Background/Purpose:  SRI is a composite endpoint designed to ensure that clinical improvement (measured by SLEDAI) is not accompanied by deterioration in other organ systems (measured by BILAG and PGA). This novel endpoint, coupled with trial completion and adherence to treatment rules, has defined response in many SLE trials. The current investigation sought to identify those components of the SRI that were critical to defining response. Additionally, individual organ systems were examined to determine those which impacted SLEDAI improvement.

Methods:  Data were analyzed from two large phase 3 multinational trials that evaluated the impact of an anti-BAFF antibody or placebo, when added to standard of care (SOC) on SLE disease activity using the SRI-5 endpoint (combined n=2262 SLE patients) (1,2).

Results: The overall SRI-5 response rate was 32.8% (743/2262). Non-response due to lack of a 5-point SLEDAI improvement, conmed violation or dropout were observed in 31% (702/2262), 16.5% (373/2262) and 19.1% (433/2262), respectively. In contrast, only 0.5% (7/2262) failed to meet responder criteria due to deterioration by BILAG or PGA after achieving ≥ 5 point reduction in SLEDAI, trial completion and adherence to concomitant medication rules. As expected,the predominant individual SLEDAI organ systems involved at baseline were mucocutaneous (90.6%), musculoskeletal (82.9%) and immunologic (71.6%) In the mucocutaneous organ system, the baseline prevalence of rash was 69.2%; alopecia 58.2%; mucosal ulcer 32.5%. In the musculoskeletal system, the baseline prevalence of arthritis was 82.6%; myositis 1.1% SLEDAI organ systems with low prevalence and high point value (≥ 4 pts/feature) were also examined. At baseline, 18.1% of patients in Trial 1 and 17.2% in Trial 2 had renal, vascular or CNS organ involvement. SRI-5 response rates for placebo + SOC were CNS: 66.7%, 57.1%; renal: 45.2%, 53.3%; and vascular: 56.7%, 48%, in Trials 1 and 2, respectively. SLEDAI improvement for the 4 most common individual features was examined in the placebo plus SOC population (analysis based on observed data). Response rate for arthritis: 58.4%, 66.5%; rash: 47.8%, 54.3%; alopecia: 43.1%, 48.4%; and mucosal ulcer 85.4%, 74.7% in Trials 1 and 2, respectively.

Conclusion: The primary drivers of SRI-5 response in these trials were SLEDAI improvement, concomitant medication adherence and trial completion, which have intrinsic clinical meaningfulness. When SLEDAI scores improved by ≥ 5 points at wk 52 in pts with stable SOC, worsening in other disease activity instruments was rare, making their contribution less relevant to the outcome of a trial. Patients with infrequent yet severe manifestations had high placebo group response rates. Thus, for clinical trials that are intended to study new therapeutics in SLE patients with non- major organ threatening disease manifestations, a simple, dichotomous improvement in SLEDAI score, coupled with successful trial completion and medication stability, may provide a simple and potentially more clinically relevant approach to assess outcome.

1. Merrill et al., Ann Rheum Dis (2016) 75:332-40.
2. Isenberg et al., Ann Rheum Dis (2016) 75:323-31

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/drivers-of-the-sle-responder-index-sri-endpoint-in-clinical-trials-of-sle/