Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus

Abstract

Objective: To assess the effects of the B lymphocyte stimulator (BLyS)-specific inhibitor belimumab on immunologic biomarkers, including B cell and T cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients.

Methods: Pooled data from 2 phase III trials, the Study of Belimumab in Subjects with SLE 52-week (BLISS-52) and 76-week (BLISS-76) trials, comparing belimumab 1 mg/kg or 10 mg/kg versus placebo (plus standard SLE therapy for each group) were analyzed for changes in autoantibody, immunoglobulin, and complement levels. BLISS-76 patients were also analyzed for changes in B cell and T cell populations and effects on prior vaccine-induced antibody levels.

Results: Belimumab-treated patients experienced significant sustained reductions in IgG and autoantibodies and improvement in C3/C4 levels, resulting in greater positive-to-negative conversion rates for IgG anti-double-stranded DNA (anti-dsDNA), anti-Sm, anticardiolipin, and anti-ribosomal P autoantibodies and normalization of hypergammaglobulinemia and low C3/C4 levels. Belimumab-treated patients experienced significant decreases in the numbers of naive and activated B cells, as well as plasma cells, whereas memory B cells and T cell populations did not decrease. Belimumab did not substantially affect preexisting antipneumococcal or anti-tetanus toxoid antibody levels. Post hoc analysis showed greater reductions in SLE disease activity and the risk of severe flares in patients treated with belimumab 10 mg/kg (P≤0.01) who were anti-dsDNA positive and had low C3/C4 levels at baseline. Normalization of the C3 or anti-dsDNA level by 8 weeks, irrespective of therapy, was predictive of a reduced risk of severe flare over 52 weeks.

Conclusion: Belimumab appears to promote normalization of serologic activity and reduce BLyS-dependent B cell subsets in serologically and clinically active SLE. Greater serologic activity may predict a better treatment response to belimumab.

Trial registration: ClinicalTrials.gov NCT00410384 NCT00424476.

Conflict of interest statement

Dr Stohl has received clinical trials support from Human Genome Sciences (HGS). Dr Hiepe has received consultancy fees from HGS and GlaxoSmithKline (GSK). Dr Latinis has received fees for consultancy and speaker’s bureau participation from HGS and GSK. Dr Clarke has received research support and consultancy fees from HGS and GSK, and clinical trials support from HGS. Dr Aranow has received consultancy fees from HGS. Dr Wellborne has received research support from HGS, and consultancy fees from HGS and GSK. Drs Hough, Pineda, Migone, Zhong, and Freimuth are employed by and own stock in HGS. The other authors declare that they have no conflicts of interest.

Copyright © 2012 by the American College of Rheumatology.

Figures

Figure 1

Effects of belimumab treatment on autoantibodies, immunoglobulin (Ig), and complement (C) at week 52 (pooled data). A, changes in IgG in all patients and in anti–double-stranded DNA (anti-dsDNA) in patients positive at baseline. B, rates of conversion from autoantibody positive to negative. C, changes in C3 and C4 in patients with low C3 (<90 mg/dL) or C4 (<16 mg/dL) at baseline (C3/4: placebo, n= 248/303, belimumab 1 mg/kg, n = 248/314, and 10 mg/kg, n = 262/314). D, rates of normalization from high to low/normal IgG and from low to normal/high C3 and C4. * P <0.05; +P <0.01; #P <0.001. aCL = anticardiolipin; ANA = antinuclear antibodies.

Figure 2

Median percent changes in (A) B-cell subsets and (B) plasma cell subsets through week 76 in BLISS-76. SLE = systemic lupus erythematosus. * P <0.05; +P <0.01; #P <0.001.

Figure 3

Changes in T-cell values at weeks 52 and 76 in BLISS-76. BL = baseline.