A 4-WEEK COURSE OF RITUXIMAB PLUS CYCLOPHOSPHAMIDE IN SEVERE SLE: PROMISING RESULTS IN 9 PATIENTS WHO FAILED CONVENTIONAL IMMUNOSUPPRESSIVE THERAPY

Background: Rituximab (Rituxan, Mabthera) is a monoclonal antibody directed against the CD20 marker of mature B-cells. In recent years, rituximab has been proposed as a treatment in certain rheumatic diseases.Objectives: To study efficacy and safety of an experimental protocol including rituximab in severe and therapy-resistant SLE.Methods: To date, 11 female patients (median age 32 years, range 18-54) with severe SLE have been included in a treatment protocol with rituximab, and 9 of these can be assessed at this time. Before inclusion, the patients had failed therapy with conventional cytotoxic drugs, including cyclophosphamide in all but one. Seven patients had severe and active nephritis: 2 had WHO grade III, 3 WHO IV, and 2 WHO V. Two patients had severe skin manifestations (in one patient combined with high-grade proteinuria); one patient had recurrent episodes of Quincke edema, and one had refractory arthritis and pleurisy.The treatment protocol consisted of 4 weekly infusions with rituximab (375 mg/m) combined with 2 infusions of cyclophosphamide (0,5 mg/m) and a time-limited increase of corticosteroids. Systematic follow-up was performed at 2, 4 and 6 months after treatment. Renal biopsies were performed in patients with nephritis before and 6 months after treatment when possible.Results: The median follow-up time is now 9 months (range 2-34). At baseline, mean SLAM score for all patients was 12.5±2.0 and mean SLEDAI score 13.1±2.9. Nine patients have now been followed for >6 months and were evaluated for response to treatment. In these nine patients, the mean SLAM decreased to 5.8±0.7 (p<0.05), SLEDAI to 2.3±0.5 (p<0.005), and prednisolone dosage also decreased significantly (p<0.05). With respect to the most serious and refractory disease manifestations in these patients, a favorable response was noted in all. In the 5 patients with nephritis evaluated at 6 months, proteinuria had decreased significantly. Four of these 5 patients had a repeat biopsy: of 3 patients with proliferative nephritis (WHO grade III/IV), one had regressed to grade I and two had transformed into membranous disease (WHO V). One patient with membranous nephritis at baseline had improved histology with resolution of immune deposits. Thus, in all cases a histopathological improvement was noted. The 2 patients with severe skin disease showed complete resolution after 6 months. The patient with recurrent angioedema has had no further events and has reduced prednisolone from 20 to 5 mg daily. The patient with severe arthritis and pleurisy is now asymptomatic and off glucocorticoids. Reappearance of CD19+ B-cells occurred in 8 patients after a median of 6 months (range 2-12). Of these patients, 2 were placed on mycophenolate but 6 remain without immunosuppressive therapy. No relapses have occurred in any patient. Drug-related adverse events in this study were a mild infusion reaction and one case of a limited herpes zoster eruption that resolved completely.Conclusion: Combined treatment with rituximab (4 infusions) plus cyclophosphamide (2 infusions) was well-tolerated. At 6 months of follow-up, all patients had responded clinically and/or histopathologically. Thus, for patients who fail to respond to conventional immunosuppressive therapy including cyclophosphamide, one combined treatment cycle with rituximab and cyclophosphamide can be very effective.Citation: , volume , supplement , year 2004, page Session: Advances in SLE – New and old therapies