COMPLEMENTARY LUPUS-SPECIFIC INDEXES INFORMED BY SELECT IMMUNE MEDIATORS CHARACTERIZE RISK OF CONCURRENT DISEASE ACTIVITY AND FUTURE IMPENDING FLARE IN SYSTEMIC LUPUS ERYTHEMATOSUS

PT002 / #417 Topic: AS09 - Emerging Approaches in SLE Management POSTER TOUR 01: CLINICAL OUTCOMES IN SLE 22-05-2025 10:00 AM - 10:40 AM Background/Purpose Systemic lupus erythematosus (SLE) is driven by immune dysregulation, with increased risk for heightened clinical disease activity and flare that lead to permanent end-organ damage, morbidity, and early mortality. Capturing immune dysregulation as lab-based screening tests would help prioritize SLE patients for early intervention. This study assesses the utility of employing a Lupus Flare Risk Index (L-FRI) and Lupus Disease Activity Index (L-DAI) in parallel to assess simultaneous risk of future disease flare and concurrent disease activity to guide therapy. Methods We assessed levels of 17 SLE-associated plasma mediators to calculate L-FRI and L-DAI scores in 80 preflare vs 76 prenonflare visits, as well as 49 flare vs 51 nonflare follow-up visits with available samples, from a unique cohort of prospectively followed SLE patients. Hybrid SLEDAI (hSLEDAI) scores, clinical features, medication usage, and the presence of SLE-associated autoantibody specificities, including dsDNA, chromatin, Ro/SSA, La/SSB, Sm, SmRNP, and RNP, were also compared. The L-FRI algorithm reflects the sum of 11 log-transformed, standardized immune mediators, weighted by the Spearman r correlation coefficient for each preflare (PF)/pre-nonflare (PNF) analyte vs subsequent hSLEDAI scores at the time of future flare/nonflare.[1,2] The L-DAI algorithm reflects the sum of 10 log-transformed, standardized immune mediators, weighted by the Spearman r correlation coefficient of each active (hSLEDAI ≥4)/low (hSLEDAI<4) disease activity analyte vs the composite of concurrent hSLEDAI scores and number of SLE-associated autoantibody specificities.[3] Results Forty of 80 (50%) preflare vs 24 of 76 (32%) pre-nonflare visits were associated with concurrent active disease (hSLEDAI≥4; p=0.0230 ). The L-FRI differentiated preflare vs pre-nonflare visits and subsequent flare vs nonflare visits, irrespective of disease activity state (Figure 1A), with severe flare visits present above the high-risk cut-off (decision curve analysis, [1,2]). The L-DAI differentiated concurrent active vs low (hSLEDAI<4) disease activity, irrespective of preflare/pre-nonflare or flare/nonflare status (Figure 1B), with renal manifestations present above the high-risk cut-off (decision curve analysis, [3]). All SLE groups had significantly higher L-FRI and L-DAI scores than demographically matched healthy Ctrl (n=71, p<0.0001 , Figure 1A,B). Plasma levels of BLyS (L-FRI, L-DAI), as well as L-FRI informing mediators MCP-3, TNFRI, and TNFRII were highest in preflare visits with concurrent active disease ( p<0.05 ), while IL-17A levels were highest in preflare visits with concurrent low disease activity ( p<0.05 ), Figure 1C. IL-7 (L-FRI, L-DAI) levels were increased with both flare and disease activity risk ( p<0.05 ), while L-DAI informing mediators IFN-α and IP-10 were highest in active disease, with preflare increased over pre-nonflare levels ( p<0.05 ), Figure 1C. Of interest, although the L-FRI and L-DAI performed well at assessing flare and disease activity risk, respectively (AUC>0.9), parallel assessment of L-FRI and L-DAI performed better than either alone to identify simultaneous risk of concurrent active disease and imminent flare risk, Table 1. Figure 1. Using Lupus Flare Risk Index (L-FRI, A ) and Lupus Disease Activity Index (L-DAI, B ) to evaluate combination of impending flare and concurrent disease activity risk. Select L-FRI and L-DAI informing mediators reflect flare and/or disease activity rsk (C) PF-Preflare; PNF=PreNonflare; Active (hSLEDAI≥4); Low (hSLEDAI<4); * p < 0.05 ; ** p < 0.01 , **** p < 0.0001 by Kruskal-Wallis test with Dunn’s multiple comparison. Table 1. Combination of L-FRI and L-DAI Tests Optimally Informs Future Flare and Concurrent Disease Activity Risk Conclusions The L-FRI used with the L-DAI optimally identified risk of imminent lupus disease flare and concurrent active disease, including severe flare and renal manifestations. A subset of mediators consistently enhanced the L-FRI and L-DAI tests to identify SLE patients who may benefit from early intervention strategies. Such an approach would improve disease management and be advantageous in prospective clinical trials for study participant recruitment and assessment. References: [1.] Munroe M. Arthritis Rheumatol 2023;75:723-5. [2.] Munroe M. Annal Rheum Dis 2024;83:402-3. [3.] Munroe M. Annal Rheum Dis 2024;83:19-20.