Rituximab safe, potentially effective adjuvant treatment for systemic sclerosis-PAH
B-cell depletion with rituximab was safe and may be a potentially effective treatment for patients with systemic sclerosis-associated pulmonary arterial hypertension, researchers reported.
“This is the first placebo-controlled trial of a B-cell depleting therapy for PAH. While a negative study, the results were suggestive of therapeutic value. Selective immunotherapy, possibly guided by biomarkers, coupled with standard-of-care vasodilators may improve the outcome for patients with a deadly cardiopulmonary disease,” Marc R. Nicolls, MD, professor in pulmonary, allergy and critical care medicine at Stanford University, and with the Vera Moulton Wall Center for Pulmonary Vascular Disease and the VA Palo Alto Health Care System, and Roham T. Zamanian, MD, associate professor in pulmonary, allergy and critical care medicine and director of the adult pulmonary hypertension program at Stanford University School of Medicine and with the Vera Moulton Wall Center for Pulmonary Vascular Disease, told Healio.
This multicenter, double-blind, randomized, placebo-controlled trial evaluated 57 adults (mean age, 58.2 years; 91.2% women) with systemic sclerosis-associated PAH on stable-dose standard medical therapy. Participants were randomly assigned to receive two infusions of rituximab (Rituxan; Genentech, Biogen) at 1,000 mg (n = 29) or placebo (n = 28) from 2010 to 2018. Using a machine learning approach, researchers predicted response to rituximab.
“B-cell immunity likely plays an important role in the evolution of systemic sclerosis-related conditions. Rituximab therapy depletes B-cells and is used for a variety of autoimmune conditions. We hypothesized that rituximab could be useful for one of the most concerning manifestations of systemic sclerosis — pulmonary arterial hypertension,” Nicolls and Zamanian said.
The primary outcome was change in 6-minute walk distance at week 24. Secondary outcomes included safety and invasive hemodynamics.
The results were published in the American Journal of Respiratory and Critical Care Medicine.
The adjusted mean change in 6-minute walking distance at week 24 was 23.6 m among those treated with rituximab, compared with 0.5 m in the placebo group (P = .12). When the researchers evaluated data through week 48, the estimated change in 6-minute walk distance at week 24 was 25.5 m in the rituximab group compared with 0.4 m in the placebo group (P = .03).
Rituximab treatment was well tolerated among both groups with no remarkable or unexpected differences in adverse events. In the rituximab group, 14 participants experienced 22 serious adverse events compared with 14 serious adverse events among nine participants in the placebo group. The most common serious adverse events were infections in 24.1% of the rituximab group and 7.1% of the placebo group. There were no deaths reported. During the study period of active participants followed to week 48, there were four deaths (three in the rituximab group vs. one in the placebo group); reasons for death included adenocarcinoma, sudden death, cardiac arrest during elective surgery and cardiac arrest related to underlying PAH.
In other results, “a machine learning approach discovered that low levels of rheumatoid factor, interleukin-12 (IL-12) and IL-17 retrospectively identified those patients who responded best to rituximab,” Nicolls and Zamanian said. “We would have predited that higher inflammatory blood biomarkers would have been more predictive.”
The researchers noted several limitations of the trial, including its underenrollment and insufficient power to detect smaller differences in the primary endpoint.
“Ultimately, this study was underpowered to conclusively address the benefit of rituximab in these patients,” Nicolls and Zamanian said. “A larger, better-powered study would more definitively conclude benefit or non-benefit. At a minimum, this study provides the basis for pursuing a larger trial.”
For more information:
Mark R. Nicolls, MD, and Roham T. Zamanian, MD, can be reached at firstname.lastname@example.org.