Biomarker-stratified efficacy and safety of biologics in systemic lupus erythematosus: a systematic review and meta-analysis.

OBJECTIVE

Biologics for systemic lupus erythematosus (SLE) demonstrate variable treatment responses across trials. We evaluated baseline biomarkers as predictors of response to guide personalised therapy selection.

METHODS

We searched PubMed, OVID, Scopus, Cochrane and PsycInfo (January 2000-October 2025) for randomised controlled trials (RCTs) evaluating biologics (anti-BAFF, JAK inhibitors, anti-interferon, anti-IL-12/23, BTK inhibitors and T-cell modulators) in adult SLE patients. Primary outcomes included SLE Responder Index-4 response and time-to-flare. We performed random-effects meta-analysis stratified by interferon gene signature (IGS), serologic activity (anti-double-stranded DNA positivity and/or low complement) and high disease activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) ≥10), with false discovery rate correction for multiple comparisons.

RESULTS

Thirty-one RCTs (17 374 participants) were included. Overall, biologics improved SLE Responder Index-4 response versus control (risk ratio (RR) 1.26, 95% CI 1.19 to 1.33, p <0.0001). Serologically active disease showed the strongest predictive value (RR 1.45, 95% CI 1.28 to 1.63, p<0.0001, I²=0%, number needed to treat (NNT)=6.5). High baseline SLEDAI ≥10 also predicted response (RR 1.22, 95% CI 1.13 to 1.32, I²=0%). IGS showed non-significant trends (RR 1.39, 95% CI 0.97 to 2.00, p=0.074, I²=68.5%). Efficacy varied by mechanism, with anti-BAFF agents showing consistent benefit (RR 1.35, 95% CI 1.26 to 1.45). Biologics reduced serious adverse events (SAE) (RR 0.90, p=0.009); this should be interpreted considering lupus flares contribute to SAE counts. Individual non-disease adverse events showed expected patterns, with herpes zoster significantly increased (RR 1.19, p=0.017).

CONCLUSION

Serologically active disease and high baseline disease activity significantly predict biologic therapy response with zero heterogeneity, while IGS showed inconsistent predictive value. These findings support using serological markers to guide biologic selection in real-world practice settings. Biologics demonstrate favourable safety profiles.

PROSPERO REGISTRATION NUMBER: CRD420251247531.