Recent Advances in Targeted Therapy for Connective Tissue Disease-associated Pulmonary Arterial Hypertension

Yuming Liang

doi:10.54097/8pxn1d10

Authors

Yuming Liang

DOI:

https://doi.org/10.54097/8pxn1d10

Keywords:

Pulmonary Arterial Hypertension, Connective Tissue Disease, Pharmacotherapy, Targeted Therapy

Abstract

Pulmonary arterial hypertension (PAH) is a common and severe vascular complication in patients with connective tissue diseases (CTDs), and it also represents a leading cause of adverse outcomes and mortality in this population. Over the past decades, the continuous emergence of effective therapeutic approaches targeting the key signaling pathways of PAH has significantly alleviated patients’ symptoms and improved their quality of life. As a crucial subtype of PAH, patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) have also gained substantial benefits from these advances. Targeted therapy serves as the core treatment modality, and in recent years, numerous breakthroughs have been achieved in the field of CTD-PAH targeted therapy. This article systematically reviews the latest research progress of both traditional and emerging targeted therapies for CTD-PAH.

Downloads

Download data is not yet available.

References

[1] Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022; 43 (38): 3618-731.

[2] Southgate L, Machado RD, Gräf S, Morrell NW. Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol. 2020; 17 (2): 85-95.

[3] Yuan K, Shamskhou EA, Orcholski ME, et al. Loss of endothelium-derived wnt5a is associated with reduced pericyte recruitment and small vessel loss in pulmonary arterial hypertension. Circulation. 2019; 139 (14): 1710-24.

[4] Lau EMT, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol. 2017; 14 (10): 603-14.

[5] Zhang C, Ding H, Li J, et al. Epidemiology, disease burden of pulmonary arterial hypertension in china: a systematic literature review. Respir Med. 2025; 240: 108007.

[6] Stacher E, Graham BB, Hunt JM, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012; 186 (3): 261-72.

[7] He X, Fang J, Gong M, et al. Identification of immune-associated signatures and potential therapeutic targets for pulmonary arterial hypertension. J Cell Mol Med. 2023; 27 (23): 3864-77.

[8] Heukels P, Corneth OBJ, van Uden D, et al. Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension. Thorax. 2021; 76 (12): 1209-18.

[9] Mocumbi A, Humbert M, Saxena A, et al. Pulmonary hypertension. Nat Rev Dis Primers. 2024; 10 (1): 1.

[10] Boucly ANS, Gerges C, Savale L, et al. Pulmonary arterial hypertension. Presse Med. 2023; 52 (3): 104168.

[11] Condon DF, Agarwal S, Chakraborty A, et al. Novel mechanisms targeted by drug trials in pulmonary arterial hypertension. Chest. 2022; 161 (4): 1060-72.

[12] Pluchart HLN, Khouri C, Blaise S, Roustit M, Cracowski JL. Targeting the prostacyclin pathway: beyond pulmonary arterial hypertension. Trends Pharmacol Sci. 2017; 38 (6): 512-23.

[13] Cansu DNSD, Korkmaz C. Pulmonary hypertension in connective tissue diseases: epidemiology, pathogenesis, and treatment. Clin Rheumatol. 2023; 42 (10): 2601-10.

[14] Zeng C, Liu J, Zheng X, Hu X, He Y. Prostaglandin and prostaglandin receptors: present and future promising therapeutic targets for pulmonary arterial hypertension. Respir Res. 2023; 24 (1): 263.

[15] Dhoble S, Patravale V, Weaver E, Lamprou DA, Patravale T. Comprehensive review on novel targets and emerging therapeutic modalities for pulmonary arterial hypertension. Int J Pharm. 2022; 621: 121792.

[16] Feenstra J, Hopkins P, Trotter M, O'Brien K. Effectiveness of epoprostenol in the management of pulmonary arterial hypertension: findings of an australian retrospective chart review. Intern Med J. 2020; 50 (11): 1377-84.

[17] Tello K, Delcroix M, Pausch C, et al. Add-on therapy with parenteral prostacyclin analogues in patients with pulmonary arterial hypertension: insights from the COMPERA registry. J Heart Lung Transplant. 2026; 45 (2): 284-8.

[18] Bruni C, Cometi L, Gigante A, Rosato E, Matucci-Cerinic M. Prediction and primary prevention of major vascular complications in systemic sclerosis. Eur J Intern Med. 2021; 87: 51-8.

[19] Gaine S, Chin K, Coghlan G, et al. Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. Eur Respir J. 2017; 50 (2).

[20] Gaine S, Escribano-Subias P, Muller A, et al. Selexipag in patients with pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD): real-world experience from EXPOSURE. Pulm Circ. 2024; 14 (3): e12403.

[21] Burger CD, Tang W, Tsang Y, Panjabi S. Early addition of selexipag to double therapy for pulmonary arterial hypertension. JAMA Netw Open. 2024; 7 (9): e2434691.

[22] Barberà J, Jansa P, Klings E, et al. Ralinepag phase II open-label extension study in patients with pulmonary arterial hypertension. Adv Ther. 2024; 41 (3): 1062-74.

[23] Torres F, Farber H, Ristic A, et al. Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial. Eur Respir J. 2019; 54 (4).

[24] Lázár ZF, Mészáros M, Bikov A. The nitric oxide pathway in pulmonary arterial hypertension: pathomechanism, biomarkers and drug targets. Curr Med Chem. 2020; 27 (42): 7168-88.

[25] Benza RL, Grünig E, Sandner P, Stasch JP, Simonneau GR. The nitric oxide-soluble guanylate cyclase-cGMP pathway in pulmonary hypertension: from PDE5 to soluble guanylate cyclase. Eur Respir Rev. 2024; 33 (171).

[26] Zhao J, Wang Q, Deng X, et al. The treatment strategy of connective tissue disease associated pulmonary arterial hypertension: evolving into the future. Pharmacol Ther. 2022; 239: 108192.

[27] Wang RR, Yuan TY, Wang JM, et al. Immunity and inflammation in pulmonary arterial hypertension: from pathophysiology mechanisms to treatment perspective. Pharmacol Res. 2022; 180: 106238.

[28] Favoino E, Prete M, Liakouli V, et al. Idiopathic and connective tissue disease-associated pulmonary arterial hypertension (PAH): similarities, differences and the role of autoimmunity. Autoimmun Rev. 2024; 23 (4): 103514.

[29] Cianciarulo C, Nguyen TH, Zacharias A, Standen N, Tucci J, Irving H. Analysis of phosphodiesterase-5 (PDE5) inhibitors in modulating inflammatory markers in humans: a systematic review and meta-analysis. Int J Mol Sci. 2025; 26 (15).

[30] Jin YS, Yang B, Ding L, Jiang B. [Mechanism of vitamin d deficiency involvement in the development of pulmonary arterial hypertension related to monocrotaline-induced connective tissue disease in rats]. Zhonghua Yi Xue Za Zhi. 2024; 104 (43): 3972-9.

[31] Adão R, Barreira B, Paternoster E, et al. Vitamin d as an add-on therapy to phosphodiesterase-5 inhibitor in experimental pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. 2025; 328 (2): L253-9.

[32] Hoeper MM, Al-Hiti H, Benza RL, et al. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. Lancet Respir Med. 2021; 9 (6): 573-84.

[33] Humbert M, Hassoun PM, Chin KM, et al. MK-5475, an inhaled soluble guanylate cyclase stimulator, for treatment of pulmonary arterial hypertension: the INSIGNIA-PAH study. Eur Respir J. 2024; 64 (5).

[34] Galiè N, Müller K, Scalise AV, Grünig E. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur Respir J. 2015; 45 (5): 1314-22.

[35] Motte S, Mcentee K, Naeije R. Endothelin receptor antagonists. Pharmacol Ther. 2006; 110 (3): 386-414.

[36] Fischer A, Denton CP, Matucci-Cerinic M, et al. Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) - a subgroup analysis of the ARIES-e clinical trial. Respir Med. 2016; 117: 254-63.

[37] Li M, Jing ZC, Li Y, et al. Efficacy and safety of ambrisentan in chinese patients with connective tissue disease-pulmonary arterial hypertension: a post-hoc analysis. BMC Cardiovasc Disord. 2020; 20 (1): 339.

[38] Kuang HY, Li Q, Du HA, Chen M, Yin YH. Efficacy and safety of long-term oral bosentan in different types of pulmonary arterial hypertension: a systematic review and meta-analysis. Am J Cardiovasc Drugs. 2021; 21 (2): 181-91.

[39] Dong S, Guo X, Wang H, Sun C. Liver injury due to endothelin receptor antagonists: a real-world study based on post-marketing drug monitoring data. Ther Adv Respir Dis. 2024; 18: 17534666231223606.

[40] Gebreselassie A, Aduli F, Howell CD. Rheumatologic diseases and the liver. Clin Liver Dis. 2019; 23 (2): 247-61.

[41] Pulido TS, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013; 369 (9): 809-18.

[42] Souza RRO, Delcroix M, Galié N, et al. Long-term safety, tolerability and survival in patients with pulmonary arterial hypertension treated with macitentan: results from the SERAPHIN open-label extension. Adv Ther. 2022; 39 (9): 4374-90.

[43] Channick R, Chin KM, Mclaughlin VV, et al. Macitentan in pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH): real-world evidence from the combined OPUS/OrPHeUS dataset. Cardiol Ther. 2024; 13 (2): 315-39.

[44] Adu-Amankwaah J, Shi Y, Song H, et al. Signaling pathways and targeted therapy for pulmonary hypertension. Signal Transduct Target Ther. 2025; 10 (1): 207.

[45] Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023; 388 (16): 1478-90.

[46] Mclaughlin V, Alsumali A, Liu R, et al. Population health model predicting the long-term impact of sotatercept on morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Adv Ther. 2024; 41 (1): 130-51.

[47] Preston IR, Badesch D, Ghofrani HA, et al. A long-term follow-up study of sotatercept for treatment of pulmonary arterial hypertension: interim results of SOTERIA. Eur Respir J. 2025; 66 (1).

[48] Ten Freyhaus H, Dumitrescu D, Berghausen E, Vantler M, Caglayan E, Rosenkranz S. Imatinib mesylate for the treatment of pulmonary arterial hypertension. Expert Opin Investig Drugs. 2012; 21 (1): 119-34.

[49] Pullamsetti SS, Sitapara R, Osterhout R, et al. Pharmacology and rationale for seralutinib in the treatment of pulmonary arterial hypertension. Int J Mol Sci. 2023; 24 (16).

[50] Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010; 182 (9): 1171-7.

[51] Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013; 127 (10): 1128-38.

[52] Rothman AMK, Villar SS, Middleton J, et al. Positioning imatinib for pulmonary arterial hypertension: a dose-finding phase 2 study. Am J Respir Crit Care Med. 2025; 211 (6): 1018-27.

[53] Galkin A, Sitapara R, Clemons B, et al. Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension. Eur Respir J. 2022; 60 (6).

[54] Frantz RP, Mclaughlin VV, Sahay S, et al. Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir Med. 2024; 12 (7): 523-34.

[55] Sitbon O, Sahay S, Escribano Subías P, et al. Seralutinib for the treatment of pulmonary arterial hypertension in adults: TORREY open-label extension study. Adv Ther. 2025; 42 (10): 5104-23.

[56] Carbonera S, Scelsi L, Greco A, et al. Pulmonary arterial hypertension onset in an adult woman with a TBX4 likely pathogenic variant following imatinib administration: a case report. Am J Med Genet A. 2025; 197 (11): e64178.

[57] Zamanian RT, Badesch D, Chung L, et al. Safety and efficacy of b-cell depletion with rituximab for the treatment of systemic sclerosis-associated pulmonary arterial hypertension: a multicenter, double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2021; 204 (2): 209-21.

[58] Touil A, Bouden S, Maazaoui S, et al. Rituximab treatment for connective tissue diseases associated-pulmonary hypertension: a systematic literature review. Expert Rev Respir Med. 2025: 1-8.