Belimumab: a technological advance for systemic lupus erythematosus patients? Report of a systematic review and meta-analysis

Ngianga-Bakwin Kandala, Martin Connock, Amy Grove, Paul Sutcliffe, Syed Mohiuddin, Louise Hartley, Rachel Court, Ewen Cummins, Caroline Gordon, Aileen Clarke, Ngianga-Bakwin Kandala, Martin Connock, Amy Grove, Paul Sutcliffe, Syed Mohiuddin, Louise Hartley, Rachel Court, Ewen Cummins, Caroline Gordon, Aileen Clarke

Abstract

Objectives: To undertake a systematic review and meta-analysis to investigate clinical effectiveness of belimumab for patients with systemic lupus erythematosus (SLE) and antinuclear and/or anti-double-stranded DNA (dsDNA) autoantibodies.

Methods: We searched eight electronic databases and reference lists for randomised controlled trials (RCTs) of belimumab against placebo or best supportive care. Quality assessment and random effects meta-analysis were undertaken.

Design: A meta-analysis of RCTs.

Participants: 2133 SLE patients.

Primary and secondary outcome measures: SLE Responder Index (SRI) at week 52.

Results: Three double-blind placebo-controlled RCTs (L02, BLISS-52 BLISS-76) investigated 2133 SLE patients. BLISS-52 and BLISS-76 trials recruited patients with antinuclear and/or anti-dsDNA autoantibodies and demonstrated belimumab effectiveness for the SRI at week 52. Ethnicity and geographical location of participants varied considerably between BLISS trials. Although tests for statistical heterogeneity were negative, BLISS-52 results were systematically more favourable for all measured outcomes. Meta-analysis of pooled 52-week SRI BLISS results showed benefit for belimumab (OR 1.63, 95% CI 1.27 to 2.09). By week 76, the primary SRI outcome in BLISS-76 was not statistically significant (OR 1.31, 95% CI 0.919 to 1.855).

Keywords: Clinical Pharmacology; Epidemiology; Preventive Medicine; Public Health.

Figures

Figure 1
Figure 1
Summary of the major clinical measures used in systemic lupus erythematosus trials.
Figure 2
Figure 2
PRISMA 2009 flow diagram for belimumab in systemic lupus erythematosus randomised controlled trials and on-going trials.
Figure 3
Figure 3
Differing centre locations in the BLISS 52 and BLISS 76 multicentre trials.
Figure 4
Figure 4
Summary of results for major binary and time to event outcomes in belimumab randomised controlled trials.
Figure 5
Figure 5
Summary of results for major continuous outcomes in BLISS 52 and BLISS 76 trials.
Figure 6
Figure 6
Meta-analysis of major outcomes in the two BLISS trials.

References

    1. Bernatsky S, Joseph L, Pineau CA, et al. A population-based assessment of systemic lupus erythematosus incidence and prevalence—results and implications of using administrative data for epidemiological studies. Rheumatology (Oxford) 2007;46:1814–18
    1. Pons-Estel GJ, Alarcon GS, Scofield L, et al. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 2010;39:257–68
    1. Gordon C, Li CK, Isenberg DA. Systemic lupus erythematosus. Medicine 2010;38:73–80
    1. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.
    1. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7
    1. Griffiths B, Mosca M, Gordon C. Assessment of patients with systemic lupus erythematosus and the use of lupus disease activity indices. Best Pract Res Clin Rheumatol 2005;19:685–708
    1. Somers EC, Thomas SL, Smeeth L, et al. Incidence of systemic lupus erythematosus in the United Kingdom, 1990–1999. Arthritis Rheum 2007;57:612–18
    1. Pons-Estel GJ, Alarcon GS, McGwin G, Jr, et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum 2009;61:830–9
    1. Pons-Estel GJ, Gonzalez LA, Zhang J, et al. Predictors of cardiovascular damage in patients with systemic lupus erythematosus: data from LUMINA (LXVIII), a multiethnic US cohort. Rheumatology (Oxford) 2009;48:817–22
    1. Bernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006;54:2550–7
    1. Kurien BT, Scofield RH. Autoantibody determination in the diagnosis of systemic lupus erythematosus. Scand J Immunol 2006;64:227–35
    1. 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;62:222–33
    1. 2012. Summary of product characteristics. Find medicine/Human medicines/European Public Assessment Reports (accessed Jan 2012)
    1. American College of Rheumatology. 2011. Belimumab for Systemic Lupus Erythematosus. (accessed Jan 2012)
    1. New Drug Bulletin. 2012. Belimumab (Benlysta—Human Genome Sciences, Inc) (accessed Jan 2012)
    1. Isenberg DA, Rahman A, Allen E, et al. BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group's disease activity index for patients with systemic lupus erythematosus. Rheumatology 2005;44:902–6
    1. Gordon C, Bertsias G, Ioannidis JPA, et al. EULAR points to consider for conducting clinical trials in Systemic lupus erythematosus. Ann Rheum Dis 2009;68:470–6
    1. Burgos PI, McGwin G, Jr, Pons-Estel GJ, et al. US patients of Hispanic and African ancestry develop lupus nephritis early in the disease course: data from LUMINA, a multiethnic US cohort (LUMINA LXXIV). Ann Rheum Dis 2011;70:393–4
    1. Khan KS, Ter Riet G, Glanville J, et al. Reviews of Research on Effectiveness. CRD's Guidance for Carrying Out or Commissioning Reviews. 2 nd Edition. (ISBN 1900640201) CRD Report No. 4 York: NHS Centre for Reviews and Dissemination (CRD), University of York, 2001. (accessed Jan 2012)
    1. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60
    1. Higgins JPT, Green S.2012. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. (accessed Jan 2012)
    1. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88
    1. 2011. STATA Statistical analysis and software. (accessed Apr 2012)
    1. Navarra SV, Guzman 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
    1. Furie R, Petri M, Zamani O, 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
    1. 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
    1. GlaxoSmithKline. 2011. GSK1550188 A 52 week study of belimumab versus placebo in the treatment of subjects with SLE located in North East Asia. (accessed Jan 2012)
    1. U.S.Food and Drugs Administration. 2010. Arthritis Advisory Committee Meeting Briefing Document for the 16 November 2010 Meeting: Belimumab: BENLYSTA (belimumab): Treatment of Systemic Lupus Erythematosus: BLA 125370. (accessed Jan 2012)
    1. U.S.Food and Drugs Administration. 2010. FDA briefing package. (accessed Jan 2012)
    1. GlaxoSmithKline. 2011. Single Technology Appraisal (STA): Belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus. (accessed Jan 2012)
    1. Egger M, Smith GD, Altman DG. Systematic reviews in health care, meta-analysis in context. 2nd edn BMJ Books, 2001
    1. Pan Z, Trikalinos TA, Kavvoura FK, et al. Local literature bias in genetic epidemiology: an empirical evaluation of the Chinese literature. PLoS Med 2005;2:e334.
    1. Vickers A, Goyal N, Harland R, et al. Do certain countries produce only positive results? A systematic review of controlled trials. Control Clin Trials 1998;19:159–66
    1. Zhang D, Freemantle N, Cheng KK. Are randomized trials conducted in China or India biased? A comparative empirical analysis. J Clin Epidemiol 2011;64:90–5
    1. O'Shea JC, DeMets DL. Statistical issues relating to international differences in clinical trials. Am Heart J 2001;142:21–8
    1. Chang WC, Midodzi WK, Westerhout CM, et al. Are international differences in the outcomes of acute coronary syndromes apparent or real? A multilevel analysis. J Epidemiol Community Health 2005;59:427–33
    1. White HD. International differences: selection, noise, or real? Eur Heart J 2000;21:339–42
    1. Fox KA, Goodman S, Bigonzi F, et al. Inter-regional differences and outcome in unstable angina; analysis of the international ESSENCE trial. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events. Eur Heart J 2000;21:1433–9
    1. Sinnaeve PR, Van de Werf FJ. Global patterns of health care for acute coronary syndromes. Curr Opin Cardiol 2004;19:625–30
    1. Faergeman O, Kjekshus J, Cook T, et al. Differences in the treatment of coronary heart disease between countries as revealed in the Scandinavian Simvastatin Survival Study (4S). Eur Heart J 1998;19:1531–7
    1. Berger JS, Stebbins A, Granger CB, et al. Initial aspirin dose and outcome among ST-elevation myocardial infarction patients treated with fibrinolytic therapy. Circulation 2008;117:192–9
    1. Welsh RC, Chang W, Goldstein P, et al. Time to treatment and the impact of a physician on prehospital management of acute ST elevation myocardial infarction: insights from the ASSENT-3 PLUS trial. Heart 2005;91:1400–6
    1. Yusuf S, Flather M, Pogue J, et al. Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. OASIS (Organisation to Assess Strategies for Ischaemic Syndromes) Registry Investigators. Lancet 1998;352:507–14
    1. Bleyer AJ, Hylander B, Sudo H, et al. An international study of patient compliance with hemodialysis. JAMA 1999;281:1211–13

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe