A LUPUS FLARE RISK INDEX INFORMED BY SELECT ADAPTIVE AND TNF SUPERFAMILY IMMUNE MEDIATORS: VALIDATION IN A CONFIRMATORY COHORT

Background: SLE is marked by immune dysregulation linked to pathogenesis, clinical disease activity, and flare. Capturing immune dysregulation prior to clinical disease flare onset may provide a window for early intervention to decrease flare frequency and severity. Objectives: This study seeks to validate a recently refined Lupus Flare Risk Index (L-FRI)[ 1 ] that reflects altered immunity prior to clinical disease flare using a unique confirmatory cohort of SLE patients. Methods: The L-FRI is the sum of log-transformed, standardized immune mediators, weighted by the Spearman r correlation coefficient for each pre-flare/pre-nonflare analyte vs. subsequent flare/nonflare hSLEDAI[ 2 ] disease activity (flare is defined by the SELENA-SLEDAI Flare Index[ 3 ]). SLE-associated plasma mediators (n=11) were evaluated by microfluidic immunoassay in 52 pre-flare (105 ± 62 days prior to flare) and 52 pre-nonflare (105 ± 55 days prior to nonflare) samples from patients with classified SLE in this validation cohort. Hybrid SLEDAI (hSLEDAI) scores, clinical features, medication usage, and the presence of SLE-associated autoantibody (AutoAb) specificities, including dsDNA, chromatin, Ro/SSA, La/SSB, Sm, SmRNP, and RNP, were also compared at pre-flare vs. pre-nonflare time points. Data from this validation cohort were compared to development and combined development/validation cohorts. Results: This validation (Val) cohort is enriched for African American (AA) SLE patients (44% pre-flare, 48% pre-nonflare vs. 11% pre-flare, 15% pre-nonflare in the development [Dev] cohort), with an associated increase in pre-flare hSLEDAI scores (4.0±3.4 preflare, 1.9±2.2 pre-non-flare, p=0.0004 [Val] vs. 2.4±2.6 pre-flare, 2.8±3.8 pre-nonflare, p=0.8953 [Dev]). Otherwise, after adjusting for multiple comparison, we did not observe differences with respect to clinical features, medication usage, or number and type of SLE-associated AutoAbs in pre-flare vs. pre-nonflare samples. The L-FRI, informed by 11 mediators ( Figure 1A ), significantly ( p<0.0001 ) differentiated pre-flare vs. pre-nonflare samples ( Figure 1B ), with low, moderate, and high flare risk cut-offs identified by decision curve analysis. The inclusion of 11 mediators in the L-FRI allowed for varied differences between pre-flare vs. pre-nonflare across cohorts ( Figure 1C-E ), yet with consistent differences in osteopontin, TNFRII, TNFRI, and TNF-α. The performance of the L-FRI in the Val cohort was similar to that of the Dev and combined (Com) cohorts, with a large (>0.8) Cohen’s effect size, AUC>0.7 ( p≤0.0003 ), and Spearman r ≥0.399 ( p<0.0001 ) vs. hSLEDAI scores at disease flare/nonflare ( Figure 2 ). Furthermore, the L-FRI differentiated SLE patients at risk of imminent severe (S) and mild-moderate (M/M) flares vs. nonflare ( Figure 2 ), with increased L-FRI scores ( p≤0.05 ), effect size (≥1.3), and AUC (≥0.843, p≤0.0002 ) in pre-severe flare samples across the Val, Dev, and Com cohorts ( Figure 2 ). Conclusion: The L-FRI identified SLE patients at low, moderate, and high risk of imminent lupus disease flare across development and validation cohorts. Of particular interest is the ability of the L-FRI to differentiate future M/M vs. severe flare risk. A subset of 11 mediators spanning varied immune pathways consistently improved the L-FRI to identify SLE patients who may benefit from early intervention strategies. Such an approach would be advantageous in prospective clinical trials for study participant recruitment and assessment, as well as improved management of lupus. REFERENCES: [1] M. E. Munroe et al. , A Flare Risk Index Informed by Select Immune Mediators in Systemic Lupus Erythematosus. Arthritis & rheumatology 75 , 723-735 (2023). [2] A. Thanou et al. , Impact of heart rate variability, a marker for cardiac health, on lupus disease activity. Arthritis Res Ther 18 , 197 (2016). [3] J. P. Buyon et al. , The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med 142 , 953-962 (2005). Acknowledgements: This study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of General Medicinal Sciences, and the National Center for Research Resources of the National Institutes of Health under award numbers M01RR001070 (DLK), P50AR070591 (JPB), R01AR077518 (HZ), R44AI142967 (MEM), P30AR073750 (JAJ), UM1AI144292 (JAJ), and U54GM104938 (JAJ), as well as Oklahoma Center for the Advancement of Science and Technology under award numbers AR16-014 (MEM) and AR18-019 (EJ).The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Disclosure of Interests: Melissa E Munroe Progentec Diagnostics, Inc. (part-time employee), Progentec Diagnostics, Inc., Derek Blankenship Progentec Diagnostics, Inc., Daniele DeFreese Progentec Diagnostics, Inc., Adrian Holloway Progentec Diagnostics, Inc., Mohan Purushothaman Progentec Diagnostics, Inc., Wade DeJager: None declared, Susan Macwana: None declared, Joel M Guthridge: None declared, Stan Kamp: None declared, Nancy Redinger: None declared, Teresa Aberle: None declared, Eliza F Chakravary: None declared, Cristina Arriens AstraZeneca, Aurinia, AstraZeneca, Bristol-Meyers Squibb, Cabaletta, GSK, Kezar, UCB, AstraZeneca, Bristol-Myers Squibb, Yanfeng Li: None declared, Hu Zeng: None declared, Stephanie Dezzutti: None declared, Peter Izmirly: None declared, Uma Thanarajasingam: None declared, Diane L. Kamen: None declared, Jill P Buyon Bristol-Myers Squibb, GSK, Related Sciences, Judith A. James GSK, Novartis, Bristol-Myers Squibb, Progentec Diagnostics, Inc., Eldon Jupe Progentec Diagnostics, Inc. DOI: 10.1136/annrheumdis-2024-eular.4561 Keywords: Innate immunity, Diagnostic test, Prognostic factors, Biomarkers, Adaptive immunity Citation: , volume 83, supplement 1, year 2024, page 402Session: Clinical Poster Tours: Facets of Systemic lupus (Poster Tours)

Innate immunity, Diagnostic test, Prognostic factors, Biomarkers, Adaptive immunity