Belimumab for the Treatment of Early Diffuse Systemic Sclerosis: Results of a Randomized, Double-Blind, Placebo-Controlled, Pilot Trial

Abstract

Objective: To assess the safety and efficacy of treatment with belimumab in patients with early diffuse cutaneous systemic sclerosis (dcSSc) treated with background mycophenolate mofetil (MMF).

Methods: In this 52-week, investigator-initiated, single-center, double-blind, placebo-controlled, pilot study, 20 patients with dcSSc recently started on MMF were randomized 1:1 to additionally receive belimumab at 10 mg/kg intravenously or placebo. We assessed safety, efficacy, and differential gene expression.

Results: In the belimumab group, the median modified Rodnan skin thickness score (MRSS) decreased from 27 (interquartile range [IQR] 26.5, 31) to 18 (IQR 11, 23) (P = 0.039). In the placebo group, the median MRSS decreased from 28 (IQR 22, 28) to 21 (IQR 14, 25) (P = 0.023). The median change in MRSS was -10 (IQR -13, -9) in the belimumab group and -3.0 (IQR -15, -1) in the placebo group (P = 0.411). There were no significant differences between the groups in the number of adverse events (AEs). A significant decrease in expression of B cell signaling and profibrotic genes and pathways was observed in patients with improved MRSS in the belimumab group but not in the placebo group.

Conclusion: Patients in both treatment groups experienced significant improvements in MRSS. The median difference was greater in the belimumab group but did not achieve statistical significance in this small pilot study. AEs were similar between the groups. Changes in gene expression were consistent with mechanism of action and showed that clinical response to treatment with belimumab is associated with a significant decrease in profibrotic genes and pathways. Additional studies are needed to determine the role of belimumab in the treatment of dcSSc.

Trial registration: ClinicalTrials.gov NCT01670565.

© 2017, American College of Rheumatology.

Figures

Figure 1.

Changes in modified Rodnan skin thickness score (MRSS) and composite response index in diffuse cutaneous systemic sclerosis (CRISS) score. A, MRSS at baseline and at week 52 in patients treated with belimumab and those treated with placebo. The median MRSS decreased from 27 (interquartile range [IQR] 26.5, 31) to 18 (IQR 11, 23) in the belimumab group (P = 0.039) and from 28 (IQR 22, 28) to 21 (IQR 14, 25) in the placebo group (P = 0.023). B, Median change in MRSS. The MRSS changed by a median of −10 (IQR −13, −9) in the belimumab group and by a median of −3.0 (IQR −15, −1) in the placebo group (P = 0.411). C, Proportion of patients achieving MRSS improvement of at least 20%. D, CRISS score at 52 weeks. The median CRISS score was 0.61 (IQR 0.34, 0.88) in the belimumab group and 0.03 (IQR 0, 0.80) in the placebo group (P = 0.345). Although CRISS scores in the belimumab group tended to be higher, statistical significance was not reached due to small sample size and distribution of placebo values. In B and D, data are presented as box plots, where the boxes represent the 25th to 75th percentiles, the lines within the boxes represent the median, and the lines outside the boxes represent minimum and maximum values. Circles represent individual patients.

Figure 2.

Gene expression changes in the belimumab arm and in belimumab improvers (patients who individually demonstrated a 20% decrease in the modified Rodnan skin thickness score). A, Sample genes that were significantly down-regulated (false discovery rate [FDR] ≤10%) posttreatment in the belimumab arm. B, Sample pathways that were significantly down-regulated (FDR ≤5%) posttreatment in the belimumab arm. C, Sample genes that were significantly down-regulated posttreatment in belimumab improvers. D, Sample pathways that were significantly down-regulated posttreatment in belimumab improvers. Base = baseline; IL-27 = interleukin-27; NK = natural killer; TGF = transforming growth factor; ECM = extracellular matrix; TGFβR = TGFβ receptor.

Figure 3.

Patients were assigned to one of the intrinsic molecular subsets based on gene expression signatures at baseline: inflammatory (purple), normal-like (green), or proliferative (red). A, In the belimumab/mycophenolate mofetil (MMF) treatment arm, improvers (patients who individually demonstrated a 20% decrease in the modified Rodnan skin thickness score [MRSS]) spanned all 3 subsets, while nonimprovers were assigned to an inflammatory or normal-like molecular subset. B, In the MMF treatment arm, improvers were assigned to either an inflammatory or a proliferative molecular subset, while nonimprovers spanned all 3 subsets. C, We used the inflammatory gene expression signature to quantify an inflammatory subset score for each patient at baseline and at 12 months, and we correlated changes in this score with changes in MRSS. Symbols represent individual patients. Regression lines are shown for all patients (solid) and for only those patients assigned to the inflammatory molecular subset (dashed).