OP0331 ASSOCIATION BETWEEN VASOACTIVE-VASODILATING THERAPY AND REDUCED DETECTION OF PRE-CAPILLARY PULMONARY HYPERTENSION IN SYSTEMIC SCLEROSIS: EVIDENCE FROM A EUSTAR STUDY

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Background: Precapillary pulmonary hypertension (PH) is a severe complication of systemic sclerosis (SSc), which benefits from therapy with vasoactive-vasodilating drugs (VVD), including categories such as endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5i) and prostanoids. Although these drugs are also commonly used to manage vascular complications in SSc, such as digital ulcers (DU) and Raynaud's phenomenon, their role in preventing precapillary PH remains unclear. Objectives: Our study, leveraging data from the extensive European Scleroderma Trials and Research (EUSTAR) cohort, aims to provide deeper insights into the effectiveness of VVD in the primary prevention of precapillary PH. Methods: SSc patients from the EUSTAR database fulfilling the 2013 ACR/EULAR criteria, who underwent their first right heart catheterization (RHC), were included; postcapillary PH cases (pulmonary wedge pressure – PWP >15 mmHg) were excluded. Four multivariable logistic regression models were employed to assess the association between exposure to VVD and detection of precapillary PH (defined as mPAP>20 mmHg, pulmonary vascular resistances >2 WU and PWP≤15 mmHg). In particular: •Model 1 & 2 tested the association between exposure "ever" and "ongoing", respectively, to VVD categories (ERAs, PDE5i and prostanoids) at the time of RHC and diagnosis of precapillary PH •Model 3 & 4 tested the association between exposure "ever" and "ongoing", respectively, to specific VVD molecules at the time of RHC and diagnosis of precapillary PH All models were adjusted for known confounders associated with precapillary PH, such as DLCO, age, current DU and systolic PAP on echocardiography. Interaction terms between VVDs and current DU were also tested. Results: Among 1271 SSc patients from the EUSTAR cohort with available RHC data, 944 were eligible for this study. Based on RHC results, 498 (53%) were diagnosed with precapillary PH. Demographics, disease features and RHC data of the study population are reported in Table 1. In all logistic regression models (Forest plots in Figure 1), we observed a significant association between precapillary PH and known confounders, such as ACA positivity, older age, lower DLCO, and higher systolic PAP on Echo. Focusing on exposure to categories of VVD and looking at interaction terms, a statistically significant association was detected for the interaction of ERAs and current DU with the detection of precapillary PH, in both logistic regression models 1 and 2. However, when calculating the marginal effects estimates, we noted a tendency towards a protective association of ongoing exposure to ERAs and current DU with detection of precapillary PH (OR 0.435, 95% CI 0.193 - 1.064), which was not noted for exposure ever (OR 0.636, 95% CI 0.349 - 1.158). Conversely, both models showed a lack of protective effectiveness of PDE5i for precapillary PH; the same positive association was detected for exposure to ERAs in patients without current DU for precapillary PH detection as outcome (ever: OR 2.090, 95% CI 1.049 – 4.163; ongoing: OR 2.976, 95% CI 0.989 – 8.953). No association was detected for the category of prostanoids. When considering exposure ever to specific VVD molecules (i.e., Model 3 ), bosentan was found to have a significant protective association with precapillary PH diagnosis, while PDE5i other than sildenafil were positively associated with a RHC result compatible with precapillary PH, independently from the presence or absence of current DU. Finally, in Model 4 (i.e., ongoing exposure to specific VVD molecules) we noted again a statistically significant interaction between ongoing bosentan and current DU, which turned into a statistically significant marginal effects estimates (OR 0.230, 95% CI 0.081 – 0.652) indicating protective effects of this medication towards the diagnosis of precapillary PH in patients with current DU. Conclusion: Our data show that bosentan, when employed in patients with current DU at the time of RHC, was associated with less frequent diagnosis of precapillary PH. This may confirm the previous hypothesis that bosentan may have a preventive effectiveness. These findings highlight the need for individualized treatment strategies and further research to optimize the timing and patient selection for VVD therapy in SSc, aiming also at potential additional preventive effects at pulmonary level. REFERENCES: NIL . Table 1. Data about demographics, disease features, immunosuppressive and vasoactive treatment exposure and right heart catheterization from the study population, compared between patients with and without precapillary pulmonary hypertension. ACA, anti-centromere antibody; b/csDMARDs, biologic/conventional synthetic anti-rheumatic disease modifying drugs; DLCO, diffusion lung capacity of carbon monoxide; ERA, endothelin receptor antagonists; FVC, forced vital capacity; NYHA, New York Heart Association; PH, pulmonary hypertension; PDE5i, phosphodisterase 5 inhibitors; SSc, systemic sclerosis; sPAP, systolic pulmonary arterial pressure. Figure 1Forest Plots of regression Models 1 ( a ), 2 ( b ), 3 ( c ), and 4 ( d ) evaluating the association between independent variables and the detection of precapillary pulmonary hypertension.ACA, anti-centromere antibody; DLCO, diffusion lung capacity of carbon monoxide; DU, digital ulcers; ERA, endothelin receptor antagonists; PAH, pulmonary arterial hypertension; sPAP, systolic pulmonary arterial pressure; PDE5i, phosphodisterase 5 inhibitors. Acknowledgements: NIL . Disclosure of Interests: Nicola Farina: None declared, Silvia Bellando Randone: None declared, Sebastien Sanges Meeting fees from Shire, Sanofi-Genzyme, SOBI, Novartis, BioCryst, Novartis, Takeda and Grifols, Novartis, BioCryst, MSD, Hilde Jenssen Bjørkekjær: None declared, Lorenzo Tofani: None declared, Marie-Elise Truchetet: None declared, Vanessa Smith: None declared, Andra Rodica Balanescu: None declared, Christina Bergmann Boehringer-Ingelheim and Janssen, German Research Association, IZKF Erlangen, BMBF, Kyverna Therapeutics, Yannick Allanore: None declared, Philipp Klemm: None declared, Simona Truglia: None declared, Luca Idolazzi Speaker fees from Abbvie, UCB Pharma, Johnson & Johnson, Eli Lilly, and Amgen, Johnson & Johnson and Eli Lilly, Christopher Denton: None declared, Rosario Foti: None declared, Anna Wojteczek: None declared, Emmanuel Chatelus: None declared, Madelon Vonk Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Johnson & Johnson, MSD, Novartis, and Roche, Boehringer Ingelheim and Johnson & Johnson; data safety monitoring board member at Corbus, Boehringer Ingelheim, Ferrer, Galapagos, Johnson & Johnson, Serena Guiducci: None declared, David Launay: None declared, Eric Hachulla: None declared, Jeska K. de Vries-Bouwstra ABBvie, Janssen, Boehringer-Ingerlheim, Pfizer, AstraZeneca, Bristol Myers Squibb, UCB, ABBvie, Janssen, Boehringer- Ingelheim, Janssen-Cilag, Galapagos, Roche, ReumaNederland, NVLE, Anna-Maria Hoffmann-Vold Boehringer Ingelheim, Janssen, Medscape, Merck Sharp & Dohme, Novartis and Roche, AbbVie, ARXX, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Janssen, Medscape, Merck Sharp & Dohme, Pliant Therapeutics, Roche and Werfen, Boehringer Ingelheim, Janssen, Marco Matucci-Cerinic: None declared, Oliver Distler 4P-Pharma, Abbvie, Acceleron, Acepodia Biotech, Aera, Alcimed, Altavant, Amgen, AnaMar, Anaveon AG, Argenx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Calluna (Arxx), Cantargia AB, Catalyze Capital, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, MSD Merck, Miltenyi Biotec, Mitsubishi Tanabe, Nkarta Inc., Novartis, Orion, Pilan, Prometheus, Quell, Redxpharma, Roivant, EMD Serono, Topadur and UCB. Patent issued "mir-29 for the treatment of systemic sclerosis" (US8247389, EP2331143). Co-founder of CITUS AG, BI, Kymera, Mitsubishi Tanabe, UCB, Cosimo Bruni Boehringer Ingelh

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