Valderilio Feijó Azevedo

The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project)

Objective To develop new composite disease activity indices for psoriatic arthritis (PsA). Methods Data from routine clinic visits at multiple centres were collected in a systematic manner. Data included all domains identified as important in randomised controlled trials in PsA. Decisions to change treatment were used as surrogates for high disease activity. New indices were developed by multiple linear regression (psoriatic arthritis disease activity score: PASDAS) and empirically, utilising physician-defined cut-offs for disease activity (arithmetic mean of desirability functions: AMDF). These were compared with existing composite measures: Composite Psoriatic arthritis Disease Activity Index (CPDAI), Disease Activity for PSoriatic Arthritis (DAPSA), and Disease Activity Score for rheumatoid arthritis (DAS28). Results 161/503 (32%) subjects had treatment changes. Although all measures performed well, compared with existing indices, PASDAS was better able to discriminate between high and low disease activity (area under receiver operating curves (ROC)) curve with 95% CI: PASDAS 0.773 (0.723, 0.822); AMDF 0.730 (0.680, 0.780); CPDAI 0.719 (0.668, 0.770); DAPSA 0.710 (0.654, 0.766); DAS28 0.736 (0.680, 0.792). All measures were able to discriminate between disease activity states in patients with oligoarthritis, although area under the receiver operating curves (AUC) were generally smaller. In patients with severe skin disease (psoriasis area and severity index >10) both nonparametric and AUC curve statistics were nonsignificant for all measures. Conclusions Two new composite measures to assess disease activity in PsA have been developed. Further testing in other datasets, including comparison with existing measures, is required to validate these instruments.

Concomitância de fibromialgia em pacientes com espondilite anquilosante

INTRODUCTION Ankylosing spondylitis (AS) is a chronic inflammatory disease that affects the axial skeletal system, causing pain and functional incapacity. To measure the impact of AS on patients life, questionnaires are used to assess disease activity (BASDAI); functional incapacity (BASFI); and quality of life (ASQoL). Fibromyalgia (FM) is one of the most common causes of generalized pain and can coexist with other diseases; it can be assessed by the Fibromyalgia Impact Questionnaire (FIQ). Few studies have demonstrated correlations between FM and AS. The present study obtained data regarding the epidemiologic profile of patients with AS and FM and evaluated the prevalence of FM in patients with AS. The FM influence on BASDAI, BASFI and ASQoL test scores was assessed. PATIENTS AND METHOD A total of 71 patients with AS, diagnosed according to the modified New York criteria, were studied. Clinical and functional assessment was performed and BASDAI, BASFI and ASQoL tests were applied. Patients with a diagnosis of FM were evaluated through the FIQ. RESULTS Eleven patients met the criteria for FM; thus a FM prevalence of 15% was observed among the patients with AS. FM was more prevalent among women (3.8:1). Age at disease onset (AS) was 27.5 years. The HLA-B27 antigen was positive in most of them (80.4%). When comparing BASDAI, BASFI and ASQoL test means, it was observed that values are significantly higher (P < 0.01) among patients with FM. We concluded that the coexistence of FM can worsen AS activity aspects, as well as functional incapacity and quality of life.

Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors

Background Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who had previously had an inadequate response to tumor necrosis factor (TNF) inhibitors. Methods In this 6‐month randomized, placebo‐controlled, double‐blind, phase 3 trial, we randomly assigned 395 patients, in a 2:2:1:1 ratio, to four regimens: 5 mg of tofacitinib administered orally twice daily (132 patients); 10 mg of tofacitinib twice daily (132 patients); placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (66 patients); or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (65 patients). Data from the patients who received placebo during the first 3 months of the trial were pooled. The primary end points were the percentage of patients who had at least 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) and the change from baseline score on the Health Assessment Questionnaire–Disability Index (HAQ‐DI; scores range from 0 to 3, with higher scores indicating greater disability) at the month 3 analysis. Results At 3 months, the rates of ACR20 response were 50% with the 5‐mg dose of tofacitinib and 47% with the 10‐mg dose, as compared with 24% with placebo (P<0.001 for both comparisons); the corresponding mean changes from baseline in HAQ‐DI score were ‐0.39 and ‐0.35, as compared with ‐0.14 (P<0.001 for both comparisons). Serious adverse events occurred in 4% of the patients who received the 5‐mg dose of tofacitinib continuously and in 6% who received the 10‐mg dose continuously. Over the course of 6 months, there were four serious infections, three herpes zoster infections, one myocardial infarction, and one ischemic stroke among the patients who received tofacitinib continuously. Elevations of aspartate and alanine aminotransferase concentrations of three or more times the upper limit of the normal range occurred in more patients who received tofacitinib continuously than in patients who received placebo followed by tofacitinib. Conclusions In this trial involving patients with active psoriatic arthritis who had had an inadequate response to TNF inhibitors, tofacitinib was more effective than placebo over 3 months in reducing disease activity. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Beyond ClinicalTrials.gov number, NCT01882439.)

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

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.

Biopharmaceuticals for rheumatic diseases in Latin America, Europe, Russia, and India: Innovators, biosimilars, and intended copies

A biosimilar is a biopharmaceutical product intended to be comparable to a previously licensed biopharmaceutical agent. The goal of such products is to increase the accessibility of biopharmaceutical therapy for rheumatoid arthritis by reducing costs. They are not like generic drugs, in that they may differ from the reference products in manufacturing, composition, and formulation. Regulatory authorities strive to ensure the absence of clinically meaningful differences between biosimilars and their reference drugs. However, small molecular differences may potentially affect pharmacodynamics (including affinity), pharmacokinetics, and immunogenicity. Intended copies are non-innovator biopharmaceutical products that, unlike biosimilars, do not have enough clinical evidence to demonstrate biosimilarity. For approval of a biosimilar, most countries require preclinical and clinical studies demonstrating comparability with the reference drug. The margin for determining equivalence or non-inferiority is determined on a case-by-case basis in each country, as there are no general criteria. The European Medicines Agency and US Food and Drug Administration have stringent regulatory processes to ensure comparability of biosimilars with their reference drugs. There are also post-marketing surveillance requirements to monitor safety. Only one biosimilar, CT-P13, has been approved for rheumatoid arthritis. However, in countries with less stringent regulation, intended copies are being commercialized and safety problems have been documented. Consequently, in such countries, there is an urgent need for appropriate regulatory processes to be established. Attempts to close the affordability gap of biopharmaceuticals should not open another gap between patients treated with an innovator drug and an intended copy.

Allopurinol, Benzbromarone, or a Combination in Treating Patients with Gout: Analysis of a Series of Outpatients

Objective. To profile a sample of gouty patients treated with allopurinol, benzbromarone, or a combination of these two drugs and to describe the impact of this therapy in reducing uric acid levels. Methods. An observational, transversal study was performed. We evaluated 48 patients diagnosed with gout who were seen at the Outpatient Rheumatology Clinic of the Federal University of Paraná between January 2009 and November 2010. Clinical data, creatinine serum levels, and basal and posttreatment levels of serum urates, transaminases, and bilirubins were recorded. Uric acid levels were measured in a 24-hour urine sample. Patients were divided into three groups: patients given only allopurinol (A), only benzbromarone (B), and both in combined therapy (A + B). Results. The average age of these patients was 56.6 ± 11.4 years, varying from 35 to 81 years. The entire patient group experienced a significant drop in serum urate levels, from 8.5 ± 1.8 mg/dL (0.472 ± 0.1 mmol/L) to 6.7 ± 2.1 mg/dL (0.372 ± 0.116 mmol/L) (P < 0.001), regardless of the prescribed medication. The number of patients taking both drugs whose serum uric acid values fell within normal range (men <7 mg/dL (0.38 mmol/L) and women <6 mg/dL (0.33 mmol/L)) was 85.7% (6/7) while this value for the group taking benzbromarone alone was 75% (3/4) and for the group taking allopurinol alone this number was 51.8% (14/27). Conclusions. The therapeutic combination of benzbromarone and allopurinol significantly decreased serum urate levels in patients with gout when compared to individual use of each of these agents. This finding is especially important in treating patients who cannot control hyperuricemia with monotherapy. Benzbromarone alone or in combination with allopurinol has an important clinical role in controlling hyperuricemia in patients with gout.

Effect of enthesitis on 1505 Brazilian patients with spondyloarthritis.

Objective. To analyze the clinical effect of enthesitis in a large Brazilian cohort of patients with spondyloarthritis (SpA). Methods. A common protocol of investigation was prospectively applied to 1505 patients with SpA in 29 centers in Brazil. Clinical and demographic variables and disease indexes were investigated. The Maastricht Ankylosing Spondylitis Enthesitis Score was used to investigate the enthesitis component. Ankylosing spondylitis was the most frequent disease in the group (65.4%). Others were psoriatic arthritis (18.4%), undifferentiated SpA (6.7%), reactive arthritis (3.3%), and enteropathic arthritis (3.2%). Results. At least 1 affected enthesis was observed in 54% of the patients with SpA, with a mean of 2.12 ± 2.98 entheses affected. According to the clinical presentation, enthesitis was significantly more frequent in patients with axial + peripheral joint involvement compared to isolated axial or peripheral involvement (p < 0.001). There was a statistical association between the presence of enthesites and axial symptoms (buttock pain, cervical pain, and hip pain), and peripheral symptoms (lower limb arthritis, number of painful and swollen joints; p < 0.05). Patients with enthesitis also presented higher mean scores of Bath Ankylosing Spondylitis Functional Index (BASFI; p < 0.001), Bath Ankylosing Spondylitis Disease Activity Index (p < 0.001), and Ankylosing Spondylitis Quality of Life (ASQoL; p < 0.001). Multivariate logistic regression showed that BASFI (p < 0.0001; OR 74.839), ASQoL (p = 0.0001; OR 14.645), and Achilles tendonitis (p = 0.0059; OR 7.593) were associated with work incapacity. Conclusion. The clinical presence of enthesitis in this large cohort of patients with SpA was frequent and was associated with a significant increase in disease activity and decline in functional capacity and quality of life.

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.

Ethnic Influence in Clinical and Functional Measures of Brazilian Patients with Spondyloarthritis

Objective. Spondyloarthritides (SpA) can present different disease spectra according to ethnic background. The Brazilian Registry of Spondyloarthritis (RBE) is a nationwide registry that comprises a large databank on clinical, functional, and treatment data on Brazilian patients with SpA. The aim of our study was to analyze the influence of ethnic background in SpA disease patterns in a large series of Brazilian patients. Methods. A common protocol of investigation was prospectively applied to 1318 SpA patients in 29 centers distributed through the main geographical regions in Brazil. The group comprised whites (65%), African Brazilians (31.3%), and people of mixed origins (3.7%). Clinical and demographic variables and various disease index scores were compiled. Ankylosing spondylitis (AS) was the most frequent disease in the group (65.1%); others were psoriatic arthritis (18.3%), undifferentiated SpA (6.8%), enteropathic arthritis (3.7%), and reactive arthritis (3.4%). Results. White patients were significantly associated with psoriasis (p = 0.002), positive HLA-B27 (p = 0.014), and use of corticosteroids (p < 0.0001). Hip involvement (p = 0.02), axial inflammatory pain (p = 0.04), and radiographic sacroiliitis (p = 0.025) were associated with African Brazilian descent. Sex distribution, family history, and presence of peripheral arthritis, uveitis, dactylitis, urethritis, and inflammatory bowel disease were similar in the 3 groups, as well as age at disease onset, time from first symptom until diagnosis, and use of anti-tumor necrosis factor-α agents (p > 0.05). Schober test and thoracic expansion were similar in the 3 groups, whereas African Brazilians had higher Maastricht Ankylosing Spondylitis Enthesitis Scores (p = 0.005) and decreased lateral lumbar flexion (p = 0.003), while whites had a higher occiput-to-wall distance (p = 0.02). African Brazilians reported a worse patient global assessment of disease (p = 0.011). Other index scores and prevalence of work incapacity were similar in the 3 groups, although African Brazilians had worse performance in the Ankylosing Spondylitis Quality of Life questionnaire (p < 0.001). Conclusion. Ethnic background is associated with distinct clinical aspects of SpA in Brazilian patients. African Brazilian patients with SpA have a poorer quality of life and report worse disease compared to whites.