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Objectives Selecting the right treatment for the right patient remains an elusive goal for patients with 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. 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 these two trials. BILAG persistent LDA is defined as no BILAG-2004 A/B scores in any organ system at 2-consecutive visits 4-weeks apart, with prednisone dose =<5mg/day (LDA5) or =<7.5mg/day (LDA7.5) at both visits, and stable immunosuppressant and hydroxychloroquine doses for the preceding 12-weeks.Results In BEAT-Lupus, patients with baseline IgA2 anti-dsDNA >=12.5AU showed a better response to combination therapy, increasing the overall percentage point difference (delta) from 13%-58%. 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 ( figure 1A). 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%-83%,p=0.0084) and onwards, reaching 56% (95%CI 19%-93%,p=0.0031) at 52-weeks (figure 1B). Whereas differences among the low IgA2 group were minimal except at 52-weeks, when more patients achieved LDA5 in the rituximab arm (delta-49%, 95%CI 13%-85%, p=0.0074; figure 1C). Similar results were also seen in LDA7.5 response.In time-to-event analysis, the time to severe-to-moderate flares was significantly delayed only in the high IgA2 anti-dsDNA group treated with belimumab (log-rank p=0.0481; figure 1D). No such difference was observed in the low IgA2group.Abstract PT2:08 Figure 1Conclusions These results underpin IgA2 anti-dsDNA as a theragnostic biomarker for predicting significant clinical responses to belimumab following rituximab therapy in 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).