B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis

Abstract

Objective: To determine the safety of rituximab, to provide preliminary data regarding the potential efficacy of rituximab, and to investigate the effects of rituximab on autoimmunity and fibrosis in patients with diffuse cutaneous systemic sclerosis (dcSSc).

Methods: Fifteen patients with dcSSc, all of whom experienced their first non-Raynaud's disease-associated disease manifestation within 18 months of trial entry, were recruited to receive 2 intravenous doses of rituximab (1,000 mg), administered 2 weeks apart. Safety, clinical, and exploratory outcomes were evaluated at baseline and at 6 months. The primary outcome was the change in the modified Rodnan skin thickness score (MRSS) at 6 months compared with baseline.

Results: Adverse events included frequent infusion reactions and rare infections (urinary tract infection and dental abscess occurred in 1 patient each). The mean change in the MRSS between baseline and 6 months was not significant. Results of pulmonary function tests and other measures of major organ involvement were stable. The modest B cell infiltrates that were present in most skin biopsy specimens at baseline were completely depleted at 6 months in most patients. Autoantibody titers showed only modest and variable changes after treatment.

Conclusion: In this pilot study, treatment with rituximab appeared to be safe and well tolerated among patients with dcSSc. Rituximab treatment resulted in both depletion of circulating B cells and depletion of dermal B cells but had little effect on the levels of SSc-associated autoantibodies. Rituximab treatment did not appear to result in a significant beneficial effect on skin disease. The potential efficacy of rituximab in other organs such as the lung could not be clearly evaluated in this small open-label trial.

Figure 1

Clinical and pathological outcomes in dcSSc patients treated with rituximab. Modified Rodnan skin score (A), myofibroblast score (B), circulating CD20+ B cell count (C) and B cells in skin sections (D) are shown at baseline, and 6 and 12 months (A) at baseline and 6 months (B and D), or at baseline and 3, 6, 9 and 12 months after rituximab treatments. The same color line represents the same patient in each of the graphs. A typical example of perivascular B cell staining in one of the patients is shown in panel E. Autoantibodies in patients with dcSSc at baseline and 6-months after rituximab treatment. (F) Autoantibodies to chromatin, Sm, topoisomerase I (topo-I), U1 ribonucleoprotein, ribosomal P protein, Jo-1 (histidyl tRNA synthetase), SS-A/Ro60, Ro52 and SS-B/La or RNA polymerase III (RNAP-III) detected by immunoassay or ELISA at 6 months were normalized to values at baseline. Patients not shown did not have detectable autoantibodies to any of the specificities tested.