Rheumatoid Arthritis: Xavier RM

Filippin LI, Vercelino R, Marroni NP, Xavier RM. · Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. · Clin Exp Immunol. · Pubmed #18422737 links to  free full text

Abstract: Reactive oxygen species (ROS) are produced mainly during oxidative phosphorylation and by activated phagocytic cells during oxidative burst. The excessive production of ROS can damage lipids, protein, membrane and nucleic acids. They also serve as important intracellular signalling that enhances the inflammatory response. Many studies have demonstrated a role of ROS in the pathogenesis of inflammatory chronic arthropathies, such as rheumatoid arthritis. It is known that ROS can function as a second messenger to activate nuclear factor kappa-B, which orchestrates the expression of a spectrum of genes involved in the inflammatory response. Therefore, an understanding of the complex interactions between these pathways might be useful for the development of novel therapeutic strategies for rheumatoid arthritis.

Brenol CV, Monticielo OA, Xavier RM, Brenol JC. · Serviço de Reumatologia, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul. · Rev Assoc Med Bras. · Pubmed #17952359 links to  free full text

Abstract: Rheumatoid arthritis is a systemic inflammatory autoimmune disease characterized by symmetric, erosive and chronic synovitis, especially of minor joints. It is associated with increased prevalence of cardiovascular disease and with high mortality. This occurs because of an accelerated atherogenic process, explained by traditional cardiovascular risk factors such as smoking, hypercholesterolemia, age, diabetes mellitus and systemic arterial hypertension. High levels of hemosedimentation velocity and C-reactive protein are directly correlated with increased cardiovascular events. Pro-inflammatory cytokines contribute with endothelial dysfunction, insulin resistance, dyslipidemia, prothrombotic effects and oxidative stress that are at the basis of the atherogenic process. Recent information about atherosclerosis in rheumatoid arthritis allows for identification of the risk factors involved in atherosclerosis that can be best controlled. This could result in a reduced manifestation of the process and its cutback, with consequent decrease of mortality and morbidity related to rheumatoid arthritis.

Ranzolin A, Brenol JC, Bredemeier M, Guarienti J, Rizzatti M, Feldman D, Xavier RM. · Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil. · Arthritis Rheum. · Pubmed #19479706 No free full text.

Abstract: OBJECTIVE: To study the association of the presence of fibromyalgia (FM) with the Disease Activity Score in 28 joints (DAS28), the Health Assessment Questionnaire (HAQ), and the Medical Outcomes Study Short Form 36 (SF-36) health survey in patients with rheumatoid arthritis (RA). METHODS: A total of 270 outpatients with RA were enrolled in a prospective cross-sectional study. The patients underwent clinical evaluation and application of the HAQ and SF-36 questionnaires. Disease activity was evaluated using the DAS28 score. FM and RA diagnoses were made according to American College of Rheumatology criteria. RESULTS: The overall prevalence of FM was 13.4%. This group of patients had a higher prevalence of female sex, older mean age, higher functional class, and longer morning stiffness than patients with only RA. Mean +/- SD DAS28 scores were significantly higher in patients with RA and FM (5.36 +/- 0.99) than in patients with RA only (4.03 +/- 1.39; P < 0.001). In a multivariable linear regression analysis, FM was an important predictor of the DAS28 score, even after adjusting for the erythrocyte sedimentation rate, number of swollen joints, functional class, number of disease-modifying antirheumatic drugs currently in use, current dose of steroids, and articular erosions. HAQ and SF-36 scores were also worse in patients with RA and associated FM. CONCLUSION: FM is related to worse scores on the DAS28, HAQ, and SF-36 in patients with RA. The presence of FM may have major implications in the interpretation of the DAS28 score because it is related to higher scores independently of objective evidence of RA activity.

de Souza TB, Mentz EF, Brenol CV, Xavier RM, Brenol JC, Chies JA, Simon D. · Curso de Biologia and Programa de Pós-Graduação em Diagnóstico Genético e Molecular, Universidade Luterana do Brasil, Canoas, Brazil. · J Rheumatol. · Pubmed #19004047 No free full text.

Abstract: OBJECTIVE: Genetic and environmental factors seem to be involved in the onset of rheumatoid arthritis (RA). We analyzed whether a variable number of tandem repeats (VNTR) polymorphism in the aggrecan gene was associated to RA. METHODS: The study population comprised 170 European-derived Brazilian patients with diagnosis of RA. The control group comprised 148 European-derived Brazilian healthy blood donors. The aggrecan VNTR polymorphism was genotyped by DNA amplification by polymerase chain reaction, followed by electrophoresis in polyacrylamide gel. RESULTS: There was a statistically significant higher frequency of alleles of shorter length in the patient group compared to controls (p = 0.001), suggesting that individuals carrying short alleles are more likely to develop RA. There was no association between short alleles and clinical characteristics of RA. CONCLUSION: Our results provide evidence of an association between the aggrecan gene VNTR polymorphism and RA.

Souza LS, Machado SH, Brenol CV, Brenol JC, Xavier RM. · Division of Rheumatology, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. · J Rheumatol. · Pubmed #18843772 No free full text.

Abstract: OBJECTIVE: .To evaluate associations of growth velocity with inflammatory markers and cumulative dose of glucocorticoid in a cohort of patients with juvenile idiopathic arthritis (JIA) followed during 1 year. METHODS: Seventy-nine patients were evaluated. Disease activity was evaluated by a pediatric rheumatologist. Anthropometric data were classified according to the World Health Organization standards. Tanner growth velocity curves were used; values below the Z-score < or = -2 were considered low growth velocity. Serum concentrations of interleukin 6 (IL-6) were measured by ELISA, and values > 1 pg/ml were considered elevated. RESULTS: The prevalence of low growth velocity was 25.3%, and it was associated with active disease on followup visit, elevated IL-6, erythrocyte sedimentation rate and C-reactive protein, and higher cumulative glucocorticoid doses. In the multiple linear regression with growth velocity as the dependent variable, only elevated IL-6 level was independently and negatively associated with growth velocity. CONCLUSION: Low growth velocity is highly prevalent in children with JIA. Elevated IL-6 levels seem to have an important negative influence on growth in these children, while total glucocorticoid exposure appears to be a secondary factor.

Brenol CV, Chies JA, Brenol JC, Monticielo OA, Franciscatto P, Birriel F, Neves AG, Xavier RM. · Division of Rheumatology, Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. · Clin Rheumatol. · Pubmed #18830734 No free full text.

Abstract: Several genetic factors were implicated in the pathogenesis of rheumatoid arthritis (RA). A case-control study was carried out to verify the associations of T-786C polymorphism in the promoter region of the endothelial nitric oxide synthase (eNOS) gene with RA. One hundred and five consecutive RA patients and 100 healthy controls were genotyped. The distribution of the T-786C genotype and alleles did not differ significantly between RA patients and controls. Nevertheless, the frequency of extraarticular manifestations was significantly greater among the carriers of the C/C genotype than among carriers of the T/C and T/T genotypes (P = 0.022). The C/C genotype was significantly associated with extraarticular manifestations compared with the T/T and T/C genotypes taken together (OR = 4.9, 95% CI = 1.3-18.9). The C allele was significantly associated with extraarticular manifestations of RA (P(corr) = 0.032). The results suggested the existence of an association between the T-786C polymorphism of the eNOS gene and extraarticular manifestations of RA.

Veit TD, Vianna P, Scheibel I, Brenol CV, Brenol C, Brenol JC, Xavier RM, Delgado-Cañedo A, Gutierrez JE, Brandalize AP, Schuler-Faccini L, Chies JA. · Genetics Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. · Tissue Antigens. · Pubmed #18331529 No free full text.

Abstract: We tested the possible association of the 14-bp polymorphism of the HLA-G gene in the course of two inflammatory diseases, rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Patients and controls were genotyped for the 14-bp polymorphism by polymerase chain reaction with specific primers for the exon 8 of the human leukocyte antigen (HLA)-G gene and the amplified fragment was visualized in a 6% polyacrylamide gel. A total of 106 JIA patients, 265 RA patients, 356 healthy adults and 85 healthy children were genotyped for the 14-bp polymorphism. Female JIA patients presented a higher frequency of the -14 bp allele when compared with female healthy children (0.743 and 0.500, corrected P=0.003), which reflected in the JIA group as a whole. This increased frequency of the -14-bp allele was observed in all JIA subtypes. In RA patients, no differences in allelic and genotypic frequencies were observed between patients and controls. No correlations were observed among genotype and disease severity or clinical manifestations. Our data suggest that the HLA-G -14 bp allele is probably a risk factor for JIA, mainly in females. Considering the differences observed in relation to gender, we suggest that hormonal differences can interfere with the development of JIA. Considering the RA patients, our data agree with results from the literature and highlight the differences in the etiology of RA and JIA.

Rohr P, Veit TD, Scheibel I, Xavier RM, Brenol JC, Chies JA, Kvitko K. · Departamento de Genética e Programa de Pós-graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil. · Clin Exp Rheumatol. · Pubmed #18328165 No free full text.

Abstract: OBJECTIVE: In this study we have analyzed GSTM1, GSTT1 and GSTP1 polymorphisms in patients with juvenile idiopathic arthritis (JIA), to investigate a possible role of these genes as genetic components of the disease. METHODS: A total of 103 individuals (49 oligoarticular, 41 polyarticular and 13 systemic) were analyzed for the three polymorphisms, using a PCR/RFLP methodology. RESULTS: We have observed significantly increased frequencies of individuals with GSTT1 null genotype in JIA patients comparing to controls (37% x 21%; p=0.0183). There was a 2-fold increased risk (OR 2.2, 95% CI 1.2-4.1) associating the disease with the GSTT1 null genotype. Considering the subgroups (oligoarticular, polyarticular and systemic), the results indicated an association between polyarticular and systemic patients and the GSTT1 null genotype. There was a 2-fold increased risk for polyarticular patients (OR 2.4, 95%, CI 1.1-5.4), and a 4-fold increased risk for systemic patients (OR 4.4, 95%, 1.3-14.5). CONCLUSION: The GSTT1 null genotype seems to be involved in polyarticular and systemic JIA.

Oliveira PG, Brenol CV, Edelweiss MI, Meurer L, Brenol JC, Xavier RM. · Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. · Clin Exp Med. · Pubmed #18188533 No free full text.

Abstract: Complete Freund's adjuvant (CFA)-induced arthritis in rats, which presents similar features to rheumatoid arthritis, is a model widely used in aetiopathogenetic and investigational drug studies. In this model, arthritis is induced by intradermal injection of Mycobacterium tuberculosis suspended in mineral oil in the hind footpad. Although the histopathology findings in the joint are well described, the marked subcutaneous features of panniculitis that concomitantly occur in this model have received no attention. The objective of this paper is to describe the subcutaneous histopathological features in 8 Wistar rats after intraplantar injection of CFA. We studied the subcutaneous histopathological features in 8 Wistar rats after intraplantar injection of CFA in the left hind paw. The levels of subcutaneous inflammation of the animals in this study were evaluated for the histological characteristics present in the tissue and scored with 4 parameters (acute inflammation, chronic inflammation with fibrosis, subcutaneous and profound soft tissue necrosis, and the presence of giant cells, neutrophils, macrophages and lymphocytes) on days 4, 7, 11 and 15 after induction. All animals developed intense subcutaneous inflammation characteristic of panniculitis, with predominance of acute changes in the initial period, with progression to a self-perpetuating chronic fibrotic process on day 15. These observations precede the joint changes. Besides being an interesting model for better studying diseases with panniculitis, our observations bring up issues concerning the possible relations between subcutaneous and joint inflammatory changes.

Zanette Sde A, Born IG, Brenol JC, Xavier RM. · Serviço de Reumatologia, Hospital de Clínicas de Porto Alegre, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil. · Clin Rheumatol. · Pubmed #17989918 No free full text.

Abstract: We evaluated the efficacy of acupuncture as a useful adjuvant treatment in the management of rheumatoid arthritis (RA). A pilot, randomized, double-blind, and controlled clinical trial was conducted. Forty RA patients with active disease despite stable therapy for at least the preceding 1 month were randomized to receive a standard protocol of acupuncture (AC) or superficial acupuncture at non-acupuncture points (controlAC) for 9 weeks. The primary outcome was achievement of 20% improvement according to the American College of Rheumatology (ACR) 20 criteria after five and ten treatment sessions and after 1 month of follow-up. Secondary measures included Disease Assessment Scale (DAS), tender and swollen joint count, morning stiffness, Health Assessment Questionnaire (HAQ), visual analogue scale (VAS) of pain, physician global assessment of activity disease, physician and patient global assessment of treatment, and inflammatory markers (erythrocyte sedimentation rate and C-reactive protein). There was not significant difference between the groups regarding the number of patients that reached ACR20 at the end of the treatment (p=0.479). However, after 1 month of follow-up, there was a trend in favor of the AC group, with p=0.068. Compared with the controlAC, the AC group also demonstrated significant improvement in the patient and physician global assessment of treatment and physician global assessment of disease activity, but there was no difference on other clinical and laboratorial measures. On the other hand, only the AC patients had within group improvement on the variables DAS, HAQ, morning stiffness, patient and physician global assessment of treatment, and physician global assessment of disease activity in comparison to baseline visit. Despite the improvement of some studied variables, there was no significant difference in the proportion of patients that reached ACR20 between the AC and controlAC groups. This negative result can be related to the small sample size, selection of patients, type of acupuncture protocol applied, and difficulties in establishing an innocuous and trustworthy placebo group to studies involving acupuncture.

Kohem CL, Brenol JC, Xavier RM, Bredemeier M, Brenol CV, Dedavid e Silva TL, de Castilhos Mello A, Cañedo AD, Neves AG, Chies JA. · Rheumatic Diseases Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. · Scand J Rheumatol. · Pubmed #17963165 No free full text.

Abstract: OBJECTIVES: To identify the genetic polymorphism of the chemokine receptor CCR5 (the Delta32 allelic variant) in patients with rheumatoid arthritis (RA) and compare the findings with healthy controls. To compare the CCR5 phenotypic expression in T cells and monocytes isolated from the peripheral blood and synovial fluid in a subgroup of RA patients. METHODS: CCR5 genes of 92 RA patients and 160 healthy controls were genotyped using specific primers flanking the region of deletion. The ethnic distribution was similar between the groups. Flow cytometric analysis was used for immunophenotyping the T cells and monocytes isolated from the peripheral blood and synovial fluid of eight RA patients. The isolated cells were triple stained with CD4 or CD8, CD25 and CCR5 monoclonal antibodies. RESULTS: There was no difference in the CCR5Delta32 genotypic frequency between the RA patients and the control group (0.055 and 0.063, respectively, p = 0.989). No homozygote for the CCR5Delta32 allele was seen in either group. Five heterozygotes were identified in the RA patient group, whose disease was shown to be aggressive. A significant enrichment of activated CCR5+ monocytes was seen in the synovial fluid of the RA patients subjected to arthrocentesis, who were all homozygotes for the CCR5 wild-type genotype. CONCLUSION: A protective role for the CCR5 allelic variant in RA development was not observed. Disease severity in the heterozygotes suggests that other proinflammatory mechanisms might overcome this mutation in vivo. The activated CCR5+ monocyte enrichment in the rheumatoid synovial fluid might indicate that this cell population has an important role in the pathogenesis of the disease.

Souza L, Machado SH, Bredemeier M, Brenol JC, Xavier RM. · Division of Rheumatology, Hospital de Clínicas de Porto Alegre, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, RS, Brazil. · J Rheumatol. · Pubmed #16511929 No free full text.

Abstract: OBJECTIVE: To assess nutritional status in patients with juvenile idiopathic arthritis (JIA) and the influence of inflammatory activity and glucocorticoid use. METHODS: One hundred sixteen patients were evaluated. Disease subtype and disease activity were defined by the attending physician, and the cumulative glucocorticoid dose was recorded from chart review. Percentiles of body mass index (BMI) and triceps skinfold (TSF) and the Z score for height were determined: low weight and low adiposity were diagnosed when BMI and TSF were below the 5th percentile. Short stature was defined by a Z score of height for age < -2. Serum concentration of insulin-like growth factor-I (IGF-I) was measured by radioimmunoassay. RESULTS: The prevalences of low weight, low adiposity, and short stature were 16.4%, 20.7%, and 10.4%, respectively. Low IGF-I serum level was found in 14 patients (12.1%). The factors negatively associated with the Z score of height in multivariable regression analysis were disease duration (partial correlation coefficient -0.370, 95% confidence interval: -0.527 to -0.188; p < 0.001), erythrocyte sedimentation rate (ESR) (-0.357, -0.516 to -0.174; p < 0.001), and polyarticular or systemic disease subtype (-0.290, -0.459 to -0.100; p = 0.003), while there was no significant correlation with the cumulative dose of glucocorticoids (0.086, -0.111 to 0.277; p = 0.391). None of these variables was significantly correlated with the percentiles of BMI and TSF, albeit confidence intervals for these correlation coefficients were relatively large. Patients with a systemic or polyarticular disease subtype tended to present lower percentiles of BMI (p = 0.051). CONCLUSION: Nutritional status is frequently compromised in patients with JIA. Duration and disease subtype and the ESR are factors independently associated with short stature. The cumulative dose of glucocorticoids was not independently associated with short stature or with other nutritional variables, although a relevant negative effect of glucocorticoid dose on BMI and TSF cannot be entirely excluded.

Capobianco KG, Xavier RM, Bredemeier M, Restelli VG, Brenol JC. · Division of Rheumatology, Hospital de Clínicas de Porto Alegre, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. · Clin Exp Rheumatol. · Pubmed #16396696 No free full text.

Abstract: OBJECTIVE: To describe the capillaroscopic abnormalities observed in patients with primary Sjögren's Syndrome (pSS), associating them with clinical and serologic features, and comparing these findings to those observed in normal controls. METHODS: Sixty-one consecutive patients with pSS were studied by clinical evaluation, serology, and nailfold capillary microscopy (NCM). Twenty-one normal controls were also examined. Capillaroscopic findings were recorded in a standardized way by a blinded observer Capillary loss on NCM was evaluated using a deletion score. RESULTS: NCM was normal in 59.0% of pSS patients; 29.5% had non-specific abnormalities, and 11.5% presented a SD-like pattern. Patients presented a higher deletion score than controls (p < 0.001). Other capillaroscopic parameters (number of dilated, bizarre, and meandering capillaries; capillary hemorrhages; venous plexus visibility) did not differ significantly between patients and controls. Among patients, the deletion score was higher in those with systemic manifestations (p = 0.022) and Raynaud's phenomenon (p = 0.050). No association between the presence of antinuclear antibodies, rheumatoid factor, anti-SSA/Ro and anti-SSB/La with qualitative or quantitative NCM findings was found. Among the 7 patients with SD-like pattern on NCM, 6 had Raynaud's phenomenon, but only 2 presented autoantibodies related to systemic sclerosis (1 with anticentromere and 1 with low titer antitopoisomerase I). None of these patients met the ACR criteria for SSc. CONCLUSIONS: SD-like pattern on NCM is observed in a small but significant proportion of pSS patients. The association of systemic involvement with a higher deletion score may be related to the hypothesis that these manifestations represent clinical expressions of systemic vasculitis.

Machado SH, von Mühlen CA, Brenol JC, Bisotto L, Xavier RM. · Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. · J Pediatr (Rio J). · Pubmed #16385368 links to  free full text

Abstract: OBJECTIVES: To assess the presence of anti-cyclic citrullinated peptide antibodies in a cohort of patients with juvenile idiopathic arthritis. METHODS: Anti-cyclic citrullinated peptide antibodies was tested for with an enzyme linked immunoabsorbent assay (ELISA) in serum samples of patients from the Hospital de Clínicas de Porto Alegre, all less than 18 years old and with previous diagnosis for at least 6 months. IgMRF (rheumatoid factor) and antinuclear antibodies in Hep-2 cells were also assayed. RESULTS: Serum samples were analyzed from 45 patients. The presence of high levels of anti-cyclic citrullinated peptide antibodies was found in the serum of just one child (2%), who presented sero-positive polyarthritis. CONCLUSIONS: Anti-cyclic citrullinated peptide antibodies can be detected in children with juvenile idiopathic arthritis, but much less frequently than in adults with rheumatoid arthritis. It still remains to be determined whether anti-cyclic citrullinated peptide antibodies can identify a subset of juvenile idiopathic arthritis patients with the potential to progress to adult rheumatoid arthritis.