Rheumatoid Arthritis: Bosello S

Bosello S, Pers JO, Rochas C, Devauchelle V, De Santis M, Daridon C, Saraux A, Ferraccioli GF, Youinou P. · Laboratory of Immunology, Medical School, Brest, France. · Int J Immunopathol Pharmacol. · Pubmed #17346422 No free full text.

Abstract: Interest in B-cells has been revived due to the description of new functions. Supporting a role for B-cells in the genesis of autoimmune diseases is the fact that the B-cell activating factor of the TNF ligand family (BAFF) is essential in their physiology. However, in each disease, this is restricted to a subgroup of patients. Based on experiments in mice, and validated in humans, this new cytokine has been highlighted. Excessive production of BAFF alters immune tolerance by rescuing self-binding B-cells. Overexpression in mice leads to autoimmune manifestation, and BAFF levels are elevated in the serum of autoimmune patients. Similar abnormalities occur in chronic lymphocytic leukemia. Recent works suggest that antagonizing the protein (or competing for its receptors) is relevant to the treatment. Advances in our understanding of the BAFF system offers the opportunity to improve our therapeutic approach.

Tolusso B, De Santis M, Bosello S, Gremese E, Gobessi S, Cuoghi I, Totaro MC, Bigotti G, Rumi C, Efremov DG, Ferraccioli G. · Division of Rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy. · Clin Immunol. · Pubmed #19136305 No free full text.

Abstract: B cells have acquired an important role in the pathogenesis of rheumatoid arthritis (RA) since B cell depletion allowed to rescue patients poorly responders to TNFalpha blockers. This study focused on the involvement of ZAP-70 as a bio-marker of B cells immune activation in RA. ZAP-70 expression in synovial fluid (SF) B cells obtained from RA patients was increased compared to SF B cells of osteoarthritis (OA) patients. Moreover we found that ZAP-70 positive/CD38 positive and ZAP-70 positive/CD5 positive B cells were enriched in SF. The analysis of B cell apoptosis in vitro showed that the percentage of ZAP-70 negative B cells spontaneously undergoing apoptosis was significantly higher than ZAP-70 positive B cells. The ZAP-70 positive B cell ratio (SF/peripheral blood (PB)) showed a positive correlation with SF autoantibody levels and with local levels of BAFF and IL6. ZAP-70 positive B cells seem to define a subset characterized by increased survival and high relationship with local inflammation and autoimmunity.

Tolusso B, Frezza D, Mattioli C, Fedele AL, Bosello S, Faustini F, Peluso G, Giambra V, Pietrapertosa D, Morelli A, Gremese E, De Santis M, Ferraccioli GF. · Division of Rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy. · Ann Rheum Dis. · Pubmed #18952640 links to  free full text

Abstract: OBJECTIVE: To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker for rheumatoid arthritis (RA) and to define the possible association with autoantibody positivity and clinical outcome. METHODS: Genomic DNA was obtained from two cohorts of patients with RA (100 with early RA (ERA) and 114 with longstanding RA (LSRA)) and from 248 gender-matched controls from the same geographical area. Clinical and immunological characteristics were recorded for all the patients. RESULTS: The percentage of the 2/2 genotype was higher in patients with ERA (27.0%), and in patients with LSRA (34.2%), than in controls (14.9%) (ERA: OR = 2.11 (95% CI 1.20 to 3.70) vs controls; LSRA: OR = 2.96 (95% CI 1.76 to 5.00) vs controls). A lower representation of allele *3 was present in patients with ERA (2.0%) than in controls (6.0%; OR = 0.32 (95% CI 0.11 to 0.91)). No significant associations were found between polymorphisms and autoantibodies positivity. CONCLUSION: The HS1,2A allele *2 associates with early and longstanding RA.

Bosello S, Youinou P, Daridon C, Tolusso B, Bendaoud B, Pietrapertosa D, Morelli A, Ferraccioli G. · Division of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy. · J Rheumatol. · Pubmed #18528969 No free full text.

Abstract: OBJECTIVE: To determine whether levels of B cell activating factor (BAFF), a member of the tumor necrosis factor family, relate to autoantibody levels, disease activity, and response to treatment in patients with early rheumatoid arthritis (ERA). METHODS: BAFF was measured by ELISA in 48 early RA patients; 21 were examined serially. These data were compared with 49 controls with longstanding RA (LSRA), 48 disease controls (DC), and 50 healthy controls (HC). RESULTS: BAFF levels were higher in ERA, compared with DC and HC [median 4.3 ng/ml (5th-95th: 0.8-38.8) vs 0.9 ng/ml (5th-95th: 0.7-4.5) and 2.0 ng/ml (5th-95th: 0.7-5.68), respectively; p <10(-4 )both comparisons], but not with LSRA controls [median 8.7 ng/ml (5th-95th: 0.8-46.1); p = nonsignificant]. BAFF correlated with the titers of IgM rheumatoid factor and anti-cyclic citrullinated peptide autoantibody (r = 0.76 and r = 0.49; p < 0.00001, p = 0.0001 for the 2 correlations), and with the number of swollen joints (r = 0.37; p = 0.01). The followup study of 21 methotrexate-treated ERA patients revealed reduced levels of BAFF, with parallel improvement in clinical activity and decrease in autoantibody titers. CONCLUSION: Elevated BAFF in a subset of ERA patients is related to autoantibody levels and synovitis. BAFF level diminished with treatment, along with autoantibody titers, suggesting a rationale to treat ERA patients with BAFF-targeted agents.

Bosello S, Santoliquido A, Zoli A, Di Campli C, Flore R, Tondi P, Ferraccioli G. · Division of Rheumatology, Department of Internal Medicine, Catholic University of the Sacred Heart, via G. Moscati, 31-00168 Rome, Italy. · Clin Rheumatol. · Pubmed #18075712 No free full text.

Abstract: Considerable evidence indicates that patients with rheumatoid arthritis (RA) are at greater risk of developing atherosclerosis and cardiovascular disease. Recent studies support the predictive ability of endothelial function measures for subsequent atherosclerotic events. We have investigated the effects of infliximab, a chimeric monoclonal anti-tumor necrosis factor (TNF) antibody, on endothelial vasodilation, measured by brachial ultrasonography and on the levels of inflammatory biomarkers and adhesion molecules in ten consecutive patients with severe long-standing RA, despite methotrexate therapy, during the loading phase of infliximab therapy. Flow-mediated dilation (FMD) in RA patients at baseline was significantly impaired compared with healthy controls (7.71 +/- 2.78% vs 14.91 +/- 6.41%; p = 0.008) and improved significantly after infliximab infusion (12.63 +/- 1.63% vs 7.71 +/- 2.78%; p = 0.005). At baseline, a statistically significant correlation between C-reactive protein levels and FMD was found (r = -0.69, p = 0.026). However, this improvement was transitory, as FMD values returned to baseline values before each infliximab infusion at weeks 2, 6 and 14. There were no significant differences in baseline brachial artery diameter between visits, although at each time, the diameter was increased. According to European League Against Rheumatism response criteria, all ten patients were good responders. No significant differences were observed in intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, vascular endothelial growth factor and E-selectin plasma levels before and after each infusions. This study demonstrates that endothelial dysfunction is a reversible phenomenon in RA. The addition of anti-TNFalpha treatment reduces inflammatory symptoms in patients with severe RA. The improvement of endothelial function during the loading phase of therapy is transitory, suggesting an enhanced and persistent TNF-alpha generation within the arterial wall.