RESUMO
The efficacy of anti-TNF-α therapies highlights the role of TNF-α in the pathogenesis of rheumatoid arthritis (RA). However, the mechanism of action of these agents is poorly understood at the molecular level. The aim of this study was to characterize the effects of anti-TNF-α treatment on the global gene expression profile in peripheral blood mononuclear cells (PBMCs) of responder RA patients. Changes in gene expression were determined using oligonucleotide microarrays (25,341 genes) in PBMCs obtained before and after 12 wk of treatment with either etanercept or adalimumab from responder RA patients. Two hundred fifty-one genes displayed significant changes (false discovery rate < 0.1%) in expression level (178 upregulations with mean fold change = 1.5 and 73 downregulations with mean fold change = -1.50) after 12 wk of treatment. Importantly, the expression of several genes, including those coding for the calcium binding proteins S100A12 and A8, CD14 antigen, Selectin P, or ribosomal protein L39, reported to be upregulated in RA patients, were found to be decreased after anti-TNF-α treatment. Globally, inflammation, immune response, apoptosis, protein synthesis, and mitochondrial oxido-reduction were the most affected pathways in response to anti-TNF-α treatment. The obtained gene expression signature in PBMCs provides new information to better understand the mechanisms of action of anti-TNF-α treatment in RA patients.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Etanercepte , Feminino , Perfilação da Expressão Gênica , Humanos , Imunoglobulina G/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Receptores do Fator de Necrose Tumoral/uso terapêuticoRESUMO
The development of methotrexate (MTX) as a therapy for rheumatoid arthritis (RA) evolved initially from positive case reports, uncontrolled case series and then several decades later placebo controlled studies followed by active comparator studies. These studies established MTX as a major therapy for RA. The importance of MTX in the treatment paradigm has only been enhanced over the past decade by the increased efficacy observed when small molecules and biologics are added to MTX. Since the first randomised studies were performed in the 1980s, MTX has now become the most well-studied disease modifying therapy to date and the most popular drug worldwide in the treatment of RA. This chapter will review the history of the development of MTX in RA.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Ensaios Clínicos como Assunto , Medicina Baseada em Evidências , Metotrexato/uso terapêutico , Antirreumáticos/história , Artrite Reumatoide/história , Ensaios Clínicos como Assunto/história , Medicina Baseada em Evidências/história , História do Século XX , Humanos , Metotrexato/história , Resultado do TratamentoRESUMO
INTRODUCTION: Rare systemic diseases such as amyloidosis can mimic inflammatory rheumatic diseases. Because of their poor prognosis, physicians should rule them out at the onset of inflammatory rheumatism. We report a case of AL amyloidosis misdiagnosed as rheumatoid arthritis. CASE REPORT: A 71-year-old woman was referred for seronegative rheumatoid arthritis, resistant to three biologic therapies. She had an IgA lambda monoclonal gammopathy of undetermined significance (MGUS). The patient subsequently developed glomerular proteinuria. Abdominal fat and accessory salivary glands biopsies revealed amyloid light-chain (AL) amyloidosis. Treatment with bortezomib-cyclophosphamide-dexamethasone, led to complete hematologic, renal and rheumatologic remission. Ten months after treatment interruption, the patient had an articular and hematologic relapse. CONCLUSION: Amyloid light-chain amyloidosis arthropathy is probably underdiagnosed. A review of amyloid arthropathy associated with multiple myeloma found that 33% of patients had been misdiagnosed with rheumatoid arthritis.
Assuntos
Artrite Reumatoide/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/etiologia , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/diagnósticoRESUMO
OBJECTIVE: The efficacy of anti-tumour necrosis factor-alpha (TNF-alpha) therapies in rheumatoid arthritis (RA) has been mainly attributed to TNF-alpha neutralisation. Other mechanism as immune cell apoptosis, which is impaired in RA, may also be induced by anti-TNF-alpha therapies. The aim of our study was to investigate whether TNF-alpha inhibitors could induce apoptosis in vitro of the peripheral blood lymphocytes of RA patients. METHODS: Peripheral blood mononuclear cells (PBMC) isolated from 24 patients with RA and 18 healthy donors were incubated with anti-TNF-alpha agents, infliximab or etanercept, in comparison with no agent and including an isotypic control, for 48 hours. Apoptosis was detected and quantified by annexin V labelling of phosphatidylserine externalization using cytofluorometric analysis and compared with PBMC production TNF-alpha in vitro. RESULTS: In healthy donors, induced apoptosis was observed in 0.3% to 3.8% of lymphocytes with both therapies. In RA patients the treatment induced lymphocyte apoptosis in 17 of 24 patients with a percentage of annexin V-positive lymphocytes ranging from 0.1% to 25%. Among these 17 RA patients, a significant in vitro lymphocyte apoptosis (> 4%) was observed in 11 patients (46%) compared with healthy donors (p < 0.01). The variability of the response to anti-TNF-alpha within the RA population was not dependent on TNF-alpha synthesis or disease activity. CONCLUSION: In vitro induction of lymphocyte apoptosis by anti-TNF-alpha was observed in a subgroup of RA patients. Based on these data, it would be of interest to further study the interindividual variations of sensitivity to apoptosis induced by TNF alpha inhibitors in relation to treatment efficacy or resistance observed in RA patients.
Assuntos
Anticorpos Monoclonais/farmacologia , Antirreumáticos/farmacologia , Apoptose/efeitos dos fármacos , Artrite Reumatoide/patologia , Leucócitos Mononucleares/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Células Cultivadas , Etanercepte , Feminino , Humanos , Imunoglobulina G/farmacologia , Técnicas In Vitro , Infliximab , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologiaRESUMO
INTRODUCTION: Antimalarial drugs are largely used for the treatment of various systemic diseases. They can cause toxic retinopathy, which can lead to blindness. OBSERVATION: We report the case of a 32-year-old male with a systemic lupus erythematosus treated with hydroxychloroquine 400mg per day and then chloroquine 300mg per day during 8 and 9years respectively. Eighteen months after his latest visual examination, the patient experienced bilateral vision loss. Fundus examination revealed a bull's eye maculopathy. Additional tests including multifocal electroretinogram showed severe bilateral functional impairment in the parafoveal area leading to diagnosis of severe toxic retinopathy induced by antimalarial drugs. DISCUSSION: In 2016, the American Academy of Ophthalmology revised the previous 2011 recommendations concerning early retinal toxicity screening strategy which should be first based on both automated 10-2 visual fields and spectral-domain optical coherence tomography (SD OCT). Multifocal electroretinogram can be more helpful for diagnostic confirmation rather than screening. Although these recommendations are essential, they are not well known in clinical practice.