Vascular biomarkers and digital ulcerations in systemic sclerosis: results from a randomized controlled trial of oral treprostinil (DISTOL-1)

Introduction Although there is abundant evidence of vascular perturbation from studies of peripheral blood in systemic sclerosis (SSc), there are few data about the ability to use biomarkers of vascular injury and growth factors to predict vascular outcomes and response to therapy. We sought to explore the association between candidate vascular biomarkers and digital ulcerations (DU) in a clinical trial context. Methods We examined 19 circulating vascular, angiogenic, and inflammatory biomarkers in 124 patients with scleroderma and DU who participated in a randomized controlled trial of oral treprostinil diolamine (ClinicalTrials.gov identifier NCT00775463). Correlation, regression, and random forest analyses were conducted to assess biomarker relationships in response to drug treatment. Results Over the 20-week trial, 82 (66%) patients had their cardinal ulcer completely heal, 54 (44%) developed new ulcers, and 72 (58%) had complete healing of all ulcers; mean change in ulcer burden comparing week 20 with baseline was − 0.36 ± 1.70. Nineteen biomarkers were analyzed for their association and ability to predict clinical DU outcomes. After adjusting for multiple comparisons, no individual biomarker (baseline level, week 20 level, or change over time) was significantly associated with any of the clinical outcomes, suggesting that traditional vascular, angiogenic or inflammatory drivers are not predictive of ulcer fate. Conclusions The lack of strong response to any of the vascular, angiogenic, or inflammatory markers suggest that these pathways are not primary drivers in the development of DU clinical outcomes in a SSc population with prevalent DU. Key Points: • Currently we lack robust biomarkers to predict vascular outcomes or response to therapy in scleroderma patients with Raynaud’s phenomenon. • Longitudinal assessment of vascular biomarkers in a clinical trial setting provides a unique opportunity to define biomarkers that predict vascular outcomes. • In a randomized controlled trial of oral treprostinil diolamine for treatment of scleroderma-associated digital ulcers, biomarkers involved in several vascular, inflammatory, and angiogenic pathways did not predict short-term clinical response to therapy or digital ulcer outcomes. • Further study of these and other biomarkers should be considered in Raynaud’s clinical trials in scleroderma patients without prevalent digital ulcers.