Background: Pulmonary arterial hypertension (PAH) is a morbid complication of systemic sclerosis (SSc). Management of SSc-PAH remains challenging and mortality is high. The postulated role of B-cells in SSc suggests a role for B-cell depletion in SSc-PAH. Methods: We conducted an NIH-sponsored proof-of-concept multicenter, double-blind, randomized controlled trial of rituximab (Rx) in SSc-PAH on stable PAH therapy. Dosing was two 1000 mg infusions 14 days apart. The primary endpoint was change in 6-minute walk distance (6MWD) at 24 weeks. Secondary endpoints included change in 6MWD at other time points, pulmonary vascular resistance (PVR), time to clinical worsening (TTCW), diffusion capacity, and SSc-specific factors. Results: Between 2010–2018, 57 subjects with similar baseline clinical characteristics were randomized 1:1 to Rx or placebo (Pc). Rx was well tolerated without unexpected toxicities. In a longitudinal analysis using data through week 24, 6MWD trended towards improvement after Rx relative to Pc, but did not differ significantly between arms (23.6±11.1m Rx, 0.5±9.7m Pc, p=0.12). A pre-specified secondary analysis using data through week 48 demonstrated improvement at week 24 (25.5±8.8m Rx, 0.4±7.4m Pc, p=0.03) with a loss of effect by week 48 (9.5±12.4m Rx, -7.0±8.6m Pc, p=0.28). Higher proportion of Pc subjects required additional PAH therapies, but changes in PVR and TTCW were not significantly different. Conclusion: Adjunctive B-cell depletion therapy is a safe and potentially effective treatment for SSc-PAH. This is the first controlled trial examining the role of immunotherapy in a serious form of PAH and warrants further study.

Late Breaking Abstract - Safety and efficacy of B-cell depletion with rituximab for the treatment of systemic sclerosis-associated pulmonary arterial hypertension