P161 Serum IgA2 anti-dsDNA as a theragnostic biomarker for low disease activity with belimumab after rituximab therapy in systemic lupus erythematosus

Background/Aims Selecting the right treatment for the right patient remains an elusive goal for patients with systemic lupus erythematosus (SLE). We have identified a theragnostic biomarker for response to belimumab following rituximab, IgA2 anti-DNA antibodies, from two independent clinical trials: BEAT-lupus and CALIBRATE both comparing belimumab after rituximab vs. rituximab alone. We further evaluated its potential as effect modifier of response and low disease activity (LDA). Methods Treatment-response-biomarker interactions were evaluated through both conventional statistics and Bayesian posterior probability analysis using data from the BEAT-lupus and CALIBRATE trials. BILAG persistent LDA is defined as no BILAG-2004 Grade A or B scores in any organ system at 2 consecutive visits 4 weeks apart (all organ systems scored as C, D, or E), with prednisone dose ≤5 mg/day (LDA5) or ≤ 7.5 mg/day (LDA7.5) at both visits, stable immunosuppressant dose for the preceding 12 weeks, and stable hydroxychloroquine dose for the preceding 4 weeks Results In BEAT-Lupus, patients with baseline IgA2 anti-dsDNA ≥ 12.5 AU showed a better response to combination therapy, increasing the percentage point difference (delta) to 58%, in contrast to 13% of overal delta. This association was independently validated in the CALIBRATE trial, which showed a similar improvement in response. Bayesian posterior probability analysis, combining data from both trials, yielded a striking 99.1% probability of clinical benefit from adding belimumab in IgA2-high patients—exceeding the 95% threshold for strong evidence. Conversely, in IgA2-low patients, rituximab monotherapy had ∼95% probability of superior response. The proportion of patients achieving BILAG LDA5 was significantly greater in the high IgA2 anti-dsDNA group at week 36 (delta 47%, 95%CI 12% to 83%, p = 0.0084) and onwards, reaching 56% (95% CI 19% to 93%, p = 0.0031) at 52 weeks. Whereas differences among the low IgA2 group were minimal except at week 52, when more patients achieved LDA5 in the rituximab arm (delta 49%, 95%CI 13% to 85%, p = 0.0074). Similar results were also seen in LDA7.5 response, which showed a significantly higher proportion of patients achieving LDA7.5 in the high IgA2 anti-dsDNA group from week 40, reaching 56% (95% CI 14% to 98%, p = 0.0089) in belimumab-treated patients. More patients achieved LDA7.5 response in the rituximab group at 52 weeks (61%, 95% CI 24% to 98%, p = 0.0012).In time-to-event analysis, the time to severe flare was significantly delayed only in the high IgA2 anti-dsDNA group treated with belimumab (log-rank p = 0.0481). No such difference was observed in the low IgA2 group. Conclusion These results underpin IgA2 anti-dsDNA as a theragnostic biomarker for achieving low disease activity with belimumab following rituximab therapy for SLE. These findings provide a feasible enrichment strategy that has directly informed the design of the first biomarker-enriched, double-blind, placebo-controlled RCT in SLE, which is set to commence recruitment in 2026 (STRATIFY-lupus trial). Disclosure M. Shipa: Corporate appointments; NA. Consultancies; NA. Shareholder/stock ownership; NA. Royalties; NA. Honoraria; NA. Member of speakers’ bureau; NA. Grants/research support; LUPUS UK. Other; NA. C. Beesley: None. L. Cooney: None. M. Ehrenstein: Grants/research support; Lupus UK, NIHR, GSK.