#227;o ultravioleta &#40;RUV&#41;&#44; f&#225;rmacos&#44; defensivos agr&#237;colas e tabaco&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">14&#44;15</span></a> Varia&#231;&#245;es epigen&#233;ticas&#44; como desregula&#231;&#227;o da express&#227;o g&#234;nica&#44; via metila&#231;&#227;o do DNA&#44; ou modifica&#231;&#245;es de histonas&#44; causadas por esses fatores externos&#44; podem ser o gatilho para a ativa&#231;&#227;o das imunidades inata e adaptativa&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;14</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Os estudos sobre os fatores gen&#233;ticos envolvidos no LEC ainda s&#227;o incipientes&#44; se comparados aos descritos no LES&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Apesar disso&#44; polimorfismos gen&#233;ticos&#44; muta&#231;&#245;es e alelos de risco j&#225; foram identificados em diferentes popula&#231;&#245;es de LEC&#44; a maioria deles associados &#224;s vias das imunidades inata e adaptativa&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;14&#44;17</span></a> Genes que atuam na apoptose&#44; migra&#231;&#227;o leucocit&#225;ria&#44; via do IFN tipo&#160;I&#44; cascata do complemento&#44; apresenta&#231;&#227;o de ant&#237;genos e produ&#231;&#227;o de anticorpos est&#227;o entre os mais frequentemente afetados&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">14&#44;17</span></a> Os genes que codificam a produ&#231;&#227;o de citocinas pr&#243;&#8208;inflamat&#243;rias s&#227;o os mais associados &#224;s vias da imunidade inata nas les&#245;es de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> Como exemplos de associa&#231;&#245;es descritas entre genes e manifesta&#231;&#245;es cut&#226;neas&#44; podem ser citados o <span class="elsevierStyleItalic">FCGR2A</span> &#40;risco para LECA&#41;&#44; <span class="elsevierStyleItalic">TYK2</span>&#44; <span class="elsevierStyleItalic">IRF5</span>&#44; <span class="elsevierStyleItalic">TNF</span>&#8208;&#945; &#40;risco para LECS&#41; e <span class="elsevierStyleItalic">ITGAM</span> &#40;risco para LED&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">15&#44;17</span></a> Variantes de HLA tamb&#233;m j&#225; foram correlacionadas &#224; progress&#227;o da doen&#231;a cut&#226;nea&#44; dentre as quais se destacam o HLA&#8208;B8&#44; HLA&#8208;DR e HLA&#8208;DQ&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> At&#233; o presente momento&#44; apenas uma variante monogen&#233;tica de LEC foi identificada&#44; uma forma rara de LE perni&#243;tico familiar associada a muta&#231;&#245;es no gene <span class="elsevierStyleItalic">TREX1</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;14&#44;17&#44;18</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Dentre os fatores ambientais&#44; a RUV &#233; o mais bem estabelecido desencadeador do LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> A irradia&#231;&#227;o da pele altera a morfologia e a fun&#231;&#227;o dos ceratin&#243;citos&#44; induzindo diretamente a produ&#231;&#227;o de citocinas pr&#243;&#8208;inflamat&#243;rias &#40;IL&#8208;1&#945;&#44; IL&#8208;1&#946;&#44; IL&#8208;6&#44; TNF&#8208;&#945; e IFN&#8208;&#945;&#44; k e ¿&#41; e apoptose&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;14&#44;17</span></a> O aumento de citocinas inflamat&#243;rias e a exposi&#231;&#227;o a res&#237;duos celulares&#44; liberados pela morte celular&#44; desencadeiam o recrutamento de linf&#243;citos e c&#233;lulas dendr&#237;ticas plasmocitoides &#40;CDP&#41;&#44; que acionar&#227;o a ativa&#231;&#227;o do sistema imune&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;18</span></a> As CDP s&#227;o raras na pele normal e abundantes nas les&#245;es de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">18</span></a> Res&#237;duos celulares&#44; especialmente nucleares&#44; s&#227;o capturados pelas CDP&#44; que tamb&#233;m podem servir como reservat&#243;rio de autoant&#237;genos frente a linf&#243;citos&#160;B&#160;e&#160;T autorreativos&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">14</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">J&#225; foi demonstrado que a apoptose dos ceratin&#243;citos&#44; como a mediada pela via do Fas&#47;FasL&#44; apresenta forte correla&#231;&#227;o com a atividade da doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> O papel dos ceratin&#243;citos no surgimento e desenvolvimento das les&#245;es de LEC tamb&#233;m envolve retroalimenta&#231;&#227;o positiva na produ&#231;&#227;o de IFN&#44; especialmente dos tipos&#160;I&#160;e&#160;III&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> O IFN produzido &#233; capaz de ativar tanto o sistema imune inato quanto adaptativo&#44; exercendo papel central na patog&#234;nese do LE&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">14&#44;19</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">A ativa&#231;&#227;o do sistema imune inato promove a inflama&#231;&#227;o tecidual&#44; especialmente mediada pelas CDP e neutr&#243;filos &#40;incluindo as redes extracelulares de neutr&#243;filos &#8211; NET&#59; do ingl&#234;s&#44; <span class="elsevierStyleItalic">neutrophil extracellular traps</span>&#41;&#44; e o aumento da express&#227;o de autoant&#237;genos&#44; inclusive o Ro&#47;SS&#8208;A &#40;prote&#237;na induz&#237;vel pelo IFN&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">18&#44;19</span></a> Esse aumento estimula o sistema imune adaptativo&#44; como os linf&#243;citos&#160;T&#160;citot&#243;xicos e os plasm&#243;citos&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> O aumento do IFN tamb&#233;m perpetua a express&#227;o de citocinas e quimiocinas&#44; intimamente relacionadas &#224; produ&#231;&#227;o de anticorpos&#44; os quais se depositam preferencialmente na jun&#231;&#227;o dermoepid&#233;rmica e resultam em agress&#227;o citot&#243;xica mediada principalmente por linf&#243;citos T CD8&#43;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">4</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">A eleva&#231;&#227;o dos n&#237;veis de IFN&#44; especialmente do tipo&#160;I&#44; tamb&#233;m leva diretamente &#224; infiltra&#231;&#227;o de linf&#243;citos Th1&#44; acelerando a inflama&#231;&#227;o tecidual e a produ&#231;&#227;o de IFN&#8208; &#947; e IL&#8208;2&#44; dentre outras citocinas&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">4</span></a> O aumento dessas citocinas estimula as vias de sinaliza&#231;&#227;o intracelulares&#44; como a via JAK&#47;STAT&#44; e altera a transcri&#231;&#227;o g&#234;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">14</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Por fim&#44; a eleva&#231;&#227;o dos n&#237;veis de citocinas&#44; o aumento da exposi&#231;&#227;o de ant&#237;genos e a atividade das c&#233;lulas Th1 estimulam a produ&#231;&#227;o de anticorpos autorreativos&#44; que se depositam principalmente na zona da membrana basal e estimulam a agress&#227;o por c&#233;lulas&#160;T CD8&#43; e c&#233;lulas <span class="elsevierStyleItalic">natural killer</span> &#40;NK&#41;<span class="elsevierStyleItalic">&#44;</span> por meio de enzimas&#44; como a granzima&#160;B&#44; que induzem apoptose pela ativa&#231;&#227;o das caspases e d&#227;o continuidade ao ciclo inflamat&#243;rio&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;19</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">O papel dos autoanticorpos permanece incerto no LEC&#46; Pacientes com LECC apresentam ocorr&#234;ncia muito menor de autoanticorpos s&#233;ricos&#44; como os antinucleares&#44; anti&#8208;DNAn&#44; anti&#8208;Sm&#44; anti&#8208;Ro&#47;SS&#8208;A e anti&#8208;La&#47;SS&#8208;B&#44; se comparados aos pacientes com LES e LECS&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">19</span></a> Por outro lado&#44; as imunoglobulinas est&#227;o fortemente envolvidas na patog&#234;nese local das les&#245;es de LEC&#46; As IgM s&#227;o as primeiras a serem recrutadas para a pele&#44; atraindo&#44; em seguida&#44; o C3 e outras imunoglobulinas&#46; Diferentemente do LES&#44; em que a IgM isolada ou em combina&#231;&#227;o com C3 &#233; a forma mais frequente de forma&#231;&#227;o de imunocomplexos&#44; no LED&#44; a IgG &#233; a respons&#225;vel pela maioria dos dep&#243;sitos de imunocomplexos&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Apesar do aumento dos n&#237;veis s&#233;ricos de IL&#8208;17 e aumento da express&#227;o cut&#226;nea da IL&#8208;17A nos pacientes com LES&#44; poucos linf&#243;citos&#160;T&#160;produtores de IL&#8208;17 s&#227;o encontrados nas les&#245;es de LED&#44; sugerindo um papel menos importante nesta manifesta&#231;&#227;o cl&#237;nica&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Foi descrita tamb&#233;m uma redu&#231;&#227;o na porcentagem de linf&#243;citos&#160;T&#160;reguladores na pele afetada pelo LEC&#46; Outro relato recente &#233; uma rela&#231;&#227;o inversamente proporcional entre a porcentagem de linf&#243;citos Th22 nas les&#245;es e escores de gravidade cl&#237;nica&#44; indicando que a IL&#8208;22 pode ser bom indicador da repara&#231;&#227;o cut&#226;nea&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">19</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Os f&#225;rmacos s&#227;o descritos como outro poss&#237;vel gatilho para o LEC&#44; especialmente para o subtipo subagudo&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">17</span></a> F&#225;rmacos classicamente reconhecidos como indutores de LEC&#44; como anti&#8208;hipertensivos&#44; antif&#250;ngicos e inibidores da bomba de pr&#243;tons&#44; dentre outros mais de cem medicamentos&#44; t&#234;m dividido import&#226;ncia com novas terapias&#8208;alvo&#44; como imunobiol&#243;gicos&#44; imunoter&#225;picos e quimioter&#225;picos&#44; em decorr&#234;ncia da crescente ocorr&#234;ncia de casos relacionados a esses medicamentos&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;17</span></a> Acredita&#8208;se que os f&#225;rmacos causadores de LEC podem ativar diretamente o sistema imune inato ou&#44; indiretamente&#44; ao reduzir a remo&#231;&#227;o de autoant&#237;genos&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> O tabagismo &#233; outro importante fator de risco associado ao LEC&#44; por estimular citocinas pr&#243;&#8208;inflamat&#243;rias&#44; a ativa&#231;&#227;o neutrof&#237;lica&#44; aumentar o estresse celular&#44; a forma&#231;&#227;o de radicais livres e a apoptose&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;14&#44;18</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Os horm&#244;nios sexuais parecem ser pe&#231;a fundamental na patog&#234;nese do LES&#46; Por outro lado&#44; sua import&#226;ncia no LEC parece ser menor&#44; especialmente no LED&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Apesar disso&#44; a incid&#234;ncia de LEC ainda &#233; maior no sexo feminino&#46; Como esse aumento ocorre mesmo fora da per&#237;odo f&#233;rtil&#44; postula&#8208;se que possa haver outras explica&#231;&#245;es para a maior incid&#234;ncia nas mulheres&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> A aus&#234;ncia de piora significante do LEC durante a gesta&#231;&#227;o ou o uso de anticoncepcionais orais tamb&#233;m corroboram esse achado&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Uma poss&#237;vel hip&#243;tese alternativa &#224; influ&#234;ncia hormonal seria um efeito de dose ligado ao cromossomo&#160;X&#44; que poderia explicar&#44; por exemplo&#44; o aumento da incid&#234;ncia de LES em pacientes do sexo masculino portadores da s&#237;ndrome de Klinefelter &#40;gen&#243;tipo&#160;XXY&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Outra hip&#243;tese seria a reativa&#231;&#227;o do cromossomo&#160;X inativado por um processo de demetila&#231;&#227;o nos linf&#243;citos&#160;T CD4&#43;&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">O papel da microbiota cut&#226;nea na patog&#234;nese do LEC ainda &#233; pouco compreendido e tem atra&#237;do maior aten&#231;&#227;o por parte dos pesquisadores&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> Aumento significante de <span class="elsevierStyleItalic">Staphylococcus</span> e <span class="elsevierStyleItalic">Corynebacterium</span>&#44; assim como redu&#231;&#227;o de <span class="elsevierStyleItalic">Cutibacterium</span>&#44; foram descritos nas les&#245;es cut&#226;neas de LES&#44; por&#233;m ainda sem evid&#234;ncias que suportem uma rela&#231;&#227;o direta&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">16&#44;17</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Apresenta&#231;&#227;o cl&#237;nica e diagn&#243;stico diferencial</span><p id="par0115" class="elsevierStylePara elsevierViewall">A <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a> relaciona os subtipos cl&#237;nicos de LEC e suas variantes&#44; assim como as manifesta&#231;&#245;es cut&#226;neas inespec&#237;ficas que podem estar associadas ao LE&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">L&#250;pus eritematoso cut&#226;neo agudo</span><p id="par0120" class="elsevierStylePara elsevierViewall">Representa&#160;15&#37; dos casos de LEC e sempre est&#225; associado ao LES&#44; geralmente correlacionando com a atividade da doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a> Presente no momento do diagn&#243;stico em cerca de&#160;50&#37; dos casos de LES&#44; pode ser desencadeado ou exacerbado pela exposi&#231;&#227;o solar aguda&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">2</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">A forma localizada &#233; a predominante &#40;90&#37;&#8208;95&#37;&#41; e corresponde &#224; t&#237;pica erup&#231;&#227;o em vespert&#237;lio ou em asa de borboleta&#44; que se manifesta como les&#227;o eritematosa e finamente escamosa&#44; acometendo de maneira sim&#233;trica as regi&#245;es malares e o dorso nasal&#44; geralmente poupando os sulcos nasolabiais &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>A&#41;&#46; Edema facial tamb&#233;m pode estar presente&#46; O eritema costuma ser ef&#234;mero&#44; resolvendo&#8208;se em alguns dias ou semanas&#46; Eventualmente&#44; afeta a fronte&#44; o mento&#44; os pavilh&#245;es auriculares e a regi&#227;o cervical anterior&#46; Seus principais diagn&#243;sticos diferenciais s&#227;o dermatomiosite e ros&#225;cea&#44; mas ainda devem ser consideradas dermatite seborreica&#44; dermatite perioral e dermatite de contato fotoal&#233;rgica&#46; O acometimento das dobras nasolabiais e das p&#225;lpebras&#44; assim como fraqueza muscular proximal&#44; favorecem a dermatomiosite&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">A forma disseminada&#44; menos comum &#40;5&#37;&#8208;10&#37;&#41;&#44; manifesta&#8208;se como erup&#231;&#227;o exantem&#225;tica urticariforme ou maculopapular predominante nas &#225;reas fotoexpostas &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>B&#41;&#46; Al&#233;m de face e pesco&#231;o&#44; afeta simetricamente o V do decote e a superf&#237;cie extensora dos membros&#44; sobretudo os superiores&#44; mas pode estender&#8208;se ao tronco e at&#233; mesmo palmas e plantas&#46; Quando atinge o dorso de m&#227;os e dedos&#44; tende a poupar as articula&#231;&#245;es&#44; ao contr&#225;rio da dermatomiosite&#46; Deve ser diferenciada de rea&#231;&#245;es de hipersensibilidade a f&#225;rmacos&#44; exantemas virais e dermatites fotot&#243;xicas ou fotoal&#233;rgicas medicamentosas&#44; al&#233;m da dermatomiosite&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">O acometimento mucoso &#233; frequente em ambas as formas&#46; A mucosa oral &#233; a mais afetada&#44; em&#160;8&#37;&#8208;45&#37; dos casos&#44; atingindo principalmente as mucosas jugal&#44; palatina e labial&#44; na forma de placas enantematosas ou purp&#250;ricas&#44; vesicobolhas&#44; eros&#245;es e &#250;lceras&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">20</span></a> Ulcera&#231;&#227;o nasal &#233; menos comum e outras mucosas s&#227;o raramente afetadas&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Uma apresenta&#231;&#227;o rara de LECA&#44; que se assemelha &#224; necr&#243;lise epid&#233;rmica t&#243;xica &#40;NET&#41;&#44; por isso conhecida como variante NET&#8208;s&#237;mile&#44; deve&#8208;se &#224; intensa dermatite de interface com necrose dos ceratin&#243;citos&#44; que resulta em descolamento epitelial de extensas &#225;reas da pele&#46; Pode haver comprometimento mucoso&#44; que costuma ser mais limitado e poupar a conjuntiva ocular&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">21</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Ap&#243;s resolu&#231;&#227;o&#44; as les&#245;es de LECA podem deixar hipercromia residual&#44; mas n&#227;o costumam resultar em cicatrizes&#44; exceto na forma NET&#8208;s&#237;mile&#44; ou quando complicadas por infec&#231;&#227;o secund&#225;ria&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">L&#250;pus eritematoso cut&#226;neo subagudo</span><p id="par0150" class="elsevierStylePara elsevierViewall">Responde por cerca de&#160;8&#37; de todos os casos de LEC&#44; tem dura&#231;&#227;o mais prolongada que o LECA e apresenta extrema fotossensibilidade&#46; Distribui&#8208;se de maneira sim&#233;trica&#44; preferencialmente nas &#225;reas expostas do pesco&#231;o&#44; tronco superior e membros superiores&#44; por&#233;m costuma poupar a regi&#227;o central da face&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a> Manifesta&#8208;se sob duas formas&#44; ambas com placas eritematosas&#44; uma anular polic&#237;clica e outra papuloescamosa psoriasiforme &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>A&#41;&#44; que eventualmente podem coexistir no mesmo paciente&#46; Atrofia e ceratose n&#227;o s&#227;o clinicamente evidentes nas les&#245;es do LECS&#46; Tamb&#233;m tendem a ser menos edematosas que as les&#245;es do LECA e menos infiltradas e discr&#244;micas que aquelas do LED&#46; Em ambas as formas&#44; surgem ocasionalmente les&#245;es vesicobolhosas e crostas na periferia das placas&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Habitualmente&#44; resolvem sem deixar cicatrizes&#44; mas pode haver hipocromia residual&#44; geralmente tempor&#225;ria&#44; por&#233;m permanente em formas mais graves&#46; Eventualmente&#44; pode haver concomit&#226;ncia de les&#245;es de LECA ou LED com les&#245;es de LECS&#44; mas nem sempre &#233; poss&#237;vel uma distin&#231;&#227;o exata dessas les&#245;es&#46; &#201; raro o acometimento da mucosa oral&#44; com placas enantematosas circulares levemente atr&#243;ficas&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">22</span></a> Deve ser diferenciado de granuloma anular&#44; eritema anular centr&#237;fugo&#44; <span class="elsevierStyleItalic">erithema gyratum repens</span>&#44; psor&#237;ase&#44; tinha do corpo&#44; entre outros&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Cerca de 1&#47;3 dos casos de LECS &#233; desencadeado por f&#225;rmacos&#46; Em geral&#44; o LECS medicamentoso &#233; indistingu&#237;vel do LECS idiop&#225;tico&#44; por&#233;m algumas particularidades devem levar &#224; suspei&#231;&#227;o da etiologia medicamentosa &#8211; idade mais avan&#231;ada&#44; quadros mais disseminados e presen&#231;a de les&#245;es bolhosas ou do tipo alvo&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">23</span></a> O quadro costuma ser revers&#237;vel&#44; resolvendo em alguns meses ap&#243;s a suspens&#227;o da medica&#231;&#227;o respons&#225;vel&#46; Os f&#225;rmacos mais frequentemente incriminados s&#227;o hidroclorotiazida&#44; inibidores do canal de c&#225;lcio&#44; inibidores da enzima conversora da angiotensina&#44; inibidores da bomba de pr&#243;tons&#44; terbinafina&#44; agentes anti&#8208;TNF e anticonvulsivantes&#44; por&#233;m a incid&#234;ncia tende a variar com o desenvolvimento de novos medicamentos e a mudan&#231;a na prescri&#231;&#227;o&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">23&#8211;25</span></a> Recente revis&#227;o da literatura&#44; com foco na d&#233;cada passada &#40;2010&#8208;2020&#41;&#44; revelou que os agentes anti&#8208;TNF&#44; os inibidores da bomba de pr&#243;tons e os antineopl&#225;sicos&#44; em particular os inibidores de <span class="elsevierStyleItalic">checkpoint</span> imune&#44; destacam&#8208;se como f&#225;rmacos emergentes desencadeantes de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">26</span></a> A lista de medicamentos respons&#225;veis &#233; extensa&#44; como pode ser observado na <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">O primeiro caso de LECS associado a doen&#231;a maligna foi descrito em&#160;1982&#44; como l&#250;pus eritematoso <span class="elsevierStyleItalic">gyratum repens</span> em paciente com c&#226;ncer de pulm&#227;o&#46; Desde ent&#227;o&#44; surgiram in&#250;meros relatos sugerindo uma rela&#231;&#227;o entre LECS e v&#225;rias neoplasias s&#243;lidas e n&#227;o s&#243;lidas&#44; com maior frequ&#234;ncia de carcinoma de pulm&#227;o e adenocarcinoma da mama&#46; Na maioria dos casos&#44; o paralelismo entre o desenvolvimento tumoral e a atividade da dermatose possibilitou caracterizar a associa&#231;&#227;o como s&#237;ndrome paraneopl&#225;sica&#46; Ainda que rara&#44; &#233; importante considerar essa possibilidade no LECS de in&#237;cio em idade avan&#231;ada&#44; em pacientes com maior risco de neoplasia e nos casos refrat&#225;rios ao tratamento convencional&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">27</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">A s&#237;ndrome de <span class="elsevierStyleItalic">Rowell</span> foi originalmente descrita em&#160;1963 como uma entidade distinta&#44; pela associa&#231;&#227;o de achados cl&#237;nicos de LE e eritema multiforme&#44; al&#233;m da presen&#231;a de algumas altera&#231;&#245;es imunol&#243;gicas&#44; como FAN salpicado&#44; anticorpo anti&#8208;SjT e fator reumatoide&#46; &#192; luz dos conhecimentos cl&#237;nicos e imunol&#243;gicos modernos&#44; essa s&#237;ndrome n&#227;o deve ser vista com identidade nosol&#243;gica&#44; mas como variante rara do LECS&#44; caracterizada por les&#245;es cut&#226;neas do tipo alvo e presen&#231;a de anticorpos anti&#8208;Ro&#47;SS&#8208;A&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">28</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">O LE neonatal tamb&#233;m &#233; considerado variante do LECS&#46; Resulta da passagem transplacent&#225;ria de autoanticorpos maternos contra ant&#237;genos Ro&#47;SS&#8208;A&#44; La&#47;SS&#8208;B e&#44; mais raramente&#44; U1&#8208;RNP&#46; Em grande parte dos casos&#44; a m&#227;e &#233; assintom&#225;tica&#44; mas pode ter s&#237;ndrome de Sj&#246;gren&#44; LECS&#44; LES ou outras doen&#231;as do tecido conjuntivo&#46; O risco &#233; pequeno na primeira gesta&#231;&#227;o ou na aus&#234;ncia da doen&#231;a em gesta&#231;&#245;es anteriores &#40;2&#37;&#41;&#44; mas aumenta substancialmente &#40;10&#160;vezes&#41; se tiver havido diagn&#243;stico em gesta&#231;&#227;o pr&#233;via&#46; As les&#245;es cut&#226;neas ocorrem em at&#233;&#160;40&#37; dos casos de LE neonatal e podem estar presentes ao nascimento&#44; mas geralmente surgem nos primeiros&#160;tr&#234;s&#160;meses de vida&#44; ap&#243;s a exposi&#231;&#227;o solar&#44; resolvendo espontaneamente em 6&#8208;12 meses&#46; S&#227;o eritematosas ou eritemato&#8208;escamosas&#44; circulares&#44; anulares ou polic&#237;clicas e afetam principalmente a face&#44; nas regi&#245;es frontal e periorbit&#225;ria &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>B&#41;&#44; podendo estender&#8208;se ao couro cabeludo&#44; mas raramente atingem tronco e membros&#46; Dermatite seborreica e tinha da face s&#227;o os principais diagn&#243;sticos diferenciais&#46; Outras manifesta&#231;&#245;es poss&#237;veis&#44; tamb&#233;m revers&#237;veis&#44; s&#227;o as citopenias &#40;trombocitopenia&#44; anemia hemol&#237;tica&#41;&#44; doen&#231;a hepatobiliar&#44; esplenomegalia e&#44; mais raras&#44; as altera&#231;&#245;es neurol&#243;gicas e pulmonares&#46; Mais graves e irrevers&#237;veis s&#227;o as altera&#231;&#245;es card&#237;acas&#44; principalmente os dist&#250;rbios de condu&#231;&#227;o&#44; inclusive bloqueio atrioventricular total&#44; miocardiopatia e valvulopatia&#44; que podem ocorrer em 25&#37; dos casos e ser detectadas antes do nascimento&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;29</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">L&#250;pus eritematoso cut&#226;neo cr&#244;nico</span><p id="par0175" class="elsevierStylePara elsevierViewall">O LECC responde por mais de&#160;70&#37; dos casos de LEC e compreende diversas variantes&#44; algumas mais comuns e outras mais raras&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">O LED &#233; a forma cl&#225;ssica e mais comum de LECC&#44; tamb&#233;m presente em&#160;20&#37;&#160;dos casos de LES&#46; Localiza&#8208;se predominantemente na cabe&#231;a e pesco&#231;o&#44; mas&#44; em cerca de&#160;30&#37;&#160;dos casos&#44; pode ser disseminado e acometer tronco e membros&#44; com prefer&#234;ncia pelas &#225;reas fotoexpostas&#44; como face&#44; pavilh&#245;es auriculares&#44; V do decote&#44; lateral do pesco&#231;o&#44; couro cabeludo e dorsal dos membros superiores&#46; As les&#245;es se iniciam como placas eritemato&#8208;infiltradas&#44; induradas &#224; palpa&#231;&#227;o&#44; evoluindo com ceratose&#44; principalmente folicular&#44; atrofia e discromia&#44; com hipocromia no centro e hipercromia na periferia&#46; Costumam ser dolorosas &#224; palpa&#231;&#227;o&#46; Podem deixar les&#245;es vitiligoides&#44; assim como resolver com cicatrizes&#44; muitas vezes mutilantes&#44; sobretudo quando acometem nariz&#44; pavilh&#245;es auriculares e p&#225;lpebras&#46; Les&#245;es em diferentes est&#225;gios costumam ser concomitantes&#46; Quando situadas nas &#225;reas pilosas&#44; como couro cabeludo&#44; barba&#44; c&#237;lios e superc&#237;lios&#44; tendem a destruir os fol&#237;culos&#44; resultando em alopecia cicatricial &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>A&#41;&#46; Les&#245;es palmoplantares s&#227;o raras&#44; costumam ser muito dolorosas e podem ulcerar&#8208;se&#46; Excepcionalmente&#44; observam&#8208;se les&#245;es ungueais e periungueais&#46; Al&#233;m da radia&#231;&#227;o solar&#44; as les&#245;es de LED podem ser provocadas por traumatismos&#44; configurando o fen&#244;meno de Koebner&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;3&#44;30</span></a> LED medicamentoso &#233; muito raro&#44; com relatos espor&#225;dicos associados a leflunomida&#44; 5&#8208;fluoruracil&#44; capecitabina&#44; palbociclibe&#44; pembrolizumabe e mais comumente aos agentes anti&#8208;TNF&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">31</span></a> As les&#245;es recentes de LED devem ser diferenciadas da erup&#231;&#227;o polimorfa &#224; luz&#44; sarcoidose&#44; pseudolinfomas&#44; granuloma facial e LE t&#250;mido&#46; As les&#245;es cr&#244;nicas merecem diferencia&#231;&#227;o com l&#250;pus vulgar&#44; ceratose act&#237;nica hipertr&#243;fica&#44; carcinoma espinocelular e ceratoacantoma&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0185" class="elsevierStylePara elsevierViewall">O LED mucoso &#233; relatado em&#160;3&#37;&#8208;25&#37; dos pacientes com LED e costuma ser assintom&#225;tico em 1&#47;4 dos casos&#46; Apresenta&#8208;se classicamente como placas de enantema&#44; com p&#225;pulas cerat&#243;sicas&#44; atrofia ou eros&#227;o central e ceratose radiada ou reticulada na periferia&#46; Pode ainda se manifestar como placas brancas estriadas ou homog&#234;neas&#44; eros&#245;es e ulcera&#231;&#245;es&#46; &#201; mais comum na mucosa oral&#44; principalmente jugal &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>B&#41;&#44; palatina e labial&#44; mas pode acometer a gengiva e a l&#237;ngua&#46; As mucosas nasal&#44; genital e anal tamb&#233;m podem ser afetadas por les&#245;es discoides&#46; &#201; caracter&#237;stica a les&#227;o da conjuntiva ocular&#44; mais comum na margem palpebral inferior&#44; que pode resultar em cicatriz&#44; perda dos c&#237;lios e ectr&#243;pio&#46; H&#225; risco de transforma&#231;&#227;o maligna em carcinoma escamocelular&#44; com maior frequ&#234;ncia nos l&#225;bios&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;22&#44;32</span></a> Seu principal diagn&#243;stico diferencial &#233; o l&#237;quen plano oral&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">O LE hipertr&#243;fico&#44; tamb&#233;m conhecido como LE verrucoso&#44; &#233; variante bastante rara do LECC que se manifesta com les&#245;es eritematosas&#44; papulosas ou nodulares&#44; de superf&#237;cie cerat&#243;sica e algo verrucosa&#44; localizadas principalmente nas regi&#245;es extensoras dos membros superiores &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>A&#41; e eventualmente na face e tronco superior&#46; Costuma haver coexist&#234;ncia de les&#245;es discoides t&#237;picas&#44; que facilitam o diagn&#243;stico&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">2</span></a> Deve ser diferenciado do l&#237;quen plano hipertr&#243;fico&#44; do ceratoacantoma e das verrugas vulgares&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">O LE l&#237;quen plano&#8208;s&#237;mile ou s&#237;ndrome de superposi&#231;&#227;o l&#250;pus eritematoso&#8208;l&#237;quen plano refere&#8208;se &#224; combina&#231;&#227;o de achados cl&#237;nicos&#44; histol&#243;gicos e imunopatol&#243;gicos de ambas as dermatoses&#46; Trata&#8208;se de condi&#231;&#227;o muito rara&#44; de evolu&#231;&#227;o cr&#244;nica e predominante em mulheres&#44; que apresenta placas dolorosas vermelho&#8208;azuladas&#44; escamosas&#44; com centro atr&#243;fico&#44; localizadas nas extremidades superiores e menos frequentemente nas pernas&#44; face e tronco&#59; o acometimento palmoplantar &#233; caracter&#237;stico&#46; Les&#245;es hipertr&#243;ficas tamb&#233;m podem ocorrer&#46; H&#225; ainda relatos de acometimento mucoso&#44; distrofia ungueal e alopecia cicatricial&#44; assim como de casos desencadeados por medicamentos&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;33&#44;34</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">O LE profundo ou paniculite l&#250;pica responde apenas por&#160;2&#37;&#8208;3&#37; dos casos de LECC&#44; &#233; mais frequente em adultos e mulheres e se manifesta com placas e n&#243;dulos subcut&#226;neos&#44; endurecidos&#44; aderidos &#224; pele sobrejacente&#44; geralmente dolorosos&#44; que se localizam principalmente na face&#44; ombros&#44; bra&#231;os&#44; coxas&#44; gl&#250;teos e mamas &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>B&#41;&#46; A pele da superf&#237;cie pode ou n&#227;o apresentar les&#245;es de LED&#46; Costumam causar intensa atrofia do subcut&#226;neo&#44; deixando &#225;reas deprimidas&#44; com desfigura&#231;&#227;o est&#233;tica&#44; sobretudo quando localizadas na face&#46; Eventualmente&#44; evoluem com calcifica&#231;&#227;o e ulcera&#231;&#227;o&#46; A doen&#231;a tem curso cr&#244;nico&#44; entrecortado por per&#237;odos de exacerba&#231;&#227;o e de remiss&#227;o&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;30</span></a> Deve ser diferenciado principalmente de outros tipos de paniculite&#44; do linfoma subcut&#226;neo de c&#233;lulas&#160;T&#160;paniculite&#8208;s&#237;mile e da sarcoidose subcut&#226;nea&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">O LE perni&#243;tico &#233; forma rara de LECC&#44; que se assemelha &#224; perniose e se manifesta por les&#245;es dolorosas&#44; papulosas&#44; nodulares ou edematosas&#44; de tonalidade eritemato&#8208;viol&#225;cea&#46; Podem evoluir com eros&#227;o ou ulcera&#231;&#227;o&#46; S&#227;o desencadeadas pela exposi&#231;&#227;o ao frio e usualmente acometem quirod&#225;tilos e dorso das m&#227;os&#46; Podod&#225;ctilos&#44; regi&#245;es plantares e calcanhares tamb&#233;m podem ser acometidos&#46; Nariz e pavilh&#245;es auriculares s&#227;o menos afetados&#46; Fen&#244;meno de Raynaud pode estar presente em alguns casos&#46; O quadro pode coexistir com les&#245;es de LED ou ocorrer no contexto de LES&#46; Estima&#8208;se que&#160;20&#37; dos pacientes com LE perni&#243;tico venham a desenvolver doen&#231;a sist&#234;mica&#46; Algumas altera&#231;&#245;es imunol&#243;gicas podem ser observadas&#44; como hipergamaglobulinemia&#44; fator reumatoide e FAN positivos&#44; assim como anticorpos antifosfol&#237;pides e antinucleares espec&#237;ficos&#44; principalmente anti&#8208;Ro&#47;SS&#8208;A&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">35</span></a> H&#225; uma forma familiar da doen&#231;a&#44; que se manifesta na inf&#226;ncia&#44; de heran&#231;a autoss&#244;mica dominante&#44; relacionada a muta&#231;&#245;es no gene TREX1 e menos frequentemente nos genes SAMHD1 ou TMEM173&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;36</span></a> O principal diagn&#243;stico diferencial &#233; a perniose idiop&#225;tica&#44; mas ainda devem ser considerados o l&#250;pus p&#233;rnio&#44; uma forma acral de sarcoidose&#44; assim como as vasculites e vasculopatias acrais&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">O LE comedoniano &#233; outra variante rara do LECC&#44; que se manifesta por comedos&#44; p&#225;pulas&#44; placas eritemato&#8208;infiltradas e cistos em &#225;reas seborreicas e fotoexpostas&#44; deixando cicatrizes acneiformes deprimidas&#46; Acomete preferencialmente mulheres jovens e de meia idade&#59; o tabagismo &#233; importante fator de risco&#44; como em outras formas de LECC&#46; Pode ser acompanhado de les&#245;es t&#237;picas de LED&#44; assim como associado ao LES&#46; Costuma ser confundido com acne vulgar&#44; nevo comedoniano e elastoidose nodular com cistos e comed&#245;es&#44; o que geralmente retarda o diagn&#243;stico e o tratamento&#44; resultando em cicatrizes inest&#233;ticas&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">37&#8211;39</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">L&#250;pus eritematoso cut&#226;neo intermitente</span><p id="par0215" class="elsevierStylePara elsevierViewall">Anteriormente categorizado entre as variantes de LECC&#44; o LE t&#250;mido foi reclassificado como LECI em raz&#227;o de seu curso cl&#237;nico&#44; em que se alternam per&#237;odos de remiss&#227;o e de recorr&#234;ncia&#46; &#201; variante rara do LEC&#44; que acomete mais as mulheres &#40;60&#37;&#160;dos casos&#41;&#44; mas a preponder&#226;ncia sobre os homens &#233; menos evidente que nas outras formas de LEC&#46; Uma caracter&#237;stica marcante do LE t&#250;mido &#233; a fotossensibilidade exacerbada&#44; talvez a mais intensa entre todas as formas de LEC&#46; Manifesta&#8208;se por placas &#250;nicas ou m&#250;ltiplas&#44; eritemato&#8208;edematosas&#44; de superf&#237;cie lisa&#44; que podem assumir configura&#231;&#227;o anular ou arciforme &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>A&#41;&#46; Localizam&#8208;se em &#225;reas fotoexpostas&#44; principalmente na face&#44; pesco&#231;o&#44; tronco superior e membros superiores&#46; &#201; usual a resolu&#231;&#227;o espont&#226;nea das les&#245;es em algumas semanas&#44; sem deixar discromia ou cicatriz&#44; mas sobrev&#234;m epis&#243;dios com novas les&#245;es&#46; &#201; mais comum a ocorr&#234;ncia na forma isolada&#44; mas pode estar associado a outras formas de LEC&#44; principalmente LED&#44; e raramente ao LES&#46; Altera&#231;&#245;es imunol&#243;gicas tamb&#233;m s&#227;o incomuns&#44; como FAN e anticorpos antinucleares espec&#237;ficos&#46; Deve ser diferenciado da erup&#231;&#227;o polimorfa &#224; luz&#44; LED inicial&#44; mucinose reticular eritematosa e pseudolinfomas cut&#226;neos&#44; como a infiltra&#231;&#227;o linfocit&#225;ria de Jessner&#44; considerada por muitos autores como o pr&#243;prio LE t&#250;mido&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;40&#44;41</span></a></p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">L&#250;pus eritematoso bolhoso</span><p id="par0220" class="elsevierStylePara elsevierViewall">O LE bolhoso &#233; dermatose bolhosa autoimune&#44; subepid&#233;rmica&#44; sempre associada ao LES&#44; mediada por autoanticorpos contra o col&#225;geno&#160;VII&#46; Manifesta&#8208;se por ves&#237;culas e bolhas tensas &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>B&#41; que surgem subitamente sobre pele s&#227; ou sobre placas eritematosas e infiltradas&#44; eventualmente assumindo configura&#231;&#227;o anular&#46; Preferem face&#44; tronco superior&#44; pesco&#231;o&#44; regi&#245;es supraclaviculares e flexuras axilares&#44; mas podem disseminar&#8208;se para outras &#225;reas n&#227;o expostas&#46; N&#227;o costumam ser acompanhadas de les&#245;es espec&#237;ficas de LEC&#44; a n&#227;o ser eritema malar&#44; que pode surgir posteriormente&#44; ao longo da evolu&#231;&#227;o da doen&#231;a&#46; As mucosas oral e genital podem ser acometidas&#59; s&#227;o t&#237;picas as les&#245;es labiais e periorais&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">42</span></a> &#201; mais comum em mulheres negras&#44; entre a segunda e quarta d&#233;cadas de vida&#46; O LE bolhoso se instala antes&#44; concomitantemente e&#44; menos frequentemente&#44; ap&#243;s o diagn&#243;stico do LES&#44; podendo ser marcador de intensa atividade sist&#234;mica&#44; com maior risco de nefrite l&#250;pica e manifesta&#231;&#245;es neuropsiqui&#225;tricas&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">43</span></a> As les&#245;es evoluem com eros&#227;o e crostas&#44; regredindo sem cicatrizes e m&#237;lios&#44; mas podem deixar discromia residual&#46; &#201; incomum a recorr&#234;ncia&#44; mesmo com a persist&#234;ncia de doen&#231;a sist&#234;mica ativa&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">44</span></a> Deve ser diferenciado da epiderm&#243;lise bolhosa adquirida&#44; dermatose bolhosa por IgA linear&#44; dermatite herpetiforme e penfigoide bolhoso&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Manifesta&#231;&#245;es cut&#226;neas inespec&#237;ficas do l&#250;pus eritematoso</span><p id="par0225" class="elsevierStylePara elsevierViewall">Exclu&#237;dos os subtipos cl&#237;nicos e respectivas variantes anteriormente expostos&#44; todas as demais manifesta&#231;&#245;es cut&#226;neas associadas ao LE devem ser consideradas inespec&#237;ficas&#46; Est&#227;o associadas ao LES e geralmente guardam rela&#231;&#227;o com a atividade da doen&#231;a&#46; No entanto&#44; n&#227;o s&#227;o exclusivas do LES&#44; podendo ocorrer em outras condi&#231;&#245;es&#44; geralmente de natureza autoimune ou autoinflamat&#243;ria&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">45&#8211;47</span></a> O LE bolhoso&#44; embora classificado como manifesta&#231;&#227;o inespec&#237;fica&#44; neutrof&#237;lica&#44; associada ao LE&#44; deveria ser considerado subtipo cl&#237;nico espec&#237;fico de LEC&#44; pelo fato de sempre estar associado ao LES&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">11</span></a> As manifesta&#231;&#245;es inespec&#237;ficas mais comuns est&#227;o listadas na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Diagn&#243;stico</span><p id="par0230" class="elsevierStylePara elsevierViewall">O diagn&#243;stico do LEC se fundamenta nos dados colhidos na anamnese e no exame f&#237;sico&#44; em combina&#231;&#227;o com os achados da histopatologia e&#44; eventualmente&#44; da imuno&#8208;histologia das les&#245;es cut&#226;neas&#44; para defini&#231;&#227;o do subtipo cl&#237;nico&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">O tipo e a abrang&#234;ncia da investiga&#231;&#227;o laboratorial devem ser adequados a cada paciente&#44; individualmente&#44; a depender do subtipo de LEC definido com base nos achados cl&#237;nicos e histopatol&#243;gicos&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Devem ser realizados exames bioqu&#237;micos de rotina que auxiliem na identifica&#231;&#227;o de poss&#237;vel doen&#231;a sist&#234;mica&#44; al&#233;m de exames espec&#237;ficos&#44; conforme o tratamento proposto&#44; antes de iniciar a medica&#231;&#227;o e para monitorar seus potenciais efeitos adversos&#46; Exames adicionais podem ser necess&#225;rios ap&#243;s a confirma&#231;&#227;o do diagn&#243;stico e defini&#231;&#227;o do subtipo de LEC&#44; que incluem testes sorol&#243;gicos para caracterizar o perfil de autoanticorpos e testes para avaliar a atividade sist&#234;mica da doen&#231;a&#44; assim como exames complementares para investigar acometimento de &#243;rg&#227;os espec&#237;ficos&#44; que podem auxiliar na determina&#231;&#227;o do progn&#243;stico&#46; Os principais exames laboratoriais recomendados no LEC est&#227;o listados na <a class="elsevierStyleCrossRef" href="#tbl0020">tabela 4</a>&#46; Nos casos de LES&#44; faz&#8208;se necess&#225;ria a interven&#231;&#227;o do reumatologista e eventualmente de outros especialistas&#44; que devem orientar a proped&#234;utica complementar individualizada para cada paciente&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">48</span></a></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0245" class="elsevierStylePara elsevierViewall">&#201; importante que a defini&#231;&#227;o de doen&#231;a sist&#234;mica n&#227;o fique estritamente condicionada aos crit&#233;rios diagn&#243;sticos inclu&#237;dos nos sistemas de classifica&#231;&#227;o&#44; como o SLICC&#160;2012 e o EULAR&#47;ACR&#160;2019&#44; que foram primordialmente desenvolvidos com objetivo de se obter uniformidade diagn&#243;stica na sele&#231;&#227;o de pacientes para ensaios cl&#237;nicos&#44; mas n&#227;o s&#227;o capazes de abranger todas as manifesta&#231;&#245;es que podem ocorrer no LES&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">30</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">O uso de escores de atividade da doen&#231;a&#44; originalmente criados para mensura&#231;&#227;o de desfechos em ensaios cl&#237;nicos&#44; &#233; recomend&#225;vel na pr&#225;tica cl&#237;nica&#44; por permitir an&#225;lise mais objetiva da evolu&#231;&#227;o da doen&#231;a no seguimento dos pacientes com LEC&#44; podendo servir de par&#226;metro na avalia&#231;&#227;o da resposta ao tratamento indicado&#46;</p><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Histopatologia</span><p id="par0255" class="elsevierStylePara elsevierViewall">As diferentes formas de LEC&#44; com exce&#231;&#227;o do LE profundo e do LE t&#250;mido&#44; compartilham os achados histopatol&#243;gicos&#44; tornando indispens&#225;vel uma estreita correla&#231;&#227;o cl&#237;nico&#8208;patol&#243;gica para defini&#231;&#227;o do subtipo&#46; A diferencia&#231;&#227;o histopatol&#243;gica depende da evolu&#231;&#227;o e do est&#225;gio das les&#245;es&#46; Assim&#44; do ponto de vista histol&#243;gico&#44; o LE poderia ser classificado em recente &#40;LECA&#44; LECS e LED inicial&#41;&#44; completamente desenvolvido &#40;LED&#41; e tardio &#40;LED atr&#243;fico&#8208;cicatricial&#41;&#46; As altera&#231;&#245;es tendem a ser mais sutis nas les&#245;es recentes e bastante evidentes nas les&#245;es totalmente desenvolvidas&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;49</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">Os principais achados s&#227;o o infiltrado inflamat&#243;rio linfoc&#237;tico perivascular e perianexial na derme superficial e profunda&#44; assim como a dermatite de interface&#44; caracterizada pela agress&#227;o de linf&#243;citos &#224; jun&#231;&#227;o dermoepid&#233;rmica&#46; Como consequ&#234;ncia&#44; outras altera&#231;&#245;es ocorrem&#44; como a degenera&#231;&#227;o vacuolar da camada basal e a necrose de ceratin&#243;citos nas camadas inferiores da epiderme&#44; seguidas por espessamento da membrana basal&#46; A epiderme torna&#8208;se atr&#243;fica e as cristas epiteliais&#44; achatadas&#46; A deposi&#231;&#227;o de mucina na derme &#233; um achado t&#237;pico do LE&#44; embora inespec&#237;fico&#44; variando em intensidade conforme o tipo de les&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">47</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">No LED&#44; prot&#243;tipo das les&#245;es completamente desenvolvidas&#44; al&#233;m das altera&#231;&#245;es j&#225; descritas&#44; bastante proeminentes&#44; s&#227;o muito evidentes os achados de hiperceratose&#44; tamp&#245;es c&#243;rneos foliculares e atrofia epid&#233;rmica&#46; O est&#225;gio tardio e cicatricial do LED mostra incontin&#234;ncia pigmentar&#44; ectasia vascular&#44; fibrose d&#233;rmica e perda dos anexos&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;47</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">No LECA&#44; as altera&#231;&#245;es costumam ser mais discretas&#44; podendo haver edema e hemorragia na derme superficial&#46; O infiltrado linfoc&#237;tico &#233; discreto&#44; apenas perivascular e superficial&#44; com presen&#231;a de neutr&#243;filos nas les&#245;es mais recentes&#46; A variante NET&#8208;s&#237;mile de LECA mostra intensa degenera&#231;&#227;o hidr&#243;pica da basal&#44; que resulta em disceratose&#44; clivagem subepid&#233;rmica e necrose completa da epiderme&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;47</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">No LECS&#44; a dermatite de interface costuma ser intensa&#44; havendo muitos corpos citoides&#46; O infiltrado linfoc&#237;tico &#233; superficial e predominantemente perivascular&#46; A atrofia da epiderme&#44; a hiperceratose&#44; os tamp&#245;es foliculares&#44; a deposi&#231;&#227;o de mucina e o espessamento da membrana basal s&#227;o menos proeminentes que no LED&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;47</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">O LE hipertr&#243;fico&#44; al&#233;m das altera&#231;&#245;es observadas no LED&#44; mostra acantose e acentuada hiperplasia pseudoepiteliomatosa&#44; al&#233;m de intensa hiperceratose&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">47&#44;49</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">O LE profundo apresenta&#8208;se como paniculite linfoc&#237;tica lobular&#44; com n&#243;dulos linfoides parasseptais e necrose hialina dos adip&#243;citos&#44; presen&#231;a de plasm&#243;citos&#44; al&#233;m de deposi&#231;&#227;o de mucina na derme reticular e ocasionalmente na hipoderme&#46; Fibrose e calcifica&#231;&#227;o podem ser observadas nos est&#225;gios finais das les&#245;es&#46; As altera&#231;&#245;es epid&#233;rmicas e d&#233;rmicas caracter&#237;sticas do LE podem estar presentes em metade dos casos&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">47&#44;49</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">O LE t&#250;mido caracteriza&#8208;se por intenso infiltrado linfoc&#237;tico perivascular na derme superficial e profunda&#44; al&#233;m de abundante deposi&#231;&#227;o de mucina&#44; sem a presen&#231;a das altera&#231;&#245;es epid&#233;rmicas e da dermatite de interface&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">47&#44;49</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">Nas les&#245;es de LE perni&#243;tico&#44; al&#233;m dos achados caracter&#237;sticos de LE&#44; em menor intensidade que no LED&#44; destacam&#8208;se a presen&#231;a de vasculite linfoc&#237;tica&#44; eventualmente com necrose fibrinoide e trombose&#44; edema da derme papilar e infiltrado linfoc&#237;tico peri&#233;crino&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">47&#44;49</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall">O LE bolhoso mostra infiltrado inflamat&#243;rio predominante de neutr&#243;filos&#44; que costuma estar alinhado &#224; jun&#231;&#227;o dermoepid&#233;rmica e formar microabscessos nas papilas d&#233;rmicas&#44; al&#233;m de clivagem subepid&#233;rmica e bolha com neutr&#243;filos no interior&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">47&#44;49</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Imuno&#8208;histologia</span><p id="par0305" class="elsevierStylePara elsevierViewall">O teste da imunofluoresc&#234;ncia direta &#40;IFD&#41;&#44; realizado em cortes de tecido obtido por bi&#243;psia da les&#227;o cut&#226;nea&#44; visa identificar imunodep&#243;sitos na jun&#231;&#227;o dermoepid&#233;rmica&#44; conhecido como teste da banda l&#250;pica &#40;TBL&#41;&#46; Geralmente&#44; faz&#8208;se a pesquisa de imunodep&#243;sitos de IgG&#44; IgM&#44; IgA e C3&#46; O TBL &#233; considerado positivo quando identificada a deposi&#231;&#227;o de material granular em faixa junto &#224; zona da membrana basal&#46; &#201; recurso que pode auxiliar no diagn&#243;stico&#44; se a histologia n&#227;o &#233; decisiva frente a les&#245;es sugestivas de LE&#44; por&#233;m n&#227;o &#233; espec&#237;fico para a doen&#231;a&#44; podendo ser observado em outras condi&#231;&#245;es dermatol&#243;gicas&#44; como dermatomiosite&#44; e mesmo na pele normal ou fotodanificada&#44; principalmente da face&#46;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">48&#44;50</span></a> O tipo de dep&#243;sito varia conforme a cronologia e a topografia da les&#227;o&#44; assim como o local biopsiado&#44; se no centro ou periferia da les&#227;o&#46; IgM e IgG s&#227;o os imunodep&#243;sitos mais detectados&#44; em associa&#231;&#227;o ou n&#227;o com C3&#59; IgA &#233; menos comum&#46; O TBL costuma ser positivo na pele lesada de quase&#160;100&#37; dos casos de LECA&#44; em cerca de&#160;60&#37; dos casos de LECS e de&#160;90&#37; dos casos de LED&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">11&#44;19&#44;47</span></a></p><p id="par0310" class="elsevierStylePara elsevierViewall">Estudo recente que avaliou 2&#46;050 bi&#243;psias cut&#226;neas submetidas &#224; histologia e imunofluoresc&#234;ncia direta&#44; com hip&#243;teses diagn&#243;sticas de diferentes dermatoses&#44; concluiu que o valor da IFD no aux&#237;lio diagn&#243;stico do LE &#233; question&#225;vel e seu uso n&#227;o &#233; recomendado como rotina&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">50</span></a> Embora o TBL positivo na pele n&#227;o lesada e n&#227;o exposta seja altamente espec&#237;fico para LES&#44; ele acrescenta pouca informa&#231;&#227;o aos achados obtidos conjuntamente pelo exame cl&#237;nico&#44; histopatologia e sorologia&#46; Al&#233;m disso&#44; foi demonstrada sua associa&#231;&#227;o com a presen&#231;a de anticorpos anti&#8208;DNAn no soro&#44; por&#233;m com taxas de sensibilidade e especificidade similares&#44; sugerindo ser redundante a utiliza&#231;&#227;o de ambos os testes&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">50</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">No LE bolhoso&#44; a IFD da pele perilesional demonstra dep&#243;sito cont&#237;nuo&#44; de padr&#227;o linear ou granular&#44; ao longo da zona da membrana basal&#44; principalmente de IgG&#44; al&#233;m de IgM&#44; IgA e C3&#46; A imunofluoresc&#234;ncia indireta&#44; pela t&#233;cnica de <span class="elsevierStyleItalic">salt&#8208;split skin</span>&#44; revela dep&#243;sito do lado d&#233;rmico da clivagem&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">42&#44;47</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Anticorpos antinucleares</span><p id="par0320" class="elsevierStylePara elsevierViewall">Os autoanticorpos antinucleares s&#227;o marcadores imunol&#243;gicos empregados tanto no diagn&#243;stico quanto na monitora&#231;&#227;o da doen&#231;a no LE&#46; O teste de triagem mais usado &#233; o fator antin&#250;cleo &#40;FAN&#41;&#44; que utiliza a t&#233;cnica da imunofluoresc&#234;ncia indireta&#44; tendo as c&#233;lulas HEp&#8208;2 como substrato&#46; O FAN tem maior relev&#226;ncia no LECA&#47;LES&#44; em que &#233; demonstrado em quase todos os pacientes &#40;94&#37;&#8208;100&#37;&#41;&#44; geralmente em t&#237;tulos elevados&#44; superiores a&#160;1&#47;160&#46; No entanto&#44; mesmo em altos t&#237;tulos&#44; n&#227;o s&#227;o espec&#237;ficos para LES&#44; j&#225; que podem ser detectados em v&#225;rias condi&#231;&#245;es&#44; como outras doen&#231;as do tecido conjuntivo&#44; doen&#231;as hematol&#243;gicas e hep&#225;ticas&#44; infec&#231;&#245;es virais&#44; uso de v&#225;rios medicamentos e at&#233; em indiv&#237;duos saud&#225;veis&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">51</span></a> O FAN &#233; demonstrado em menor propor&#231;&#227;o nas outras formas de LEC&#44; em&#160;52&#37;&#8208;80&#37; dos pacientes de LECS e em&#160;5&#37;&#8208;17&#37; dos pacientes de LED&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0325" class="elsevierStylePara elsevierViewall">Por n&#227;o ser um teste espec&#237;fico para LE&#44; &#233; fundamental que&#44; frente a FAN positivo&#44; a especificidade do anticorpo antinuclear seja determinada por meio de testes adicionais&#46;</p><p id="par0330" class="elsevierStylePara elsevierViewall">Os anticorpos anti&#8208;DNAn e anti&#8208;Sm s&#227;o os mais relevantes por serem espec&#237;ficos para LES&#44; embora apresentem menor sensibilidade&#44; de&#160;56&#37;&#8208;70&#37; e 19&#37;&#8208;25&#37;&#44; respectivamente&#46; Al&#233;m do valor diagn&#243;stico&#44; o anticorpo anti&#8208;DNAn pode ser usado para monitora&#231;&#227;o da doen&#231;a&#44; j&#225; que seus n&#237;veis s&#233;ricos tendem a refletir a atividade da doen&#231;a&#44; em especial a nefropatia&#44; sobretudo quando h&#225; concomit&#226;ncia com o anticorpo anti&#8208;Sm&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;51</span></a> &#201; baixa a preval&#234;ncia dos anticorpos anti&#8208;DNAn e anti&#8208;Sm nos pacientes de LECS&#44; e praticamente nula nos pacientes de LECC&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">19&#44;25</span></a></p><p id="par0335" class="elsevierStylePara elsevierViewall">Os anticorpos anti&#8208;Ro&#47;SS&#8208;A e anti&#8208;La&#47;SS&#8208;B n&#227;o s&#227;o espec&#237;ficos do LE e est&#227;o frequentemente associados &#224; s&#237;ndrome de Sj&#246;gren&#46; Ocorrem&#44; respectivamente&#44; em 36&#37;&#8208;64&#37; e 8&#37;&#8208;33&#37; dos pacientes de LES e guardam rela&#231;&#227;o com as manifesta&#231;&#245;es cut&#226;neas e hematol&#243;gicas&#44; como as citopenias&#46; Os anticorpos anti&#8208;Ro&#47;SS&#8208;A e anti&#8208;La&#47;SS&#8208;B est&#227;o presentes entre 70&#37;&#8208;90&#37; e&#160;30&#37;&#8208;40&#37;&#44; respectivamente&#44; dos casos de LECS&#44; e em at&#233;&#160;25&#37;&#160;e&#160;5&#37;&#44; respectivamente&#44; dos casos de LED&#46; Particularmente&#44; os anticorpos anti&#8208;Ro&#47;SS&#8208;A s&#227;o considerados marcadores do LECS e est&#227;o relacionados com a extrema fotossensibilidade deste subtipo de LEC&#46; Al&#233;m disso&#44; quando presentes na gestante&#44; esses anticorpos atravessam a barreira placent&#225;ria e podem causar LE neonatal&#46; Os anticorpos especificamente dirigidos contra a subunidase&#160;52&#160;kD do ant&#237;geno Ro&#47;SS&#8208;A est&#227;o associados a maior risco de bloqueio card&#237;aco cong&#234;nito&#46; Adultos com esses anticorpos tamb&#233;m podem apresentar prolongamento do intervalo QT&#44; com maior risco de desenvolver arritmias ventriculares&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">51</span></a></p><p id="par0340" class="elsevierStylePara elsevierViewall">Anticorpos anti&#8208;RNP s&#227;o caracter&#237;sticos da doen&#231;a mista do tecido conjuntivo&#44; mas podem estar presentes em&#160;23&#37;&#8208;49&#37; dos pacientes de LES e n&#227;o mostram correla&#231;&#227;o com quaisquer manifesta&#231;&#245;es da doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">51</span></a> Podem ocorrer entre&#160;8&#37;&#8208;10&#37; dos casos de LECS e muito raramente no LECC&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Avalia&#231;&#227;o da atividade e dano cut&#226;neos</span><p id="par0345" class="elsevierStylePara elsevierViewall">Pacientes diagnosticados com LEC devem ser submetidos a exame dermatol&#243;gico completo&#44; n&#227;o apenas durante epis&#243;dios de exacerba&#231;&#227;o da doen&#231;a&#44; mas tamb&#233;m a intervalos regulares&#44; com o objetivo de se avaliar a atividade e a progress&#227;o da doen&#231;a&#44; assim como identificar poss&#237;veis danos decorrentes do acometimento cut&#226;neo&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">V&#225;rios escores de atividade da doen&#231;a est&#227;o bem estabelecidos na avalia&#231;&#227;o de pacientes com LES&#44; para uso em ensaios cl&#237;nicos e na pr&#225;tica cotidiana&#44; como o SLEDAI &#40;<span class="elsevierStyleItalic">Systemic Lupus Erythematosus Disease Activity Index</span>&#41;&#46; Apesar de inclu&#237;rem alguns crit&#233;rios dermatol&#243;gicos&#44; esses escores carecem de sensibilidade para avaliar a atividade cut&#226;nea nos diferentes subtipos de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">12</span></a></p><p id="par0355" class="elsevierStylePara elsevierViewall">Por essa raz&#227;o&#44; foi criado o CLASI &#40;<span class="elsevierStyleItalic">Cutaneous Lupus Area and Severity Index</span>&#41;&#44; um instrumento desenvolvido especificamente para quantificar o acometimento cut&#226;neo no LE&#44; com escores de atividade &#40;CLASI&#8208;A&#41; e de dano &#40;CLASI&#8208;D&#41;&#46; Esse instrumento avalia a morfologia &#40;eritema&#44; descama&#231;&#227;o&#47;ceratose&#44; discromia e cicatriz&#47;atrofia&#41; e a localiza&#231;&#227;o anat&#244;mica &#40;13&#160;s&#237;tios&#41; das les&#245;es cut&#226;neas&#44; assim como o acometimento de mucosas e couro cabeludo&#46; Foi originalmente estabelecido como recurso para mensurar desfechos em ensaios cl&#237;nicos e validado por dermatologistas e reumatologistas&#46; O CLASI ainda demonstrou boa correla&#231;&#227;o com indicadores da qualidade de vida dos pacientes e revelou&#8208;se instrumento &#250;til e de f&#225;cil aplica&#231;&#227;o na pr&#225;tica cl&#237;nica&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">11&#44;12&#44;53</span></a></p><p id="par0360" class="elsevierStylePara elsevierViewall">Posteriormente&#44; surgiu o CLASI revisado &#40;RCLASI&#41;&#44; que acrescentou novos par&#226;metros &#8211; edema&#47;infiltra&#231;&#227;o e placas&#47;n&#243;dulos subcut&#226;neos &#8211; com o intuito de melhorar a acur&#225;cia na avalia&#231;&#227;o da atividade da doen&#231;a cut&#226;nea&#44; sendo capaz de abranger aspectos importantes de alguns subtipos de LEC&#44; como o LE t&#250;mido e o LE profundo&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">48</span></a></p><p id="par0365" class="elsevierStylePara elsevierViewall">Entretanto&#44; uma recente revis&#227;o sistem&#225;tica constatou que&#44; dentre os ensaios que utilizaram o CLASI como medida de desfecho de interven&#231;&#245;es terap&#234;uticas&#44; s&#227;o poucos com alta qualidade de evid&#234;ncia&#46; Esse estudo concluiu que &#233; necess&#225;ria valida&#231;&#227;o adicional para averiguar a efetividade do CLASI na avalia&#231;&#227;o dos diferentes subtipos de LEC&#46; Os autores sugerem que o uso de medidas de desfecho padronizadas&#44; referidas por paciente e m&#233;dico&#44; poderiam reduzir a heterogeneidade e permitir compara&#231;&#245;es entre pacientes inclu&#237;dos em diferentes ensaios cl&#237;nicos&#46; Tamb&#233;m recomendam que o CLASI&#8208;50 &#40;redu&#231;&#227;o de&#160;50&#37; na pontua&#231;&#227;o do CLASI&#8208;A&#41; poderia ser mais efetivo como medida de resposta terap&#234;utica que o CLASI&#8208;20 &#40;redu&#231;&#227;o de&#160;20&#37; no CLASI&#8208;A&#41;&#44; usualmente utilizado como crit&#233;rio de boa resposta nos ensaios cl&#237;nicos&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">54</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Progress&#227;o de l&#250;pus cut&#226;neo a l&#250;pus eritematoso sist&#234;mico</span><p id="par0370" class="elsevierStylePara elsevierViewall">De&#160;5&#37;&#8208;25&#37; dos casos de LEC isolado&#44; independentemente do subtipo&#44; podem progredir para LES durante sua evolu&#231;&#227;o&#44; com tempo m&#233;dio de&#160;oito&#160;anos entre o diagn&#243;stico da doen&#231;a cut&#226;nea e o desenvolvimento da doen&#231;a sist&#234;mica&#46; Estudo de base populacional desenvolvido na Su&#233;cia mostrou que a maior possibilidade de desenvolver LES ocorre at&#233;&#160;tr&#234;s&#160;anos ap&#243;s o diagn&#243;stico da doen&#231;a cut&#226;nea&#44; al&#233;m de ser mais prov&#225;vel nas mulheres&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0375" class="elsevierStylePara elsevierViewall">Por outro lado&#44; aproximadamente&#160;50&#37;&#8208;60&#37; dos pacientes de LECS experimentam transi&#231;&#227;o ou j&#225; podem ser classificados como LES quando do diagn&#243;stico da doen&#231;a cut&#226;nea&#44; geralmente preenchendo crit&#233;rios cut&#226;neos&#44; musculoesquel&#233;ticos e sorol&#243;gicos&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0380" class="elsevierStylePara elsevierViewall">Entretanto&#44; os pacientes de LEC que progridem para LES tendem a apresentar sintomas sist&#234;micos mais leves&#59; s&#227;o raras as manifesta&#231;&#245;es cardiopulmonares e neurol&#243;gicas&#44; assim como outras complica&#231;&#245;es graves da doen&#231;a&#46; Crit&#233;rios relacionados &#224; nefropatia s&#227;o indicadores relevantes de diferencia&#231;&#227;o entre doen&#231;a cut&#226;nea isolada e doen&#231;a sist&#234;mica&#46; Quando presente&#44; o acometimento renal tende a ser menos grave naqueles que evoluem de LEC a LES&#44; por&#233;m faltam estudos mais consistentes para permitir essa conclus&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0385" class="elsevierStylePara elsevierViewall">H&#225; evid&#234;ncia de que LED e LECS com les&#245;es disseminadas exibem maior probabilidade de evolu&#237;rem com manifesta&#231;&#245;es sist&#234;micas que aqueles com les&#245;es localizadas&#46; Estudo retrospectivo&#44; que comparou pacientes de LED com doen&#231;a localizada e pacientes de LED e LECS com doen&#231;a disseminada&#44; mostrou que&#160;30&#37; dos casos com les&#245;es disseminadas apresentaram manifesta&#231;&#245;es extracut&#226;neas&#44; como nefrite&#44; pleurite e poliartrite&#44; enquanto aqueles com doen&#231;a localizada n&#227;o tiveram manifesta&#231;&#245;es sist&#234;micas&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0390" class="elsevierStylePara elsevierViewall">As les&#245;es cut&#226;neas inespec&#237;ficas prevalecem no LES&#44; principalmente com doen&#231;a em atividade&#46; Por isso&#44; quando presentes&#44; implica maior probabilidade de doen&#231;a sist&#234;mica&#44; em particular a ocorr&#234;ncia de telangiectasias periungueais&#46; A presen&#231;a dessas les&#245;es foi verificada em&#160;76&#37; dos pacientes de LES com LED concomitante e em nenhum paciente com LED exclusivo&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0395" class="elsevierStylePara elsevierViewall">Pacientes de LEC com potencial de desenvolver LES t&#234;m maior probabilidade de apresentar FAN com t&#237;tulos elevados em compara&#231;&#227;o com aqueles de LEC exclusivo&#46; Al&#233;m de marcadores de acometimento sist&#234;mico importante nos pacientes de LES&#44; t&#237;tulos elevados do FAN e a presen&#231;a dos anticorpos espec&#237;ficos anti&#8208;DNAn ou anti&#8208;Sm tamb&#233;m s&#227;o indicativos de evolu&#231;&#227;o para doen&#231;a sist&#234;mica nos pacientes com LEC&#46;</p><p id="par0400" class="elsevierStylePara elsevierViewall">Outras altera&#231;&#245;es laboratoriais persistentes&#44; como anemia&#44; leucopenia&#44; trombocitopenia e eleva&#231;&#227;o da velocidade de hemossedimenta&#231;&#227;o&#44; tamb&#233;m s&#227;o consideradas importantes marcadores de progress&#227;o para LES&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0405" class="elsevierStylePara elsevierViewall">Tamb&#233;m &#233; mat&#233;ria de discuss&#227;o se a administra&#231;&#227;o precoce de antimal&#225;ricos em pacientes de LEC&#44; com potencial de desenvolver doen&#231;a sist&#234;mica&#44; poderia prevenir a progress&#227;o a LES ou atenuar danos a &#243;rg&#227;os vitais&#44; uma vez instalada a doen&#231;a sist&#234;mica&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p><p id="par0410" class="elsevierStylePara elsevierViewall">Recomenda&#8208;se seguimento peri&#243;dico&#44; a intervalos mais curtos&#44; de pacientes com LEC que apresentam fatores de risco para progress&#227;o a LES&#44; com exame cl&#237;nico minucioso e adequada revis&#227;o laboratorial&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Tratamento</span><p id="par0415" class="elsevierStylePara elsevierViewall">O tratamento do LEC envolve medidas farmacol&#243;gicas e n&#227;o farmacol&#243;gicas&#46; Escolher a terapia mais eficaz para cada caso pode ser desafiador e exige aten&#231;&#227;o &#224;s manifesta&#231;&#245;es cl&#237;nicas e familiaridade com as terapias dispon&#237;veis&#46; &#201; importante avaliar a ades&#227;o do paciente ao tratamento em cada consulta&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Embora existam apenas tr&#234;s f&#225;rmacos aprovados pela ag&#234;ncia norte&#8208;americana Food and Drug Administration &#40;FDA&#41; para uso no LES &#8211; corticosteroides&#44; hidroxicloroquina e belimumabe &#8211; e nenhuma aprovada especificamente para LEC&#44; &#233; poss&#237;vel encontrar dados na literatura que permitem racionalizar a abordagem terap&#234;utica&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">56</span></a></p><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Medidas gerais</span><p id="par0420" class="elsevierStylePara elsevierViewall">A fotoprote&#231;&#227;o &#233; pilar fundamental do tratamento do LEC&#46; Os fotoprotetores podem prevenir o surgimento de les&#245;es nos pacientes com LEC&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;55&#8211;58</span></a> Entretanto&#44; outras medidas de cuidado tamb&#233;m se somam a seu uso&#44; como mudan&#231;as comportamentais&#44; uso de chap&#233;us e vestes longas&#44; preferencialmente com tecnologia para prote&#231;&#227;o &#224; RUV&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;58&#44;59</span></a></p><p id="par0425" class="elsevierStylePara elsevierViewall">A cessa&#231;&#227;o do tabagismo deve ser averiguada e encorajada a cada consulta&#44; de prefer&#234;ncia com referenciamento do paciente a programas e terapias de apoio&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;57</span></a> A suplementa&#231;&#227;o de vitamina D nos pacientes com defici&#234;ncia pode ser ben&#233;fica para o controle da doen&#231;a&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">56&#44;57&#44;60</span></a> Em caso de LEC induzido por f&#225;rmacos&#44; a medica&#231;&#227;o suspeita deve ser prontamente suspensa&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a></p><p id="par0430" class="elsevierStylePara elsevierViewall">Contracep&#231;&#227;o pode ser necess&#225;ria quando do uso de f&#225;rmacos teratog&#234;nicos&#46; Mulheres com LEC podem utilizar contraceptivos orais combinados&#44; se n&#227;o houver hist&#243;ria de tromboembolismo ou altos n&#237;veis de anticorpos antifosfol&#237;pides&#59; caso contr&#225;rio&#44; deve&#8208;se optar por dispositivo intrauterino ou uso de progest&#225;genos isolados&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">45&#44;61</span></a></p><p id="par0435" class="elsevierStylePara elsevierViewall">O uso de camuflagem cosm&#233;tica e pr&#243;teses de cabelos podem ocultar cicatrizes e alopecia&#44; melhorando a qualidade de vida e a autoestima dos pacientes&#46;<a class="elsevierStyleCrossRefs" href="#bib0645"><span class="elsevierStyleSup">59&#44;62</span></a> &#201; importante que pacientes com LEC sejam orientados a evitar interven&#231;&#245;es que traumatizem a pele&#44; pelo risco de koebneriza&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">62</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Tratamento t&#243;pico</span><p id="par0440" class="elsevierStylePara elsevierViewall">Os corticosteroides s&#227;o considerados a primeira linha de tratamento t&#243;pico&#44; por seu efeito anti&#8208;inflamat&#243;rio&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;6</span></a> Podem ser utilizados nos casos de les&#245;es localizadas ou como terapia adjuvante nos pacientes em tratamento sist&#234;mico&#46; Corticosteroides potentes&#44; como o clobetasol&#44; s&#227;o mais eficazes para o controle da doen&#231;a que os de baixa pot&#234;ncia&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">56&#44;61</span></a> Entretanto&#44; essas medica&#231;&#245;es est&#227;o associadas a maior risco de efeitos colaterais&#44; como estrias e telangiectasias&#44; por seu efeito nos fibroblastos e vasos sangu&#237;neos&#44; respectivamente&#44; al&#233;m de dermatite perioral rosaceiforme&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;60</span></a> Por isso&#44; a terapia com corticosteroides t&#243;picos potentes deve ser usada pelo menor tempo poss&#237;vel&#46; A inje&#231;&#227;o intralesional de corticoide pode ser aplicada em les&#245;es hipertr&#243;ficas localizadas&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;55</span></a></p><p id="par0445" class="elsevierStylePara elsevierViewall">Os inibidores t&#243;picos da calcineurina &#8211; tacrolimo&#160;0&#44;03&#37;&#160;ou&#160;0&#44;1&#37; em pomada e pimecrolimo&#160;1&#37; em creme &#8211; podem ser utilizados como substitutos dos corticosteroides nos casos que exijam tratamento prolongado ou com maior risco de efeitos colaterais&#44; como les&#245;es na face de crian&#231;as&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;61</span></a> S&#227;o menos eficazes que os corticoides t&#243;picos potentes&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> Os efeitos colaterais relacionados ao uso dessas medica&#231;&#245;es incluem sensa&#231;&#227;o de ard&#234;ncia&#44; prurido e eritema no local da aplica&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">57</span></a> Alguns estudos mostraram bons resultados com a aplica&#231;&#227;o combinada de clobetasol&#160;0&#44;05&#37; e tacrolimo&#160;0&#44;03&#37;&#46;</p><p id="par0450" class="elsevierStylePara elsevierViewall">O R&#8208;salbutamol &#233; um agonista do receptor &#946;2&#8208;adren&#233;rgico que inibe a produ&#231;&#227;o de IL&#8208;2 e IFN&#8208;&#947;&#44; podendo melhorar les&#245;es de LEC&#44; quando utilizado a&#160;0&#44;5&#37; em creme&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;60</span></a> Entretanto&#44; n&#227;o &#233; comercialmente dispon&#237;vel para uso t&#243;pico&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a> Os retinoides t&#243;picos j&#225; foram utilizados com sucesso em algumas pequenas s&#233;ries de casos&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Tratamento sist&#234;mico</span><p id="par0455" class="elsevierStylePara elsevierViewall">Pacientes com les&#245;es localizadas refrat&#225;rias ao tratamento t&#243;pico ou com les&#245;es disseminadas geralmente necessitam de tratamento sist&#234;mico&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> A <a class="elsevierStyleCrossRef" href="#tbl0025">tabela 5</a> mostra o n&#237;vel de evid&#234;ncia e o grau de recomenda&#231;&#227;o dos principais medicamentos de uso sist&#234;mico no tratamento do LEC&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Antimal&#225;ricos</span><p id="par0460" class="elsevierStylePara elsevierViewall">Os antimal&#225;ricos &#40;AM&#41; constituem a primeira linha de tratamento sist&#234;mico&#59; &#233; prov&#225;vel que previnam a progress&#227;o do LEC para doen&#231;a sist&#234;mica&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;59&#44;61&#44;63</span></a> S&#227;o capazes de inibir a apresenta&#231;&#227;o de ant&#237;genos pelas CDP&#44; a forma&#231;&#227;o de complexos ant&#237;geno&#8208;anticorpo e a sinaliza&#231;&#227;o via receptores <span class="elsevierStyleItalic">Toll&#8208;like&#44;</span> reduzindo a produ&#231;&#227;o de IFN tipo&#160;I&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">14&#44;55&#44;59</span></a> A hidroxicloroquina &#40;HCQ&#41; &#233; o AM mais utilizado pelo melhor perfil de seguran&#231;a quanto &#224; toxicidade ocular em rela&#231;&#227;o &#224; cloroquina &#40;CQ&#41;&#46; A dose recomendada de HCQ&#44; em parte da literatura&#44; &#233; de&#160;6&#44;5&#160;mg&#47;kg&#47;dia&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Contudo&#44; em&#160;2016&#44; a American Academy of Ophthalmology recomendou que doses maiores que&#160;5&#160;mg&#47;kg&#47;dia de HCQ e 2&#44;3&#160;mg&#47;kg&#47;dia de CQ sejam evitadas&#44; por risco aumentado de retinopatia&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">58</span></a></p><p id="par0465" class="elsevierStylePara elsevierViewall">O &#237;ndice de resposta dos AM &#233; de cerca de&#160;63&#37; dentre os diversos subtipos de LEC e pode ser um pouco maior para a CQ em rela&#231;&#227;o &#224; HCQ&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">64</span></a> A taxa m&#233;dia de resposta foi de&#160;91&#37; nos casos de LECA&#44; 57&#37;&#160;no LED e apenas&#160;31&#37; no LE perni&#243;tico&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">64</span></a> Pacientes de LECC tendem a responder mais lentamente aos AM que aqueles de LECA&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">56</span></a></p><p id="par0470" class="elsevierStylePara elsevierViewall">Em casos refrat&#225;rios&#44; um AM pode ser substitu&#237;do por outro &#8211; HCQ por CQ ou CQ por HCQ&#59; nesses casos&#44; a taxa de resposta ao segundo AM pode chegar a&#160;56&#37;&#44; mas cair para&#160;42&#37; ap&#243;s&#160;um&#160;ano e 22&#37; ap&#243;s&#160;dois&#160;anos&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;6&#44;45&#44;60&#44;64</span></a> A adi&#231;&#227;o de quinacrina&#44; f&#225;rmaco n&#227;o dispon&#237;vel no Brasil&#44; na dose de&#160;100&#8208;200&#160;mg&#47;dia&#44; nos casos refrat&#225;rios aos AM em monoterapia&#44; pode aumentar a taxa de resposta para&#160;66&#37;&#44; sem aumentar o risco de retinopatia&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">45&#44;57&#44;58&#44;61&#44;64</span></a> O uso de AM durante a gesta&#231;&#227;o e lacta&#231;&#227;o &#233; recomendado&#44; especialmente nas pacientes com les&#245;es cut&#226;neas e LES&#44; podendo reduzir o risco de acometimento card&#237;aco pelo LE neonatal&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">65</span></a></p><p id="par0475" class="elsevierStylePara elsevierViewall">Os efeitos colaterais dos AM incluem n&#225;useas&#44; v&#244;mitos&#44; pigmenta&#231;&#227;o cut&#226;nea&#44; tonteira&#44; cefaleia&#44; ototoxicidade e neuropatia perif&#233;rica&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> A retinopatia &#233; o efeito colateral mais relevante e ocorre em at&#233;&#160;1&#37; dos casos&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Os pacientes devem ser avaliados no in&#237;cio do tratamento e&#44; caso n&#227;o tenham nenhum fator de risco adicional&#44; anualmente&#44; ap&#243;s o quinto ano de uso do medicamento&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> Pacientes com doses acima de&#160;5&#44;0&#160;mg&#47;kg&#47;dia&#44; insufici&#234;ncia renal&#44; uso concomitante de tamoxifeno e maculopatia retiniana preexistente est&#227;o sob maior risco de retinopatia e devem ser monitorados com maior frequ&#234;ncia&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">56</span></a> A campimetria e o exame de fundo de olho podem n&#227;o detectar altera&#231;&#245;es iniciais&#59; a tomografia de coer&#234;ncia &#243;ptica &#233; recomendada para auxiliar no diagn&#243;stico precoce&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">65</span></a> Existem raros relatos de toxicidade card&#237;aca&#44; com prolongamento do intervalo QT&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">65</span></a></p><p id="par0480" class="elsevierStylePara elsevierViewall">Quando dispon&#237;vel&#44; a dosagem s&#233;rica de HCQ pode ser utilizada para avalia&#231;&#227;o do tratamento ap&#243;s&#160;seis&#160;meses de uso sem resposta&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">45&#44;60</span></a> Valores inferiores a&#160;200&#160;ng&#47;mL indicam m&#225;&#8208;ades&#227;o ao tratamento&#44; enquanto valores acima de&#160;750&#160;ng&#47;mL est&#227;o correlacionados a melhores taxas de controle da atividade da doen&#231;a&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">45&#44;56</span></a> Pacientes com contraindica&#231;&#227;o aos AM ou com dose otimizada de AM&#44; mas sem resposta ou com resposta parcial&#44; t&#234;m indica&#231;&#227;o de f&#225;rmacos de segunda linha de tratamento&#46; Tabagistas s&#227;o mais propensos a n&#227;o responderem aos AM&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">57</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Metotrexato</span><p id="par0485" class="elsevierStylePara elsevierViewall">O metotrexato &#40;MTX&#41; &#233; a primeira escolha dentre os f&#225;rmacos de segunda linha para pacientes refrat&#225;rios ou com contraindica&#231;&#227;o ao uso dos AM&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;66</span></a> &#201; um inibidor da diidrofolato&#8208;redutase&#44; que afeta a replica&#231;&#227;o celular e suprime a produ&#231;&#227;o de anticorpos&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">59</span></a> A dose recomendada pode variar de&#160;7&#44;5&#8208;25&#160;mg&#47;semana&#44; via oral ou subcut&#226;nea&#46; Os efeitos colaterais s&#227;o n&#225;useas&#44; v&#244;mitos&#44; dor abdominal&#44; hepatotoxidade&#44; ulcera&#231;&#227;o de mucosas&#44; supress&#227;o medular&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;55&#44;60</span></a> A aplica&#231;&#227;o subcut&#226;nea e a administra&#231;&#227;o de &#225;cido f&#243;lico nos dias posteriores ao uso da medica&#231;&#227;o podem reduzir significantemente os efeitos colaterais gastrintestinais&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">58&#44;61</span></a> Os pacientes devem ser monitorados laboratorialmente nas primeiras semanas de uso&#44; ap&#243;s aumento das doses e&#44; trimestralmente&#44; no acompanhamento regular&#46;</p><p id="par0490" class="elsevierStylePara elsevierViewall">O uso de MTX deve ser evitado em pacientes etilistas&#44; naqueles em uso concomitante de f&#225;rmacos hepatot&#243;xicos&#44; com esteatose hep&#225;tica grave&#44; insufici&#234;ncia renal ou doen&#231;a hep&#225;tica de base&#44; incluindo hepatites virais&#44; condi&#231;&#245;es que devem ser pesquisadas antes do in&#237;cio do tratamento com MTX&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">58&#44;61</span></a> O risco de hepatoxicidade fora dessas condi&#231;&#245;es &#233; baixo&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> Pneumonite intersticial &#233; complica&#231;&#227;o rara e potencialmente fatal&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">4&#44;55</span></a> MTX &#233; teratog&#234;nico e deve ser recomendada contracep&#231;&#227;o adequada&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Retinoides sist&#234;micos</span><p id="par0495" class="elsevierStylePara elsevierViewall">Os retinoides s&#227;o utilizados com sucesso no tratamento de LEC refrat&#225;rio&#44; especialmente nas formas verrucosas&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;55&#44;61</span></a> Eles inibem a produ&#231;&#227;o de citocinas pr&#243;&#8208;inflamat&#243;rias&#44; como a IL&#8208;6 e o IFN&#8208;&#947;&#44; al&#233;m de regular e normalizar a diferencia&#231;&#227;o dos ceratin&#243;citos&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Dados da literatura n&#227;o mostram diferen&#231;a significante de efic&#225;cia entre HCQ e acitretina em pacientes com diferentes subtipos de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">57</span></a> A isotretino&#237;na tamb&#233;m j&#225; foi utilizada em pequenas s&#233;ries de casos&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a></p><p id="par0500" class="elsevierStylePara elsevierViewall">A dose de acitretina e isotretino&#237;na &#233; de&#160;0&#44;2&#8208;1&#44;0&#160;mg&#47;kg&#47;dia&#46; A resposta&#44; em geral&#44; &#233; r&#225;pida e ocorre em duas a seis semanas&#46; A recidiva tamb&#233;m costuma sobrevir logo ap&#243;s a interrup&#231;&#227;o da medica&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a></p><p id="par0505" class="elsevierStylePara elsevierViewall">Pacientes em uso de retinoides devem ser monitorados regularmente pelo risco de hepatotoxicidade e aumento dos n&#237;veis s&#233;ricos de triglic&#233;rides&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Outros efeitos colaterais incluem xerose mucocut&#226;nea e altera&#231;&#245;es &#243;sseas&#44; como a hiperostose&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">67</span></a> O uso de fotoprotetores deve ser intensificado&#44; pelo risco de agravamento da fotossensibilidade&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">67</span></a> Em decorr&#234;ncia do risco de teratogenicidade&#44; mulheres em idade f&#233;rtil devem ser submetidas a contracep&#231;&#227;o adequada durante e ap&#243;s o t&#233;rmino do tratamento &#40;isotretino&#237;na&#44; at&#233;&#160;um&#160;m&#234;s&#44; e acitretina&#44; at&#233;&#160;dois a tr&#234;s&#160;anos&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;55</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Dapsona</span><p id="par0510" class="elsevierStylePara elsevierViewall">A dapsona &#233; agente imunomodulador e antimicrobiano que inibe a mieloperoxidase presente em neutr&#243;filos e mon&#243;citos&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;59&#44;68</span></a> Pode ser usada isoladamente ou em combina&#231;&#227;o com os AM&#46; Mais de&#160;50&#37; dos pacientes com LEC respondem favoravelmente ao uso da dapsona&#44; inclusive aqueles com LED&#44; subtipo classicamente mais resistente&#44; em que a taxa de resposta se aproxima de&#160;60&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;68</span></a> A dapsona &#233; considerada f&#225;rmaco de primeira escolha no tratamento do LE bolhoso e de outras manifesta&#231;&#245;es neutrof&#237;licas no LE&#44; como a urtic&#225;ria vasculite&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">56&#44;61</span></a> As variantes hipercerat&#243;sicas usualmente n&#227;o respondem bem &#224; dapsona&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a></p><p id="par0515" class="elsevierStylePara elsevierViewall">A dose inicial &#233; de&#160;50&#160;mg&#47;dia e pode ser aumentada at&#233;&#160;200&#160;mg&#47;dia&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;61</span></a> Os pacientes devem ser avaliados quanto &#224; defici&#234;ncia de glicose&#8208;6&#8208;fosfatodesidrogenase antes do in&#237;cio do tratamento&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">58</span></a></p><p id="par0520" class="elsevierStylePara elsevierViewall">Os efeitos colaterais podem ser graves&#44; como erup&#231;&#227;o ao f&#225;rmaco com eosinofilia e sintomas sist&#234;micos&#44; a s&#237;ndrome DRESS &#40;do ingl&#234;s&#44; <span class="elsevierStyleItalic">drug reaction with eosinophilia and systemic symptoms</span>&#41;&#44; meta&#8208;hemoglobinemia e agranulocitose&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;57</span></a> Anemia hemol&#237;tica pode ocorrer em at&#233;&#160;50&#37; dos pacientes&#46;<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">57&#44;68</span></a> Os n&#237;veis de hemoglobina devem ser monitorados durante o primeiro m&#234;s de tratamento e&#44; ent&#227;o&#44; a cada tr&#234;s meses&#46; Os n&#237;veis de meta&#8208;hemoglobina podem ser avaliados entre o&#160;8&#176;&#160;e&#160;14&#176;&#160;dia ap&#243;s a introdu&#231;&#227;o da medica&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a> A dapsona &#233; o &#250;nico f&#225;rmaco de segunda linha que pode ser utilizado durante a gesta&#231;&#227;o e a amamenta&#231;&#227;o&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">60&#44;61</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Micofenolato de mofetila</span><p id="par0525" class="elsevierStylePara elsevierViewall">O micofenolato de mofetila &#40;MFM&#41; &#233; considerado agente de terceira linha para o tratamento do LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> O MFM causa deple&#231;&#227;o do trifosfato de guanosina&#44; necess&#225;rio para ades&#227;o de linf&#243;citos e mon&#243;citos ao endot&#233;lio durante o processo de inflama&#231;&#227;o&#44; al&#233;m de induzir apoptose de linf&#243;citos&#160;T e reduzir a ativa&#231;&#227;o dos linf&#243;citos&#160;B&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Foi relatada uma taxa de resposta completa ou significante em&#160;62&#37; dos pacientes de LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> MFM pode ser usado isoladamente ou em combina&#231;&#227;o com AM&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">4</span></a> A dose inicial &#233; de&#160;500&#160;mg&#47;dia e pode ser aumentada at&#233;&#160;3&#160;g&#47;dia&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a></p><p id="par0530" class="elsevierStylePara elsevierViewall">Os efeitos colaterais mais frequentes s&#227;o gastrintestinais&#44; citopenias&#44; hepatotoxicidade e infec&#231;&#245;es virais e urin&#225;rias&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Os pacientes devem realizar revis&#245;es laboratoriais mensalmente&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> O f&#225;rmaco &#233; da categoria&#160;X e n&#227;o pode ser utilizado durante a gesta&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a></p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Azatioprina</span><p id="par0535" class="elsevierStylePara elsevierViewall">A azatioprina &#233; um an&#225;logo da purina que deprime a fun&#231;&#227;o dos linf&#243;citos&#160;T&#160;e&#160;B e reduz a apresenta&#231;&#227;o de ant&#237;genos&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">59</span></a> Pode ser indicada no LEC em caso de insucesso dos tratamentos descritos anteriormente&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> S&#233;ries de caso t&#234;m mostrado sucesso no tratamento do LEC&#44; embora n&#227;o existam grandes estudos que suportem essa recomenda&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Pode ser usada nas gestantes com LES&#44; mas sua rela&#231;&#227;o risco&#8208;benef&#237;cio deve ser ponderada&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> A dose recomendada &#233; de&#160;1&#8208;3&#160;mg&#47;kg&#47;dia&#46; Os efeitos adversos s&#227;o gastrintestinais&#44; infec&#231;&#245;es oportunistas e citopenias&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">58</span></a></p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Talidomida</span><p id="par0540" class="elsevierStylePara elsevierViewall">A talidomida &#233; um f&#225;rmaco utilizado como terapia de resgate nos casos graves&#44; refrat&#225;rios e com alto risco de forma&#231;&#227;o de cicatrizes&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">66</span></a> Atua inibindo a s&#237;ntese de TNF&#8208;&#945;&#44; a angiog&#234;nese e a apoptose de ceratin&#243;citos induzida pela RUV&#44; reduzindo a produ&#231;&#227;o de IFN&#8208;&#947; e a fagocitose por polimorfonucleares&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#44;69</span></a> A taxa de resposta &#233; superior a&#160;90&#37; nos diferentes subtipos de LEC&#44; a mais alta dentre todos os tratamentos dispon&#237;veis&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;57&#44;70</span></a> Por&#233;m&#44; com alto risco de reca&#237;das&#44; de at&#233;&#160;70&#37;&#44; ap&#243;s a suspens&#227;o da medica&#231;&#227;o&#44; especialmente no LED&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;56&#44;70</span></a> A dose inicial recomendada &#233; de&#160;100&#160;mg&#47;dia&#44; que deve ser reduzida assim que a resposta cl&#237;nica for alcan&#231;ada&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a></p><p id="par0545" class="elsevierStylePara elsevierViewall">A alta frequ&#234;ncia de eventos adversos pode limitar seu uso&#44; afetando&#160;24&#37; dos pacientes &#40;16&#37;&#160;com neuropatia perif&#233;rica e 2&#37;&#160;com eventos tromboemb&#243;licos&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">56&#44;70</span></a> A polineuropatia &#233; classicamente sim&#233;trica&#44; dolorosa e afeta m&#227;os e p&#233;s&#46; &#201; usualmente acompanhada de perda sensorial e preserva&#231;&#227;o da for&#231;a muscular&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">69</span></a> Deve ser realizada eletroneuromiografia no in&#237;cio do tratamento e&#44; como controle&#44; a cada&#160;seis&#160;meses&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">69</span></a> Outros efeitos colaterais s&#227;o seda&#231;&#227;o&#44; hipotens&#227;o ortost&#225;tica&#44; erup&#231;&#227;o maculopapular&#44; constipa&#231;&#227;o e xerostomia&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">67&#44;69</span></a></p><p id="par0550" class="elsevierStylePara elsevierViewall">A teratogenicidade &#233; um dos efeitos colaterais mais tem&#237;veis relacionados ao uso da talidomida&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">69</span></a> Seu uso em mulheres em idade f&#233;rtil deve ser excepcional e apenas ap&#243;s falha de todos os tratamentos dispon&#237;veis&#46; Nesses casos&#44; recomenda&#8208;se a ado&#231;&#227;o de dois m&#233;todos contraceptivos&#44; um de alta efetividade e o outro de barreira&#46; Deve ser realizado teste de gravidez&#160;24&#160;horas antes do in&#237;cio do tratamento&#44; repetido semanalmente no primeiro m&#234;s e&#44; posteriormente&#44; a cada duas a quatro semanas&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">69</span></a></p><p id="par0555" class="elsevierStylePara elsevierViewall">&#193;cido acetilsalic&#237;lico&#44; em baixas doses&#44; pode ser associado &#224; talidomida em pacientes com alto risco cardiovascular ou presen&#231;a de anticorpos antifosfol&#237;pides&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">60&#44;69</span></a></p><p id="par0560" class="elsevierStylePara elsevierViewall">A lenalidomida&#44; um derivado da talidomida&#44; exibe melhor perfil de seguran&#231;a quanto ao risco de neuropatia&#44; por&#233;m ainda existem poucos dados na literatura sobre seu uso em pacientes com LEC&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;61</span></a> Alguns autores contraindicam seu uso no LEC devido ao risco de induzir LES&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a></p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Corticosteroides sist&#234;micos</span><p id="par0565" class="elsevierStylePara elsevierViewall">Os corticosteroides sist&#234;micos podem ser utilizados no in&#237;cio do tratamento das formas agressivas e disseminadas de LEC&#44; at&#233; que as outras medica&#231;&#245;es iniciem sua a&#231;&#227;o terap&#234;utica&#46; Devem ser reduzidos e suspensos o mais brevemente poss&#237;vel&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;6</span></a> Apresentam maior taxa de resposta no LECA&#44; provavelmente pela associa&#231;&#227;o com LES&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> A dose usual &#233; de&#160;0&#44;5&#8208;1&#160;mg&#47;kg&#47;dia de prednisona e deve ser reduzida&#44; logo que poss&#237;vel&#44; at&#233; atingir doses di&#225;rias inferiores a&#160;7&#44;5&#160;mg&#46; A terapia de longo prazo com corticosteroides sist&#234;micos n&#227;o &#233; indicada no LEC&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">60&#44;61</span></a></p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Outros tratamentos</span><p id="par0570" class="elsevierStylePara elsevierViewall">A clofazimina apresenta propriedades antimicrobianas&#44; anti&#8208;inflamat&#243;rias e imunossupressoras&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">59</span></a> A dose &#233; de&#160;100&#8208;200&#160;mg&#47;dia e pode ser utilizada como tratamento adjuvante&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Os principais efeitos colaterais s&#227;o hiperpigmenta&#231;&#227;o cinza&#8208;acastanhada&#44; xerose cut&#226;nea&#44; n&#225;useas e v&#244;mitos&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> Os &#233;steres do &#225;cido fum&#225;rico j&#225; foram usados com sucesso no LED&#44; por&#233;m os dados ainda s&#227;o limitados na literatura&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;57</span></a></p><p id="par0575" class="elsevierStylePara elsevierViewall">O uso de antiagregantes plaquet&#225;rios &#233; recomendado nos pacientes com livedo racemoso&#44; les&#245;es do tipo papulose maligna atr&#243;fica &#40;doen&#231;a de Degos&#41;&#44; ulcera&#231;&#227;o&#44; tromboflebite e anetodermia&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">45</span></a></p><p id="par0580" class="elsevierStylePara elsevierViewall">O uso de <span class="elsevierStyleItalic">pulsed&#8208;dye&#8208;laser</span> &#40;<span class="elsevierStyleItalic">laser</span> pulsado de corante&#41; &#233; descrito como tratamento de cicatrizes&#46; Entretanto&#44; dado o risco de fotossensibilidade&#44; seu uso n&#227;o &#233; recomendado na presen&#231;a de les&#245;es cut&#226;neas ativas&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">6&#44;7&#44;61</span></a></p><p id="par0585" class="elsevierStylePara elsevierViewall">Ciclosporina&#44; ciclofosfamida e imunoglobulina endovenosa n&#227;o s&#227;o indicadas no tratamento do LEC sem acometimento sist&#234;mico&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;61</span></a></p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Terapias&#8208;alvo</span><p id="par0590" class="elsevierStylePara elsevierViewall">Os avan&#231;os na compreens&#227;o da patog&#234;nese&#44; especialmente das vias de ativa&#231;&#227;o dos sistemas imunes inato e adaptativo&#44; abriram um novo campo de pesquisa para uma nova gera&#231;&#227;o de f&#225;rmacos&#44; os chamados imunobiol&#243;gicos&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">56</span></a> Os principais alvos terap&#234;uticos s&#227;o as vias de ativa&#231;&#227;o das c&#233;lulas&#160;B&#44; c&#233;lulas&#160;T e CDP&#44; al&#233;m das citocinas pr&#243;&#8208;inflamat&#243;rias&#44; seus receptores e vias de sinaliza&#231;&#227;o intracelular&#44; como IL&#8208;6&#44; IL&#8208;12&#44; IL&#8208;23&#44; IFN e via de sinaliza&#231;&#227;o JAK&#47;STAT&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;14&#44;60</span></a></p><p id="par0595" class="elsevierStylePara elsevierViewall">Alvo nas c&#233;lulas&#160;B&#58; o belimumabe &#233; um anticorpo monoclonal contra o fator de ativa&#231;&#227;o de c&#233;lulas&#160;B &#40;<span class="elsevierStyleItalic">Blys</span>&#41;&#44; aprovado pelo FDA para uso no LES&#46; Os estudos originais n&#227;o inclu&#237;ram an&#225;lise espec&#237;fica do desfecho das les&#245;es cut&#226;neas&#44; embora an&#225;lises posteriores tenham demonstrado melhora do quadro cut&#226;neo&#46; A efic&#225;cia no LEC est&#225; em investiga&#231;&#227;o em estudos de fase&#160;III&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> Tr&#234;s estudos observacionais&#44; com uso do rituximabe&#44; anticorpo monoclonal anti&#8208;CD20&#44; nas manifesta&#231;&#245;es mucocut&#226;neas do LE&#44; apresentaram taxas de resposta variando entre&#160;35&#37;&#160;e&#160;76&#37;&#46; Resposta mais favor&#225;vel foi verificada no LECA &#8211; no entanto&#44; sem evid&#234;ncia de efeito ben&#233;fico nos subtipos subagudo e cr&#244;nico do LEC&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">57</span></a></p><p id="par0600" class="elsevierStylePara elsevierViewall">Alvo nas vias do interferon&#58; as tentativas de inibi&#231;&#227;o espec&#237;fica dos IFN n&#227;o apresentaram resultados satisfat&#243;rios nos ensaios cl&#237;nicos&#44; provavelmente pela grande redund&#226;ncia entre os diferentes tipos de IFN&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> O bloqueio do receptor de IFN apresenta uma perspectiva mais animadora&#46; O anifrolumabe&#44; um anticorpo monoclonal contra o receptor do IFN tipo&#160;I&#44; reduziu os escores de atividade das les&#245;es cut&#226;neas em pacientes com LES em ensaio cl&#237;nico de fase&#160;IIb&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a></p><p id="par0605" class="elsevierStylePara elsevierViewall">Alvo na via JAK&#47;STAT&#58; essa via &#233; importante para o mecanismo de retroalimenta&#231;&#227;o positiva do IFN&#46; A primeira gera&#231;&#227;o de inibidores &#8211; baricitinibe e ruxolitinibe &#8211; mostrou efic&#225;cia em pequeno n&#250;mero de pacientes com LE perni&#243;tico&#46; A segunda gera&#231;&#227;o de inibidores est&#225; sendo testada em ensaios cl&#237;nicos&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">14</span></a></p></span></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Considera&#231;&#245;es finais</span><p id="par0610" class="elsevierStylePara elsevierViewall">LEC &#233; doen&#231;a autoimune multifatorial&#44; resultante da intera&#231;&#227;o de fatores ambientais&#44; gen&#233;ticos e imunol&#243;gicos&#44; que se apresenta com variada manifesta&#231;&#227;o dermatol&#243;gica&#46; O reconhecimento do subtipo cl&#237;nico &#233; importante na abordagem diagn&#243;stica&#44; na decis&#227;o terap&#234;utica e na determina&#231;&#227;o do progn&#243;stico&#44; tanto na doen&#231;a exclusivamente cut&#226;nea quanto no contexto do LES&#46;</p><p id="par0615" class="elsevierStylePara elsevierViewall">Crit&#233;rios diagn&#243;sticos para defini&#231;&#227;o dos diferentes subtipos de LEC ainda s&#227;o incipientes&#46; Aguardam&#8208;se crit&#233;rios mais assertivos que possam ser futuramente incorporados na pr&#225;tica cl&#237;nica e nos ensaios terap&#234;uticos&#44; auxiliando na avalia&#231;&#227;o das manifesta&#231;&#245;es cut&#226;neas do LE&#46;</p><p id="par0620" class="elsevierStylePara elsevierViewall">Fotoprote&#231;&#227;o&#44; corticosteroides t&#243;picos e antimal&#225;ricos ainda permanecem como primeira linha no tratamento do LEC&#46; Medica&#231;&#245;es alternativas de uso sist&#234;mico incluem MTX&#44; retinoides orais&#44; dapsona e talidomida&#44; entre outros&#46; Com o avan&#231;o no conhecimento da patog&#234;nese da doen&#231;a&#44; novas estrat&#233;gias terap&#234;uticas v&#234;m sendo desenvolvidas&#44; tendo como alvos as diferentes vias de ativa&#231;&#227;o imune que t&#234;m sido identificadas&#46;</p></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Suporte financeiro</span><p id="par0625" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Contribui&#231;&#227;o dos autores</span><p id="par0630" class="elsevierStylePara elsevierViewall">Everton Carlos Siviero do Vale&#58; Concep&#231;&#227;o e desenho do estudo&#59; Revis&#227;o cr&#237;tica da literatura&#59; Elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; Revis&#227;o cr&#237;tica do manuscrito&#59; Aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0635" class="elsevierStylePara elsevierViewall">Lucas Campos Garcia&#58; Revis&#227;o cr&#237;tica da literatura&#59; Elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; Aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Conflito de interesses</span><p id="par0640" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">O l&#250;pus eritematoso cut&#226;neo &#233; doen&#231;a autoimune de express&#227;o cl&#237;nica variada&#44; que pode apresentar&#8208;se como doen&#231;a exclusivamente cut&#226;nea ou ser uma das m&#250;ltiplas manifesta&#231;&#245;es do l&#250;pus eritematoso sist&#234;mico&#46; Sua classifica&#231;&#227;o engloba os subtipos agudo&#44; subagudo&#44; intermitente&#44; cr&#244;nico e bolhoso&#44; que s&#227;o usualmente identificados com base nas caracter&#237;sticas cl&#237;nicas e nos achados histopatol&#243;gicos e laboratoriais&#46; Outras manifesta&#231;&#245;es cut&#226;neas n&#227;o espec&#237;ficas podem estar associadas ao l&#250;pus eritematoso sist&#234;mico e geralmente guardam rela&#231;&#227;o com a atividade da doen&#231;a&#46; Fatores ambientais&#44; gen&#233;ticos e imunol&#243;gicos participam da patog&#234;nese das les&#245;es cut&#226;neas do l&#250;pus eritematoso&#46; Recentemente&#44; tem havido consider&#225;vel progresso na elucida&#231;&#227;o dos mecanismos envolvidos no seu desenvolvimento&#44; o que possibilita antever futuros alvos de tratamentos mais efetivos&#46; Esta revis&#227;o se prop&#245;e a discutir os principais aspectos etiopatog&#234;nicos&#44; cl&#237;nicos&#44; diagn&#243;sticos e terap&#234;uticos do l&#250;pus eritematoso cut&#226;neo&#44; visando &#224; atualiza&#231;&#227;o de internistas e de especialistas de diferentes &#225;reas&#46;</p></span>"
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Crit&#233;rio de entrada&#58;</span> nenhum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Crit&#233;rio de entrada&#58;</span> FAN&#160;&#8805;&#160;1&#58;80&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="elsevierStyleItalic">Crit&#233;rios cl&#237;nicos &#40;&#61; 9&#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"><span class="elsevierStyleItalic">Crit&#233;rios cl&#237;nicos &#40;&#61; 11&#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"><span class="elsevierStyleItalic">Crit&#233;rios cl&#237;nicos &#40;pontos&#41;</span>&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">Erup&#231;&#227;o malar</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"><span class="elsevierStyleBold">LEC agudo&#44; subagudo ou LE bolhoso</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">Constitucional&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">Erup&#231;&#227;o discoide</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"><span class="elsevierStyleBold">LEC cr&#244;nico &#40;inclui LEC t&#250;mido&#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"><span class="elsevierStyleHsp" style=""></span>Febre &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Fotossensibilidade</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"><span class="elsevierStyleBold">&#218;lceras orais ou nasais</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">Hematol&#243;gicos&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">&#218;lceras orais</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"><span class="elsevierStyleBold">Alopecia n&#227;o cicatricial</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"><span class="elsevierStyleHsp" style=""></span>Leucopenia &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Artrite n&#227;o erosiva &#40;&#8805; 2&#160;articula&#231;&#245;es&#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">Sinovite &#40;&#8805; 2&#160;articula&#231;&#245;es&#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"><span class="elsevierStyleHsp" style=""></span>Trombocitopenia &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serosite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serosite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hem&#243;lise autoimune &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pleurite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pleurite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neuropsiqui&#225;tricos&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="elsevierStyleHsp" style=""></span>Pericardite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pericardite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Del&#237;rio &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Derrame pleural ou peric&#225;rdico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Derrame pleural ou peric&#225;rdico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Psicose &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acometimento renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Convuls&#227;o &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Protein&#250;ria<span class="elsevierStyleHsp" style=""></span>&#62; 0&#44;5 g&#47;24 horas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Protein&#250;ria<span class="elsevierStyleHsp" style=""></span>&#62; 0&#44;5 g&#47;24 horas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucocut&#226;neos&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="elsevierStyleHsp" style=""></span>Cilindros celulares&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cilindros hem&#225;ticos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">Alopecia n&#227;o cicatricial &#40;2&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Altera&#231;&#245;es neurol&#243;gicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;a neurol&#243;gica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">&#218;lceras orais &#40;2&#41;</span>&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="elsevierStyleHsp" style=""></span>Convuls&#245;es&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Convuls&#245;es&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">LEC subagudo ou LE &#40;4&#41;</span>&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="elsevierStyleHsp" style=""></span>Psicose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Psicose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">LEC agudo &#40;6&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Altera&#231;&#245;es hematol&#243;gicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mononeurite m&#250;ltipla&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serosite&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="elsevierStyleHsp" style=""></span>Anemia hemol&#237;tica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Mielite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Derrame pleural ou peric&#225;rdico &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Leucopenia &#40;&#60; 4&#46;000&#160;mm<span class="elsevierStyleSup">3</span>&#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"><span class="elsevierStyleHsp" style=""></span>Neuropatia craniana ou perif&#233;rica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pericardite aguda &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Linfopenia &#40;&#60; 1&#46;500&#160;mm<span class="elsevierStyleSup">3</span>&#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"><span class="elsevierStyleHsp" style=""></span>Estado confusional agudo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Musculoesquel&#233;tico&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="elsevierStyleHsp" style=""></span>Trombocitopenia &#40;&#60; 100&#46;000&#47;mm<span class="elsevierStyleSup">3</span>&#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">Altera&#231;&#245;es hematol&#243;gicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Acometimento articular &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anemia hemol&#237;tica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucopenia &#40;&#60; 4&#46;000&#160;mm<span class="elsevierStyleSup">3</span>&#41; ou linfopenia &#40;&#60; 1&#46;000 mm<span class="elsevierStyleSup">3</span>&#41;Trombocitopenia &#40;&#60; 100&#46;000&#47;mm<span class="elsevierStyleSup">3</span>&#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">Renais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Protein&#250;ria<span class="elsevierStyleHsp" style=""></span>&#62; 0&#44;5&#160;g&#47;24 horas &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Bi&#243;psia renal &#8211; nefrite l&#250;pica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Classe II ou V &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Bi&#243;psia renal &#8211; nefrite l&#250;pica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Classe III ou IV &#40;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Crit&#233;rios imunol&#243;gicos &#40;&#61; 2&#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"><span class="elsevierStyleItalic">Crit&#233;rios imunol&#243;gicos &#40;&#61; 6&#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"><span class="elsevierStyleItalic">Crit&#233;rios imunol&#243;gicos &#40;pontos&#41;</span>&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">FAN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">FAN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpos antifosfol&#237;pides&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">Autoanticorpos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;DNAn&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anticardiolipina &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Anti&#8208;DNAn&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;Sm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti&#8208;&#946;2&#8208;glicoprote&#237;na 1 &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Anti&#8208;Sm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpo antifosfol&#237;pide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anticoagulante l&#250;pico &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Anticorpo antifosfol&#237;pide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anticoagulante l&#250;pico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complemento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Teste n&#227;o trepon&#234;mico falso&#8208;positivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>C3 ou C4 baixo &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anticardiolipina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>C3 e C4 baixos &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti&#8208;&#946;2&#8208;glicoprote&#237;na 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">Anticorpos LES&#8208;espec&#237;ficos&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">Complemento baixo &#40;C3&#44; C4 ou CH50&#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"><span class="elsevierStyleHsp" style=""></span>Anti&#8208;DNAn &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Coombs direto &#40;na aus&#234;ncia de anemia hemol&#237;tica&#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"><span class="elsevierStyleHsp" style=""></span>Anti&#8208;Sm &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "pt" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Crit&#233;rios de classifica&#231;&#227;o do l&#250;pus eritematoso sist&#234;mico &#8211; ACR 1997&#44; SLICC 2012 e EULAR&#47;ACR 2019</p>"
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        "etiqueta" => "Tabela 2"
        "tipo" => "MULTIMEDIATABLA"
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            "identificador" => "at2"
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            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">LE&#44; l&#250;pus eritematoso&#59; NET&#44; necr&#243;lise epid&#233;rmica t&#243;xica&#46;</p>"
          "tablatextoimagen" => array:2 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Subtipos de LE cut&#226;neo&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">Variantes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE cut&#226;neo agudo</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Localizado&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">Disseminado&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">NET&#8208;s&#237;mile&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE cut&#226;neo subagudo</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anular polic&#237;clico&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">Papuloescamoso psoriasiforme&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">S&#237;ndrome de Rowell&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">LE neonatal&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">LE cut&#226;neo intermitente&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE t&#250;mido&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE cut&#226;neo cr&#244;nico</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE discoide&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">LE discoide mucoso&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">LE hipertr&#243;fico&#47;verrucoso&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">LE profundo&#47;paniculite l&#250;pica&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">LE perni&#243;tico&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">LE l&#237;quen plano&#8208;s&#237;mile&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">LE comedoniano&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">LE bolhoso&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3171298.png"
              ]
            ]
            1 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Natureza da altera&#231;&#227;o&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">Manifesta&#231;&#245;es inespec&#237;ficas&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">Vascular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fen&#244;meno de Raynaud&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">Livedo reticular&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">Livedo racemoso&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">Vasculites&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">Vasculopatia livedoide&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">Papulose do tipo doen&#231;a de Degos&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">Necrose cut&#226;nea&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">Hemorragia em estilha&#231;o&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">Tromboflebite&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Neutrof&#237;lica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LE bolhoso&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">Urtic&#225;ria vasculite&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">Dermatose urticariana neutrof&#237;lica&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">Pustulose amicrobiana das dobras&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">S&#237;ndrome de Sweet&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">Pioderma gangrenoso&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">N&#227;o definida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alopecia n&#227;o cicatricial difusa&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">&#218;lceras mucosas&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">N&#243;dulos reumatoides&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">Dermatite granulomatosa intersticial&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">Dermatofibroma eruptivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3171297.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Subtipos cl&#237;nicos e manifesta&#231;&#245;es cut&#226;neas inespec&#237;ficas do l&#250;pus eritematoso</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Tabela 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0011" class="elsevierStyleSimplePara elsevierViewall">Adaptado de Borucki &#38; Werth&#44; 2020&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">23</span></a>&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Classe&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">Subclasse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Medicamento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></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">Anti&#8208;hipertensivos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diur&#233;ticos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hidroclorotiazida&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  " rowspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidores da enzima conversora da angiotensina</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Captopril&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">Cilazapril&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">Enalapril&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">Lisinopril&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">Ramipril&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">Betabloqueadores&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acebutolol&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">Bloqueadores do canal de c&#225;lcio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diltiazem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nifedipina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nitrendipina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Verapamil&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Inibidores da bomba de pr&#243;tons&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Esomeprazol<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lasanoprazol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Omeprazol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pantoprazol&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Antif&#250;ngicos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Griseofulvina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Terbinafina&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Anticonvulsivantes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carbamazepina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fenito&#237;na&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Estatinas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pravastatina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sinvastatina&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;histam&#237;nicos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bromofeniramina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cinarizina &#43; tietilperazina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ranitidina&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Antibi&#243;ticos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amoxicilina &#43; clavulanato&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ciprofloxacina&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;inflamat&#243;rios n&#227;o esteroides&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Naproxeno&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Piroxicam&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Quimioter&#225;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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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&#8208;fluoruracil<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Capecitabina<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doxorubicina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gencitabina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Masitinibe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mitotane&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nivolumabe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Paclitaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Palbociclibe<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pembrolizumabe<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tamoxifeno&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tegafur&#47;uracil<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Biol&#243;gicos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti&#8208;TNF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Adalimumabe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Etanercepte&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Golimumabe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infliximabe<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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">Anti&#8208;CD80&#47;86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abatacepte&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">Anti&#8208;CD11a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Efalizumabe&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">Anti&#8208;IL12&#47;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ustekinumabe&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">Anti&#8208;IL17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Secukinumabe&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Antidepressivos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bupropiona&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  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></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">Outras&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alopurinol<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anastrazol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interferon&#8208;&#945; e &#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Imuglobulina intravenosa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leflunomida<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leuprorrelina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ticlopidina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tiotr&#243;pio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab3171295.png"
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Tamb&#233;m desencadeantes de l&#250;pus eritematoso cut&#226;neo cr&#244;nico&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Medicamentos referidos como desencadeantes de l&#250;pus eritematoso cut&#226;neo subagudo</p>"
        ]
      ]
      8 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Tabela 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Adaptado de Kuhn et al&#46;&#44; 2014&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">48</span></a>&#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=""><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"><span class="elsevierStyleBold">Exames de rotina</span> &#40;suspeita de LEC&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hemograma&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">Velocidade de hemossedimenta&#231;&#227;o eritrocit&#225;ria&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">Prote&#237;na C reativa&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">FAN &#40;HEp&#8208;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Enzimas hep&#225;ticas &#40;TGO&#44; TGP&#44; FA&#44; GGT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fun&#231;&#227;o renal &#40;ureia&#44; creatinina&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Urina &#40;EAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Exames especiais</span> &#40;LEC confirmado&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpos espec&#237;ficos &#40;anti&#8208;DNAn&#44; &#8208;Sm&#44; &#8208;Ro&#47;SS&#8208;A&#44; &#8208;La&#47;SS&#8208;B&#44; &#8208;RNPn&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complemento s&#233;rico &#40;C3&#44; C4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpos antifosfol&#237;pides &#40;anticardiolipinas IgG e IgM&#59;&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">anticoagulante l&#250;pico&#59; &#946;2&#8208;glicoprote&#237;na I&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fator reumatoide&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">Imunoglobulinas &#40;imunoeletroforese&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TSH&#44; T4&#44; anticorpos antitireoidianos&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">Prote&#237;nas urin&#225;rias 24 horas&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="elsevierStyleItalic">Clearance</span> da creatinina&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">Glicose&#8208;6&#8208;fosfato desidrogenase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "pt" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Avalia&#231;&#227;o laboratorial recomendada no l&#250;pus eritematoso cut&#226;neo &#40;LEC&#41;</p>"
        ]
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        "identificador" => "tbl0025"
        "etiqueta" => "Tabela 5"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N&#237;vel de evid&#234;ncia<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Metotrexato&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\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">4&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">Talidomida&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">B&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Azatioprina&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">Belimumabe&nbsp;\t\t\t\t\t\t\n
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">N&#237;vel de evid&#234;ncia&#58; 1 &#8211; Ensaio cl&#237;nico randomizado &#40;ECR&#41;&#44; revis&#245;es sistem&#225;ticas &#40;RS&#41;&#47;metan&#225;lise de ECR&#59; 2 &#8211; RS de estudos de coorte&#44; coortes&#59; 3 &#8211; RS de estudos caso&#8208;controle&#44; estudos de caso&#8208;controle&#59; 4 &#8211; S&#233;rie de casos&#44; coorte e caso&#8208;controle de baixa qualidade&#59; 5 &#8211; Opini&#227;o de especialistas&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Grau de recomenda&#231;&#227;o&#58; A &#8211; Estudos observacionais ou experimentais de maior consist&#234;ncia &#40;metan&#225;lises ou ECR&#41;&#59; B &#8211; Estudos observacionais de menor consist&#234;ncia &#40;outros ensaios cl&#237;nicos n&#227;o randomizados ou observacionais ou caso&#8208;controle&#41;&#59; C &#8211; Relatos ou s&#233;ries de casos &#40;estudos n&#227;o controlados&#41;&#59; D &#8211; Opini&#227;o desprovida de avalia&#231;&#227;o cr&#237;tica&#44; baseadas em consensos&#44; estudos fisiol&#243;gicos ou modelos animais&#46;</p>"
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          "pt" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">N&#237;vel de evid&#234;ncia e grau de recomenda&#231;&#227;o dos principais medicamentos de uso sist&#234;mico no l&#250;pus eritematoso cut&#226;neo</p>"
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                    0 => array:2 [
                      "titulo" => "Cutaneous lupus erythematosus&#58; new insights into pathogenesis and therapeutic strategies"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46; Wenzel"
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                      "doi" => "10.1038/s41584-019-0272-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Rheumatol&#46;"
                        "fecha" => "2019"
                        "volumen" => "15"
                        "paginaInicial" => "519"
                        "paginaFinal" => "532"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous manifestations of &#8220;lupus&#8221;&#58; systemic lupus erythematosus and beyond"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "E&#46;E&#46; Cooper"
                            1 => "C&#46;E&#46; Pisano"
                            2 => "S&#46;C&#46; Shapiro"
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                    ]
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                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Int J Rheumatol&#46;"
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                        "volumen" => "2021"
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              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous lupus erythematosus&#58; clinico&#8208;pathologic correlation"
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46; Filotico"
                            1 => "V&#46; Mastrandrea"
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                      "doi" => "10.23736/S0392-0488.18.05929-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "G Ital Dermatol Venereol&#46;"
                        "fecha" => "2018"
                        "volumen" => "153"
                        "paginaInicial" => "216"
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                        "link" => array:1 [
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                      "titulo" => "Cutaneous lupus erythematosus&#58; progress and challenges"
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                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;J&#46; Petty"
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                      "titulo" => "Cutaneous lupus erythematosus&#58; a review of the literature"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46;C&#46; Blake"
                            1 => "B&#46;S&#46; Daniel"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijwd.2019.07.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Womens Dermatol&#46;"
                        "fecha" => "2019"
                        "volumen" => "5"
                        "paginaInicial" => "320"
                        "paginaFinal" => "329"
                        "link" => array:1 [
                          0 => array:2 [
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                      "titulo" => "A quality&#8208;of&#8208;life study of cutaneous lupus erythematosus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Batalla"
                            1 => "I&#46; Garc&#237;a-Doval"
                            2 => "G&#46; Pe&#243;n"
                            3 => "C&#46; de la Torre"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.ad.2013.04.005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Actas Dermosifiliogr&#46;"
                        "fecha" => "2013"
                        "volumen" => "104"
                        "paginaInicial" => "800"
                        "paginaFinal" => "806"
                        "link" => array:1 [
                          0 => array:2 [
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                0 => array:2 [
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                      "titulo" => "Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus"
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                            1 => "A&#46;M&#46; Orbai"
                            2 => "G&#46;S&#46; Alarc&#243;n"
                            3 => "C&#46; Gordon"
                            4 => "J&#46;T&#46; Merrill"
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                        "tituloSerie" => "Arthritis Rheum&#46;"
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                      "titulo" => "2019 European League Against Rheumatism&#47;American College of Rheumatology classification criteria for systemic lupus erythematosus"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Aringer"
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                            2 => "D&#46; Daikh"
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Informação do artigo
ISSN: 26662752
Idioma original: Português
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Anais Brasileiros de Dermatologia (Portuguese)
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