Effect of long‐term belimumab treatment on b cells in systemic lupus erythematosus: Extension of a phase II, double‐blind, placebo‐controlled, dose‐ranging study

Abstract

Objective. To understand the effects of long-term BLyS inhibition in human systemic lupus erythematosus (SLE).Methods. Seventeen patients with SLE who were enrolled in a clinical trial of belimumab, a BLyS-specific inhibitor, plus standard of care therapy were studied. Phenotypic analysis of lymphocytes was performed using flow cytometry. Circulating antibody-secreting cells were enumerated using enzyme-linked immunospot assay. Serum was analyzed by enzyme-linked immunosorbent assay using an antibody that recognizes products of the V H 4-34 gene. Lymphocyte counts, Ig levels, and anti-double-stranded DNA antibody levels were available as part of the clinical trial analyses.Results. Samples were collected on days 0, 84, 168, 365, and 532 and after day 730. The total number of B cells started to decrease from baseline between days 84 and 168. This was due to a decrease in naive and transitional B cells. CD27؉IgD؉ memory B cells and plasmablasts decreased only after 532 days, whereas CD27؉IgD؊ memory B cells were not affected, and there were no changes in T cells. Serum IgM levels began to decline between days 84 and 168, but there were no changes in serum levels of IgG, IgG anti-DNA antibodies, or V H 4-34 antibodies during the study. SLE patients had more IgM-, IgG-, and autoantibodyproducing B cells than did normal controls on day 0. There was only a modest decrease in the frequency of total IgM-producing, but not IgG-producing, cells on days 365 and 532, consistent with the phenotypic and serologic data.Conclusion. Our data confirm the dependence of newly formed B cells on BLyS for survival in humans. In contrast, memory B cells and plasma cells are less susceptible to selective BLyS inhibition.

Long‐Term Safety and Efficacy of Belimumab in Patients With Systemic Lupus Erythematosus

“…The results presented are consistent with those of a small 2‐year study that investigated the effects of belimumab treatment on levels of B cell subsets 29. Over the duration of the study, there was a decrease in levels for the majority of B cell subsets, but no subsets were completely depleted.…”

Updates on the Treatment of Lupus Nephritis

“…54 Early phase trials with belimumab in patients with SLE showed efficacy in reducing levels of peripheral B cell but have yet to show this B-cell depletion translates into serologic (antibody levels) or clinical (lupus activity scores or, in patients with lupus nephritis, markers of renal function) improvements. [55][56][57] In case reports from Europe, adrenocorticotropic hormone (ACTH) shows promising results in patients with nephrotic syndrome of various etiologies, including membranous nephropathy, membranoproliferative glomerulonephritis, minimal change disease, and focal segmental glomerulosclerosis. 58,59 In a randomized trial in idiopathic membranous nephropathy conducted by Ponticelli et al, 60 ACTH and cyclophosphamide achieved equal rates of disease remission.…”

New Therapeutic Strategies in Lupus Nephritis

“…The majority of clinical studies in emerging biologic therapies have not addressed the issue of variable clinical response in different ethnic groups. Of note, belimumab was found to be less efficacious in African American patients in phase III clinical trials (Wallace et al, 2009) (Jacobi et al, 2010). Several of the studies of emerging therapeutic strategies described in this chapter, while encouraging, have targeted SLE disease manifestations in general rather than focusing on outcomes in lupus nephritis.…”

“…Belimumab was approved by the FDA for treatment of SLE in March 2011, the first lupus drug to be approved since hydroxychloroquine and corticosteroids were approved in 1955. The safety and effectiveness of belimumab was demonstrated in two clinical trials (BLISS-52, and BLISS-76) that randomized a total of 1684 patients to receive either belimumab or placebo in combination with standard therapy (Wallace et al, 2009) (Jacobi et al, 2010). Treatment with belimumab plus standard therapy reduced disease activity and steroid use.…”