Objective To assess the efficacy/safety of the B-lymphocyte stimulator inhibitor belimumab/standard-of-care (SOC) versus placebo/SOC in active systemic lupus erythematosus (SLE). Methods In a multicenter, randomized, controlled, phase 3 trial, 819 antinuclear antibody- or anti-dsDNA-positive SLE patients with Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) ≥ 6 were randomized (1:1:1 ratio) to receive intravenous belimumab 1 or 10 mg/kg, or placebo on days 0, 14, and 28, and then every 28 days for 72 weeks. Primary efficacy analyses: SLE Responder Index (SRI) at week 52 (≥ 4-point reduction in SELENA-SLEDAI; no new British Isles Lupus Assessment Group A and < 2 new B organ domain scores; no worsening in Physician’s Global Assessment). Results Belimumab 10 mg/kg plus SOC met the primary efficacy endpoint: significantly greater SRI response at week 52 than placebo (43.2% versus 33.5%; P = 0.017); the rate with belimumab 1 mg/kg was 40.6% (P = 0.089). Week-76 response rates: 32.4%, 39.1%, and 38.5% with placebo, and belimumab 1 and 10 mg/kg, respectively. In post-hoc sensitivity analyses evaluating higher SELENA-SLEDAI thresholds, belimumab 10 mg/kg achieved better discrimination at weeks 52/76. Risk of severe SELENA-SLEDAI flares over 76 weeks was reduced with belimumab 1 mg/kg (34%; P = 0.023) and 10 mg/kg (23%; P = 0.13). Serious and severe adverse events including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups. Conclusion Belimumab plus SOC significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well-tolerated in SLE.

Objective To determine whether serum levels of B lymphocyte stimulator (BLyS) are elevated in patients with systemic immune–based rheumatic diseases and correlate with serum Ig levels and/or autoantibody titers. Methods Sera from 185 patients with various systemic immune–based rheumatic diseases (95 with systemic lupus erythematosus [SLE], 67 with rheumatoid arthritis [RA], 23 with other diagnoses) were assayed for BLyS and Ig. In 7 patients who required arthrocentesis of a swollen knee, coincident serum and synovial fluid samples were assayed for BLyS. Medical charts were retrospectively reviewed for elevated autoantibody titers and proteinuria within a 1‐month period before or after collection of sera for BLyS and Ig determination. Sera concurrently collected from 48 normal healthy subjects served as controls. Results Serum BLyS levels were elevated in 38 of 185 patients (21%) and correlated significantly with serum IgG levels. Serum BLyS levels did not correlate with the patients' age, sex, race, or medications, but correlated positively with anti–double‐stranded DNA antibody titers among SLE patients and with rheumatoid factor titers among seropositive RA patients. In contrast, serum BLyS levels correlated inversely with nephrotic‐range proteinuria among SLE patients. In every case tested, BLyS levels in clinically inflamed synovial fluids were greater than those in simultaneously obtained sera. Conclusion BLyS may be an important factor in driving polyclonal hypergammaglobulinemia and elevated autoantibody titers in patients with systemic immune–based rheumatic diseases. Local production of BLyS in the joints may contribute to joint pathology. Patients with elevated serum BLyS levels may be ideal candidates for therapeutic targeting of BLyS.

Objective. To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE). Methods. Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score >4 (n ‫؍‬ 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52-week study. Coprimary end points were the percent change in the SELENA-SLEDAI score at week 24 and the time to first SLE flare. Results. Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA-SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24 -52 was significantly longer with belimumab treatment (154 versus 108 days; P ‫؍‬ 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer >1:80 and/or anti-double-stranded DNA [anti-dsDNA] >30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA-SLEDAI score (؊28.8% versus ؊14.2%; P ‫؍‬ 0.0435), physician's global assessment (؊32.7% versus ؊10.7%; P ‫؍‬ 0.0011), and Short Form 36 physical component score (؉3.0 versus ؉1.2 points; P ‫؍‬ 0.0410). Treatment with belimumab resulted in a 63-71% reduction of naive, activated, and plasmacytoid CD20؉ B cells, and a 29.4% reduction in anti-dsDNA titers (P ‫؍‬ 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups. Conclusion. Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

Objective. To assess the overexpression of B lymphocyte stimulator (BLyS) over time in patients with systemic lupus erythematosus (SLE).Methods. Sixty-eight SLE patients were followed up longitudinally for a median 369 days. At each physician encounter, disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index, and blood was collected for determination of the serum BLyS level, blood BLyS messenger RNA (mRNA) level, and cell surface BLyS expression. Twenty normal control subjects underwent similar laboratory evaluations.Results. In contrast to the uniformly normal serum BLyS and blood BLyS mRNA phenotypes in control subjects, SLE patients displayed marked heterogeneity, with 50% and 61% of patients manifesting persistently or intermittently elevated serum BLyS and blood BLyS mRNA phenotypes, respectively. Surface BLyS expression by SLE peripheral blood mononuclear cells was also often increased. Treatment of patients who had elevated serum BLyS levels with intensive courses of high-dose corticosteroids resulted in marked reductions in serum BLyS levels, and tapering of the corticosteroid dosage often resulted in increases in serum BLyS levels. Serum BLyS levels generally correlated with anti-double-stranded DNA (anti-dsDNA) titers (in those with detectable anti-dsDNA titers), but changes in serum BLyS levels did not correlate with changes in disease activity in individual patients. Serum BLyS phenotype did not associate with specific organ system involvement.Conclusion. Dysregulation of BLyS over extended periods of time is common in patients with SLE. Neutralization of BLyS activity with an appropriate BLyS antagonist may be therapeutically beneficial.