13 Years in the Making – Immunotherapy for Scleroderma
By Adrienne Mueller, PhD
March 17, 2021
From Hard Skin to Hard to Breathe
Scleroderma, from the Greek ‘hard skin,’ is a condition that afflicts approximately 100,000 people in the US and is characterized by a buildup of scar tissue in the skin and other organs. Scleroderma is an autoimmune disorder, meaning that the body’s immune system mistakenly identifies its own healthy tissue as a foreign substance and attacks it, causing tissue damage. Although the disease usually primarily affects the skin, it can also result in inflammation of many other organs including the lungs, esophagus, kidneys and heart. One of the most serious and potentially fatal complications patients with scleroderma develop is a lung condition called pulmonary arterial hypertension (PAH). PAH, high blood pressure in the arteries of the lungs, causes the heart to work harder to pump blood and, over time, makes the heart more likely to weaken and fail. Current medications to treat scleroderma-associated PAH all act by dilating lung blood vessels to reduce blood pressure and there is currently no treatment that acts directly against the underlying autoimmune response.
Treating the Cause, not the Symptom
In their recent American Journal of Respiratory and Critical Care Medicine article, first author Roham Zamanian, MD and senior-author Mark Nicolls, MD report the results of a 13-year clinical trial devoted to identifying an immunotherapy treatment to scleroderma-incited PAH. For their study, they chose to target B-cells, a type of immune cell that is thought to contribute to the autoimmune response in scleroderma.
B-cells may trigger tissue scarring in the lungs, thereby causing increased blood pressure and PAH. Zamanian et al chose to test the safety and efficacy of rituximab, an immunotherapy agent that is known to deplete B-cells and to decrease tissue scarring, in patients suffering from scleroderma-associated PAH.
Does Rituximab Improve Lung Function?
This study was not an easy one to complete. Even though the investigators faced repeated challenges due to difficulties recruiting sufficient patients, the updating of protocols, lengthy processing times, and the collection of longitudinal data – they persevered for 13 years to finish the work and obtain the results. Ultimately 57 patients were enrolled in their multi-center study, which was sponsored by the National Institute of Health. The hypothesis: B-cell depletion with rituximab would improve lung function in patients with scleroderma-associated PAH.
Patients enrolled in the study were prescribed either rituximab or a placebo for a period of 48 weeks. Their lung function was assessed using an exercise test after both 24 weeks and 48 weeks of treatment. After 24 weeks of treatment, the patients who receive rituximab had improved lung function, although the difference did not reach statistical significance. However, a secondary analysis that evaluated all the time points out to 48 weeks discerned a statistically meaningful improvement at 24 weeks. The investigators also established that rituximab was safe and well-tolerated throughout the entire treatment period. Further, the investigators used machine learning techniques on patient-provided biomarkers and were able to identify a subset of patients who had the best response to the treatment. In the future, clinicians will be able to test for these biomarkers to determine whether rituximab is an appropriate treatment.
Promise for the Future
Scleroderma-associated PAH is a severe and often fatal condition, and this trial is the first to evaluate the safety and efficacy of an entirely new, immunotherapy-based treatment using B-cell depletion. The investigators identified a trend in the data that suggested that the B-cell depleting drug rituximab reduces symptoms of PAH in patients. A secondary analysis then revealed a significant improvement in lung function caused by rituximab treatment. Future work is necessary to determine rituximab’s specific mechanism of action and to further investigate the potential of this promising drug for treating scleroderma-associated PAH.
Additional Stanford Cardiovascular Institute-affiliated authors who contributed to this study include Lorinda Chung, Andrew J. Sweatt and Holden Maecker.