Early Changes in B and Plasma Cell Subsets and Traditional Serological Markers as Predictors of SRI-4 Response to Therapy in Systemic Lupus Erythematosus

OBJECTIVE: With the premise of the hypothesis that early biological responses to therapy for active systemic lupus erythematosus (SLE) portend later clinical improvements, we studied changes in B cell subsets and traditional serological markers in relation to clinical response to standard therapy (ST) with or without the addition of belimumab. PATIENTS AND METHODS: We analyzed data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials (N = 1712). Circulating CD19(+) B cell subsets were determined by flow-cytometry. We studied associations of relative to baseline percentage changes in circulating B and plasma cell subsets, anti-dsDNA antibody levels and complement levels with SLE Responder Index (SRI)-4 response after 52 weeks of treatment. Changes occurring through week 8 were deemed “rapid,” through week 24 “early,” and thereafter “delayed”. RESULTS: In the analysis of the entire cohort, SRI-4 responders showed more prominent decreases from baseline through week 52 in CD19(+)CD20(+)CD27(–) naïve B cells (median change: −61.2% versus −50.0%; P = 0.004), CD19(+)CD20(–)CD27(bright) plasmablasts (−44.9% versus −33.3%; P = 0.011), and CD19(+)CD20(–)CD138(+) long-lived plasma cells (−48.2% versus −37.1%; P = 0.024), and a more prominent rapid (+92.0% versus +66.7%; P = 0.002) and early (+60.0% versus +49.5%; P = 0.033) expansion of CD19(+)CD20(+)CD27(+) memory B cells than non-responders. More prominent rapid reductions in anti-dsDNA (−14.8% versus −8.7%; P = 0.043) and increases in C3 (+4.9% versus +2.1%; P = 0.014) and C4 levels (+11.5% versus +8.3%; P = 0.017) were documented in SRI-4 responders compared with non-responders among patients who received add-on belimumab, but not among patients who received non-biological ST alone. CONCLUSION: SRI-4 responders showed a more prominent rapid expansion of memory B cells and more prominent delayed reductions in naïve B cells, plasmablasts and long-lived plasma cells. Moreover, clinical response to belimumab was associated with preceding more prominent reductions of anti-dsDNA and increases in C3 and C4 levels. Monitoring biological changes may prove useful in SLE patient surveillance and early treatment evaluation.