Sub-Setting Systemic Lupus Erythematosus by Combined Molecular Phenotypes Defines Divergent Populations in Two Phase III Randomized Trials.

OBJECTIVES Heterogeneity of systemic lupus erythematosus (SLE) patients in clinical trials remains a challenge for developing new therapies. This study used a combinatorial analysis of four molecular biomarkers to define key sources of heterogeneity. METHODS Combinations of IFN(high/low), anti-dsDNA(+/-), C3 and C4(low/normal) were used to subset n = 1747 patients from two randomized phase 3 trials. A dichotomous classification scheme defined SLE(+) as: IFNhigh, anti-dsDNA(+), C3(low) and/or C4(low). SLE(-) required all of the following: IFNlow, anti-dsDNA(-), C3(normal) and C4(normal). Additional analyses subset the data further by IFN, anti-dsDNA and complement. RESULTS The trials enrolled n = 2262 patients of which n = 1747 patients had data for IFN, anti-dsDNA, C3 and C4 at baseline. There were n = 247 patients in the SLE(-) population and n = 1500 patients in the SLE(+) population. The SLE(-) population had more mucocutaneous and musculoskeletal disease at baseline, while SLE(+) had more hematologic, renal and vascular involvement. There was lower concomitant medication use in the SLE(-) population for corticosteroids and immunosuppressants, except for methotrexate. Time to severe flare was significantly longer in SLE(-) vs SLE(+) (p < 0.0001) and SRI-4 response rate was significantly lower in SLE(-) vs SLE(+) (p = 0.00016). The United States had more SLE(-) patients (22%) than Mexico/Central America/South America (10%), Europe (7%) and the rest of the world (5%). CONCLUSION Combinatorial analysis of 4 molecular biomarkers revealed subsets of SLE patients that discriminated by disease manifestations, concomitant medication use, geography, time to severe flare and SRI-4 response. These data may be useful for designing clinical trials and identifying subsets of patients for analysis.