The Biomarkers of Lupus Disease Study: A Bold Approach May Mitigate Interference of Background Immunosuppressants in Clinical Trials

Abstract

Objective: Molecular medicine raised expectations for strategically targeted biologic agents in systemic lupus erythematosus (SLE), but clinical trial results have been disappointing and difficult to interpret. Most studies add investigational agents to various, often effective, standard therapy immunosuppressants used at baseline, with unknown treatment interactions. Eliminating polypharmacy in trials of active lupus remains controversial. We undertook the Biomarkers of Lupus Disease study to test withdrawal of immunosuppressants as a novel approach to rendering SLE trials interpretable.

Methods: In 41 patients with active, non-organ-threatening SLE flare (group A), temporary steroids were given while background immunosuppressants were withdrawn. Time to loss of disease suppression (time to disease flare) and safety were evaluated; standard therapy was immediately resumed when symptoms recurred. Immunologic impacts of standard therapy were studied at baseline by multiplex assay, enzyme-linked immunosorbent assay, and messenger RNA array in group A patients plus 62 additional patients donating a single sample (group B).

Results: Patients with lower or higher baseline disease activity had median times to flare of 71 or 45 days, respectively; 40 of 41 patients (98%) had disease flares by 6 months. All flares were treated and resolved within 6 weeks. No serious adverse events occurred from flare or infection. Type I interferon (IFN), Th17, and B lymphocyte stimulator pathways tracked together. Baseline immunosuppressants had distinct impacts on Th17 and B lymphocyte stimulator, depending on IFN signature.

Conclusion: Trials in active, non-organ-threatening SLE can safely withdraw background treatments if patients who have disease flares are designated nonresponders and returned to standard therapy. Immunologic effects of standard therapy vary between IFN-defined subsets. These findings provide a strategy for minimizing or optimizing treatment combinations in lupus trials and clinical care.

Trial registration: ClinicalTrials.gov NCT00987831.

© 2017, American College of Rheumatology.

Figures

Figure 1. Standardized disease activity measures at Baseline, Improving, and Flare Visits

Improving and Flare Visits in Group A were designated based on clinician’s opinion with minimal input from the (A) SLEDAI or (B) BILAG tool, and no input from the (C) PGA, (D) CLASI, or Joint Counts (see Supplementary Figure 1). All disease activity measures significantly decreased from Baseline to Improving Visit and significantly increased from Improving Visit to Flare Visit. Disease activity measures are defined in detail in the Methods section. Changes from Baseline to Improving Visit and from Improving to Flare Visit were evaluated using the nonparametric Wilcoxon’s rank sum test.

Figure 2. Time from Baseline to Flare Visit

Flare occurred in 40 of 41 Group A patients (97.6%) within six months of Baseline. (A) Time to flare was reduced in patients with high BILAG scores (≥17; n=16) compared to those with low BILAG scores (<17; n=25). (B) Time to flare was not distinctly different in patients receiving high (≥360 mg) total depomedrol vs those receiving low (≤240 mg) depomedrol. (C) Flare was significantly delayed in patients with low BILAG scores who received high depomedrol compared to patients with high BILAG scores who were treated with low depomedrol. (D) Time to flare was reduced in African-American patients compared to all others. Comparisons were made by Kaplan-Meier analysis and log-rank test.