Abstract
Objectives
The objectives of this study were to evaluate the efficacy, safety, and tolerability of biologic drugs compared with placebo for systemic lupus erythematosus (SLE) treatment.
Methods
A systematic review evaluating the efficacy and safety of biologic therapies compared with placebo in adult SLE patients treatment was performed. Data from studies performed before September 2013 were collected from several databases (MEDLINE, Cochrane Library, SCIELO, Scopus, and International Pharmaceutical Abstracts). Study eligibility criteria included randomized, double-blind, placebo-controlled trials; regarding treatment with biologic agents in SLE adult patients; and published in English, German, Portuguese, and Spanish. Extracted data were statistically analyzed in a meta-analysis using the Review Manager (RevMan) 5.1 software. Efficacy outcomes included the SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index) score, the SRI (Systemic Lupus Erythematosus Responder Index), normalization of low C3 (<90 mg/dL), anti-double-stranded DNA positive to negative, and no new BILAG (British Isles Lupus Assessment Group index) 1A or 2B flares. Data on safety profile included adverse events, serious and severe adverse events, death, malignancy, infections, and infusion reactions. We also evaluated withdrawals from treatment due to lack of efficacy or adverse events.
Results
Thirteen randomized placebo-controlled trials met the criteria for data extraction for systematic review. A meta-analysis regarding the efficacy and safety of belimumab compared with placebo involving four of these trials was undertaken and the remainder contributed to a meta-analysis of the safety of biologic agents. In addition, two trials allowed the performance of a meta-analysis regarding the efficacy and safety of rituximab compared with placebo. Belimumab was more effective than placebo in most evaluated outcomes. No significant differences in the safety and tolerability data were observed between the belimumab and placebo groups. No differences were observed between the rituximab and placebo groups for the efficacy outcomes or safety parameters. Extracted data from the 13 studies were pooled, allowing assessment of the safety of biologic drugs. The meta-analysis revealed a satisfactory safety profile of these agents when used for SLE treatment, as there were no significant differences between the two evaluated groups (biologic agents and placebo) for all outcomes analyzed.
Conclusion
Belimumab exhibited a satisfactory profile regarding efficacy, safety, and tolerability. Rituximab showed no superiority over placebo in terms of efficacy, despite its suitable safety profile. Biologic agents exhibited a good safety profile for SLE treatment, indicating that these agents are promising therapies and should be further investigated.
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References
Achour A, Mankai A, Thabet Y, Sakly W, Braham F, Kechrid C, et al. Systemic lupus erythematosus in the elderly. Rheumatol Int. 2012;32(5):1225–9.
Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008;358(9):929–39.
Postal M, Costallat LT, Appenzeller S. Biological therapy in systemic lupus erythematosus. Int J Rheumatol. 2012;2012:578641.
Ezra N, Jorizzo J. Hydroxychloroquine and smoking in patients with cutaneous lupus erythematosus. Clin Exp Dermatol. 2012;37(4):327–34.
Manson JJ, Rahman A. Systemic lupus erythematosus. Orphanet J Rare Dis. 2006;1:6.
Sweetman S. Martindale: the complete drug reference. 37th ed. London: Pharmaceutical Press; 2011. http://www.thomsonhc.com. Accessed 1 Aug 2013.
Tullus K. New developments in the treatment of systemic lupus erythematosus. Pediatr Nephrol. 2012;27(5):727–32.
Thompson CA. First new lupus drug approved in half-century. Am J Health Syst Pharm. 2011;68(8):646.
Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. http://www.cochrane-handbook.org. Accessed 1 Aug 2013.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.
Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356(9237):1255–9.
Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006;11(2):193–206.
Cardiel MH, Tumlin JA, Furie RA, Wallace DJ, Joh T, Linnik MD. Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial. Arthritis Rheum. 2008;58(8):2470–80.
Dall’Era M, Chakravarty E, Wallace D, Genovese M, Weisman M, Kavanaugh A, et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum. 2007;56(12):4142–50.
Furie RA, Cash JM, Cronin ME, Katz RS, Weisman MH, Aranow C, et al. Treatment of systemic lupus erythematosus with LJP 394. J Rheumatol. 2001;28(2):257–65.
Furie R, Stohl W, Ginzler EM, Becker M, Mishra N, Chatham W, et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Res Ther. 2008;10(5):R109.
Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova 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(12):3918–30.
Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, 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. 2010a;62(1):222–33.
Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D’Cruz D, Wallace DJ, 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. 2010b;62(10):3077–87.
Merrill JT, Wallace DJ, Petri M, Kirou KA, Yao Y, White WI, et al. Safety profile and clinical activity of sifalimumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study. Ann Rheum Dis. 2011;70(11):1905–13.
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(9767):721–31.
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(9):1168–78.
Petri M, Wallace DJ, Spindler A, Chindalore V, Kalunian K, Mysler E, et al. Sifalimumab, a human anti-interferon-α monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study. Arthritis Rheum. 2013;65(4):1011–21.
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, randomised, double-blind, placebo-controlled, multicentre study. Ann Rheum Dis. Epub 2013 Jan 12.
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.
Wallace DJ, Gordon C, Strand V, Hobbs K, Petri M, Kalunian K, et al. Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double-blind, placebo-controlled, multicentre studies (ALLEVIATE) and follow-up. Rheumatology (Oxford). 2013;52(7):1313–22.
Borba EF. Consenso de Lúpus Eritematoso Sistêmico. Rev Bras Reumatol. 2008;48(4):196–207.
Luijten KM, Tekstra J, Bijlsma JW, Bijl M. The Systemic Lupus Erythematosus Responder Index (SRI); a new SLE disease activity assessment. Autoimmun Rev. 2012;11(5):326–9.
Lam GK, Petri M. Assessment of systemic lupus erythematosus. Clin Exp Rheumatol. 2005;23(5 Suppl 39):S120–32.
Nowling TK, Gilkeson GS. Mechanisms of tissue injury in lupus nephritis. Arthritis Res Ther. 2011;13(6):250.
Andrejevic S, Jeremic I, Sefik-Bukilica M, Nikolic M, Stojimirovic B, Bonaci-Nikolic B. Immunoserological parameters in SLE: high-avidity anti-dsDNA detected by ELISA are the most closely associated with the disease activity. Clin Rheumatol. Epub 2013 Jul 16.
Dooley MA, Houssiau F, Aranow C, D’Cruz DP, Askanase A, Roth DA, et al. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus. 2013;22(1):63–72.
Chugh PK. Lupus: novel therapies in clinical development. Eur J Int Med. 2012;23(3):212–8.
Ding HJ, Gordon C. New biologic therapy for systemic lupus erythematosus. Curr Opin Pharmacol. 2013;13(3):405–12.
Murphy G, Lisnevskaia L, Isenberg D. Systemic lupus erythematosus and other autoimmune rheumatic diseases: challenges to treatment. Lancet. 2013;382(9894):809–18.
Rozenfeld S, Valente J. Estudos de utilização de medicamentos – considerações técnicas sobre coleta e análise de dados. Epidemiologia e Serviços de Saúde. 2004;13(2):115–23.
Abud-Mendoza C, Moreno-Valdes R, Cuevas-Orta E, Borjas A, Aranda F, Irazoque F, et al. Treating severe systemic lupus erythematosus with rituximab. An open study. Reumatol Clin. 2009;5(4):147–52.
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(10):2673–7.
Ramos-Casals M, Brito-Zeron P, Munoz S, Soto MJ. A systematic review of the off-label use of biological therapies in systemic autoimmune diseases. Medicine (Baltimore). 2008;87(6):345–64.
Linnik MD, Hu JZ, et al. Relationship between anti-double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus. Arthritis Rheum. 2005;52(4):1129–1137.
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No sources of external funding were used in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this article.
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Borba, H.H.L., Wiens, A., de Souza, T.T. et al. Efficacy and Safety of Biologic Therapies for Systemic Lupus Erythematosus Treatment: Systematic Review and Meta-Analysis. BioDrugs 28, 211–228 (2014). https://doi.org/10.1007/s40259-013-0074-x
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DOI: https://doi.org/10.1007/s40259-013-0074-x