Objective To compare anti-Smith (aSm) seropositive and seronegative patients with systemic lupus erythematosus (SLE) in terms of treatment response indices and disease activity thresholds over a one-year treatment with belimumab.

Methods Pooled trial data from five clinical trials of belimumab (BLISS-52, BLISS-76, BLISS-Northeast Asia, EMBRACE, and BLISS-SC) were used for analysis. Seropositivity for aSm was defined according to baseline status, and participants without aSm data at baseline were excluded from analysis. Binary logistic regression models were conducted across four outcomes every fourth week from baseline, up to and including week 52: SLE Responder Index (SRI)-4, British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA), Lupus Low Disease Activity State (LLDAS), and Definitions Of Remission In SLE (DORIS) remission. Models were adjusted for trial variance.

Results Of the 3086 patients who received either belimumab in approved dose (N=1869) or placebo (N=1217), 1949 patients had data on aSm at baseline, three of which lacked data on SRI-4. Response according to the SRI-4 definition favoured belimumab in both aSm-negative (odds ratio [95% confidence interval]: 1.41 [1.13−1.76], p=0.002) and aSm-positive (1.69 [1.22−2.35], p=0.002) individuals at week 20 and 24, respectively, and response was sustained up to and including the 52-week landmark (p<0.05 for every subsequent timepoint). In contrast, BICLA response differed widely between subgroups, with aSm-negative individuals showing belimumab response at every timepoint (p<0.05, week 4 to week 52 inclusive), and aSm-positive individuals not showing a clear response at week 52 (1.35 [0.95−1.93], p=0.092). Analysis of disease states at week 52 showed that belimumab met the LLDAS (2.16 [1.59−2.93], p<0.001) and DORIS remission (1.49 [1.02−2.20], p=0.041) endpoints in the aSm-negative subgroup, but not in the aSm-positive one (LLDAS: 1.66 [0.98−2.82], p=0.062; DORIS remission: 1.46 [0.73−2.92], p=0.287).

Conclusion Although patients with SLE appear to benefit from belimumab irrespective of aSm serology status, presence of aSm signifies a patient subgroup that attains the target states LLDAS and DORIS remission to a lesser extent.

Acknowledgement IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia, Bristol Myers Squibb (BMS), Elli Lilly, Gilead, GlaxoSmithKline (GSK), Janssen, Novartis, Otsuka, and Roche. The other authors declare that they have no conflicts of interest related to this work. The funders had no role in the design of the study, the analyses or interpretation of data, or the writing of the manuscript.