Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response
Ronald F van Vollenhoven, Michelle A Petri, Ricard Cervera, David A Roth, Beulah N Ji, Christi S Kleoudis, Z John Zhong, William Freimuth, Ronald F van Vollenhoven, Michelle A Petri, Ricard Cervera, David A Roth, Beulah N Ji, Christi S Kleoudis, Z John Zhong, William Freimuth
Abstract
Objectives: To identify factors that predict response to belimumab treatment in the phase 3 BLISS trials of autoantibody-positive systemic lupus erythematosus (SLE) and further analyse clinical efficacy in various patient subsets.
Methods: The BLISS trials compared belimumab 1 and 10 mg/kg versus placebo, all plus standard SLE therapy, over 52 or 76 weeks. Pooled subgroup analyses of week 52 SLE responder index rates (the primary endpoint in both trials) were performed based on demographic characteristics and baseline disease activity indicators. Pooled multivariate analysis was performed to determine predictors of response and treatment effect.
Results: Pooled univariate and multivariate analyses (N=1684) identified baseline factors associated with an increased benefit of belimumab versus placebo. These factors included the Safety Of Estrogens In Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) ≥10, low complement, anti-dsDNA positivity and corticosteroid use. Efficacy outcomes were assessed in the low complement/anti-dsDNA-positive and SELENA-SLEDAI ≥10 subgroups. Week 52 SLE Responder Index rates in the low complement/anti-dsDNA-positive subgroup were 31.7%, 41.5% (p=0.002) and 51.5% (p<0.001) with placebo and belimumab 1 mg/kg and 10 mg/kg, respectively; corresponding rates in the SELENA-SLEDAI ≥10 subgroup were 44.3%, 58.0% (p<0.001) and 63.2% (p<0.001). Further analysis of secondary endpoints in the low complement/anti-dsDNA-positive subgroup showed that compared with placebo, belimumab produced greater benefits regarding severe flares, corticosteroid use and health-related quality of life.
Conclusions: These findings suggest that belimumab has greater therapeutic benefit than standard therapy alone in patients with higher disease activity, anti-dsDNA positivity, low complement or corticosteroid treatment at baseline. CLINICALTRIALS.GOV: identifiers NCT00424476 and NCT00410384.
Conflict of interest statement
Competing interests: RFvV has received consultancy fees and honoraria from Human Genome Sciences and GlaxoSmithKline. MAP and RC have received payment for board membership and consultancy from Human Genome Sciences and GlaxoSmithKline. DAR, BNJ and CSK are employed by and own stock in GlaxoSmithKline. ZJZ and WF are employed by and own stock in Human Genome Sciences.
Figures
References
- Lau CS, Mak A. The socioeconomic burden of SLE. Nat Rev Rheumatol 2009;5:400–4
- Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008;358:929–39
- Biesen R, Dähnrich C, Rosemann A, et al. Anti-dsDNA-NcX ELISA: dsDNA-loaded nucleosomes improve diagnosis and monitoring of disease activity in systemic lupus erythematosus. Arthritis Res Ther 2011;13:R26.
- Merrill JT, Buyon JP. The role of biomarkers in the assessment of lupus. Best Pract Res Clin Rheumatol 2005;19:709–26
- Nasiri S, Karimifar M, Bonakdar ZS, et al. Correlation of ESR, C3, C4, anti-DNA and lupus activity based on British Isles Lupus Assessment Group Index in patients of rheumatology clinic. Rheumatol Int 2010;30:1605–9
- Petri M, Singh S, Tesfasyone H, et al. Prevalence of flare and influence of demographic and serologic factors on flare risk in systemic lupus erythematosus: a prospective study. J Rheumatol 2009;36:2476–80
- Schur PH, Sandson J. Immunologic factors and clinical activity in systemic lupus erythematosus. N Engl J Med 1968;278:533–8
- van den Berg L, Nossent H, Rekvig O. Prior anti-dsDNA antibody status does not predict later disease manifestations in systemic lupus erythematosus. Clin Rheumatol 2006;25:347–52
- Bertsias G, Ioannidis JP, Boletis J, et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 2008;67:195–205
- Furie R, Petri M, Zamani O, et al. ; BLISS-76 Study Group 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
- Navarra SV, Guzmán RM, Gallacher AE, 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
- Wallace DJ, Stohl W, Furie RA, 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 RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Care Res 2009;61:1143–51
- Gladman DD, Urowitz MB, Kagal A, et al. Accurately describing changes in disease activity in systemic lupus erythematosus. J Rheumatol 2000;27:377–9
- Baker KP, Edwards BM, Main SH, et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum 2003;48:3253–65
- Halpern WG, Lappin P, Zanardi T, et al. Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: pharmacokinetic, pharmacodynamic, and toxicologic effects. Toxicol Sci 2006;91:586–99
Source: PubMed