Rituximab and RA Antony Lin, MD Division of Rheumatology Fontana Medical Center Rituximab Background: • Chimeric monoclonal antibody • Targets the CD-20 antigen – Expressed on B-cell precursors and mature B-cells – NOT expressed on stem cells, plasma cells, dendritic cells, and other normal tissues CD20: An Ideal B-cell Target • 297 amino acid membrane- associated phosphoprotein (33–37 kD) – Not shed – No known membrane/secreted molecular analogues (target interference) – Calcium channel function (?) • B-cell lineage antigen, not on: – Stem cells, early pre-B cells, or plasma cells • Anti-CD20 binding: – Does not down-modulate expression of CD20 – Does not cause internalization of CD20 Johnson P, Glennie M. Semin Oncol. 2003;30:3-8. Golay J et al. Blood. 2000;95:3900–3908. Postulated B-cell Role(s) in Rheumatoid Arthritis • Autoantibody production • Direct cell–cell interaction (T cells, APC) • Indirect cell–cell interaction: cytokine production Pathogenesis of RA • B-cell activation and proliferation – Germinal centers were found in RA synovium – Linked with the production of IgG-RF autoAbs • Activation of T-cells by B-cells was shown in human synovium-SCID mouse models Mechanism of Actions • Depletion of B-cells – In patients with NHL, circulating B-cells (measured as CD19+ cells as CD20 is blocked) are depleted within the first three doses of Rituxan therapy – B-cells remain depleted for up to 6 to 9 months post-treatment – Recovery occurring at approximately 6 months after completion of treatment. – Median B-cell levels return to normal by 12 months following completion of treatment. Rituximab and RA In 1998, the first prospective study of B-cell depletion therapy in RA was started by University College London – Rituximab was used with cyclophosphamide – All of five cases had major improvement Rheumatology 2001;40: 205-11 Rituximab and RA • In 2002, 17 more cases of successful treatments were reported Ann Rheum Dis 2002; 61:1-5. • In 2004, randomized open-label study was published. – Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis Edwards JC - N Engl J Med - 17-JUN-2004; 350(25): 2572-81 NEJM by Edwards et al. • 161 RA patients with active RA – From 26 centers in 11 countries – > 21 years old with seropositive RA (>20U) – Mean disease duration 9-12 years – Receiving at least 16 week of MTX – NSAIDs or prednisone < 12.5mg/d – Other DMARDs or anti-TNF agents are NOT used NEJM by Edwards et al. • Patients were randomized to 4 groups – Oral MTX alone (>10mg qweek) – Rituximab alone – Rituximab with CTX (750mg IV on days 3 and 17) – Rituximab with MTX NEJM by Edwards et al. • Single short course of Rituximab – 2 doses of 1000mg IV on Days 1 and 15 – With oral MTX or cyclophosphamide vs MTX alone • Significant response at 24 and 48 weeks NEJM by Edwards et al. • The primary endpoint was the proportion of patients achieving ACR 50 response at 24 weeks. • The secondary endpoints were the ACR20, ACR70 and patient responses based on the EULAR criteria. NEJM by Edwards et al. 80 70 60 50 40 ACR 20 30 ACR 50 ACR 70 20 10 0 MTX Ritux Ritux + Ritux + control only CTX MTX NEJM by Edwards et al. • Responses were not observed in seronegative patients. Administration • Premedications – Acetaminophen – Diphenhydramine • Infusion of rituxan – 1000 mg given on Days 1 and 15 – Administered over 4 hours Monitoring of Safety • Adverse outcomes – Well-tolerated – Antibody production – Infusion-related reactions • Fever, chills occurs often in first infusion • Often seen in lymphoma patients because high B-cell load – Anaphylaxis/angioedema – More severe • Lymphopenia (40%) • Neutropenia (6%) • Leukopenia (4%) • Anemia (3%) • Thrombocytopenia (2%) • Rare pancytopenia – Mild immunosuppression • Sepsis (2%) Monitoring of Safety • Severe autoimmune events including serum sickness, polyarticular arthritis, and vasculitis with rash have been reported in patients with NHL. • To treat the hypersensitivity reaction – Acetaminophen – Bronchodilators – Corticosteroids – Diphenhydramine – Epinephrine – Fluid IV Monitoring of Safety • One case of serious infection was reported from 300 patients using the med • Nahir et al. (2004) reported that there were no significant differences in the incidence and types of adverse events and infections between the treatment groups at 48 weeks. Rituximab and RA Conclusion – B-cell depletion with rituximab is increasingly being used for refractory cases worldwide Rituximab and Autoimmune Diseases Antony Lin, MD Division of rheumatology Fontana Medical Center Potential Treatments for other Rheumatic Diseases • Systemic lupus erythematosus (SLE) • ANCA-associated vasculitis – Wegener’s Granulomatosis • Autoimmune thrombocytopenia • Dermatomyositis • Cryoglobulinemia • Amyloidosis Rituximab and SLE Leandro MJ - Arthritis Rheum - 01-OCT-2002; 46(10): 2673-7 – Evaluate the safety and efficacy of B lymphocyte depletion therapy in refractory systemic lupus erythematosus (SLE) – METHODS: Six female patients with active SLE, resistant to standard immunosuppressive therapy, were treated on an open-label basis – During a 2-week period, each patient received two 500-mg infusions of rituximab, two 750-mg infusions of cyclophosphamide, and high-dose oral corticosteroids Rituximab and SLE Leandro MJ - Arthritis Rheum - 01-OCT-2002; 46(10): 2673-7 – RESULTS- Clinical: – Patient 1 had not improved at 3 months but was then lost to follow up. At 6 months, all 5 remaining patients had improved, as evidenced by improvement in – British Isles Lupus Assessment Group global scores Decrease from a median of 14 (range 9-27) at baseline to a median of 6 (range 3-8) at 6 months. – Manifestations of SLE such as fatigue, arthralgia/arthritis, and serositis responded particularly well to this protocol. Rituximab and SLE Leandro MJ - Arthritis Rheum - 01-OCT-2002; 46(10): 2673-7 – RESULTS- LAB: – Hemoglobin levels increased in patients 2, 3, 5, and 6. – ESR decreased in patients 2, 3, 4, and 5 and was stable in patient 1. – C3 serum levels increased in all 5 patients who had low levels at baseline; in two of these patients, patients 2 and 5, C3 values were normal at 6 months. – The variation in the level of anti-double-stranded DNA antibody was different in individual patients. Rituximab and SLE Leandro MJ - Arthritis Rheum - 01-OCT- 2002; 46(10): 2673-7 – No significant adverse events were observed during follow up. – CONCLUSION: • Combination of B cell depletion and steroid/CTX was associated with improvement in global lupus activity • This study provides sufficient evidence for the safety and possible efficacy of B lymphocyte depletion therapy in SLE to justify a formal controlled trial. Rituximab and SLE Anolik JH - Arthritis Rheum - 01-NOV-2004; 50(11): 3580-90 – This study showed that specific B cell depletion therapy with rituximab dramatically improves abnormalities in B cell homeostasis and tolerance that are characteristic of this disease. Rituximab and SLE Anolik JH - Arthritis Rheum - 01-NOV-2004; 50(11): 3580-90 – Compared with normal controls, SLE patients displayed several abnormalities in peripheral B cell homeostasis at baseline, including naive lymphopenia, expansion of a CD27-,IgD- (double negative) population, and expansion of circulating plasma blasts. Rituximab and SLE Anolik JH - Arthritis Rheum - 01-NOV-2004; 50(11): 3580-90 • RESULTS: – lab abnormalities resolved after effective B cell depletion with rituximab and immune reconstitution. The frequency of autoreactive VH4.34 memory B cells also decreased 1 year post-treatment, despite the presence of low levels of residual memory B cells at the point of maximal B cell depletion and persistently elevated serum autoantibody titers in most patients Wegener’s Granulomatosis • Characterized by granulomatous inflammation. • Cyclophosphamide remains the most effective treatments for severe diseases. – Some patients may be refractory to the treatments. – CTX may be contraindicated in some patients. Rituximab and WG • Pathogenesis of WG • B lymphocytes may play a central pathogenic role • ANCA are produced mostly by Short-lived plasma cells. Rituximab and WG • Mechanism of Actions • ANCA play a major role in the pathogenesis of WG • Treatment can effectively reduce precursors of ANCA-producing plasma cells • Depletion of their CD20+ will stop ANCA production Rituximab and WG ANCA-associated vasculitis (AAV) Keogh KA, et. Arthritis Rheum. 2005 Jan;52(1):1-5 – 11 patients with active refractory AAV, reactive to anti-proteinase 3 – Mean disease duration was 57.8 months – received maximal tolerated doses of CTX or CTX-contraindicated – Rituximab infusion and glucocorticoids Keogh KA, et. Arthritis Rheum. 2005;52:1-5 • Treatment protocol • 4 weekly doses of Rituximab of 375mg/m2 • prednisone up to 1mg/kg/day • 3 patients with renal disease also received plasma exchange. Keogh KA, et. Arthritis Rheum. 2005;52:1-5 • Results • Remissions was maintained in every patients as long as B lymphocytes were undetectable. – Remissions is defined as a BVAS/WG score of 0. Keogh KA, et. Arthritis Rheum. 2005;52:1-5 ANCA-associated vasculitis (AAV) RESULTS: Rituximab therapy was well tolerated by all patients, and adverse events were rare. Following the rituximab infusions, circulating B lymphocytes became undetectable, and ANCA titers decreased significantly. Remission was achieved in all patients and was maintained while B lymphocytes were absent. Keogh KA, et. Arthritis Rheum. 2005;52:1-5 ANCA-associated vasculitis (AAV) RESULTS: Rituximab therapy was well tolerated by all patients, and adverse events were rare. Following the rituximab infusions, circulating B lymphocytes became undetectable, and ANCA titers decreased significantly. Remission was achieved in all patients and was maintained while B lymphocytes were absent.