Investigating Synergistic Drug Combinations for Vasodilation in Systemic Sclerosis

Recent studies presented at the EULAR 2025 congress in Barcelona have shed light on potential advancements in the treatment of systemic sclerosis (SSc), a condition where vasculopathy plays a crucial role in its pathogenesis. Current guidelines from the European Alliance of Associations for Rheumatology (EULAR) emphasize the importance of exploring various vasoactive vasodilating drugs (VVD) and their synergistic effects, alongside the need for robust clinical trials and real-world data to substantiate findings.

VVD have been recognized for their anti-fibrotic properties; however, their effectiveness in enhancing pulmonary function and preventing the progression of SSc-associated interstitial lung disease (ILD) remains inconclusive. A post-hoc analysis conducted by researchers aimed to assess the effects of these drugs on functional progression and overall mortality in patients with SSc-ILD. Utilizing data from the EUSTAR database, the study evaluated outcomes for over 2,100 individuals who had been treated with endothelin-receptor antagonists (ERA), phosphodiesterase-5 inhibitors (PDE5i), or prostanoids for a minimum of three months.

The analysis revealed a protective association of prostanoids in patients without digital ulcers, which are known to be linked to ILD development. Additionally, exposure to ERA significantly reduced the risk of symptom deterioration, a benefit that was independent of the presence of digital ulcers. Interestingly, the analysis indicated varying interactions between diffusing capacity for carbon monoxide (DLCO) and VVD categories; while DLCO served as a risk factor in conjunction with ERA, it acted as a protective factor alongside prostanoids.

Despite the lack of a significant independent impact on mortality from VVD exposure, the findings suggest that prostanoids could lower the risk of ILD progression in patients exhibiting mild vasculopathy. Conversely, ERA appears to mitigate symptom worsening, particularly in those with more severe vasculopathy. These preliminary results highlight the need for further research to confirm the beneficial effects of VVD in the context of SSc-ILD.

Another study presented at the congress examined the relationship between VVD, immunosuppressants, and ILD development in a cohort of over 4,000 patients. This investigation reaffirmed that PDE5i and prostanoids were significantly associated with the onset of ILD. Notably, the association for PDE5i emerged predominantly in patients with digital ulcers, where it was linked to a reduced risk of ILD onset. Additionally, while conventional immunosuppressants showed some interaction with diffuse cutaneous SSc concerning ILD risk, this was only suggestive of a protective trend.

The presenting researcher concluded that treatment with key VVD, specifically sildenafil and iloprost, may offer protective benefits against the development of SSc-ILD within the first year of treatment, independent of immunosuppressants. An analysis comparing patient data before and after the 2015 EULAR treatment recommendations indicated an increase in digital ulcer prevalence, attributed to improved detection methods. This analysis also noted a slight uptick in the use of VVD over the same period.

When examining the treatment outcomes based on the timing of the EULAR recommendations, the researchers identified consistent protective associations involving prostanoids and the interaction of sildenafil with digital ulcers, particularly in the pre-2015 cohort. For the post-2015 group, the benefits of PDE5i were reconfirmed for ILD onset, while the associations for prostanoids were not as pronounced.

Collectively, these studies underscore the need for tailored therapeutic approaches in managing systemic sclerosis, particularly in light of the varying impacts of VVD based on individual clinical characteristics such as the presence of digital ulcers. The call for further randomized controlled trials remains paramount to validate these findings and enhance treatment protocols for patients suffering from this complex disease.