Mauro Keiserman

Subcutaneous abatacept versus intravenous abatacept : a phase IIIb noninferiority study in patients with an inadequate response to methotrexate.

Objective To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. Methods In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. Results Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept–treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept–treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval –4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept–treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept–treated group and 65.2% and 4.9%, respectively, in the IV abatacept–treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)–treated patients (2.6%) and 18 IV abatacept (SC placebo)–treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept–treated patients and 2.3% of IV abatacept–treated patients. Conclusion SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.

Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results From Two Phase III Randomized, Double-Blind, Placebo-Controlled Trials

Epratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double‐blind, placebo‐controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).

Consenso Brasileiro de Espondiloartropatias: espondilite anquilosante e artrite psoriásica diagnóstico e tratamento - primeira revisão

1. Assistente-doutor da Disciplina de Reumatologia do Departamento de Clinica Medica da Faculdade de Ciencias Medicas da Universidade Estadual de Campinas (FCM-UNICAMP). Presidente da Comissao de Espondiloartropatias da Sociedade Brasileira de Reumatologia (SBR). 2. Professor Assistente da Disciplina de Reumatologia da Universidade Federal do Parana (UFPR). Mestre em Medicina Interna. 3. Professor Assistente da Disciplina de Reumatologia da Pontificia Universidade Catolica de Campinas (PUCCAMP). 4. Professor Adjunto, Doutor em Oftalmologia da Universidade Federal de Minas Gerais (UFMG). 5. Professora Adjunta da Faculdade de Ciencias Medicas da Universidade Estadual do Rio de Janeiro (UERJ) e Professora do Programa de Pos-Graduacao em Medicina da Universidade Federal do Rio de Janeiro (UFRJ). 6. Professor Adjunto, Doutor de Reumatologia do Departamento do Aparelho Locomotor da Universidade Federal de Minas Gerais (UFMG). 7. Professor Doutor-Assistente e Coordenador da Unidade de Espondiloartropatias da Disciplina de Reumatologia da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP). 8. Professora Associada e Responsavel pelo Setor de Reumatologia Pediatrica da Universidade Federal de Sao Paulo (UNIFESP). 9. Professor Regente da Disciplina de Reumatologia da Faculdade de Medicina da Pontificia Universidade Catolica do Rio Grande do Sul (PUC-RS). 10. Professor Titular de Reumatologia da Faculdade de Medicina Souza Marques, Rio de Janeiro – RJ. 11. Professora da Disciplina de Coloproctologia da Fundacao Faculdade Federal de Ciencias Medicas de Porto Alegre (FFFCMPA). 12. Assistente-Doutor e Chefe do Grupo de Reumatologia do Instituto de Ortopedia e Traumatologia da FMUSP. 13. Chefe do Servico de Reumatologia e Coordenador da Residencia Medica do Hospital Geral de Fortaleza. 14. Chefe do Departamento de Medicina Interna do Hospital Geral de Goiânia. Doutor em Reumatologia pela FMUSPUniversidade Estadual de Campinas Faculdade de Ciencias Medicas Departamento de Clinica Medica

The effect of antidrug antibodies on the sustainable efficacy of biologic therapies in rheumatoid arthritis: practical consequences

Biologic therapies, predominantly TNF-α inhibitors, have revolutionized the treatment of rheumatoid arthritis (RA). However, their clinical utility can be limited by the development of antidrug antibodies (ADAs). Immunogenicity is a complex phenomenon related to various drug, disease, and patient characteristics, and may be more common with the monoclonal antibodies than with etanercept, a soluble TNF receptor-Fc immunoglobulin fusion protein. Neutralizing antibodies – those that hinder bioactivity by preventing drug molecules from binding to TNF – are correlated with reduced serum drug concentrations, loss of therapeutic response, adverse events, and treatment discontinuation. Cost-effective use of these agents will depend on further research into drug and ADA assays, and how they should guide dose reduction or switching strategies.

Gender characterization in a large series of Brazilian patients with spondyloarthritis

An increasing number of women have been diagnosed with spondyloarthritis (SpA) in recent decades. While a few studies have analyzed gender as a prognostic factor of the disease, no studies have addressed this matter with a large number of patients in South America, which is a peculiar region due to its genetic heterogeneity. The aim of the present study was to analyze the influence of gender on disease patterns in a large cohort of Brazilian patients with SpA. A prospective study was carried out involving 1,505 patients [1,090 males (72.4%) and 415 females (27.6%)] classified as SpA according to the European Spondyloarthropaties Study Group criteria who attended at 29 reference centers for rheumatology in Brazil. Clinical and demographic variables were recorded and the following disease indices were administered: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Radiologic Index (BASRI), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), and Ankylosing Spondylitis Quality of Life (ASQoL). Ankylosing spondylitis (AS) was the most frequent disease in the group (65.4%), followed by psoriatic arthritis (18.4%), undifferentiated SpA (6.7%), reactive arthritis (3.3%), arthritis associated to inflammatory bowel disease (3.2%), and juvenile SpA (2.9%). The male-to-female ratio was 2.6:1 for the whole group and 3.6:1 for AS. The females were older (p < 0.001) and reported shorter disease duration (p = 0.002) than the male patients. The female gender was positively associated to peripheral SpA (p < 0.001), upper limb arthritis (p < 0.001), dactylitis (p = 0.011), psoriasis (p < 0.001), nail involvement (p < 0.001), and family history of SpA (p = 0.045) and negatively associated to pure axial involvement (p < 0.001), lumbar inflammatory pain (p = 0.042), radiographic sacroiliitis (p < 0.001), and positive HLA-B27 (p = 0.001). The number of painful (p < 0.001) and swollen (p = 0.006) joints was significantly higher in the female gender, who also achieved higher BASDAI (p < 0.001), BASFI (p = 0.073, trend), MASES (p = 0.019), ASQoL (p = 0.014), and patient’s global assessment (p = 0.003) scores, whereas the use of nonsteroidal anti-inflammatory drugs (p < 0.001) and biological agents (p = 0.003) was less frequent in the female gender. Moreover, BASRI values were significantly lower in females (p < 0.001). The female gender comprised one third of SpA patients in this large cohort and exhibited more significant peripheral involvement and less functional disability, despite higher values in disease indices.

Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results from the Phase 3, Randomized, Double-blind, Placebo-controlled Trials, EMBODY™ 1 and EMBODY™ 2.

Epratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double‐blind, placebo‐controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).

Subcutaneous abatacept for the treatment of rheumatoid arthritis: longterm data from the ACQUIRE trial.

Objective. Assess longterm tolerability, safety, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate-refractory patients with rheumatoid arthritis (RA). Methods. The phase III, multinational Abatacept Comparison of Sub[QU]cutaneous Versus Intravenous in Inadequate Responders to MethotrexatE (ACQUIRE) trial comprised a 6-month, randomized, double-blind (DB) period, in which patients received intravenous (IV) or SC ABA, plus MTX, followed by an open-label, longterm extension (LTE), in which patients received SC ABA, 125 mg/week. Safety and efficacy from the LTE (∼3.5 yrs of exposure) are reported. Results. Patients who completed the DB period (1372/1385, 99.1%) entered the LTE; 1134 patients (82.7%) kept taking the treatment at time of reporting. Mean (SD) was 31.9 months (6.8); median (range) exposure was 33.0 (8–44) months. Patients entering the LTE had longstanding, moderate-to-severe disease [mean 7.6 (7.9) yrs and DAS28 (C-reactive protein) 6.2 (0.9)]. Incidence rates (events/100 patient-yrs) were reported for serious adverse events (8.76, 95% CI 7.71, 9.95), infections (44.80, 95% CI 41.76, 48.01), serious infections (1.72, 95% CI 1.30, 2.27), malignancies (1.19, 95% CI 0.86, 1.66), and autoimmune events (1.31, 95% CI 0.95, 1.79). Twenty-seven patients (2%) experienced injection-site reactions; all except 1 were mild. American College of Rheumatology 20, 50, and 70 responses achieved during the DB period were maintained through the LTE, and on Day 981 were 80.2% (95% CI 77.2, 83.2), 63.5% (95% CI 58.2, 68.9), and 39.5% (95% CI 34.0, 44.9) for patients who kept taking SC ABA, and 80.0% (95% CI 77.0, 83.0), 63.2% (95% CI 57.8, 68.7), and 39.2% (95% CI 33.7, 44.7) for those who switched from IV to SC ABA. Conclusion. These findings support SC ABA as a well-tolerated and efficacious longterm treatment for patients with RA and inadequate response to MTX (ClinicalTrials.gov identifier NCT00559585).

Yellow fever vaccination and Kawasaki disease.

DISCUSSION This is the first report of the use of oral linezolid for the successful treatment of staphylococcal liver abscess in CGD. Linezolid is an oxazolidinone antibiotic that has a bacteriostatic action by inhibition of the 70s ribosomal initiation complex. Linezolid is rapidly and completely absorbed after oral administration. It is used in complex or resistant gram-positive infections, and is an oral option where intravenous therapy would be the normal route of administration. In this case it was used with caution and as a last resort because of reports of serious adverse events related to mitochondrial toxicity in treatment courses beyond 28 days. Short courses of linezolid are well tolerated in children. Common adverse events include nausea, vomiting, and diarrhea. Teeth and tongue discoloration with taste disturbance has also been reported. Anemia and thrombocytopenia are frequently seen but are reversible and often do not require discontinuation of therapy. The more serious adverse events relate to its mitochondrial toxicity. The main risk of long-course therapy is irreversible peripheral neuropathy; optic neuropathy can also occur but rapidly improves after discontinuation of therapy. Michel Erlewyn-Lajeunesse, MRCPCH, DM Woolf Walker, BM, MRCPCH Adriana Basarab, MRCP, FRCPath Efrem Eren, FRCPath, PhD Nadeem Afzal, MRCPCH, MRCP(UK) Southampton University Hospitals NHS Trust Southampton, United Kingdom

Long‐Term Safety and Efficacy of Epratuzumab in the Treatment of Moderate‐to‐ Severe Systemic Lupus Erythematosus: Results From an Open‐Label Extension Study

The primary objective was to assess the long‐term safety of repeated courses of epratuzumab therapy in patients with moderate‐to‐severe systemic lupus erythematosus. Secondary objectives were to assess long‐term efficacy and health‐related quality of life (HRQOL).

Recomendações sobre diagnóstico e tratamento da espondilite anquilosante

Descricao do metodo de elaboracao das evidencias Os integrantes da Comissao de Espondiloartrites da Sociedade Brasileira de Reumatologia (bienio 2010-2012) participaram do Curso de Elaboracao de Evidencias da Associacao Medica Brasileira, em Sao Paulo, durante o primeiro semestre de 2011. As questoes foram concluidas em reuniao presencial da Comissao de Espondiloartrites no dia 15 de outubro de 2011, durante a XVIII Jornada Cone Sul de Reumatologia, em Florianopolis (SC, Brasil), e foram posteriormente aprovadas por todos os coordenadores do Registro Brasileiro de Espondiloartrites. As 15 questoes clinicas consideradas relevantesforam estruturadas por meio da estrategia do P.I.C.O. (Paciente; Intervencao ou Indicador; Comparacao; Outcome). As estrategias de busca avaliaram as bases de dados MEDLINE, EMBASE, Scielo/Lilacs, Cochrane Library ate fevereiro de 2012 (Apendice). Os artigos selecionados na primeira estrategia de busca foram submetidos a avaliacao critica das evidencias, utilizando-se o escore de Jadad. Posteriormente, foram elaboradas as respostas das recomendacoes – cada referencia bibliografica selecionada apresentava o correspondente grau de recomendacao e forca de evidencia cientifica. Para as recomendacoes finais, as referencias bibliograficas foram atualizadas ate agosto de 2012, redigidas em texto unico pelo coordenador, e submetidas aos coautores em dois turnos, para elaboracao do texto final. Grau de recomendacao e forca de evidencia A: Estudos experimentais e observacionais de melhor consistencia. B: Estudos experimentais e observacionais de menor consistencia. C: Relatos de casos (estudos nao controlados). D: Opiniao desprovida de avaliacao critica, baseada em consensos, estudos fisiologicos ou modelos animais. Objetivo Estabelecer as recomendacoes para o manejo (criterios classificatorios e avaliacao por ressonância magnetica e genetica) das espondiloartrites e para o tratamento da espondilite anquilosante.