Atypical lymphoproliferation progressing into B-cell lymphoma in rheumatoid arthritis treated with different biological agents: clinical course and molecular characterization.

10noA patient with rheumatoid arthritis (RA) developed an atypical lymphoproliferative disorder (LPD) after methotrexate and cyclosporine A, which regressed after suspension of both drugs. After subsequent treatment with rituximab, the LPD was still undetectable. Anti-tumor necrosis factor a therapy was used when the arthritis relapsed, but an aggressive B-cell non Hodgkin's lymphoma developed. Molecular analyses showed an oligoclonal B-cell expansion at the LPD step. A minor clone with significant sequence homology to B-cell lymphomas arising in Sjogren's syndrome and mixed cryoglobulinemia syndrome, given rise to the non-Hodgkin's lymphoma. Treatment of rheumatoid arthritis associated with lymphoproliferation represents a clinical challenge, and common pathogenetic pathways to lymphoma may occur in different autoimmune diseases.openopenQuartuccio, Luca; De Re, V.; Fabris, M; Marzotto, A.; Franzolini, N; Gasparotto, D.; Caggiari, L.; Ferraccioli, G.; Scott, Cathryn Anne; DE VITA, SalvatoreQuartuccio, Luca; De Re, V.; Fabris, M; Marzotto, A.; Franzolini, N; Gasparotto, D.; Caggiari, L.; Ferraccioli, G.; Scott, Cathryn Anne; DE VITA, Salvator

INTEGRIN ALPHA2BBETA3 GENE POLYMORPHISM AND THE MICROVASCULAR SYSTEM IN SCLERODERMA

Background: Immunosuppression induced by drugs administrated to patients with autoimmune diseases can affect the course of HBV infection, both in terms of reactivation and precipitation of a pre-existing chronic hepatitis (1, 2). Anti TNF-α drugs have been recently reported to be safe in patients with potentially occult hepatitis B (3). Objectives: At the best of our knowledge, the role of traditional DMARDs in altering the course of HBV infection has not yet been assessed. In our study we evaluated this role. Methods: 148 non HCV-infected patients with autoimmune rheumatic disease (i.e. Rheumatoid arthritis, 78; psoriatic arthritis, 36; systemic vasculitides, 14; Sjogren syndrome and UCTD, 11; systemic lupus erythematosus, 9) were assessed for HBV markers at baseline and followed for 5-31 months (median 21 months). They were administered the following DMARDS: methotrexate (MTX)74; azatioprine 30; cyclosporine A (CyA) 16; leflunomide 12; mofetil mycophenolate 5; middle or high steroid dose 8; cyclophosphamide 1; MTX+CyA 2. Patients undergoing low-risk treatments(1), including hydroxychloroquine, sulfasalazine and low dose steroids were excluded. Results: At baseline 9 (6%) were HBsAg positive; 22 (15%) were HBsAb and HBcAb positive; 11 (7.4%) were HBcAb positive (without HBsAg or HBsAb); 5 (3.4%) were HBsAb positive (without HBcAb) because of a previous vaccination. During treatment, abnormal liver function test (LFT) were detected in 42 patients: 29(52.7%) were drug-related; 9 (16.4%) were due to a coexisting autoimmune liver dysfunction; 1 (1.8) was due to a steatosis; 3 (5.5%) were due to a HBV infection reactivation: 2 among the 9 HBsAg positive patients (22%), and 1 among the 33 potential occult HBV carriers (3%). Conclusions: Spontaneous flares in chronic hepatitis B have been reported (4). Zacharakis et al (5) found 4 cases (2%) of reactivation among 195 HBsAg positive inactive carriers. In our cohort 3 cases of HBV reactivation occurred (2 out of 9 HBsAg positive carriers, and 1 out of 33 potential occult carriers). National and International guidelines suggest a careful assessment of HBV infection in rheumatic patients undergoing immunosuppressive therapies. Our data support the safety of such drugs pointing out a low prevalence (3%) of HBV reactivation in potentially occult carriers

Reduced type I collagen gene expression by skin fibroblasts of patients with systemic sclerosis after one treatment course with rituximab

Objective. There is evidence that B lymphocytes play a role in the pathogenesis of systemic sclerosis (scleroderma). Stimulatory autoantibodies targeting and activating normal human fibroblasts in vitro have been demonstrated in sera from scleroderma patients. Rituximab is a monoclonal antibody which selectively targets and depletes CD20+ B lymphocytes. We investigated the biological effects of rituximab in six patients affected by scleroderma with severe skin involvement. Methods. Six patients with severe skin fibrosis, unresponsive to immunosuppressive treatment, were treated with 375 mg/m2 per week of intravenous rituximab for a total of four doses. Serum stimulatory autoantibodies to the PDGF receptor were detected. Fibroblast activation was evaluated in fibroblasts grown from skin biopsies performed at baseline and at months 3 and 6 post-treatment. The modified Rodnan's skin score, health assessment questionnaire (HAQ) and visual analogic scale (VAS) for global wellness and B lymphocyte count were performed monthly. Results. A significant reduction of anti- PDGF receptor autoantibodies was observed in the serum of all patients 3 months after treatment. Fibroblasts showed a significant downregulation of type I collagen gene expression and of the intracellular signalling triggered by anti-PDGFR autoantibodies. A decrease of the skin score and an improvement of disability indexes matched with the in vitro results. A single course of rituximab reduced scleroderma fibroblast activation in vitro and the serum levels of anti-PDGFR stimulatory autoantibodies. Conclusion. These data provide further evidence of B-cell involvement in the pathogenesis of scleroderma. Targeting B cells may be a promising treatment for scleroderma patients, and controlled clinical trials are warranted. \ua9 Clinical and Experimental Rheumatology 2015