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1.
J Alzheimers Dis ; 79(3): 931-948, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33459706

RESUMO

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer's disease and Parkinson's disease sufferers. In contrast, Alzheimer's disease and Parkinson's disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.


Assuntos
Lesões Encefálicas/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Fator de Necrose Tumoral alfa/fisiologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/terapia , Anti-Inflamatórios não Esteroides/uso terapêutico , Encéfalo/fisiopatologia , Lesões Encefálicas/diagnóstico , Lesões Encefálicas/terapia , /fisiopatologia , Progressão da Doença , Etanercepte/uso terapêutico , Parada Cardíaca/diagnóstico , Parada Cardíaca/fisiopatologia , Parada Cardíaca/terapia , Humanos , Locus Cerúleo/fisiopatologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/terapia , Norepinefrina/fisiologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/terapia , Sobreviventes , Fator de Necrose Tumoral alfa/antagonistas & inibidores
2.
PLoS One ; 15(12): e0243729, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33315881

RESUMO

This study aimed to directly analyze the potential relationship of anti-nuclear antibodies (ANA) before and after the administration of TNF-α inhibitors (TNFi) with the appearance of anti-drug antibodies (ADrA) in patients with rheumatoid arthritis (RA). A total of 121 cases, viz., 38, 53, and 30 cases treated with infliximab (IFX), adalimumab (ADA), and etanercept (ETN), respectively, were enrolled. The ANA titers were measured using indirect immunefluorescence assay (IF-ANA) and multiplex flow immunoassay (ANA Screen) before and serially during the therapy. The anti-IFX antibodies (HACA) and anti-ADA antibodies (AAA) were measured with a radioimmunoassay. ADrA turned positive in 14 (36.8%) among 38 patients treated with IFX, and 16 (30.2%) among 53 treated with ADA. All of them were positive for IF-ANA before TNFi administration, while ADrA never appeared in any of the 15 patients negative for IF-ANA (< 40). IF-ANA of high titers (≥ 320 and ≥ 640) before IFX treatment showed a significant association with the appearance of HACA 52 weeks after IFX (P = 0.040 and 0.017, respectively), whereas AAA appearance was not related to IF-ANA titers before treatment. Moreover, IF-ANA of high titers before IFX treatment was significantly associated with inefficacy and discontinuation of the treatment. The positivity of anti-SS-A antibodies before therapy might be a risk factor for ADrA appearance in patients treated with IFX or ADA. The percentage of patients whose IF-ANA titers increased was significantly higher with IFX than with ADA or ETN treatments (P = 0.026 and 0.022, respectively). High ANA titers and positive ANA Screen after IFX therapy showed a significant association with HACA appearance and possibly led to treatment failure. Among the three TNFi, only IFX showed a close relationship with IF-ANA and ADrA appearance, suggesting the interaction of immunogenicity with autoimmunity as well as the advantage of ANA measurement before TNFi therapy.


Assuntos
Adalimumab/imunologia , Anticorpos/imunologia , Antirreumáticos/imunologia , Artrite Reumatoide/tratamento farmacológico , Etanercepte/imunologia , Infliximab/imunologia , Adalimumab/uso terapêutico , Adulto , Idoso , Anticorpos Antinucleares/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Etanercepte/uso terapêutico , Feminino , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/antagonistas & inibidores
3.
Pan Afr Med J ; 35(Suppl 2): 134, 2020.
Artigo em Francês | MEDLINE | ID: mdl-33193949

RESUMO

Hydroxychloroquine is an agent used as a treatment but also considered as a prophylaxis for SARS-CoV-2 infection. We report the case of a patient who developed COVID-19 while on hydroxychloroquine for mixed connectivitis associated with spondyloarthritis. Although more work is needed before any conclusions can be drawn, this raises questions about the protective role of this drug against infection. Are they really protected against COVID-19 or will they develop pauci-symptomatic forms?


Assuntos
Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Etanercepte/uso terapêutico , Hidroxicloroquina/uso terapêutico , Doença Mista do Tecido Conjuntivo/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Dermatopatias Virais/etiologia , Espondiloartropatias/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Urticária/etiologia , Antirreumáticos/efeitos adversos , Infecções por Coronavirus/complicações , Suscetibilidade a Doenças , Etanercepte/efeitos adversos , Humanos , Masculino , Doença Mista do Tecido Conjuntivo/complicações , Pandemias , Pneumonia Viral/complicações , Espondiloartropatias/complicações , Fator de Necrose Tumoral alfa/efeitos adversos , Adulto Jovem
4.
Int J Hematol ; 112(6): 841-850, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32875487

RESUMO

Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes.


Assuntos
Beclometasona/uso terapêutico , Cidofovir/uso terapêutico , Etanercepte/uso terapêutico , Foscarnet/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infliximab/uso terapêutico , Ácido Micofenólico/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Sistema de Registros , Viroses/tratamento farmacológico , Viroses/etiologia , Doença Aguda , Adulto , Doença Crônica , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Uso Off-Label , Transplante Homólogo
5.
Medicine (Baltimore) ; 99(31): e21447, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756163

RESUMO

BACKGROUND: The comparative efficacy and safety of small molecule and biological agents in the treatment of psoriatic arthritis (PsA) remain unknown. OBJECTIVES: To compare the efficacy and safety of 14 small molecule and biological agents by network meta-analysis (NMA). METHODS: Relevant randomized controlled trials involving biological treatments for PsA were identified by searching PubMed, Cochrane Library, EMBASE, Web of Science, and Clinicaltrials.gov and by manual retrieval, up to June 2018. NMA was conducted with Stata 14.0 based on the frequentist method. Effect measures were odds ratios (ORs) with 95% confidence intervals (CIs). Intervention efficacy and safety were ranked according to the surface under the cumulative ranking curve (SUCRA). RESULTS: A total of 30 studies involving 10,191 adult subjects were included. According to NMA, ≥ 20% improvement in modifed American College of Rheumatology response criteria (ACR20) response, Psoriasis Area and Severity Index 75 (PASI75) response, and serious adverse events rate (SAEs) were observed. In direct comparisons, most of the biologics performed better than placebo in terms of ACR20 response rate and PASI75 response rate. Additionally, all medicines were comparable to placebo in terms of SAEs except secukinumab. In terms of mixed comparisons, with regard to the ACR20 response, etanercept (ETN) and infliximab (IFX) were more effective than golimumab (GOL), with ORs of 3.33 (95% CI: 1.17-9.48) and 1.24 (95% CI: 0.61-2.52), respectively. For PASI75 response, IFX was superior to certolizumab pegol (OR = 10.08, 95% CI: 1.54-75.48). In addition, these medicines were comparable to each other in terms of SAEs. ETN and IFX were shown to have the most favorable SUCRA for achieving improved ACR20 and PASI75 responses, respectively, while ABT-122 exhibited the best safety according to the SUCRA for SAEs. Considering both the efficacy (ACR20, PASI75) and safety (SAEs), GOL, ETN, and IFX are the top 3 treatments. CONCLUSIONS AND IMPLICATIONS: Direct and indirect comparisons and integrated results suggested that the 3 anti- tumor necrosis factor -α biologics (GOL, ETN, and IFX) can be considered the best treatments for PsA after comprehensive consideration of efficacy and safety.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores Biológicos/efeitos adversos , Estudos de Casos e Controles , Certolizumab Pegol/uso terapêutico , Etanercepte/uso terapêutico , Feminino , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Placebos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Índice de Gravidade de Doença , Resultado do Tratamento
6.
Lima; Instituto Nacional de Salud; ago. 2020.
Não convencional em Espanhol | BRISA/RedTESA | ID: biblio-1122096

RESUMO

INTRODUCCIÓN: Este documento técnico se realiza a solicitud del SIS-GREP. A. Cuadro clínico: La psoriasis es una enfermedad sistémica crónica que afecta al 3.2% de la población, se caracteriza por inflamación e induración epidérmica. Dentro de su patogenia se encuentran procesos mediados por el sistema inmune, en la que los cambios genéticos y epigenéticos resultan en un fenotipo de enfermedad caracterizada por una función inmune alterada, activación e hiperproliferación de queratinocitos, y el desarrollo de placas descamativas induradas y eritematosas. Entre el 20 y 30% de los pacientes con psoriasis asocian una artritis psoriásica (APs), la cual puede preceder, ser concomitante o posterior a las manifestaciones cutáneas de la psoriasis. B. Tecnología sanitária: Etanercept (ETN) fue el primer inhibidor de TNF-α que demostró una respuesta significativa en APs. El uso de ETN modula la respuesta biológica severa que es inducida o regulada por TNF, incluyendo la expresión de moléculas de adhesión responsables por la migración leucocítica, nivel sérico de citocinas (ej. IL-6) y niveles séricos de metaloproteinasas de la matriz. Se recomienda el uso de ETN en pacientes con APs para reducir los signos y síntomas, además de inhibir la progresión del daño estructural de la artritis activa, y mejorar la función física. OBJETIVO: Evaluar la eficacia y seguridad, así como documentos relacionados a la decisión de cobertura de etanercept para psoriasis de placa moderada a severa y artritis psoriásica. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas: MEDLINE, LILACS, COCHRANE, así como en buscadores genéricos de Internet incluyendo Google Scholar y TRIPDATABASE. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales de reumatología, y agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se identificaron una RS, cinco GPC y tres ETS. No se encontraron evaluaciones económicas de Perú o la región latinoamericana. CONCLUSIONES: La evidencia comparativa de ETN versus otros inhibidores TNF-α se basa en comparaciones indirectas. Una RS utilizando metaanálisis en red sugiere que adalimumab sería más eficaz que ETN en artritis psoriásica sin diferencias en los eventos adversos. Las 5 GPC seleccionadas consideran ETN como una opción de tratamiento en segunda línea y mencionan que la elección de medicamentos se debería hacer a través de criterio clínico. Una ETS peruana menciona que ETN es una mejor opción comparada con ustekinumab. Una ETS (España) mencionan a ETN como superior por sobre otros anti TNF-α mientras que otra ETS (Reino Unido) no la encuentra costo-efectiva para el manejo de pacientes con artritis psoriásica.


Assuntos
Humanos , Psoríase/tratamento farmacológico , Artrite Psoriásica/tratamento farmacológico , Etanercepte/uso terapêutico , Peru , Avaliação da Tecnologia Biomédica , Análise Custo-Benefício
7.
Brasília; CONITEC; ago. 2020. ilus, tab.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1122923

RESUMO

INTRODUÇÃO: A artrite psoriaca (AP) e a doenca articular inflamatoria associada a psoriase, tambem autoimune, poligenica, de etiologia indefinida, na qual as citocinas relacionadas aos linfocitos T tem um papel central como na psoriase. Estima-se que a prevalencia geral da AP esteja em torno de 0,02% a 0,25% e que 1 em cada 4 pacientes com psoriase tem artrite psoriaca: 23,8% (IC 95%: 20,1% a 27,6%). No Sistema Unico de Saude (SUS) e garantido aos pacientes o acesso as opcoes de tratamentos com medicamentos, incluindo os antiinflamatorios nao esteroidais (AINE) ibuprofeno e naproxeno; os glicocorticoides prednisona e metilprednisolona; os medicamentos modificadores do curso da doenca sinteticos (MMCD-s) sulfassalazina (SSZ), metotrexato (MTX), leflunomida e ciclosporina; os MMCD biológicos (MMCD-b) adalimumabe, etanercepte, infliximabe e golimumabe; e o inibidor de citocinas anti-IL-17 secuquinumabe. PERGUNTA: O uso de ixequizumabe e eficaz, seguro e custo-efetivo para o tratamento de pacientes adultos com AP ativa, com uma resposta insuficiente ou intolerantes ao tratamento com um MMCD biologico? TECNOLOGIA: Ixequizumabe (TaltzR). EVIDÊNCIAS CIENTÍFICAS: Uma revisao sistematica com meta-analise em rede objetivou avaliar a eficacia e seguranca comparativa dos biologicos pertencentes a classe dos inibidores da interleucina (IL-6, IL-12/23 e IL-17) em pacientes com artrite psoriaca ativa. Foi avaliado o desempenho das tecnologias quanto as respostas no instrumento ACR (ACR20, ACR50), na semana 24; qualquer evento adverso (EA); eventos adversos graves (EAG); e tolerabilidade (descontinuacao devido a EA), na semana 16 ou 24. Apos recuperar 329 estudos, a revisão incluiu 6 estudos avaliando os inibidores de interleucina secuquinumabe, ustequinumabe, clazaquizumabe e ixequizumabe, com um total de 2.411 pacientes. Na analise de risco de vies, nao foram identificados pontos criticos, exceto o fato de que todos os seis estudos relataram o uso da ultima observacao transportada para imputacao de dados ausentes (Do ingles, last observation carried forward - LOCF) e que todos os estudos incluidos receberam financiamento de um organismo comercial com fins lucrativos. Ao realizar o ranqueamento com todos os tratamentos disponiveis no SUS (nao apenas os medicamentos em discussao neste relatorio), com base nas estimativas de SUCRA, os resultados do estudo indicam que o secuquinumabe 300 mg mensalmente tem a maior efetividade na obtencao de respostas ACR20 (SUCRA = 96,42) e ACR50 (SUCRA = 91,64). O estudo tambem indica que clazaquizumabe 200mg mensalmente, ustequinumabe 45mg a cada 12 semanas e secuquinumabe 150mg mensalmente tenham a menor probabilidade de ter EA, EAG e descontinuacao devido a EA. Na relacao geral do desempenho dos tratamentos em todos os desfechos de efetividade e seguranca, o secuquinumabe se destaca como a melhor opcao de tratamento em ambas as doses de 300 mg e 150 mg e o ixequizumabe a pior opcao para o tratamento da artrite psoriaca. Apos a condução de uma atualizacao da meta-analise em rede para incluir dois novos estudos do ixequizumabe (SPIRIT-P2 e SPIRIT-H2H), nao considerados na meta-analise original, pode-se observar que o secuquinumabe ainda se mantem com maior probabilidade no ranking de melhor tratamento. Em ambos os desfechos de efetividade e seguranca, o nivel de certeza das evidencias foi considerado moderado, com reducoes de efetividade devido a limitada similaridade das populacoes estudadas com ixequizumabe, secuquinumabe, a linha de tratamento em discussão (falha aos anti-TNF) e reducoes devido a imprecisao no desfecho de EAG. AVALIAÇÃO ECONÔMICA: Para a analise economica, o demandante encaminhou um estudo de "analise de custo por resposta" ou "custo por respondedor", que foi atualizado incluindo a comparacao com o secuquinumabe. Nessa linha, ao considerar os custos e benefícios incrementais em relacao ao adalimumabe, seriam necessarios R$ 19.350,54 para cada resposta adicional no ACR50 com o secuquinumabe. O medicamento ixequizumabe nao demonstrou superioridade na obtencao do ACR50 quando comparado ao adalimumabe, mas sim no desfecho combinado do ACR50/PASI100, onde seriam necessarios R$ 71.284,24 por cada resposta adicional no ACR50/PASI100. Ressalta-se que tal analise carece do rigor metodologico das avaliacoes economicas completas e seus resultados possuem serias limitacoes de interpretacao. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O demandante encaminhou um modelo de impacto orcamentario com o objetivo de analisar o impacto da incorporacao de ixequizumabe ao longo de 5 anos no tratamento de pacientes com artrite psoriaca na perspectiva do SUS. Apos a analise critica do modelo encaminhado, considerou-se possuir um racional adequado e coerente com a perspectiva do SUS, contudo, com pontos criticos a serem revisados. Em sua proposta original, o demandante apresenta uma estimativa de economia de R$ 5,6 milhoes em cinco anos. Com a revisao e atualizacao dos dados, sobretudo ao considerar os custos do tratamento de inducao, essa economia deixa de existir e passa a ser estimado um impacto incremental de mais de R$ 58 milhoes. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectadas no horizonte seis potenciais tecnologias para o tratamento de pacientes com artrite psoriaca com uma resposta insuficiente ou intolerantes ao tratamento com um ou mais MMCD: apremilaste, bimequizumabe, filgotinibe, guselcumabe, risanquizumabe, upadacitinibe. CONSIDERAÇÕES: A partir das estimativas de efetividade comparativa disponiveis, por meio de meta-analises em rede, e possivel observar que o secuquinumabe, tratamento disponivel no SUS, se destaca como a melhor opcao de tratamento na indicacao dessa submissao quando comparado a outras opcoes, inclusive o ixequizumabe, que foi considerada a pior opcao para o tratamento da artrite psoriaca na relacao geral do desempenho nos desfechos de efetividade e seguranca. Alem disso, estima-se que a incorporacao do ixequizumabe possa implicar um impacto incremental de mais de R$ 58 milhoes. RECOMENDAÇÃO PRELIMINAR DA CONITEC: A Conitec, em sua 85a reuniao ordinaria, no dia 04 de fevereiro de 2020, recomendou a nao incorporacao no SUS do ixequizumabe para artrite psoriaca ativa com resposta insuficiente ou intolerante ao tratamento com medicamentos modificadores do curso da doenca. CONSULTA PÚBLICA: Foram recebidas 134 contribuicoes tecnico-cientificas e 222 contribuicoes de experiencia ou opiniao, sendo a maioria discordante da recomendacao preliminar da Conitec. Apos analise do texto das contribuicoes, foram identificados pontos como o anseio por novas opcoes terapeuticas, dificuldade de acesso pelo alto custo unitario do medicamento, assim como foram apresentados novos dados tecnicos e ressaltadas limitacoes da analise preliminar. No entanto, nao foram fornecidas evidencias cientificas que dessem suporte a superioridade do ixequizumabe frente ao secuquinumabe ou que fornecessem melhores subsidios de comparacao do que o uso da comparacao indireta. O laboratorio fabricante ofereceu uma nova proposta de preco equivalente a reducao de 2,7% do preco proposto inicialmente e um novo modelo de impacto orcamentario indicando uma reducao de gastos de ate R$ 49.893.362,00 ao longo dos 5 anos na ocasiao de incorporacao na mesma linha e indicacao do secuquinumabe. A Conitec entendeu que nao houve argumentacao suficiente para alterar sua recomendação inicial, pela nao incorporacao do ixequizumabe, devido a incerteza de beneficios em relacao ao perfil de desempenho de efetividade e seguranca das opcoes terapeuticas ja disponiveis no SUS. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 89a reuniao ordinaria no dia 06 de agosto de 2020, deliberaram, por unanimidade, por recomendar a nao incorporacao no SUS do ixequizumabe para artrite psoriaca ativa com resposta insuficiente ou intolerante ao tratamento com medicamentos modificadores do curso da doenca. Considerou-se os mesmos argumentos para a recomendacao preliminar, o ixequizumabe nao apresenta beneficios em relacao ao perfil de desempenho de efetividade e seguranca das opcoes terapeuticas ja disponiveis no SUS. DECISÃO: Nao incorporar o ixequizumabe para tratamento de pacientes adultos com artrite psoriaca ativa com resposta insuficiente ou intolerante ao tratamento com um ou mais medicamentos modificadores do curso da doenca, no ambito do Sistema Unico de Saude - SUS, conforme Portaria no 31, publicada no Diario Oficial da Uniao no 160, secao 1, pagina 118, em 20 de agosto de 2020.


Assuntos
Humanos , Artrite Psoriásica/tratamento farmacológico , Interleucinas/uso terapêutico , Adalimumab/uso terapêutico , Infliximab/uso terapêutico , Etanercepte/uso terapêutico , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
8.
PLoS One ; 15(7): e0236508, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726333

RESUMO

Extracellular vesicles (EVs) are cell membrane-derived phospholipid bilayer nanostructures that contain bioactive proteins, enzymes, lipids and polymers of nucleotides. They play a role in intercellular communication and are present in body fluids. EVs can be isolated by methods like ultracentrifugation (UC), polyethylene-glycol-precipitation (PEG) or size exclusion chromatography (SEC). The co-presence of immunoglobulins (Ig) in EV samples isolated from plasma (pEVs) is often reported and this may influence the assessment of the biological function and phenotype of EVs in bio- and immunoassay. Here, we studied the presence of an Ig-based therapeutic (etanercept) in pEV samples isolated from rheumatoid arthritis (RA) patients and improved the isolation method to obtain purer pEVs. From plasma of etanercept (Tumor-necrosis-factor (TNF)-α antibodies)-treated RA patients pEVs were isolated by either UC, PEG or SEC. SEC isolated pEVs showed the highest particle-to-protein ratio. Strong TNF-α inhibition determined in a TNF-α sensitive reporter assay was observed by pEVs isolated by UC and PEG, and to a lesser extent by SEC, suggesting the presence of functional etanercept. SEC isolation of etanercept or labelled immunoglobulin G (IgG) showed co-isolation of these antibodies in the pEV fraction in the presence of plasma or a high protein (albumin) concentration. To minimize the presence of etanercept or immunoglobulins, we extended SEC (eSEC) column length from 56mm to 222mm (total stacking volume unchanged). No effect on the amount of isolated pEVs was observed while protein and IgG content were markedly reduced (90%). Next, from six etanercept- treated RA patients, pEVs were isolated on a eSEC or standard SEC column, in parallel. TNF-α inhibition was again observed in pEVs isolated by conventional SEC but not by eSEC. To confirm the purer pEVs isolated by eSEC the basal IL-8 promoter activation in human monocytes was determined and in 4 out of 5 SEC isolated pEVs activation was observed while eSEC isolated pEVs did not. This study shows that extended SEC columns yielded pEVs without detectable biologicals and with low protein and IgG levels. This isolation method will improve the characterization of pEVs as potential biomarkers and mediators of disease.


Assuntos
Produtos Biológicos/sangue , Proteínas Sanguíneas/análise , Vesículas Extracelulares/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Cromatografia em Gel , Etanercepte/sangue , Etanercepte/uso terapêutico , Vesículas Extracelulares/química , Humanos , Imunoglobulina G/análise , Interleucina-8/genética , Regiões Promotoras Genéticas , Ativação Transcricional , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
9.
Rheumatol Int ; 40(9): 1423-1431, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32661928

RESUMO

Concerns regarding the comorbidity as a significant risk factor for Coronavirus Disease-2019 (COVID-19), gave rise to an urgent need for studies evaluating patients with chronic conditions such as autoinflammatory diseases (AIDs). We prepared a web-based survey investigating the clinical findings and contact histories among pediatric patients with AIDs. Confirmed COVID-19 cases, patients with contact history and those with symptoms which were highly suggestive of COVID-19 were called via phone or recruited to a video or face to face appointment. Data of AIDs were obtained from their medical records, retrospectively. Laboratory and screening findings were confirmed by our national health registry website. There were 404 patients (217 female) eligible for the enrollment. During pandemic, 375 (93%) were on colchicine treatment and 48 (11.8%) were receiving biologic treatment. Twenty-four out of 404 patients were admitted to hospital due to COVID-19 suspicion. Severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) was identified through rhinopharyngeal swabs in seven patients, six of whom were only on colchicine treatment. Only one patient with no finding of any severe respiratory complications was hospitalized. All of seven patients recovered completely. Among patients on biologic drugs, neither a symptom nor a positive polymerase chain reaction test for COVID 19 was detected. In conclusion, pediatric patients with AIDs, those receiving biologic treatment and/or colchicine, may not be at increased risk for neither being infected nor the severe disease course.


Assuntos
Colchicina/uso terapêutico , Infecções por Coronavirus/fisiopatologia , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Moduladores de Tubulina/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adalimumab/uso terapêutico , Adolescente , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Produtos Biológicos , Criança , Pré-Escolar , Estudos de Coortes , Infecções por Coronavirus/complicações , Infecções por Coronavirus/terapia , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Etanercepte/uso terapêutico , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Doenças Hereditárias Autoinflamatórias/complicações , Humanos , Lactente , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/terapia , Turquia , Adulto Jovem
10.
Brasília; s.n; 17 jul. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1117678

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 13 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Ribavirina/uso terapêutico , Avaliação da Tecnologia Biomédica , Dexametasona/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Vancomicina/uso terapêutico , Ganciclovir/uso terapêutico , Estudos de Coortes , Corticosteroides/uso terapêutico , Azitromicina/uso terapêutico , Ritonavir/uso terapêutico , Oseltamivir/uso terapêutico , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Lopinavir/uso terapêutico , Linezolida/uso terapêutico , Darunavir/uso terapêutico , Cobicistat/uso terapêutico , Interferon beta-1a/uso terapêutico , Adalimumab/uso terapêutico , Abatacepte/uso terapêutico , Etanercepte/uso terapêutico , Cefepima/uso terapêutico , Meropeném/uso terapêutico , Hidroxicloroquina/uso terapêutico
11.
Ter Arkh ; 92(5): 39-45, 2020 Jun 05.
Artigo em Russo | MEDLINE | ID: mdl-32598774

RESUMO

AIM: Analysis of survival on biological therapy in previously bionaive patients with rheumatoid arthritis (RA) during the first year of therapy in real clinical practice. MATERIALS AND METHODS: The retrospective study included 204 adult patients with RA. In the hospital, patients were first prescribed therapy with various biological disease-modifying antirheumatic drugs (bDMARDs): infliximab, adalimumab, etanercept, certolizumab pegol, tocilizumab, abatacept (ABA), rituximab (RTM). Patients were divided by age in accordance with the classification adopted by WHO. Clinical forms of RA were presented: RA, seropositive for rheumatoid factor, RA, seronegative for rheumatoid factor, RA with extra-articular manifestations, adult-oneset Stills disease, juvenile RA. The reasons for the cancellation of bDMARD during the first year of treatment were: insufficient effectiveness (including primary inefficiency), adverse events, administrative reasons, clinical and laboratory remission, death. RESULTS: A year after being included in the study, treatment was continued in 92 (45%) patients and was discontinued in 112 patients. The average time of treatment amounted to 0.750.33 years. The longest duration of treatment was in the RTM and ABA groups (0.920.22 and 0.830.29 years, respectively). In 56 (50%) patients, bDMARD was canceled due to insufficient effectiveness (including primary inefficiency), 28 patients (25%) due to the development of adverse reactions, 19 (17%) patients for administrative reasons, 7 (6.25%) patients due to drug remission. During the first year of therapy, there were 2 (1.75%) deaths due to severe comorbid conditions in patients, one of whom received RTM, the other tocilizumab. CONCLUSION: Study showed that 45% of patients with RA continue treatment with first-time bDMARD for more than 12 months. The most common reason for discontinuation of therapy was its lack of effectiveness. The best survival rate of bDMARDs was observed in RTM and ABA. When selecting bDMARD in each case, it is necessary to take into account the continuity at all stages of treatment.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Adulto , Etanercepte/uso terapêutico , Seguimentos , Humanos , Estudos Retrospectivos
12.
Rev Med Liege ; 75(5-6): 376-381, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32496683

RESUMO

Psoriasis is a chronic inflammatory skin disease affecting around 2-3 % of the population. The disease spectrum evolves from to the knees and elbows limited disease to erythrodermic psoriasis. The impact on the quality of life, the pruritus, the pain from palmo-plantar disease, arthropathic psoriasis and the comorbidities are the major complaints of the patients. The treatment relies on topical treatments with dermocorticosteroids with or without vitamin D derivatives, UVA or UVB phototherapy, conventional treatments including methotrexate, ciclosporin and acitretin, and, since around 15 years, biological treatments. The biological treatments for moderate to severe psoriasis progressed in a spectacular way with an improvement of clinical results and an amelioration of the safety profile at every step. This article discusses these developments from the TNF? antagonists, including etanercept, adalimumab and infliximab to the newly arrivals, the anti-IL17 and anti-IL23 antagonists, the anti-PDE-4 antagonists and the JAK inhibitors.


Assuntos
Imunossupressores , Psoríase , Qualidade de Vida , Adalimumab/uso terapêutico , Etanercepte/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Infliximab/uso terapêutico , Psoríase/tratamento farmacológico
13.
J Korean Med Sci ; 35(21): e201, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32476306

RESUMO

The neurologic manifestations concerning coronavirus disease 2019 (COVID-19) are highly penetrated. Anosmia and ageusia are one of the common acute neurologic symptoms, which develop in the early stage of COVID-19. However, it is not reported that how immunosuppressive agents affect these symptoms. We report olfactory and gustatory dysfunctions in a patient with ankylosing spondylitis (AS) treated with etanercept during COVID-19. A 53-year-old female showing AS controlled with tumor necrosis factor-α inhibitor, etanercept, had been diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, presenting cough and rhinorrhea. One month after diagnosis, she complained about hyposmia and hypogeusia two days before the seronegative conversion of SARS-CoV-2, which were confirmed by a neurological examination. We speculate that the etanercept may have delayed the development of olfactory and gustatory dysfunction in the patient.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Etanercepte/uso terapêutico , Transtornos do Olfato/etiologia , Pneumonia Viral/complicações , Espondilite Anquilosante/tratamento farmacológico , Distúrbios do Paladar/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Pandemias
15.
Ther Adv Respir Dis ; 14: 1753466620926800, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32436460

RESUMO

Increased inflammatory cytokines [such as tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6)] are observed in COVID-19 patients, especially in the severe group. The phenomenon of a cytokine storm may be the central inducer of apoptosis of alveolar epithelial cells, which leads to rapid progression in severe group patients. Given the similarities of clinical features and pathogenesis between toxic epidermal necrolysis (TEN) and COVID-19, we hypothesize that the application of etanercept, an inhibitor of TNFα, could attenuate disease progression in severe group COVID-19 patients by suppressing systemic auto-inflammatory responses. The reviews of this paper are available via the supplemental material section.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Etanercepte/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Síndrome de Stevens-Johnson/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Betacoronavirus/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/fisiopatologia , Humanos , Pandemias
17.
PLoS One ; 15(3): e0229819, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32203525

RESUMO

This large, retrospective case-control study of electronic health records from 56 million unique adult patients examined whether or not treatment with a Tumor Necrosis Factor (TNF) blocking agent is associated with lower risk for Alzheimer's disease (AD) in patients with rheumatoid arthritis (RA), psoriasis, and other inflammatory diseases which are mediated in part by TNF and for which a TNF blocker is an approved treatment. The analysis compared the diagnosis of AD as an outcome measure in patients receiving at least one prescription for a TNF blocking agent (etanercept, adalimumab, and infliximab) or for methotrexate. Adjusted odds ratios (AORs) were estimated using the Cochran-Mantel-Haenszel (CMH) method and presented with 95% confidence intervals (CIs) and p-values. RA was associated with a higher risk for AD (Adjusted Odds Ratio (AOR) = 2.06, 95% Confidence Interval: (2.02-2.10), P-value <0.0001) as did psoriasis (AOR = 1.37 (1.31-1.42), P <0.0001), ankylosing spondylitis (AOR = 1.57 (1.39-1.77), P <0.0001), inflammatory bowel disease (AOR = 2.46 (2.33-2.59), P < 0.0001), ulcerative colitis (AOR = 1.82 (1.74-1.91), P <0.0001), and Crohn's disease (AOR = 2.33 (2.22-2.43), P <0.0001). The risk for AD in patients with RA was lower among patients treated with etanercept (AOR = 0.34 (0.25-0.47), P <0.0001), adalimumab (AOR = 0.28 (0.19-0.39), P < 0.0001), or infliximab (AOR = 0.52 (0.39-0.69), P <0.0001). Methotrexate was also associated with a lower risk for AD (AOR = 0.64 (0.61-0.68), P <0.0001), while lower risk was found in patients with a prescription history for both a TNF blocker and methotrexate. Etanercept and adalimumab also were associated with lower risk for AD in patients with psoriasis: AOR = 0.47 (0.30-0.73 and 0.41 (0.20-0.76), respectively. There was no effect of gender or race, while younger patients showed greater benefit from a TNF blocker than did older patients. This study identifies a subset of patients in whom systemic inflammation contributes to risk for AD through a pathological mechanism involving TNF and who therefore may benefit from treatment with a TNF blocking agent.


Assuntos
Doença de Alzheimer/epidemiologia , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adalimumab/uso terapêutico , Adolescente , Adulto , Idoso , Artrite Psoriásica/epidemiologia , Artrite Reumatoide/epidemiologia , Estudos de Casos e Controles , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Etanercepte/uso terapêutico , Feminino , Humanos , Infliximab/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Adulto Jovem
18.
Autoimmun Rev ; 19(5): 102509, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173513

RESUMO

Up to 40% of patients treated with tumor necrosis factor alpha inhibitors (TNFi) do not respond to therapy. Testing drug bioavailability and/or anti-drug antibody (ADAb) levels may justify dosage adjustment or switch to different drugs, enabling a personalized medicine approach. We report a multicenter cross-sectional study on different methods [ELISA and a cell based functional assay (reporter gene assay - RGA)] for drug/ADAb detection, and on the relationship between drug bioavailability and ADAb. 163 patients with rheumatoid arthritis (RA) treated with infliximab (IFX; n = 67), adalimumab (ADL; n = 49) or etanercept (ETA; n = 47) were tested for drug and ADAb levels. Furthermore, we report prospective data from additional 70 patients (59 RA and 11 juvenile idiopathic arthritis - JIA) tested for drug and ADAb levels at baseline (T0) and after 3 (T3) and 6 months (T6) of treatment with ADL or ETA only. IFX-treated patients were not included because of the increasing use of IFX biosimilars. Stringent inclusion criteria were used in order to avoid unwanted variables in both studies; none of the patients used TNFi before the study, and TNFi was used only in combination with methotrexate. Clinical response was defined according to EULAR response criteria. The two assays performed comparably in the comparison study. Accordingly, ELISA was selected for the prospective study because of its feasibility in the clinical setting. The cross-sectional study found ADAb in IFX and ADL treated groups only, that were associated with a decrease in pharmacological drug availability in the blood. Comparable results were found for the ADL-treated group in the prospective study which also showed a relationship between drug/ADAb levels and the loss of clinical response. Altogether our findings support drug and anti-drug Ab monitoring in the real-world clinical setting thus enabling individualized treatment and reducing disability in chronic inflammatory arthritis.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Medicina de Precisão , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adalimumab/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Estudos Transversais , Etanercepte/uso terapêutico , Feminino , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
19.
Pharmacol Rep ; 72(2): 379-388, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32048253

RESUMO

BACKGROUND: There are conflicting data regarding angiotensin receptor blockers (ARBs) induced anemia and its beneficial anti-inflammatory effect in rheumatoid arthritis. The aim of the present study was to investigate the effect of telmisartan administration either alone or in combination with etanercept on anemia of chronic inflammatory diseases in a model of rheumatoid arthritis in rats. METHODS: Rheumatoid arthritis (RA) was induced by Freund's Complete Adjuvant (FCA; 1 mg/0.1 ml paraffin oil), injected subcutaneously on days 0, 30 and 40. Rats with RA received dimethyl sulfoxide (DMSO), etanercept (0.3 mg/kg 3 times/week; sc), telmisartan (1.5 mg/kg/day; orally) or combination of etanercept and telmisartan. Arthritis parameters (footpad circumference change and paw volume change), erythrocyte indices (hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin level changes), iron profile (serum iron and serum ferritin), serum levels of erythropoietin (EPO), hepcidin, tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 were evaluated, along with measuring serum urea and creatinine levels. RESULTS: All treated groups showed improvement of the measured parameters in comparison to RA-control subgroup. Telmisartan either alone or in combination with etanercept significantly improved arthritis and erythrocyte indices. Telmisartan showed significant increase in EPO and decrease in hepcidin compared to etanercept. Combination group showed significant improvement in serum iron, ferritin, EPO, hepcidin, TNF-α, IL-6, urea and creatinine, compared to etanercept. Telmisartan either alone or in combination, but not etanercept alone, significantly decreased creatinine level. CONCLUSION: Telmisartan improved anemia and arthritis parameters and showed anti-inflammatory and reno-protective effects, in a rat model of rheumatoid arthritis.


Assuntos
Anemia/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Etanercepte/uso terapêutico , Telmisartan/uso terapêutico , Anemia/complicações , Anemia/imunologia , Animais , Anti-Inflamatórios/administração & dosagem , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Creatinina/sangue , Citocinas/sangue , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada , Etanercepte/administração & dosagem , Adjuvante de Freund/administração & dosagem , Ferro/sangue , Ratos Wistar , Telmisartan/administração & dosagem , Ureia/sangue
20.
Medicine (Baltimore) ; 99(3): e16635, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011430

RESUMO

OBJECTIVE: This study aimed to explore the cost-effectiveness of etanercept plus methotrexate (ETN+MTX) compared to triple disease-modifying anti-rheumatic drugs (DMARDs) in treating Chinese rheumatoid arthritis (RA) patients. METHODS: The 134 Chinese RA patients who were about to initiate ETN+MTX or triple DMARDs therapy based on treat-to-target strategy were consecutively recruited and categorized into ETN+MTX group (N = 49) or triple DMARDs group (N = 85). Treatment efficacy was assessed at month 3 (M3)/M6/M9/M12 after initiation of treatment. Also, 1-year treatment cost was evaluated, and cost-effectiveness analysis and sensitivity analysis were conducted. RESULTS: RA patients in ETN+MTX group exhibited similar disease activity and quality of life at each time point while elevated 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) change (M0-M12) and low disease activity rate compared with triple DMARDs group. For 1-year treatment cost, ETN+MTX required increased drug cost, decreased other medical cost, and finally elevated total cost compared with triple DMARDs. Meanwhile, compared to triple DMARDs, ETN+MTX produced an additional quality-adjusted life year (QALY) of 0.015, resulting in an incremental cost-effectiveness ratio (ICER) of ¥2,939,506.7 per QALY that was 53.1 folds of gross domestic product (GDP) per capita in China. More interestingly, sensitivity analysis revealed that the ETN price had to be reduced at least by 71.3% before ETN+MTX became cost-effectiveness compared to triple DMARDs. CONCLUSION: ETN+MTX is less cost-effective in treating Chinese RA patients compared with triple DMARDs.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Etanercepte/uso terapêutico , Metotrexato/uso terapêutico , Adulto , Idoso , Antirreumáticos/administração & dosagem , Antirreumáticos/economia , Sedimentação Sanguínea , China , Análise Custo-Benefício , Quimioterapia Combinada , Etanercepte/administração & dosagem , Etanercepte/economia , Feminino , Gastos em Saúde , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/economia , Pessoa de Meia-Idade , Qualidade de Vida , Indução de Remissão , Índice de Gravidade de Doença
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