Rheumatoid Arthritis: Mello SB

Lotito AP, Silva CA, Mello SB. · Department of Paediatrics, University of Sao Paulo, Brazil. · Autoimmun Rev. · Pubmed #17317618 No free full text.

Abstract: Interleukin-18 is a cytokine member of the IL-1 super family that seems to exert powerful Th1-promoting activities in synergy with IL-12. Here we describe the participation of IL-18 in inflammatory joint diseases, in particular rheumatoid arthritis, adult onset Still's disease and juvenile idiopathic arthritis. The emphasis of this study was to summarize in vivo and in vitro studies that focused the action of this pro-inflammatory cytokine on the arthritic process as well as its role in the complex network of chemical mediators involved.

Lotito AP, Campa A, Silva CA, Kiss MH, Mello SB. · Department of Pediatrics, University of Sao Paulo, Sao Paulo, Brazil. · J Rheumatol. · Pubmed #17343316 No free full text.

Abstract: OBJECTIVE: To verify the importance of interleukin 18 (IL-18) in the pathogenesis of juvenile idiopathic arthritis (JIA). We measured IL-18 levels in synovial fluid (SF) and serum, and determined their correlation with measures of disease activity and severity. METHODS: Fifty patients with JIA (13 systemic, 13 polyarticular, 24 oligoarticular) and 25 matched controls were analyzed. Cytokine levels (IL-1beta, IL-1Ra, IL-6, and IL-18) were quantified in serum and SF by ELISA, and disease activity measures were evaluated immediately after knee articular puncture. Radiological assessment was made according to the Steinbrocker method. Statistical analysis was performed by Spearman's rank-order correlation and Mann-Whitney rank test. RESULTS: All the analyzed cytokine levels (IL-1, IL-1Ra, IL-6, and IL-18) were higher in patients' sera than in controls. Remarkably, in patients with JIA, IL-18 SF levels did not differ from those of serum; they were positively correlated. The levels of IL-18 (SF and serum) were positively correlated with measures of disease activity: C-reactive protein, number of active joints, and radiological score, as well as with levels of IL-1, IL-1Ra, and IL-6. Moreover, IL-18 and IL-6 levels in SF and serum were much higher in patients with systemic disease compared to the other types of disease onset. In contrast, IL-1 and IL-1Ra were not different among JIA subtypes. CONCLUSION: Our results strongly suggest the participation of IL-18 in the pathophysiology of JIA. The positive correlation of this cytokine with several measures of articular inflammation and disease severity suggests that IL-18 could be a better target for the treatment of arthritis.

Lotito AP, Muscará MN, Kiss MH, Teixeira SA, Novaes GS, Laurindo IM, Silva CA, Mello SB. · Paediatric Division, Department of Internal Medicine, School of Medicine, Institute of Biomedical Sciences, University of São Paulo, Brazil. · J Rheumatol. · Pubmed #15124263 No free full text.

Abstract: OBJECTIVE: To evaluate superoxide anion (O2-), nitrite/nitrate (NO2-/NO3-), and nitrotyrosine (NT) production and the contribution of myeloperoxidase (MPO) to the production of NT-containing proteins in the synovial fluid (SF) of patients with juvenile idiopathic arthritis (JIA). The affected tissues in inflammatory arthritis produce large amounts of nitric oxide (NO) or peroxynitrite (ONOO-) but there are no reports of NO or ONOO- participation in JIA. We also attempted to correlate our findings with variables of disease activity and articular damage. METHODS: We analyzed 40 patients with JIA, mean age 12.7 years, mean disease duration 7.8 years. O2- production was measured by cytochrome C reduction after incubation of 106 synovial fluid (SF) cells with or without phorbol myristate acetate (PMA), formyl-methionyl-leucyl-phenylalanine (FMLP) or opsonized zymosan. SF and serum NO2-/NO3- levels were measured by Griess reaction; NT was detected by Western blot. Myeloperoxidase (MPO) activity was estimated spectrophotometrically. Clinical and laboratory variables [erythrocyte sedimentation rate, C reactive protein (CRP), and radiological score] and interleukin 6 (IL-6) levels were evaluated. RESULTS: NO2-/NO3- production was greatly enhanced in the joints of JIA patients (54.6 +/- 3.2 micro M) when compared with serum (13.9 +/- 0.6 micro M; p < 0.001). NO2-/NO3- levels in SF were positively correlated with the number of infiltrating lymphomononuclear cells. NT-modified proteins detected in the SF showed a high correlation with radiological score, disease duration, CRP, and IL-6. CONCLUSION: Our results confirm the increased oxidative stress in children with JIA, suggesting a high in situ production of NO. The positive correlation between the expression of NT-modified proteins and variables of disease activity and damage is additional evidence that nitrogen and oxygen species may be involved in the joint destruction seen in patients with JIA.

Mello SB, Barros DM, Silva AS, Laurindo IM, Novaes GS. · Rheumatology Division, Department of Internal Medicine, School of Medicine, University of Sao Paulo, Brazil. · Rheumatology (Oxford). · Pubmed #10852985 links to  free full text

Abstract: OBJECTIVE: To investigate the regulation of whole-blood cyclooxygenase-1 and -2 (COX-2 and COX-1) activities by methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHODS: Whole blood was withdrawn from nine healthy volunteers, 12 RA patients treated with MTX (RA/MTX) and six RA patients treated with chloroquine (RA/CQ). COX-1 activity was quantified as platelet thromboxane B(2) production in unstimulated blood and COX-2 activity was measured as prostaglandin E(2) (PGE(2)) production in whole blood stimulated with LPS. Thromboxane B(2) and PGE(2) were measured by radioimmunoassay. We studied the drug effect in vitro by direct incubation of MTX with blood obtained from normal donors. Ex vivo assays were performed with blood collected from RA/MTX and RA/CQ patients. The influence of serum factors on enzyme activities was analysed in blood collected from normal donors and incubated with RA/MTX, autologous or heterologous serum. RESULTS: In vitro assays showed no direct action of MTX on the activity of either enzyme. Assays performed with blood from RA/MTX patients showed preferential inhibition of COX-2 activity (PGE(2) = 10.11 +/- 2.42 ng/ml) when compared with blood of normal donors (PGE(2) = 37.7 +/- 4.36 ng/ml; P = 0.001). Inhibition of COX-2 activity was also observed when blood of normal donors was co-incubated with RA/MTX serum. CONCLUSION: Our results clearly show that the anti-inflammatory action of low-dose MTX is partly mediated by a serum factor induced by MTX or a MTX metabolite that preferentially inhibits the activity of COX-2.