Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: The randomized, double-blind, phase ii/iii systemic lupus erythematosus evaluation of rituximab trial†
Corresponding Author
Joan T. Merrill
Oklahoma Medical Research Foundation, Oklahoma City
Dr. Merrill has received speaking fees, consulting fees, and/or honoraria from Genentech, Bristol-Myers Squibb, MedImmune, UCB, Wyeth, and Cephalon (less than $10,000 each), and has consulted with investment analysts.
Oklahoma Medical Research Foundation, Clinical Pharmacology Research Program, MS 22, 825 Northeast 13th Street, Oklahoma City, OK 73104Search for more papers by this authorC. Michael Neuwelt
Alameda County Medical Center, Oakland, California
Search for more papers by this authorDaniel J. Wallace
Cedars-Sinai Medical Center, Los Angeles, California, and University of California, Los Angeles
Dr. Wallace has received speaking fees, consulting fees, and/or honoraria from Genentech (less than $10,000).
Search for more papers by this authorJoseph C. Shanahan
Duke University, Durham, North Carolina
Dr. Shanahan has received speaking fees, consulting fees, and/or honoraria from Genentech, Actelion, and Cypress (less than $10,000 each), and owns stock or stock options in Schering-Plough.
Search for more papers by this authorKevin M. Latinis
University of Kansas Medical Center, Kansas City
Dr. Latinis has received speaking fees, consulting fees, and/or honoraria from Genentech (less than $10,000).
Search for more papers by this authorJames C. Oates
Ralph H. Johnson VA Medical Center, Charleston, South Carolina, and Medical University of South Carolina, Charleston
Dr. Oates has received speaking fees, consulting fees, and/or honoraria from Genentech (less than $10,000).
Search for more papers by this authorTammy O. Utset
University of Chicago, Chicago, Illinois
Dr. Utset has received advisory board fees from Genentech (more than $10,000).
Search for more papers by this authorCaroline Gordon
University of Birmingham, Birmingham, UK
Dr. Gordon has received speaking fees, consulting fees, and/or honoraria from Roche Pharmaceuticals and Genentech (less than $10,000 each).
Search for more papers by this authorHsin-Ju Hsieh
Genentech, San Francisco, California
Dr. Hsieh owns stock or stock options in Genentech.
Search for more papers by this authorCorresponding Author
Joan T. Merrill
Oklahoma Medical Research Foundation, Oklahoma City
Dr. Merrill has received speaking fees, consulting fees, and/or honoraria from Genentech, Bristol-Myers Squibb, MedImmune, UCB, Wyeth, and Cephalon (less than $10,000 each), and has consulted with investment analysts.
Oklahoma Medical Research Foundation, Clinical Pharmacology Research Program, MS 22, 825 Northeast 13th Street, Oklahoma City, OK 73104Search for more papers by this authorC. Michael Neuwelt
Alameda County Medical Center, Oakland, California
Search for more papers by this authorDaniel J. Wallace
Cedars-Sinai Medical Center, Los Angeles, California, and University of California, Los Angeles
Dr. Wallace has received speaking fees, consulting fees, and/or honoraria from Genentech (less than $10,000).
Search for more papers by this authorJoseph C. Shanahan
Duke University, Durham, North Carolina
Dr. Shanahan has received speaking fees, consulting fees, and/or honoraria from Genentech, Actelion, and Cypress (less than $10,000 each), and owns stock or stock options in Schering-Plough.
Search for more papers by this authorKevin M. Latinis
University of Kansas Medical Center, Kansas City
Dr. Latinis has received speaking fees, consulting fees, and/or honoraria from Genentech (less than $10,000).
Search for more papers by this authorJames C. Oates
Ralph H. Johnson VA Medical Center, Charleston, South Carolina, and Medical University of South Carolina, Charleston
Dr. Oates has received speaking fees, consulting fees, and/or honoraria from Genentech (less than $10,000).
Search for more papers by this authorTammy O. Utset
University of Chicago, Chicago, Illinois
Dr. Utset has received advisory board fees from Genentech (more than $10,000).
Search for more papers by this authorCaroline Gordon
University of Birmingham, Birmingham, UK
Dr. Gordon has received speaking fees, consulting fees, and/or honoraria from Roche Pharmaceuticals and Genentech (less than $10,000 each).
Search for more papers by this authorHsin-Ju Hsieh
Genentech, San Francisco, California
Dr. Hsieh owns stock or stock options in Genentech.
Search for more papers by this authorClinicalTrials.gov identifier: NCT00137969.
Abstract
Objective
B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately-to-severely active extrarenal SLE.
Methods
Patients entered with ≥1 British Isles Lupus Assessment Group (BILAG) A score or ≥2 BILAG B scores despite background immunosuppressant therapy, which was continued during the trial. Prednisone was added and subsequently tapered. Patients were randomized at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182.
Results
In the intent-to-treat analysis of 257 patients, background treatment was evenly distributed among azathioprine, mycophenolate mofetil, and methotrexate. Fifty-three percent of the patients had ≥1 BILAG A score at entry, and 57% of the patients were categorized as being steroid dependent. No differences were observed between placebo and rituximab in the primary and secondary efficacy end points, including the BILAG-defined response, in terms of both area under the curve and landmark analyses. A beneficial effect of rituximab on the primary end point was observed in the African American and Hispanic subgroups. Safety and tolerability were similar in patients receiving placebo and those receiving rituximab.
Conclusion
The EXPLORER trial enrolled patients with moderately-to-severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse. No differences were noted between placebo and rituximab in the primary and secondary end points. Further evaluation of patient subsets, biomarkers, and exploratory outcome models may improve the design of future SLE clinical trials.
REFERENCES
- 1 Gill JM, Quisel AM, Rocca PV, Walters DT. Diagnosis of systemic lupus erythematosus. Am Fam Physician 2003; 68: 2179–86.
- 2 Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008; 358: 929–39.
- 3 Stoll T, Seifert B, Isenberg DA. SLICC/ACR damage index is valid, and renal and pulmonary organ scores are predictors of severe outcome in patients with systemic lupus erythematosus. Br J Rheumatol 1996; 35: 248–54.
- 4 Dooley MA, Hogan S, Jennette C, Falk R, for the Glomerular Disease Collaborative Network. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Kidney Int 1997; 51: 1188–95.
- 5 Alarcon GS, Roseman JM, McGwin G Jr, Uribe A, Bastian HM, Fessler BJ, et al, for the LUMINA study group. Systemic lupus erythematosus in three ethnic groups. XX. Damage as a predictor of further damage. Rheumatology (Oxford) 2004; 43: 202–5.
- 6 Lam GK, Petri M. Assessment of systemic lupus erythematosus. Clin Exp Rheumatol 2005; 23 Suppl 39: S120–32.
- 7 Gladman DD, Urowitz MB, Rahman P, Ibanez D, Tam LS. Accrual of organ damage over time in patients with systemic lupus erythematosus. J Rheumatol 2003; 30: 1955–9.
- 8 Borchers AT, Keen CL, Shoenfeld Y, Gershwin ME. Surviving the butterfly and the wolf: mortality trends in systemic lupus erythematosus. Autoimmun Rev 2004; 3: 423–53.
- 9 Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nature Immunol 2001; 2: 764–6.
- 10 Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol 2003; 56: 481–90.
- 11 Renaudineau Y, Pers JO, Bendaoud B, Jamin C, Youinou P. Dysfunctional B cells in systemic lupus erythematosus. Autoimmun Rev 2004; 3: 516–23.
- 12 Swaak T, Smeenk R. Clinical significance of antibodies to double stranded DNA (dsDNA) for systemic lupus erythematosus (SLE). Clin Rheumatol 1987; 6: 56–73.
- 13 Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349: 1526–33.
- 14 Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, Nadler LM. Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation. Blood 1984; 63: 1424–33.
- 15 Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994; 84: 2457–66.
- 16 Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994; 83: 435–45.
- 17 Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004; 350: 2572–81.
- 18 Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al. Rituximab for rheumatoid arthritis refractory to anti–tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006; 54: 2793–806.
- 19 Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIb randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006; 54: 1390–400.
- 20 Albert D, Khan S, Stansberry J, Kolasinski S, Tsai D, Kamoun M, et al. A phase I trial of rituximab (anti-CD20) for treatment of systemic lupus erythematosus [abstract]. Arthritis Rheum 2004; 50 Suppl: S446–7.
- 21 Ryan JP, Singer NG, Scalzi LV. Treatment of resistant SLE with rituximab administered without cyclophosphamide [abstract]. Arthritis Rheum 2004; 50 Suppl: S413–4.
- 22 Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002; 46: 2673–7.
- 23 Leandro MJ, Cambridge G, Edwards JC, Ehrenstein MR, Isenberg DA. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology 2005; 44: 1542–5.
- 24 Van Vollenhoven RF, Gunnarsson I, Welin-Henriksson E, Sundelin B, Osterborg A, Jacobson SH, et al. Biopsy-verified response of severe lupus nephritis to treatment with rituximab (anti-CD20 monoclonal antibody) plus cyclophosphamide after biopsy-documented failure to respond to cyclophosphamide alone. Scand J Rheumatol 2004; 33: 423–7.
- 25 Van Vollenhoven RF, Gunnarsson I, Welin-Henriksson E, Jonsdottir T, Sundelin B, Jacobsson S, et al. Rituximab plus cyclophosphamide in severe SLE: results in 15 patients who failed conventional immunosuppressive therapy [abstract]. Arthritis Rheum 2005; 52 Suppl: S741.
- 26 Cambridge G, Leandro MJ, Teodorescu M, Manson J, Rahman A, Isenberg DA, et al. B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum 2006; 54: 3612–22.
- 27 Smith KG, Jones RB, Burns SM, Jayne DR. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment. Arthritis Rheum 2006; 54: 2970–82.
- 28 Tokunaga M, Saito K, Kawabata D, Imura Y, Fujii T, Nakayamada S, et al. Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann Rheum Dis 2007; 66: 470–5.
- 29 Sutter JA, Kwan-Morley J, Dunham J, Du YZ, Kamoun M, Albert D, et al. A longitudinal analysis of SLE patients treated with rituximab (anti-CD20): factors associated with B lymphocyte recovery. Clin Immunol 2008; 126: 282–90.
- 30 Lu TY, Jonsdottir T, van Vollenhoven RF, Isenberg DA. Prolonged B-cell depletion following rituximab therapy in systemic lupus erythematosus: a report of two cases. Ann Rheum Dis 2008; 67: 1493–4.
- 31 Kumar S, Benseler SM, Kirby-Allen M, Silverman ED. B-cell depletion for autoimmune thrombocytopenia and autoimmune hemolytic anemia in pediatric systemic lupus erythematosus. Pediatrics 2009; 123: 159–63.
- 32 Reynolds J, Toescu V, Yee C, Prabu A, Situnayake D, Gordon C. Effects of rituximab on resistant SLE disease including lung involvement. Lupus 2009; 18: 67–73.
- 33 American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria. The American College of Rheumatology response criteria for systemic lupus erythematosus clinical trials: measures of overall disease activity. Arthritis Rheum 2004; 50: 3418–26.
- 34 Hay EM, Bacon PA, Gordon C, Isenberg DA, Maddison P, Snaith ML, et al. The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. Q J Med 1993; 86: 447–58.
- 35 Isenberg DA, Gordon C, and the British Isles Lupus Assessment Group. From BILAG to BLIPS: disease activity assessment in lupus past, present and future. Lupus 2000; 9: 651–4.
- 36 Yu EB, Shikiar R, Howard K, Kalunian KC, Petrillo J, Thompson C, et al. Validation of LUP-QOL: a lupus-specific measure of health-related quality of life (HRQL) [abstract]. Ann Rheum Dis 2006; 65 Suppl II: 601.
- 37 Ware JE Jr, Sherbourne CD. The MOS 36-item Short-Form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30: 473–83.
- 38 Ehrenstein MR, Conroy SE, Heath J, Latchman DS, Isenberg DA. The occurrence, nature and distribution of flares in a cohort of patients with systemic lupus erythematosus: a rheumatological view. Br J Rheumatol 1995; 34: 257–60.
- 39 Ahuja A, Shupe J, Dunn R, Kashgarian M, Kehry MR, Shlomchik MJ. Depletion of B cells in murine lupus: efficacy and resistance. J Immunol 2007; 179: 3351–61.
- 40 Tanaka Y, Yamamoto K, Takeuchi T, Nishimoto N, Miyasaka N, Sumida T, et al. A multicenter phase I/II trial of rituximab for refractory systemic lupus erythematosus. Mod Rheumatol 2007; 17: 191–7.
- 41 Shlomchik MJ, Madaio MP, Ni D, Trounstein M, Huszar D. The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med 1994; 180: 1295–306.
- 42 Gong Q, Ou Q, Ye S, Lee WP, Cornelius J, Diehl L, et al. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol 2005; 174: 817–26.
- 43 Gordon C, Sutcliffe N, Skan J, Stoll T, Isenberg DA. Definition and treatment of lupus flares measured by the BILAG index. Rheumatology 2003; 42: 1372–9.
- 44 Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM, for the Lupus Nephritis Collaborative Study Group. A controlled trial of plasmapheresis therapy in severe lupus nephritis. N Engl J Med 1992; 326: 1373–9.
- 45 Uribe AG, McGwin G Jr, Reveille JD, Alarcon GS. What have we learned from a 10-year experience with the LUMINA (Lupus in Minorities; Nature vs. nurture) cohort? Where are we heading? Autoimmun Rev 2004; 3: 321–9.
- 46 Anolik JH, Barnard J, Cappione A, Pugh-Bernard AE, Felgar RE, Looney RJ, et al. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 2004; 11: 3580–90.
- 47 Voog E, Morschhauser F, Solal-Celigny P. Neutropenia in patients treated with rituximab. N Engl J Med 2003; 348: 2691–4.
- 48 Marotte H, Paintaud G, Watier H, Miossec P. Rituximab-related late-onset neutropenia in a patient with severe rheumatoid arthritis. Ann Rheum Dis 2008; 67: 893–4.
