B Cell Kinetics upon Therapy Commencement for Active Extrarenal Systemic Lupus Erythematosus in Relation to Development of Renal Flares: Results from Three Phase III Clinical Trials of Belimumab

Ioannis Parodis, Alvaro Gomez, Julius Lindblom, Jun Weng Chow, Christopher Sjöwall, Savino Sciascia, Mariele Gatto, Ioannis Parodis, Alvaro Gomez, Julius Lindblom, Jun Weng Chow, Christopher Sjöwall, Savino Sciascia, Mariele Gatto

Abstract

Renal flares constitute major determinants of poor prognosis in people living with systemic lupus erythematosus (SLE). The aim of the present study was to investigate changes in B cell subsets in relation to renal flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with SLE. Using data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) percentage changes in circulating CD19+ B cell subsets characterised through flow cytometry, anti-dsDNA antibodies, and complement levels with the occurrence of renal flares over one year. Patients who developed renal flares showed more prominent rapid decreases in CD19+CD20+CD138+ short-lived plasma cells (-50.4% vs. -16.7%; p = 0.019) and CD19+CD20-CD27bright plasmablasts (-50.0% vs. -29.9%; p = 0.020) compared to non-flaring patients, followed by a subsequent return. Less prominent rapid reductions in CD19+CD27-CD24brightCD38bright transitional B cells (-42.9% vs. -75.0%; p = 0.038) and CD19+CD20-CD138+ peripheral long-lived plasma cells (-11.3% vs. -29.2%; p = 0.019) were seen in belimumab-treated-but not placebo-treated-patients who developed renal flares compared to belimumab-treated patients who did not. Rapid and early changes in anti-dsDNA or complement levels showed no clear association with renal flares. In summary, a rapid drop followed by a subsequent return in circulating short-lived plasma cells and plasmablasts upon treatment for active extra-renal SLE portended renal flares, indicating a need for therapeutic adjustments in patients showing such B cell patterns. Rapid decreases in transitional B cells and peripheral long-lived plasma cells upon belimumab therapy commencement may signify a greater protection against renal flares. B cell kinetics may prove useful in early drug evaluation.

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

Conflict of interest statement

IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, and F. Hoffmann-La Roche AG. The other authors declare that they have no conflicts of interest related to this work. The funders had no role in the design of the study, the analyses or interpretation of data, or the writing of the manuscript.

Figures

Figure 1
Figure 1
B cell alterations in relation to renal flares. The graphs delineate relative to baseline percentage changes in selected B cell and peripheral plasma cell subsets in patients who developed at least one renal flare during the study period (continuous lines) and patients who did not (dashed lines). Comparisons between patients who flared and patients who did not were conducted using multivariable logistic regression analysis to account for potential confounders and are illustrated for patients who received non-biological standard therapy plus belimumab (red lines) and patients who received non-biological standard therapy alone (blue lines). Comparisons between treatment arms were conducted using non-parametrical Mann–Whitney U tests. Whiskers indicate the interquartile range of distributions. The number of patients with available data at each time point is indicated for each patient subgroup.
Figure 2
Figure 2
Transitional and naïve B cell alterations in relation to renal flares. The graphs delineate relative to baseline percentage changes in transitional and naïve B cell subsets in patients who developed at least one renal flare during the study period (continuous lines) and patients who did not (dashed lines) in a subanalysis of data from the BLISS-SC trial. Comparisons between patients who flared and patients who did not were conducted for patients with available data, stratified into patients who received non-biological standard therapy plus belimumab (red lines) and patients who received non-biological standard therapy alone (blue lines). P values are derived from non-parametric Mann–Whitney U tests. Whiskers indicate the interquartile range of distributions. The number of patients with available data at each time point is indicated for each patient subgroup.
Figure 3
Figure 3
Changes in serological markers in relation to renal flares. The graphs delineate relative to baseline percentage changes in anti-dsDNA, C3, and C4 levels in patients who developed at least one renal flare during the study period (continuous lines) and patients who did not (dashed lines). Comparisons between patients who flared and patients who did not were conducted using multivariable logistic regression analysis to account for potential confounders and are illustrated for patients who received non-biological standard therapy plus belimumab (red lines) and patients who received non-biological standard therapy alone (blue lines). For anti-dsDNA levels, a separate analysis for patients with positive anti-dsDNA levels (≥30 IU/mL) at baseline is also demonstrated. Comparisons between treatment arms were conducted using non-parametrical Mann–Whitney U tests. Whiskers indicate the interquartile range of distributions. 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.

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