Most VVD in clinical trials have been shown to exert anti-fibrotic effects – but findings are mixed around whether they also improve pulmonary function tests and prevent progression of SSc-associated interstitial lung disease (ILD). A post-hoc analysis presented by Adela-Cristina Sarbu aimed to address this by assessing the impact of VVD on functional progression and all-cause mortality in people with SSc-ILD. Using data from the EUSTAR database, they looked at three different outcomes for 2,156 people receiving endothelin-receptor antagonists (ERA), phosphodiesterase-5 inhibitors (PDE5i), or prostanoids for at least 3 months. The first two outcomes looked at functional progression as measured by forced vital capacity (FVC) plus diffusing capacity for carbon monoxide (DLCO) at different thresholds, while the third outcome looked solely at subjective worsening, assessed in heart failure categories.
When predicting the first two types of progression, there appeared to be a protective association of prostanoids in patients who did not have digital ulcers – which are known to be associated with ILD development. Conversely, when looking at progression defined by heart failure categories, exposure to ERA was significantly protective against worsening, independently from the presence of digital ulcers. Interestingly, DLCO was found to interact differently with VVD categories in the analysis: as a risk factor when combined with ERA, but as a protective factor when interacting with prostanoids. In the survival analysis, VVD exposure did not show any significant independent impact on mortality.
The authors conclude that exposure to prostanoids is associated with lower risk of ILD progression in patients with mild vasculopathy (defined as no digital ulcers but higher DLCO). Conversely, exposure to ERA appears to be associated with lower risk of symptoms worsening, which seems more prominent in patients with more severe vasculopathy (lower DLCO). Further studies are needed to confirm the beneficial effects of VVD in SSc-ILD, but this is a promising step.
Another abstract presented in Barcelona also used EUSTAR data to evaluate the association between use of VVD and immunosuppressants and the development of SSc-ILD, this time in 4,091 patients. This work again looked at ERA, PDE5i, and prostanoids, but also conventional and biologic immunosuppressants. The results showed that PDE5i and prostanoids were significantly associated with ILD onset. While this independent result was seen for the prostanoid class, a statistically significant interaction for PDE5i emerged only in combination with digital ulcers, where exposure to PDE5i was associated with a reduced risk of ILD onset. Although there was a significant association between the interaction of conventional immunosuppressants and diffuse cutaneous SSc with the risk of ILD onset, this finally translated into only a trend towards protection from ILD onset.
In conclusion, the presenting author Cosimo Bruni, said "We showed that treatment with major VVD, specifically sildenafil and iloprost – but not immunosuppressants – might have a protective effect on the development of SSc-ILD within 1 year."
Of note, the authors also performed a sensitivity analysis that divided the observation time into two periods: before and after the previous EULAR SSc treatment recommendations were presented in 2015,2 to test if and how a change in practice might influence the results. Comparing the two periods, they identified an increase in the prevalence of patients ever having had a digital ulcer, rising from 18.5% to 42.1%. This was attributed to better identification thanks to awareness campaigns, as well as an element of survivor bias. Between these two periods, there was a marginal increase in the use of major VVD. When the models from the overall population were applied to the visits before 2015, they confirmed all protective associations of prostanoids, iloprost, and the interaction between sildenafil and digital ulcers. For data after 2015, they confirmed the protective interaction of PDE5i, sildenafil, and digital ulcers for ILD onset, but not for prostanoids or iloprost.
Taken together, these two abstracts suggest that the beneficial effect of VVD might vary according to the presence of digital ulcers, and reinforce the need to adjust interventions according to a person's unique clinical scenario. More work is needed to investigate the preventive effects of these medications in randomised controlled trials.
Source
Sarbu A-C, et al. Can vasoactive vasodilating drugs influence progression and prognosis of systemic sclerosis-associated interstitial lung disease A EUSTAR cohort study. Presented at EULAR 2025; OP0003. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B1560.
Petelytska L, et al. Vasodilation reduces the risk of new onset of interstitial lung disease in systemic sclerosis: an association study from the EUSTAR database. Presented at EULAR 2025; OP0334. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B1232.
References
1. Del Galdo F, et al. EULAR recommendations for the treatment of systemic sclerosis: 2023 update. Ann Rheum Dis 2025;84(1):29–40. DOI: 10.1136/ard-2024226430.
2. Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis 2017;76:1327–39. DOI: 10.1136/annrheumdis-2016-209909.
About EULAR
EULAR is the European umbrella organisation representing scientific societies, health professional associations and organisations for people with rheumatic and musculoskeletal diseases (RMDs). EULAR aims to reduce the impact of RMDs on individuals and society, as well as improve RMD treatments, prevention, and rehabilitation. To this end, EULAR fosters excellence in rheumatology education and research, promotes the translation of research advances into daily care, and advocates for the recognition of the needs of those living with RMDs by EU institutions.
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