Paulo Louzada-Junior

IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy

Objectives Interleukin 33 (IL-33) is a new member of the IL-1 family of cytokines which signals via its receptor, ST2 (IL-33R), and has an important role in Th2 and mast cell responses. This study shows that IL-33 orchestrates neutrophil migration in arthritis. Methods and results Methylated bovine serum albumin (mBSA) challenge in the knee joint of mBSA-immunised mice induced local neutrophil migration accompanied by increased IL-33R and IL-33 mRNA expression. Cell migration was inhibited by systemic and local treatments with soluble (s)IL-33R, an IL-33 decoy receptor, and was not evident in IL-33R-deficient mice. IL-33 injection also induced IL-33R-dependent neutrophil migration. Antigen- and IL-33-induced neutrophil migration in the joint was dependent on CXCL1, CCL3, tumour necrosis factor α (TNFα) and IL-1β synthesis. Synovial tissue, macrophages and activated neutrophils expressed IL-33R. IL-33 induces neutrophil migration by activating macrophages to produce chemokines and cytokines and by directly acting on neutrophils. Importantly, neutrophils from patients with rheumatoid arthritis successfully treated with anti-TNFα antibody (infliximab) expressed significantly lower levels of IL-33R than patients treated with methotrexate alone. Only neutrophils from patients treated with methotrexate alone or from normal donors stimulated with TNFα responded to IL-33 in chemotaxis. Conclusions These results suggest that suppression of IL-33R expression in neutrophils, preventing IL-33-induced neutrophil migration, may be an important mechanism of anti-TNFα therapy of inflammation.

HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis

Until recently, neuromyelitis optica (NMO) was considered to be a sub-type of multiple sclerosis (MS), which has a strong predilection for Caucasian populations, whereas NMO is more frequent in non-Caucasian individuals. The objective of this study was to compare the HLA-DRB profile in Brazilian Mulatto patients with NMO spectrum disorders (NMOSDs) with that observed for Mulatto MS patients and healthy Mulatto controls. Twenty seven NMOSD patients (20 women), all seropositive for NMO-IgG, 29 MS patients and 28 Mulatto healthy blood donors were evaluated for HLA-DRB allele groups. HLA-DRB1*03 allele group was overrepresented in NMO patients compared with healthy controls (p = 0.0401; OR = 3.23, 95%CI: 1.07—9.82). In contrast, the HLA-DRB1*15 allele group was overrepresented in Brazilian MS patients (OR = 15.89, 95%CI: 3.51—71.85; p < 0.0001). DRB3 was overrepresented in NMO (p = 0.0064), and DRB5 overrepresented in MS patients (p = 0.0001). The low frequency of HLA-DRB1*15 alleles was associated with the presence of long and central cord lesions at magnetic resonance. In addition, DRB1*15 alleles were associated with the fulfillment of the Barkhof criteria. In conclusion, these results indicate that the DRB profile of NMO patients is different from that observed for MS patients, further corroborating the distinction between NMO and MS.

Consenso da Sociedade Brasileira de Reumatologia 2011 para o diagnóstico e avaliação inicial da artrite reumatoide

OBJETIVO: Elaborar recomendacoes para o manejo da artrite reumatoide (AR) no Brasil, com enfoque no diagnostico e na avaliacao inicial da doenca. METODO: Revisao da literatura e opiniao de especialistas membros da Comissao de AR da Sociedade Brasileira de Reumatologia. RESULTADOS E CONCLUSOES: Foram estabelecidas 10 recomendacoes: 1) O diagnostico da AR deve ser estabelecido considerando-se achados clinicos e exames complementares; 2) Deve-se dedicar especial atencao ao diagnostico diferencial dos casos de artrite; 3) O fator reumatoide (FR) e um teste diagnostico importante, porem com sensibilidade e especificidade limitadas, sobretudo na AR inicial; 4) O anti-CCP (teste para anticorpos antipeptideos citrulinados ciclicos) e um marcador com sensibilidade semelhante a do FR, mas com especificidade superior, sobretudo na fase inicial da doenca; 5) Embora inespecificas, provas de atividade inflamatoria devem ser solicitadas a pacientes com suspeita clinica de AR; 6) A radiografia convencional deve ser empregada para avaliacao de diagnostico e prognostico da doenca. Quando necessario e disponivel, a ultrassonografia e a ressonância magnetica podem ser utilizadas; 7) Podem-se utilizar criterios de classificacao de AR (ACR/EULAR 2010), embora ainda nao validados, como um guia para auxiliar no diagnostico de pacientes com artrite inicial; 8) Deve-se utilizar um dos indices compostos para avaliacao de atividade de doenca; 9) Recomenda-se a utilizacao regular de ao menos um instrumento de avaliacao da capacidade funcional; 10) Deve-se verificar, na avaliacao inicial da doenca, a presenca ou nao de fatores de pior prognostico, como o acometimento poliarticular, FR e/ou anti-CCP em titulos elevados e erosao articular precoce.

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

Significance Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis (RA). However, about 40% of patients are resistant to MTX. Furthermore, MTX resistance is only apparent after a prolonged continuous MTX treatment (>3 mo), by which time the disease of the nonresponders would have aggravated. Thus, there is a considerable unmet need for a biomarker to select MTX-resistant patients and place them immediately on alternative therapy. We found here that the low density of CD39 on peripheral regulatory T cells in RA patients is a rapid, convenient, and reliable (P < 0.01) biomarker for MTX resistance. Our findings also provide previously unrecognized information on aspects of immune regulation in RA and the mechanism of action of MTX. Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4+CD25+FoxP3+) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39+CD4+CD25+FoxP3+ Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.

Análise descritiva das características demográficas e clínicas de pacientes com artrite reumatóide no estado de São Paulo, Brasil

OBJECTIVE: to perform a retrospective analysis of clinical and demographic characteristics of rheumatoid arthritis (RA) patients followed in outpatient clinics in the State of Sao Paulo, Brazil. METHODS: 1.381 medical records of rheumatoid arthritis patients were reviewed in the period between 2002 and 2005. These data were analyzed using a standardized form, based on the following parameters: sex, age, race, weight, follow-up time, disease progression, functional status, rheumatoid factor positivity, social status, pain in the last visit, radiologic progression, extra-articular manifestations, quantitative assessment of functional status and disease active score (DAS), pharmacological treatment, and physical therapy. RESULTS: 86% were female Caucasians. Age of disease onset varied between the forth and fifth decades. Mean follow-up was 7.2 years and mean body weight was 65.6 kg. Less than 5% of the patients were classified as severe and the majority of the patients presented functional class I and II. Extra-articular manifestations were observed in 23.3% and the rheumatoid factor was positive in 71%. Only 33% of the patients had radiological evaluation and were working regularly. Methotrexate was the most common medication (15-19 mg/week). Only 25% of these patients were attending physical therapy and 30% had quantitative assessment of functional status and DAS. CONCLUSION: this analysis provided a partial analysis of the RA Brazilian population, identified demographic and clinical characteristics, the therapeutic drugs used, and the difficulty of the patients in attending rehabilitation services.

Registro brasileiro de biológicos: processo de implementação e resultados preliminares do BiobadaBrasil

OBJETIVOS: O presente estudo teve por objetivo descrever o processo de implementacao de um registro nacional em um pais em desenvolvimento (Brasil) e relatar os principais resultados preliminares do registro BiobadaBrasil. MATERAL E METODOS: Atraves de um acordo com a PANLAR, o protocolo Biobadaser foi utilizado como modelo para a implementacao de um novo registro no nosso pais. Durante os dois primeiros anos desse esforco, o protocolo original foi adaptado, traduzido e apresentado a todos os reumatologistas brasileiros. Durante dez meses, dados de 1.037 pacientes (750 tratados com biologicos e 287 controles) de 15 centros foram coletados. RESULTADOS: A maioria dos pacientes tinha artrite reumatoide (AR) (n = 723). Infliximabe foi o agente anti-TNF mais usado, e a exposicao total a biologicos foi 2.101 pacientes-ano. A razao mais comum para suspensao da droga foi ineficiencia ou perda de efetividade (50%), e 30% dos pacientes interromperam o tratamento devido a eventos adversos. Tres casos de tuberculose foram observados no grupo biologico, representando maior incidencia do que aquela da populacao brasileira geral. Infeccoes foram observadas em 23% dos pacientes do grupo biologico, sendo o trato respiratorio superior o local mais comumente afetado. Apenas um caso de hanseniase tuberculoide foi observado. Nenhuma morte nem malignidade atribuivel ao efeito dos medicamentos foi observada ate fevereiro de 2010. CONCLUSOES: A implementacao do registro foi bem sucedida. Embora recente, o registro BiobadaBrasil ja forneceu importantes dados.

CCR2 Expression in Neutrophils Plays a Critical Role in Their Migration Into the Joints in Rheumatoid Arthritis

Infiltration of neutrophils into the joints plays an important role in bone erosion and articular destruction in rheumatoid arthritis (RA). Neutrophil trafficking during inflammation is a process that involves activation of chemotactic receptors. Recent findings suggest that changes in chemotactic receptor patterns could occur in neutrophils under certain inflammatory conditions. The aim of this study was to evaluate the gain of responsiveness of neutrophils to CCL2 in RA patients and to assess the role of CCL2 in driving neutrophil infiltration into the joints.

Association of the HLA-DRB1⁎15 allele group and the DRB1⁎1501 and DRB1⁎1503 alleles with multiple sclerosis in White and Mulatto samples from Brazil

Multiple sclerosis (MS) is a multifactorial inflammatory disease that primarily affects the central nervous system. Genes and environmental factors probably interact in MS susceptibility and outcome; however, their roles have not been elucidated yet. The evaluation of the HLA-DRB1 gene in the Brazilian population is of particular interest in evidencing the behavior of HLA-DRB1 alleles in a highly admixed population inserted in an environment of low MS prevalence. The present results suggest that a given HLA-DRB1 allele may exhibit different behaviors, i.e. confer resistance or susceptibility, in response to the environmental and/or genetic (ethnic) backgrounds that characterize a sampled population.

Frequency of HLA-B27 alleles in Brazilian patients with psoriatic arthritis

This prospective study analyzed the frequency of HLA-B27 and its alleles in 102 Brazilian patients with psoriatic arthritis (PsA). The association of the HLA-B27 alleles with these variants was compared to a control healthy HLA-B27 positive group of 111 individuals. There was a predominance of male gender (59.8%), Caucasian race (89.2%), and negative HLA-B27 (79.4%) patients. Asymmetric oligoarthritis (62.7%) was the most frequently observed clinical PsA subgroup, followed by spondylitis (16.7%), and polyarthritis (15.7%). Male gender and the spondylitis subgroup were statistically associated to the positive HLA-B27, and the oligoarthritis subgroup was associated to the negative HLA-B27. Among the 21 HLA-B27-positive PsA patients, there was a significant prevalence of the HLA-B*2705 allele (90.5%), similar to that observed in the control group (80.2%); HLA-B*2703 and HLA-B*2707 were statistically associated to the control group.

HLA class I and class II profiles of patients presenting with Sydenham's chorea

Abstract Sydenham’s chorea (SC) may occur in rheumatic fever (RF) patients without arthritis and carditis. In this study we typed HLA antigens and alleles in patients presenting with the distinct major clinical manifestations of RF, i.e., chorea, carditis, or arthritis, in population and family studies. We evaluated 91 patients with RF for HLA-A, HLA-B, and HLA-DR antigens; of these, 33 had pure chorea, 26 pure carditis, 16 pure arthritis, and 16 carditis plus arthritis. We also typed 24 SC patients and their unaffected siblings for HLA-DRB1 and HLA-DQB1 alleles using molecular methods. HLA-B49 and HLA-DR1 antigens were overrepresented in the total group of patients with RF and in all the subgroups studied, excluding the SC subgroup in which the frequency of HLA-DR1 antigen was not increased. The frequencies of the HLA-DRB1 and HLA-DQB1 alleles in patients with pure chorea were not significantly different from those observed in controls. Similarly, the frequencies of HLA class II alleles in SC patients did not differ significantly from those observed in unaffected siblings. These findings show that immunogenetic susceptibility to RF varies according to the major clinical manifestation presented by the patient.