The Biomarkers of Lupus Disease Study (BOLD)

Objectives: Molecular medicine raised expectations for strategically targeted biologics in systemic lupus erythematosus (SLE), but clinical trials have been disappointing and difficult to interpret. Most studies add investigational agents to various, often effective, standard of care (SoC) immunosuppressants used at baseline, with unknown treatment interactions. Eliminating polypharmacy in trials of active lupus patients remains controversial. The BOLD study tested immunosuppressant withdrawal as a novel approach to interpretable SLE trials. 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non-organ threatening SLE flare (Group A), temporary steroids were given while background immunosuppressants were withdrawn.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 (“flare”) and safety were evaluated; SoC was immediately resumed when symptoms recurred. Immunologic impacts of SoC treatments were studied at baseline by multiplex assay, ELISA, and mRNA array in Group A plus 62 additional patients donating a single sample (Group B). Results: Patients with lower or higher baseline disease had median times-to-flare of 71 or 45 days, respectively; 98% (40/41) flared by six months. All flares were treated and resolved within six weeks. No serious adverse events occurred from flare or infection. Type I interferon, TH17, and BLyS pathways tracked together. Baseline immunosuppressants had distinct impacts on TH17 and BLyS, depending on interferon signature. Conclusion: Trials in active, non-organ-threatening SLE can safely withdraw background treatments if patients who flare are designated non-responders and returned to SoC. Immunologic effects of SoC vary between interferon-defined subsets. These findings provide a strategy for minimizing or optimizing treatment combinations in lupus trials and clinical care. This series of samples comprises mRNA from whole blood, assayed using Taqman Low Density Arrays (Applied Biosystems, Grand Island, NY USA). Subjects included SLE patients (Group A and B) and Healthy Volunteers (Group C).