S13:5 | Association between vasoactive-vasodilating therapy and reduced detection of pulmonary arterial hypertension in systemic sclerosis: evidence from a European Scleroderma Trials and Research study

Nicola Farina¹, Silvia Bellando-Randone¹, Sebastien Sanges², Hilde Jenssen Bjørkekjær³, Lorenzo Tofani⁴, Marie-Elise Truchetet⁵, Vanessa Smith⁶, Andra Balanescu⁷, Christina Bergmann⁸, Yannick Allanore⁹, Philipp Klemm¹⁰, Simona Truglia¹¹, Luca Idolazzi¹², Christopher Denton¹³, Roberta Foti¹⁴, Anna Wojteczek¹⁵, Emmanuel Chatelus¹⁶, Madelon Vonk¹⁷, Serena Guiducci¹, David Launay², Eric Hachulla², Jeska De Vries-Bouwstra¹⁸, Anna-Maria Hoffmann-Vold¹⁹, Oliver Distler²⁰, Marco Matucci-Cerinic¹, Cosimo Bruni¹. | ¹Department of Experimental and Clinical Medicine, Scleroderma Unit, Division of Rheumatology, University of Florence, Az, Firenze, Italy; ²Univ. Lille, Inserm, CHU Lille, Department of Internal Medicine and Clinical Immunology, Reference Center for Rare Autoi, Lille, France; ³Department of Rheumatology, Hospital of Southern Norway, Kristiansand, Norway; ⁴Department of Statistics, Informatics and Applications, University of Florence, Firenze, Italy; ⁵Rheumatology department, CHU de Bordeaux, Bordeaux, France; ⁶University of Ghent, Department of Rheumatology, Gent, Belgium; ⁷Department of Rheumatology, St. Maria Hospital, Carol Davila, University of Medicine and Pharmacy Bucharest Romania; ⁸Department Internal Medicine 3, University Hospital Erlangen, Erlangen, Germany; ⁹Rheumatology Department, Université Paris Cité, Cochin Hospital, Paris, France; ¹⁰Department of Rheumatology and Clinical Immunology Center, JLU Giessen, Campus Kerckhoff Bad Nauheim Germany; ¹¹Reumatologia, Azienda Ospedaliero-Universitaria Policlinico Umberto I, Roma, Italy; ¹²Section of Rheumatology, Department of Medicine, University of Verona, Verona, Italy; ¹³Centre for Rheumatology, Royal Free London and University College London Medical School, London, United Kingdom; ¹⁴Division of Rheumatology, A.O.U. Policlinico-San Marco, Catania, Italy; ¹⁵Department of Rheumatology, Clinical Immunology, Geriatrics and Internal Medicine, Medical University of Gdansk, Univers Gdansk Poland; ¹⁶Department of Rheumatology, University Hospital Strasbourg Strasbourg France; ¹⁷Department of rheumatology, Radboud University Nijmegen Medical Center Nijmegen The Netherlands; ¹⁸Department of Rheumatology, Leiden University Medical Center Leiden The Netherlands; ¹⁹Department of Rheumatology, Oslo University Hospital, Oslo, Norway; ²⁰Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background. Vasoactive-vasodilating drugs (VVD) are the cornerstone of the treatment of pulmonary arterial hypertension (PAH), a form of precapillary pulmonary hypertension (pPH) that represents a complication of systemic sclerosis (SSc). VVD categories include endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5i) and prostanoids, which are commonly used to treat digital ulcers (DU) and Raynaud’s phenomenon. As protective effects remain unclear, we investigated the effectiveness of VVD on the primary prevention of pPH.

Materials and Methods. SSc patients from the EUSTAR cohort who underwent right heart catheterization (RHC) were included; postcapillary PH cases (pulmonary wedge pressure – PWP >15 mmHg) were excluded. Multivariable logistic regression assessed the association between exposure to VVD and detection of pPH (mPAP>20 mmHg, PVR>2 WU and PWP<15 mmHg) and of PAH (pPH, ILD extent <20% and FVC >70%). Models 1 and 2 tested the exposure at the time of RHC ever and ongoing to VVD categories, models 3 and 4 tested the same for specific VVD molecules. The primary outcome was the diagnosis of precapillary PH; PAH was analyzed as sensitivity analyses. All models were adjusted for known confounders. Interaction terms between VVDs and current DU were also tested.

Results. Among 944 eligible patients, 498 (53%) were diagnosed with pPH, of whom 367 (74%) had PAH (Table 1). For VVD classes, a statistically significant association was detected for the interaction of ERAs and current DU with the detection of pPH, in both logistic regression models 1 and 2 (Figure 1a and 1b). However, this finally resulted in a non-significant association between ERAs exposure in patients with current DU and PH detection when calculating marginal effects estimates (ERAs ongoing: OR 0.435, 95%CI 0.193-1.064; ERAs ever: OR 0.636, 95%CI 0.349-1.158). Additionally, both models showed lack of effectiveness of ERAs in patients without current DU, as well as for PDE5i or prostanoids overall. When focusing on specific VVD molecules, exposure “ever” to bosentan showed a significant protective association with pPH diagnosis, independently from the presence or absence of current DU (Figure 1c). Finally, we noted a statistically significant interaction between ongoing bosentan and current DU, which turned into a significant marginal effects estimate (OR 0.230, 95% CI 0.081 – 0.652) indicating protective effects of this medication towards the diagnosis of pPH in patients with current DU (Figure 1d). The protective effects of bosentan were confirmed in all sensitivity analyses targeting PAH detection.

Conclusions. Our data show that bosentan is associated with less frequent diagnosis of PAH and precapillary PH, in particular when employed in patients with current DU at the time of RHC. Our results support further research to optimize the timing and patient selection for VVD therapy in SSc, aiming also at additional preventive effects at pulmonary level.