POS1109 EVALUATING THE CONCORDANCE BETWEEN SRI-4 AND BICLA IN THE EXPLORER AND ATHOS TRIALS IN ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: A. Askanase, E. M. Vital, O. Meier, A. Turchetta, H. A. Mao, J. Maller, J. A. Ross Terres, M. Dall’era
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Systemic Lupus Erythematosus Responder Index 4 (SRI-4) and British Isles Lupus Assessment Group (BILAG)–based Composite Lupus Assessment (BICLA) responses are the most common primary endpoints in systemic lupus erythematosus (SLE) randomized controlled trials (RCTs). Discordance between SRI-4 and BICLA effect sizes in RCTs has engendered skepticism about the utility of these composite indices. <h3>Objectives:</h3> In this post hoc analysis of 2 SLE RCTs, we examined concordance in SRI-4 and BICLA outcome measures among participants receiving placebo and standard of care (SOC) and explored reasons for SRI-4 and BICLA discordance. <h3>Methods:</h3> This analysis included data from participants on SOC with evaluable BICLA and SRI-4 response enrolled in the placebo arms of the EXPLORER (n=87; NCT00137969)1 and ATHOS (n=80; NCT02908100)2 RCTs. SRI-4 and BICLA data from Weeks 24 and 52 in EXPLORER and Weeks 24 and 48 in ATHOS were analyzed. Both RCTs had the entry criterion of an SLE Disease Activity Index (SLEDAI) score of ≥6. The trials applied 2 different corticosteroid taper protocols: EXPLORER had an oral corticosteroid target dose of prednisone (or equivalent) of ≤10 mg/d by Week 12 and ≤5 mg/d by Week 52, and ATHOS had a target of &lt;10 mg/d by Weeks 12 and 36. Disease activity was measured using BILAG and SELENA-SLEDAI in EXPLORER and BILAG-2004 and SLEDAI-2K in ATHOS. For this analysis, participants were classified as either responders or nonresponders based on the SRI-4 and BICLA composite indices, as well as the presence of an intercurrent event, and concordance and discordance frequencies between SRI-4 and BICLA were determined. Overall concordance between SRI-4 and BICLA was estimated by the Cohen κ score. <h3>Results:</h3> In EXPLORER, SRI-4 placebo response rates were greater than BICLA response rates, whereas in ATHOS, SRI-4 and BICLA placebo response rates were similar (Figure 1). Across both trials, SRI-4 and BICLA placebo responses ranged from 40.2% to 45.0% and 29.9% to 47.5%, respectively. At Weeks 24 and 48/52, SRI-4 and BICLA concordance was 0.43 and 0.46 in EXPLORER and 0.60 and 0.54 in ATHOS, respectively (Figure 2). Discordance between SRI-4 and BICLA varied by trial (range, 25.3%-26.4% in EXPLORER and 20.0%-22.5% in ATHOS). In EXPLORER, SRI-4+/BICLA− discordance was high at 18.4% at Week 52. In ATHOS, the low SRI-4+/BICLA− discordance of 12.5% was in line with the similar SRI-4 and BICLA responses at Week 48. <h3>Conclusion:</h3> Discordance between SRI-4 and BICLA in the EXPLORER and ATHOS trials varied, with the largest difference found in SRI-4 and BICLA placebo responders at Week 52 in EXPLORER; however, the trials cannot be directly compared due to differences in the use of rescue therapies and variants of instruments used. Potential reasons for discordance within studies warranting further evaluation include differences in how domain-specific changes are captured in the SLEDAI and BILAG instruments, especially with regard to the musculoskeletal, mucocutaneous and serologic domains. While BILAG does not capture any immunologic changes (eg, low complement or elevated anti–double-stranded DNA antibody), it does enable capture of partial improvement in each domain, whereas the SLEDAI instruments only permit a binary (present or absent) response for each disease manifestation. As such, BICLA has the advantage over SRI-4 in better detecting partial—but clinically meaningful—changes in SLE disease activity. Evaluating patient-level data inclusive of patient-reported outcomes may also provide insights into the reasons for the SRI-4+/BICLA− discordance. <h3>REFERENCES:</h3> [1] Merril JT, et al. <i>Arthritis Rheumatol</i>. 2010;62(1):222-233. [2] Isenberg D, et al. <i>Arthritis Rheumatol</i>. 2021;73(10):1835-1846. <h3>Acknowledgements:</h3> Funded by F. Hoffmann-La Roche Ltd. Editorial assistance was provided by Nucleus Global and funded by F. Hoffmann-La Roche Ltd. <h3>Disclosure of Interests:</h3> Anca Askanase has been an investigator and/or consultant for AbbVie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly and Company, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer and UCB, Edward M. Vital has received consulting fees from Roche/Genentech, AstraZeneca, Otsuka, Novartis, Eli Lilly and Company, Pfizer, Merck, AbbVie and UCB., Oliver Meier is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Armando Turchetta is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Huiyan (Ashley) Mao is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Justine Maller is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of Genentech, Inc, Jorge A. Ross Terres is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of Genentech, Inc, Maria Dall'Era reports professional services for Genentech, Aurinia, GSK, AstraZeneca and Eli Lilly and Company.