Efficacy and Safety of Subcutaneous Belimumab in Anti–Double‐Stranded DNA–Positive, Hypocomplementemic Patients With Systemic Lupus Erythematosus

Abstract

ObjectiveTo investigate the efficacy and safety of belimumab, a human immunoglobulin monoclonal antibody against B lymphocyte stimulator, in a subset of patients with systemic lupus erythematosus (SLE) who were hypocomplementemic (C3 <90 mg/dl and/or C4 <10 mg/dl) and anti–double‐stranded DNA (anti‐dsDNA) positive (≥30 IU/ml) at baseline.MethodsIn this phase III, double‐blind, placebo‐controlled study (BEL112341; ClinicalTrials.gov identifier: NCT01484496), patients with moderate to severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index [SELENA–SLEDAI] score ≥8) were randomized (2:1) to receive weekly subcutaneous (SC) belimumab 200 mg or placebo, plus standard SLE therapy, for 52 weeks. The primary end point was SLE Responder Index 4 (SRI‐4) response rate at week 52. Secondary end points were time to severe flare and reduction in corticosteroid dose (weeks 40–52). Safety was assessed throughout.ResultsOf the 836 patients in the intent‐to‐treat (ITT) population, 356 were hypocomplementemic and anti‐dsDNA positive at baseline (108 in the placebo group and 248 in the SC belimumab 200 mg group). Compared with placebo, the belimumab group contained more SRI‐4 responders (47.2% versus 64.6%; P = 0.0014), had a lower incidence of severe flare according to the SELENA‐SLEDAI flare index (31.5% versus 14.1%), and had a greater percentage of patients who reduced corticosteroid dosage by ≥25% to ≤7.5 mg/day during weeks 40–52 (11.4% versus 20.7%; P = 0.0844). Adverse events (AEs) were similar between treatment groups.ConclusionOur findings indicate that in hypocomplementemic, anti‐dsDNA–positive SLE patients, weekly SC belimumab 200 mg significantly improves SRI‐4 response, decreases severe flare incidence, and reduces corticosteroid use versus placebo; a trend toward greater benefit compared with the overall ITT population was observed. AEs were consistent with the known safety profile of belimumab.

A Novel System to Categorize the Symptoms of Systemic Lupus Erythematosus

“…Such symptoms tend to be chronic. Of note, belimumab, an anti-BAFF/B lymphocyte stimulator monoclonal antibody, may affect fatigue in SLE although it is unclear whether this reduction relates to downstream effects of this cytokine or a more generalized reduction in disease activity (26). The usual lack of responsiveness to immunosuppressive therapy may differ from that in rheumatoid arthritis and other forms of inflammatory arthritis, in which therapies such as tumor necrosis factor blockers can reduce fatigue, depression, and anxiety (22)(23)(24)(25).…”

“…The usual lack of responsiveness to immunosuppressive therapy may differ from that in rheumatoid arthritis and other forms of inflammatory arthritis, in which therapies such as tumor necrosis factor blockers can reduce fatigue, depression, and anxiety (22)(23)(24)(25). Of note, belimumab, an anti-BAFF/B lymphocyte stimulator monoclonal antibody, may affect fatigue in SLE although it is unclear whether this reduction relates to downstream effects of this cytokine or a more generalized reduction in disease activity (26). Because of their effects on HRQoL, type 2 symptoms can dominate in patient-reported outcomes and serve as determinants of both health status and quality of life (12,19,20).…”

Belimumab promotes negative selection of activated autoreactive B cells in systemic lupus erythematosus patients

“…The human anti-BAFF antibody belimumab is therapeutic for active systemic lupus erythematosus (SLE), especially in patients with high titers of anti-dsDNA antibodies and low serum levels of complement (19)(20)(21)(22)(23). Belimumab has modest and variable effects on anti-DNA antibody synthesis; however, it has not yet been shown in humans whether the basis of its therapeutic effect is an alteration in selection of either the naive or antigen-induced immunoglobulin repertoire.…”

Impact of Recent Clinical Trials on Nephrology Practice: Are We in a Stagnant Era?

“…The LUNAR study failed to demonstrate the superiority of adding rituximab to the standard MMF-plus-corticosteroid therapy in patients with active proliferative lupus nephritis [49]. In a recent double-blinded phase III trial, belimumab (a monoclonal antibody against B lymphocyte stimulator) significantly reduced proteinuria in moderate-to-severe systemic lupus erythematosus patients [50]. Furthermore, belimumab was well tolerated and its efficacy was maintained during the extension phase [51].…”