2055: SRI-4 and BICLA: How Well Do They Agree Across Trials of Active Systemic Lupus Erythematosus?

Alfredo Aguirre¹, Mimi Kim², Kosalaram Goteti³, Ying Li³, Amy Kao⁴, Nathalie Franchimont⁵, George Kong⁵, Catherine Barbey⁶, Qing Zuraw⁷, Robert Gordon⁷, David Manner⁸, Maria Silk⁹, Teodora Staeva¹⁰, Hoang Nguyen¹¹, Richard Furie¹², Matthew Linnik¹³ and Maria Dall'Era¹⁴, ¹University of California, San Francisco, San Francisco, CA, ²Albert Einstein College of Medicine, Larchmont, NY, ³EMD Serono, Boston, MA, ⁴EMD Serono, Billerica, MA, ⁵Biogen, Cambridge, MA, ⁶Biogen, Baar, Switzerland, ⁷Janssen Research and Development, LLC, Spring House, PA, ⁸Eli Lilly and Company, Indianapolis, IN, ⁹Eli Lilly, Carmel, IN, ¹⁰Lupus Research Alliance, New York, NY, ¹¹Lupus Research Alliance, Houston, TX, ¹²Northwell Health, Great Neck, NY, ¹³Eli Lilly and Company, San Diego, CA, ¹⁴University of California, Division of Rheumatology, San Francisco, CA

Background/Purpose: The Systemic Lupus Erythematosus Responder Index 4 (SRI-4) and the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) are currently the most common primary endpoints in systemic lupus erythematosus (SLE) randomized-controlled trials (RCTs). However, discordance between SRI-4 and BICLA effect sizes in studies has engendered skepticism about the utility of these composite indices. In this post-hoc analysis of data from six RCTs of non-renal SLE, we examined concordance and discordance in the SRI-4 and BICLA outcome measures among placebo recipients, and explored reasons for SRI-4/BICLA nonresponse.

Methods: Placebo data from SLE RCTs of 24- or 52-week duration that collected the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and BILAG 2004 Index were included. Participants in each study were classified as either a responder or nonresponder by the SRI-4 and BICLA composite indices, and frequencies of concordance and discordance between the SRI-4 and BICLA were determined. Overall agreement between SRI-4 and BICLA was estimated by Cohen's kappa. For each participant, the leading reason for nonresponse by the SRI-4 and BICLA was identified by the following hierarchical order: concomitant medication violation; study withdrawal; lack of improvement by SLEDAI or BILAG, respectively; worsening disease by BILAG; worsening disease by SLEDAI (as a criterion for BICLA nonresponse); and worsening physician global assessment.

Results: Five of six RCTs had a requirement for minimum total or clinical SLEDAI score at entry (Table 1). Four trials had primary endpoints of SRI-4 or SRI-5, and all had steroid dose limits at baseline. Placebo response rates ranged from 29-48% with SRI-4 as the outcome and 28-45% with BICLA as the outcome. As shown in Figure 1, SRI-4 and BICLA concordance varied by clinical trial with a Cohen's kappa ranging from 0.39-0.76. Within trials that provided data at both timepoints, agreement of SRI-4 and BICLA was higher at 52 weeks than at 24 weeks. The three most common reasons for SRI-4 and BICLA nonresponse were lack of SLEDAI or BILAG improvement, respectively, study withdrawal, or concomitant medication violation (Figure 2).

Conclusion: Discordance between the SRI-4 and BICLA varied by clinical trial, ranging from 11.8-30.3%, with SRI-4 classifying more responders than the BICLA. Nonresponse to SRI-4 and BICLA was largely due to lack of clinical improvement by the SLEDAI or BILAG, respectively, study withdrawal, or concomitant medication violation. The remaining components of the SRI-4 and BICLA provided minimal impact to nonresponder frequencies. Further research will identify the specific factors associated with SRI-4 and BICLA discordance.
Table 1: Summary of the SLE RTCs and their respective SRI-4 and BICLA responses among the placebo groups

Figure 1: Concordance between SRI-4 and BICLA outcomes among placebo recipients of each clinical trial.

Figure 2: Reasons for SRI-4 and BICLA nonresponse among placebo recipients, by clinical trial. 2A) Reasons for SRI-4 nonresponse. 2B) Reasons for BICLA nonresponse. SLEDAI: Systemic Lupus Erythematosus Disease Activity Index. BILAG: British Isles Lupus Assessment Group Index. PGA: Physician Global Assessment.
Disclosures: A. Aguirre, None; M. Kim, None; K. Goteti, EMD Serono; Y. Li, EMD Serono; A. Kao, EMD Serono, Billerica, MA, USA; N. Franchimont, Biogen, OMass Therapeutics, Alexion (spouse), AstraZeneca (spouse); G. Kong, None; C. Barbey, Biogen; Q. Zuraw, Janssen Research & Development, LLC; R. Gordon, Janssen Research & Development, LLC; D. Manner, Eli Lilly; M. Silk, Eli Lilly; T. Staeva, None; H. Nguyen, None; R. Furie, AstraZeneca, Biogen; M. Linnik, Eli Lilly; M. Dall'Era, GlaxoSmithKline (GSK), AstraZeneca, Aurinia, BMS, Amgen.