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

Abstract

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.

Keywords: B cells; B lymphocyte; belimumab; biologics; biomarkers; plasma cells; prediction; systemic lupus erythematosus.

FIGURE 1

B and plasma cell subset alterations in relation to clinical response. The graphs delineate relative to baseline percentage changes in selected B cell and plasma cell subsets in patients who attained SRI-4 response at week 52 from baseline (continuous lines) and patients who did not (dashed lines). Comparisons between SRI-4 responders and non-responders were conducted for the entire population with available data (black lines), and after stratification into patients who received standard therapy plus belimumab (terracotta lines) and patients who received standard therapy alone (gray lines). P-values derived from non-parametric Mann–Whitney U tests. The number of patients with available data at each timepoint is indicated for each patient subgroup. SRI, Systemic lupus erythematosus Responder Index.

FIGURE 2

Changes in selected serological markers in relation to clinical response. The graphs delineate relative to baseline percentage changes in anti-dsDNA, C3, and C4 levels in patients who attained SRI-4 response at week 52 from baseline (continuous lines) and patients who did not (dashed lines). Comparisons between SRI-4 responders and non-responders were conducted for the entire population with available data (black lines), and after stratification into patients who received standard therapy plus belimumab (terracotta lines) and patients who received standard therapy alone (gray lines). For anti-dsDNA levels, a separate analysis for patients with positive anti-dsDNA levels (≥30 IU/mL) at baseline is also demonstrated. P-values derived from non-parametric Mann–Whitney U tests. The number of patients with available data at each time point is indicated for each patient subgroup. Anti-dsDNA: anti-double stranded DNA antibodies; C3: complement component 3; C4: complement component 4; SRI: Systemic lupus erythematosus Responder Index.