Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response

Abstract

Objectives: To identify factors that predict response to belimumab treatment in the phase 3 BLISS trials of autoantibody-positive systemic lupus erythematosus (SLE) and further analyse clinical efficacy in various patient subsets.

Methods: The BLISS trials compared belimumab 1 and 10 mg/kg versus placebo, all plus standard SLE therapy, over 52 or 76 weeks. Pooled subgroup analyses of week 52 SLE responder index rates (the primary endpoint in both trials) were performed based on demographic characteristics and baseline disease activity indicators. Pooled multivariate analysis was performed to determine predictors of response and treatment effect.

Results: Pooled univariate and multivariate analyses (N=1684) identified baseline factors associated with an increased benefit of belimumab versus placebo. These factors included the Safety Of Estrogens In Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) ≥10, low complement, anti-dsDNA positivity and corticosteroid use. Efficacy outcomes were assessed in the low complement/anti-dsDNA-positive and SELENA-SLEDAI ≥10 subgroups. Week 52 SLE Responder Index rates in the low complement/anti-dsDNA-positive subgroup were 31.7%, 41.5% (p=0.002) and 51.5% (p<0.001) with placebo and belimumab 1 mg/kg and 10 mg/kg, respectively; corresponding rates in the SELENA-SLEDAI ≥10 subgroup were 44.3%, 58.0% (p<0.001) and 63.2% (p<0.001). Further analysis of secondary endpoints in the low complement/anti-dsDNA-positive subgroup showed that compared with placebo, belimumab produced greater benefits regarding severe flares, corticosteroid use and health-related quality of life.

Conclusions: These findings suggest that belimumab has greater therapeutic benefit than standard therapy alone in patients with higher disease activity, anti-dsDNA positivity, low complement or corticosteroid treatment at baseline. CLINICALTRIALS.GOV: identifiers NCT00424476 and NCT00410384.

Figure 1

OR for SLE Responder Index rates in univariate disease activity subgroup analysis. Horizontal lines are 95% CI. Vertical dashed reference lines represent OR of 1, which indicates no difference between belimumab and placebo, while points to right of lines indicate higher responses for belimumab versus placebo and points to left of line indicate lower responses for belimumab versus placebo. Point estimates for OR for overall treatment effect (coloured solid vertical lines) are 1.41 for belimumab 1 mg/kg and 1.68 for 10 mg/kg. *Interaction p<0.1. C, complement; SELENA–SLEDAI, Safety Of Estrogens In Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index.

Figure 2

Systemic Lupus Erythematosus Responder Index rates in (a) pooled low complement/anti-dsDNA-positive subgroup (n=876), (b) pooled low complement/anti-dsDNA-positive subgroup with analysis excluding serology (n=876) and (c) low complement/anti-dsDNA-positive subgroup in BLISS-76 (n=390). *p<0.05; ⁺p<0.01; ^#p<0.001.

Figure 3

BLISS trial secondary endpoints in pooled low complement/anti-dsDNA-positive subgroup. (a) Proportions of patients with reduction in corticosteroid dose to 7.5 mg/day or less in patients receiving more than 7.5 mg/day at baseline (n=556). (b) Proportions of patients with increase in corticosteroid dose to more than 7.5 mg/day in patients receiving 7.5 mg/day or less at baseline (n=320). (c) Time to first severe flare (n=876). Hazard ratio (95% CI; p value) versus placebo: 0.67 (0.48–0.94; 0.02) for belimumab 1 mg/kg and 0.61 (0.44–0.85; 0.004) for belimumab 10 mg/kg. (D) Mean change in Functional Assessment Of Chronic Illness Therapy (FACIT)–Fatigue score (n=858). SLE, systemic lupus erythematosus. *p<0.05; ⁺p<0.01; ^#p<0.001.