Manoel Barros Bertolo

Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet

Non-alcoholic fatty liver disease, induced by nutritional factors, is one of the leading causes of hepatic dysfunction in the modern world. The activation of proinflammatory signaling in the liver, which is induced by systemic and locally produced cytokines, and the development of hepatic insulin resistance are two important factors associated with the progression from steatosis to steatohepatitis, a pre-cirrhotic condition. The objective of the present study was to evaluate the effect of inhibition of tumour necrosis factor (TNF)-alpha , using the monoclonal antibody infliximab, on the expression of cytokines, induction of steatosis and fibrosis, and insulin signal transduction in the liver of Wistar rats fed a high-fat diet. Ten days of treatment with infliximab significantly reduced the expression of the proinflammatory markers, TNF-alpha , IL-6, IL-1beta , and SOCS-3, in the liver of rats fed a high-fat diet. This was accompanied by reduced fat deposition and fibrosis and by improved insulin signal transduction through insulin receptor (IR)/IR substrate/Akt/FOXO1 and JAK2/STAT3 pathways. In conclusion, short-term inhibition of TNF-alpha with infliximab reduces inflammation and steatosis/fibrosis, while improving insulin signal transduction in an animal model treated with a high-fat diet.

Methotrexate in the treatment of ankylosing spondylitis.

The authors carried out an open prospective study analyzing methotrexate (MTX) ef®cacy and toxicity in 34 patients with ankylosing spondylitis (AS) for a period of one year. All the patients presented with active axial disease, characterized by in ̄ammatory spinal pain, prolonged morning stiffness, erythrocyte sedimentation rate (ESR) §25 mm, and failure on treatment with non-steroidal anti-in ̄ammatory drugs for a period of more than two years. MTX was taken at a single weekly intramuscular dose of 12.5 mg. Thirty-one patients (91%) concluded treatment. Eighteen patients (53%) were considered responders to MTX; most of them presented peripheral arthritis. Despite clinical improvement, axial measures were unaltered at the end of the study. The mean value of ESR decreased signi®cantly at the end of the treatment (p~0.0001), predominantly in the responders group. Side effects were observed in 23 patients (68%) and included dyspeptic syndrome, transient elevation of liver enzymes, and dizziness. The results of this one year open study suggest that MTX can be an ef®cient drug in the treatment of AS.The authors carried out an open prospective study analyzing methotrexate (MTX) efficacy and toxicity in 34 patients with ankylosing spondylitis (AS) for a period of one year. All the patients presented with active axial disease, characterized by inflammatory spinal pain, prolonged morning stiffness, erythrocyte sedimentation rate (ESR) > or = 25 mm, and failure on treatment with non-steroidal anti-inflammatory drugs for a period of more than two years. MTX was taken at a single weekly intramuscular dose of 12.5 mg. Thirty-one patients (91%) concluded treatment. Eighteen patients (53%) were considered responders to MTX; most of them presented peripheral arthritis. Despite clinical improvement, axial measures were unaltered at the end of the study. The mean value of ESR decreased significantly at the end of the treatment (p=0.0001), predominantly in the responders group. Side effects were observed in 23 patients (68%) and included dyspeptic syndrome, transient elevation of liver enzymes, and dizziness. The results of this one year open study suggest that MTX can be an efficient drug in the treatment of AS.

Undifferentiated Spondyloarthritis: A Longterm Followup

Objective. To analyze the longterm followup of a series of Brazilian patients with undifferentiated spondyloarthritis (uSpA). Methods. Prospective study analyzing a group of 111 patients with the diagnosis of uSpA, fulfilling the European Spondylarthropathy Study Group and the Amor criteria, who were followed for 5 to 10 years in a single university referral center. Patients had their outcome analyzed at 5, 7, and 10 years. Results. There was a predominance of men (81.1%), white ethnicity (78.4%), and positive HLA-B27 (61.3%), with a mean age at onset of 27.2 years. Twenty-seven patients presented development to ankylosing spondylitis (AS; 24.3%) and 3 to psoriatic arthritis (PsA; 2.7%), while 25 patients (22.5%) went into remission during the followup. Univariate logistic regression analysis revealed that ethnicity, HLA-B27, buttock pain, inflammatory low back pain, ankle involvement, grade I sacroiliitis at the beginning of the study, and the use of sulfasalazine were statistically associated with progression to AS. Multivariate logistic regression analysis revealed that HLA-B27 (p = 0.035, OR 6.720, 95% CI 11.45–39.43) and buttock pain (p = 0.009, OR 6.211, 95% CI 1.591–24.25) were statistically associated with progression to AS. Conclusion. In a longterm followup of 111 Brazilian patients with uSpA, HLA-B27 and buttock pain were significant predictors of progression to a definite disease.

Undifferentiated Spondyloarthropathies: A 2-Year Follow-up Study

Abstract: The aim of the study was to analyse the 2-year follow-up of a series of patients with the diagnosis of undifferentiated spondyloarthropathy (uSpA). A prospective study was carried out analysing 68 patients with symptomatic uSpA who fulfilled the European Spondylarthropathy Study Group (ESSG) criteria for seronegative spondyloarthropathies (SpA) and were aged between 18 and 50 years. Inclusion criteria included inflammatory low back pain (ILBP) (without radiographic sacroiliitis), asymmetric oligoarthritis (predominantly affecting large joints in the lower limbs) and heel enthesopathies (Achilles tendinitis and/or plantar fasciitis). Imaging methods included pelvic radiography (at study entry and after 2 years) and calcaneal radiography (at study entry). There was a predominance of male gender (78%), caucasoid race (72%) and positive HLA-B27 (54%), with a mean age of 31 years and mean disease duration of 5 years. The first disease manifestations were ILBP (49%), asymmetric oligoarthritis (35%) and heel enthesopathies (16%). A positive family history of a definite SpA was mentioned by 9% of the patients. Seventeen patients (25%) scored 5 points in the Amor set of SpA criteria; logistic regression analysis showed that HLA-B27, heel enthesopathy and asymmetric oligoarthritis were significantly associated with Amor criteria ≥6, whereas ILBP was associated with Amor criteria <6. Male sex was associated with heel enthesopathies (p = 0.041) and ankle involvement (p = 0.015). Caucasoid race was associated with ILBP (p = 0.015) and buttock pain (p = 0.047). Positive HLA-B27 was associated with wrist involvement (p = 0.019) and Amor criteria ≥6 (p = 0.001). After a 2-year follow-up the following outcomes were observed: uSpA 75%; disease remission 13%; ankylosing spondylitis 10%; psoriatic arthritis 2%. Logistic regression analysis showed that buttock pain and positive HLA-B27 (trend) were statistically associated with progression to a definite SpA. In conclusion, uSpA can represent a provisional diagnosis in the group of SpA and a systematic follow-up is necessary in order to better establish the different patterns of the disease.

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.

Tumor necrosis factor-alpha activates signal transduction in hypothalamus and modulates the expression of pro-inflammatory proteins and orexigenic/anorexigenic neurotransmitters.

Tumor necrosis factor‐α (TNF‐α) is known to participate in the wastage syndrome that accompanies cancer and severe infectious diseases. More recently, a role for TNF‐α in the pathogenesis of type 2 diabetes mellitus and obesity has been shown. Much of the regulatory action exerted by TNF‐α upon the control of energy stores depends on its action on the hypothalamus. In this study, we show that TNF‐α activates canonical pro‐inflammatory signal transduction pathways in the hypothalamus of rats. These signaling events lead to the transcriptional activation of an early responsive gene and to the induction of expression of cytokines and a cytokine responsive protein such as interleukin‐1β, interleukin‐6, interleukin‐10 and suppressor of cytokine signalling‐3, respectively. In addition, TNF‐α induces the expression of neurotransmitters involved in the control of feeding and thermogenesis. Thus, TNF‐α may act directly in the hypothalamus inducing a pro‐inflammatory response and the modulation of expression of neurotransmitters involved in energy homeostasis.

Update on the brazilian consensus for the diagnosis and treatment of rheumatoid arthritis

Manoel Barros Bértolo(1), Claiton Viegas Brenol(2), Cláudia Goldenstein Schainberg(3), Fernando Neubarth(4), Francisco Aires Correa de Lima(5), Ieda Maria Laurindo(6), Inês Guimarães Silveira(7), Ivanio Alves Pereira(8), Marco Antonio Rocha Loures(9), Mario Newton de Azevedo(10), Max Victor Carioca de Freitas(11), Milton da Silveira Pedreira Neto(12), Ricardo Machado Xavier(13), Rina Dalva N. Giorgi(14), Sergio Candido Kowalski(15), Sonia Maria Alvarenga Anti(16)

Pulmonary involvement in ankylosing spondylitis.

This is a prospective study analyzing 52 asymptomatic, consecutive patients with ankylosing spondylitis (AS), who submitted to a pulmonary investigation that included plain chest radiography, pulmonary function test (PFT), and thoracic high-resolution computed tomography (HRCT). The results were compared according to sex, race, dorsal spine involvement, thoracic diameter, smoking status, and HLA-B27. There were four patients (8%) with an altered plain chest radiograph. PFT presented a restrictive pattern in 52% of the patients. Thoracic HRCT showed abnormalities in 21 patients (40%), predominantly nonspecific linear parenchymal opacities (19%), lymphadenopathy (12%), emphysema (10%), bronchiectasis (8%), and pleural involvement (8%). Linear parenchymal opacities were associated with a smoking history (p=0.026) and dorsal spine involvement (p=0.032). HLA-B27 was not associated with any abnormality. A lower thoracic diameter was observed in patients with dorsal spine involvement (p=0.0001), restrictive pattern at PFT (p=0.023), and linear parenchymal opacities (p=0.015). The study concluded that nonspecific subclinical pulmonary involvement is frequent in AS.

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.

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.