Stratifying patients by TNFSF13B genotype revealed increased flare and renal flare risk, but a greater benefit from belimumab: a potential biomarker for personalized treatment in systemic lupus erythematosus

Objective: To examine whether SLE patients carrying the TNFSF13B variant (BAFF-var) differ in the risk of overall and renal flares and the benefits from belimumab. Methods: This retrospective study analyzed data from a monocentric cohort of Sardinian SLE patients between January 2006 and December 2022. We recorded demographic, clinical, serological, and treatment variables. A flare was defined as a new SLE manifestation or worsening of an existing one that required a change in therapy. Renal flares, categorized as nephritic or nephrotic, were recorded. Soluble B-cell activating factor (sBAFF) levels were evaluated in patients naïve to any treatment. We used Kaplan-Meier curves, Cox regression, and Poisson regression to investigate the association between BAFF-var and flares. Results: Among 233 screened patients, 194 (89.2 % female, 61.3 % BAFF-var carriers) were included. The mean age was 41.1 (±14.8) years, and the mean number of follow-up visits was 17 (±8). sBAFF levels increased according to BAFF-var genotype (p < 0.001). BAFF-var was significantly associated with an increased risk of flares (HR 1.5 per copy variant; 95 %CI 1.2–2.0; p = 0.002), and the frequency of flares (IRR 1.3 per copy variant; 95 %CI 1.1–1.6; p = 0.009). In 38 biopsy-confirmed lupus nephritis patients, the BAFF-var was associated with a higher risk of renal flare (HR 9.3; 95 %CI 1.7–49.5; p = 0.008). In 35 relapsing-remitting patients, belimumab reduced both the risk and frequency of flares, with higher effectiveness in patients carrying the BAFF-var (HR 0.12; 95 %CI 0.02–0.58; p = 0.009). Conclusions: Pending further validation, BAFF-var may serve as a predictive and prognostic biomarker for personalized treatment in SLE.