Abstract
Belimumab has recently been approved, and several other types of biological therapy with different mechanisms of action are currently in phase II and III studies. This review puts these approaches in context, emphasizing mechanistic categories and clinical trial designs. Most of the promising approaches involve B cell depletion or modulation. Post-approval experience with belimumab is critically reviewed.
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Panopalis P, Clarke AE, Yelin E. The economic burden of systemic lupus erythematosus. Best Prac Res Clin Rheumatol. 2012;26:695–704.
Bernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematous. Arthritis Rheum. 2006;54:2550–7.
Pineau CA. A comparison of damage accrual across different calendar periods in systemic lupus erythematosus patients. Lupus. 2006;15:590–4.
Balow JE, Austin HA 3rd. Renal disease in systemic lupus erythematosus. Rheum Dis Clin North Am. 1988;14:117–133.
• Merrill JT, Neuwelt CM, Wallace DJ, et al. 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. Arthritis Rheum. 2010;62:222. A flawed, but comprehensive study demonstrating that rituximab was less effective than believed for SLE.
Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012;64(4):1215–26.
• Merrill JT, Borgos-Vargas R, Westhovens R, et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62:3077–87. Did not meet its primary endpoint, but subanalysis indicated that this agent has efficacy for some SLE patients.
Cardiel MH, Tumlin JA, Furie RA, Wallace DJ, Joh T, Linnik MD, et al. Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized controlled phase III trial. Arthritis Rheum. 2008;58(8):2470–80.
Crosbie D, Black C, McIntyre L, et al. Dehydroepiandrosterone for systemic lupus erythematosus. Cochrane Database Syst Rev 2007; :CD005114.
Urowitz M, Isenberg D, Wallace DJ. Prelude—Edratide Phase-II study outcome—from predefined analyses to more recent assessment approaches. Ann Rheum Dis. 2011;70(S3):315. abstract.
Boumpas DR, Furie R, Manzi S, Ilei GG, Wallace DJ, Balow JE, et al. A short course of BG9588 (anti-CD 40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 2003;48:719–27.
Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM. A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. N Engl J Med. 1992;326(21):1373–9.
Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20(5):1103–12.
U.S. Food and Drug Administration. Guidance for Industry on Systemic Lupus Erythematosus: Developing Medical Products for Treatment. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM07263.pdf, Accessed March 11, 2013
Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29:288.
Yee CS, Farewell V, Isenberg DA, et al. British Isles Lupus Assessment Group 2004 index is valid for assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum. 2007;56:4113–9.
Furie RA, Petri MA, Wallace DJ, Ginzler EM, Merrill JT, Stohl W, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009;61(9):1143–51.
Wallace D, Strand V, Furie R, Petri M, Kalunian K, Pike M, et al. Evaluation of treatment success in systemic lupus erythematosus clinical trials: Development of the BILAG based composite lupus assessment endpoint. Arthritis Rheum. 2011;63:S885–6.
Klein R, Moghadam-Kia S, LoMonico J, Okawa J, Coley C, Taylor L, et al. Development of the CLASI as a tool to measure disease severity and responsiveness to therapy in cutaneous lupus erythematosus. Arch Dermatol. 2011;147(2):203–8.
Wofsy, Hillson JL, Diamond B. Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions. Arthritis Rheum. 2012;64:3660.
•• Hahn BH, Mc Machon MA, Wilkinson A, Wallace WD, Daikh D, Fitzgerald JD, et al. American College of Rheumatology Guidelines for Screening, Treatment and Management of Lupus Nephritis. Arthritis Care Res. 2012;64:797–808. The most comprehensive guidance document to date on managing lupus nephritis.
Mosley K, Tam FW, Edwards RJ, et al. Urinary proteomic profiles distinguish between active and inactive lupus nephritis. Rheumatology (Oxford). 2006;45:1497.
Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, Merrill JT, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61:1168–78.
• Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzová D, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63:3918–30. A large study accompanying Ref. [25] which met its primary endpoints and enabled belimumab to receive FDA approval.
•• Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:721–31. The largest, most detailed lupus clinical trial ever conducted.
Merrill JT, Ginzler EM, Wallace DJ, McKay JD, Lisse JR, Aranow C, et al. Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. Arthritis Rheum. 2012;64:3364–73.
Stohl W, Hiepe F, Latinis KM, Thomas M, Scheinberg MA, Clarke A, et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus. Arthritis Rheum. 2012;64:2328–37.
van Vollenhoven RF, Petri MA, Cervera R, Roth DA, Ji BN, Kleoudis CS, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012;71:1343–9.
Manzi S, Sánchez-Guerrero J, Merrill JT, Furie R, Gladman D, Navarra SV, et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis. 2012;71:1833–8.
Wallace D, Navarra S, Petri M, Gallacher A, Thomas M, Furie R, et al. Safety profile of belimumab: pooled data from placebo-controlled phase 2 and 3 studies in patients with systemic lupus erythematosus, Lupus. 2012 Dec 4. [Epub ahead of print]
Ginzler EM, Wax S, Rajeswaran A, Copt S, Hillson J, Ramos E, et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther. 2012;14:R33. doi:10.1186/ar3738.
Genovese MC, Bojin S, Biagini I, Mociran E, Cristei D, Mirea G, et al. Tabalumab in patients with rheumatoid arthritis with an inadequate response to methotrexate and naïve to biologic therapy. Arthritis Rheum. 2013. doi:10.1002/art.37820 [Epub ahead of print].
Stohl W. Biologic differences between various inhibitors of the BLyS/BAFF pathway: should we expect differences between belimumab and other inhibitors in development? Curr Rheumatol Rep. 2012;14(4):303–9.
Furie RA, Scheinberg MA, Leon G, et al. Blisbimod, an inhibitor of B cell activating factor, in patients with moderate-to-sever systemic lupus erythematosus. Arthritis Rheum. 2012;64:4169. abstract.
Wallace DJ, Goldenberg DM, Epratuzumab for SLE, Lupus 2013; in press
Goldenberg DM et al. Trogocytosis as a mechanism of action of epratuzumab. Madrid: EULAR; 2013.
• Wallace DJ, Kalunian K, Petri MA, Strand V, Houssiau FA, Pike M, et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomized, double-blind, placebo-controlled multicentre study, Ann Rheum Dis 2013 Jan 12, E Pub ahead of print. A large phase II trial demonstrating efficacy using the BICLA.
Wallace D, Gordon C, Strand V, et al. Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double-blind, placebo –controlled, multicenter studies (ALLEVIATE) and follow up. Rheumatology. 2013. doi:10.1093/rheumatology/ket129.
Jónsdóttir T, Gunnarsson I, Risselada A, et al. Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response. Ann Rheum Dis. 2008;67:330.
Lehman TJA, Baird E, Ramanathan, et al. Prolonged improvement of systemic lupus erythematous following systemic administration of rituximab and cyclophosphamide. Arthritis Rheum. 2012;64. abstract 621.
Furie R, Nichols K, Cheng T-T, et al. Efficacy and safety of abatacept over 12 months in patients with lupus nephritis: Results from a multicenter, randomized, double-blind placebo controlled, Phase II/III study. Arthritis Rheum. 2011;63. abstract 2469.
Wallace DJ. Advances in drug therapy for systemic lupus erythematosus. BMC Med. 2010;8(77):1–19.
Merrill JT, Wallace DJ, Petri M, Kirou KA, Yao Y, White WI, et al. Safety profile and clinical activity of sifalumumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomized study. Annals Rhem Dis. 2011;70:1905–13.
Mc Bride JM, Jiang J, Abbas A, Morimoto A, Li J, Maciuca R, et al. Safety and pharmacodynamics results of rontilzumab in a phase I, placebo-controlled, double-blind, dose-escalation study in systemic lupus erythematosus. Arthritis Rheum. 2012;64:3666–76.
Kahlenberg JM, Thacker SG, Berthier CC, Cohen CD, Kretzler M, Kaplan MJ. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus. J Immunol. 2011;187(11):6143–56.
Sthoeger ZM, Sharabi A, Molad Y, Asher I, Zinger H, Dayan M, et al. Treatment of lupus patients with a tolerogenic peptide, hCDR1 (Edratide): immunomodulation of gene expression. J Autoimmun. 2009;33(1):77–82.
Zimmer R, Wallace DJ, Muller S. Randomized, double-blind, placebo-controlled studies of P140 peptide in mannitol (Lupozor) and trehalose (Forigerimod) in patients with SLE. Arthritis Rheum. 2012;64:S1110.
Illei GG, Shirota Y, Yarboro CH, Daruwalla J, Tackey E, Takada K, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010;62(2):542–52.
Nakou M, Papadimitraki ED, Fanouriakis A, Bertsias GK, Choulaki C, Goulidaki N, et al. Interleukin-21 is increased in active systemic lupus erythematosus patients and contributes to generation of plasma B cells, Clin Exp Rheumatol. 2012 Nov 6. [Epub ahead of print]
Zimmer R, Scherbarth HR, Rillo OL, Gomez-Reino JJ, Muller S, Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial, Ann Rheum Dis. 2012 Nov 21.
Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366:1000–9.
NCT01597058, Safety and Efficacy of Topical R333 in Patients With Discoid Lupus Erythematosus (DLE) and Systemic Lupus Erythematosus (SLE) Lesions.
Furie R, Matis L, Rollins S, et al. A single dose, placebo-controlled, double blind, phase I study of the humanized anti-C5 antibody hbG1.1 in patients with systemic lupus erythematosus, Arthritis Rheum Abstract presented at the 64th Annual Scientific Meeting of the American College of Rheumatology, Philadelphia.
Conflict of interest
Dr Wallace consults for UCB, Pfizer, Amgen, and Lilly and consults and is on the speaker's bureau for Glaxo Smith Kline.
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Wallace, D.J. Ten Developments in the Use of Biologicals for Systemic Lupus Erythematosus. Curr Rheumatol Rep 15, 337 (2013). https://doi.org/10.1007/s11926-013-0337-z
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DOI: https://doi.org/10.1007/s11926-013-0337-z