Skip to main content

Pulmonary hypertension in connective tissue diseases: epidemiology, pathogenesis, and treatment

Clinical Rheumatology (2022)Cite this article

Abstract

Pulmonary hypertension (PH) is a clinical condition characterized by increased pulmonary arterial pressure arising from a heterogeneous range of diseases that has a deteriorating effect on the quality of life and may cause early mortality if left untreated. Connective tissue disorders (CTD)-associated PH is the second most common cause of pulmonary arterial hypertension (PAH), after the idiopathic form, categorized as group I. Systemic scleroderma (SSc) accounts for 75% of CTD-associated PH cases. Although SSc ranks first place for CTD-associated PH, SSc is followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), having a lesser frequency of PH occurrence, while it occurs as a rare complication in cases with rheumatoid arthritis (RA) and inflammatory myositis. PH may also occur during non-SSc CTDs and even other rheumatic diseases, including Behcet’s disease and adult-onset Still’s disease, albeit to a lesser extent. The prognosis of CTD-associated PH is worse than the other forms of PH. Although, as in idiopathic pulmonary arterial hypertension (IPAH), the mechanism of CTD-related PH is associated with an increase in vasoconstrictors like endothelin-1 and a decrease in vasodilators like prostacyclin and nitric oxide production, inflammation, and autoimmune mechanisms also play a role in the development and progression of PH. This may lead to the involvement of more than one mechanism in CTD-associated PH. Knowing which mechanism is dominant is very important in determining the treatment option. This review will primarily focus on the epidemiology, risk factors, and prognosis of PH that develops during rheumatic diseases; the pathogenesis and treatment will be briefly mentioned in light of the newly published guidelines.

Key Points

•Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) in Western countries is the second most common type of PAH after idiopathic PAH (IPAH).

•CTD-PH can be seen most often in systemic scleroderma (SSc), less in systemic lupus erythematosus (SLE), mixed CTD (MCTD), and rarely in other CTDs.

•While current guidelines recommend annual transthoracic echocardiography as a screening test for asymptomatic SSc patients, screening for PH is not advised in the absence of symptoms suggestive of PH in other CTDs.

•CTD-PH treatment can be divided into specific vasodilator PH treatments and immunosuppressive therapy. Current treatment guidelines recommend the same treatment algorithm for patients with CTD-associated PH as for patients with IPAH. Several case series have shown the beneficial effect of immunosuppressive agents in patients with SLE-PH and MCTD-PH.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Data availability

Data is available upon a reasonable request.

Materials availability

Data is available upon a reasonable request.

Code availability

Not applicable.

References

  1. Sarzi-Puttini P, Atzeni F, Gerli R, Bartoloni E, Doria A, Barskova T, Matucci-Cerinic M, Sitia S, Tomasoni L, Turiel M (2010) Cardiac involvement in systemic rheumatic diseases: an update. Autoimmun Rev 9(12):849–852. https://doi.org/10.1016/j.autrev.2010.08.002

    Article  PubMed  Google Scholar 

  2. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, VonkNoordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, ESC Scientific Document Group (2016) 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1):67–119. https://doi.org/10.1093/eurheartj/ehv317

    Article  PubMed  Google Scholar 

  3. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R (2019) Hemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 53(1):1801913. https://doi.org/10.1183/13993003.01913-2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, VonkNoordegraaf A, Delcroix M, Rosenkranz S, ESC/ERS Scientific Document Group (2022) 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 43(38):3618–3731. https://doi.org/10.1093/eurheartj/ehac237

    Article  PubMed  Google Scholar 

  5. Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD (2011) Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int 31(11):1409–1417. https://doi.org/10.1007/s00296-011-1999-3

    Article  PubMed  Google Scholar 

  6. McGoon MD, Miller DP (2012) REVEAL: a contemporary US pulmonary arterial hypertension registry. Eur Respir Rev 21(123):8–18. https://doi.org/10.1183/09059180.00008211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JS, Vrapi F, Das C, Elliot CA, Johnson M, DeSoyza J, Torpy C, Goldsmith K, Hodgkins D, Hughes RJ, Pepke-Zaba J, Coghlan JG (2009) Connective tissue disease-associated pulmonary arterial hype`rtension in the modern treatment era. Am J Respir Crit Care Med 179(2):151–157. https://doi.org/10.1164/rccm.200806-953OC

    Article  PubMed  Google Scholar 

  8. Zhao J, Wang Q, Liu Y, Tian Z, Guo X, Wang H, Lai J, Huang C, Yang X, Li M, Zeng X (2017) Clinical characteristics and survival of pulmonary arterial hypertension associated with three major connective tissue diseases: a cohort study in China. Int J Cardiol 236:432–437. https://doi.org/10.1016/j.ijcard.2017.01.097

    Article  PubMed  Google Scholar 

  9. Jeon CH, Chai JY, Seo YI, Jun JB, Koh EM, Lee SK, pulmonary hypertension study group of Korean College of Rheumatology (2012) Pulmonary hypertension associated with rheumatic diseases: baseline characteristics from the Korean registry. Int J Rheum Dis 15(5):e80-9. https://doi.org/10.1111/j.1756-185X.2012.01815.x

    Article  PubMed  Google Scholar 

  10. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G (2006) Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 173(9):1023–1030. https://doi.org/10.1164/rccm.200510-1668OC

    Article  PubMed  Google Scholar 

  11. Mathai SC (2022) Pulmonary hypertension associated with connective tissue disease.Cardiol Clin 40(1):29-43. https://doi.org/10.1016/j.ccl.2021.08.003.

  12. Zanatta E, Polito P, Famoso G, Larosa M, De Zorzi E, Scarpieri E, Cozzi F, Doria A (2019) Pulmonary arterial hypertension in connective tissue disorders: pathophysiology and treatment. Exp Biol Med (Maywood) 244(2):120–131. https://doi.org/10.1177/1535370218824101 (Epub 2019 Jan 22)

    Article  CAS  Google Scholar 

  13. Tselios K, Gladman DD, Urowitz MB (2016) Systemic lupus erythematosus and pulmonary arterial hypertension: links, risks, and management strategies. Open Access Rheumatol 9:1–9. https://doi.org/10.2147/OARRR.S123549

    Article  PubMed  PubMed Central  Google Scholar 

  14. Young A, Nagaraja V, Basilious M, Habib M, Townsend W, Gladue H, Badesch D, Gibbs JSR, Gopalan D, Manes A, Oudiz R, Satoh T, Torbicki A, Torres F, McLaughlin V, Khanna D (2019) Update of screening and diagnostic modalities for connective tissue disease-associated pulmonary arterial hypertension. Semin Arthritis Rheum 48(6):1059–1067. https://doi.org/10.1016/j.semarthrit.2018.10.010

    Article  PubMed  Google Scholar 

  15. Hao Y, Thakkar V, Stevens W, Morrisroe K, Prior D, Rabusa C, Youssef P, Gabbay E, Roddy J, Walker J, Zochling J, Sahhar J, Nash P, Lester S, Rischmueller M, Proudman SM, Nikpour M (2015) A comparison of the predictive accuracy of three screening models for pulmonary arterial hypertension in systemic sclerosis. Arthritis Res Ther 17(1):7. https://doi.org/10.1186/s13075-015-0517-5

    Article  PubMed  PubMed Central  Google Scholar 

  16. Naranjo M, Hassoun PM (2021) Systemic sclerosis-associated pulmonary hypertension: spectrum and impact. Diagnostics (Basel) 11(5):911. https://doi.org/10.3390/diagnostics11050911

    Article  CAS  Google Scholar 

  17. Dimitroulas T, Giannakoulas G, Papadopoulou K, Sfetsios T, Karvounis H, Dimitroula H, Parcharidou D, Koliakos G, Garyfallos A, Styliadis I, Settas L (2010) Left atrial volume and N-terminal pro-B type natriuretic peptide are associated with elevated pulmonary artery pressure in patients with systemic sclerosis. Clin Rheumatol 29(9):957–964. https://doi.org/10.1007/s10067-010-1494-3 (Epub 2010 Jun 5)

    Article  PubMed  Google Scholar 

  18. Coghlan JG, Denton CP, Grünig E, Bonderman D, Distler O, Khanna D, Müller-Ladner U, Pope JE, Vonk MC, Doelberg M, Chadha-Boreham H, Heinzl H, Rosenberg DM, McLaughlin VV, Seibold JR, DETECT study group (2014) Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis 73(7):1340–9. https://doi.org/10.1136/annrheumdis-2013-203301

    Article  PubMed  Google Scholar 

  19. Thakkar V, Stevens WM, Prior D, Moore OA, Byron J, Liew D, Patterson K, Hissaria P, Roddy J, Zochling J, Sahhar J, Nash P, Tymms K, Celermajer D, Gabbay E, Youssef P, Proudman SM, Nikpour M (2012) The N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: a case-control study. Arthritis Res Ther 14(3):R143. https://doi.org/10.1186/ar3876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Allcock RJ, Forrest I, Corris PA, Crook PR, Griffiths ID (2004) A study of the prevalence of systemic sclerosis in northeast England. Rheumatology (Oxford) 43(5):596–602. https://doi.org/10.1093/rheumatology/keh124

    Article  CAS  Google Scholar 

  21. Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D (2003) Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 48(8):2246–2255. https://doi.org/10.1002/art.11073

    Article  PubMed  Google Scholar 

  22. Condliffe R, Howard LS (2015) Connective tissue disease-associated pulmonary arterial hypertension. F1000Prime Rep 7:06. https://doi.org/10.12703/P7-06

  23. Fayed H, Coghlan JG (2019) Pulmonary hypertension associated with connective tissue disease. Semin Respir Crit Care Med 40(2):173–183. https://doi.org/10.1055/s-0039-1685214

    Article  PubMed  Google Scholar 

  24. Steen V, Medsger TA Jr (2003) Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 48(2):516–522. https://doi.org/10.1002/art.10775

    Article  PubMed  Google Scholar 

  25. Launay D, Sitbon O, Hachulla E, Mouthon L, Gressin V, Rottat L, Clerson P, Cordier JF, Simonneau G, Humbert M (2013) Survival in systemic sclerosis-associated pulmonary arterial hypertension in the modern management era. Ann Rheum Dis 72(12):1940–1946. https://doi.org/10.1136/annrheumdis-2012-202489

    Article  PubMed  Google Scholar 

  26. Brown Z, Proudman S, Morrisroe K, Stevens W, Hansen D, Nikpour M (2021) Screening for the early detection of pulmonary arterial hypertension in patients with systemic sclerosis: a systematic review and meta-analysis of long-term outcomes. Semin Arthritis Rheum 51(3):495–512. https://doi.org/10.1016/j.semarthrit.2021.03.011

    Article  PubMed  Google Scholar 

  27. Onuora S (2020) Treatment of pulmonary hypertension in SSc. Nat Rev Rheumatol 16(11):602. https://doi.org/10.1038/s41584-020-00512-y

    Article  PubMed  Google Scholar 

  28. Haque A, Kiely DG, Kovacs G, Thompson AAR, Condliffe R (2021) Pulmonary hypertension phenotypes in patients with systemic sclerosis. Eur Respir Rev 30(161):210053. https://doi.org/10.1183/16000617.0053-2021

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dhala A (2012) Pulmonary arterial hypertension in systemic lupus erythematosus: current status and future direction. Clin Dev Immunol 2012:854941. https://doi.org/10.1155/2012/854941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Prabu A, Patel K, Yee CS, Nightingale P, Situnayake RD, Thickett DR, Townend JN, Gordon C (2009) Prevalence and risk factors for pulmonary arterial hypertension in patients with lupus. Rheumatology (Oxford) 48(12):1506–1511. https://doi.org/10.1093/rheumatology/kep203

    Article  Google Scholar 

  31. Szodoray P, Hajas A, Kardos L, Dezso B, Soos G, Zold E, Vegh J, Csipo I, Nakken B, Zeher M, Szegedi G, Bodolay E (2012) Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus 21(13):1412–1422. https://doi.org/10.1177/0961203312456751

    Article  CAS  PubMed  Google Scholar 

  32. Gunnarsson R, Andreassen AK, Molberg Ø, Lexberg ÅS, Time K, Dhainaut AS, Bertelsen LT, Palm Ø, Irgens K, Becker-Merok A, Nordeide JL, Johnsen V, Pedersen S, Prøven A, Garabet LS, Garen T, Aaløkken TM, Gilboe IM, Gran JT (2013) Prevalence of pulmonary hypertension in an unselected, mixed connective tissue disease cohort: results of a nationwide, Norwegian cross-sectional multicentre study and review of current literature. Rheumatology (Oxford) 52(7):1208–1213. https://doi.org/10.1093/rheumatology/kes430

    Article  CAS  Google Scholar 

  33. Khanna D, Gladue H, Channick R, Chung L, Distler O, Furst DE, Hachulla E, Humbert M, Langleben D, Mathai SC, Saggar R, Visovatti S, Altorok N, Townsend W, FitzGerald J, McLaughlin VV, Foundation S, Association PH (2013) Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheum 65(12):3194–3201. https://doi.org/10.1002/art.38172

    Article  PubMed  Google Scholar 

  34. Sadeghi S, Granton JT, Akhavan P, Pasarikovski CR, Roos AM, Thenganatt J, Moric J, Johnson SR (2015) Survival in rheumatoid arthritis-associated pulmonary arterial hypertension compared with idiopathic pulmonary arterial hypertension. Respirology 20(3):481–487. https://doi.org/10.1111/resp.12464

    Article  PubMed  Google Scholar 

  35. Bhansing KJ, Vonk-Noordegraaf A, Oosterveer FP, van Riel PL, Vonk MC (2017) Pulmonary arterial hypertension, a novelty in idiopathic inflammatory myopathies: insights and first experiences with vasoactive therapy. RMD Open 3(1):e000331. https://doi.org/10.1136/rmdopen-2016-000331

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sanges S, Yelnik CM, Sitbon O, Benveniste O, Mariampillai K, Phillips-Houlbracq M, Pison C, Deligny C, Inamo J, Cottin V, Mouthon L, Launay D, Lambert M, Hatron PY, Rottat L, Humbert M, Hachulla E (2016) Pulmonary arterial hypertension in idiopathic inflammatory myopathies: data from the French pulmonary hypertension registry and review of the literature. Medicine (Baltimore) 95(39):e4911. https://doi.org/10.1097/MD.0000000000004911

    Article  Google Scholar 

  37. Goulabchand R, Roubille C, Montani D, Fesler P, Bourdin A, Malafaye N, Morel J, Arnaud E, Lattuca B, Barateau L, Guilpain P, Mura T (2021) Cardiovascular events, sleep apnoea, and pulmonary hypertension in primary Sjögren’s syndrome: data from the French health insurance database. J Clin Med 10(21):5115. https://doi.org/10.3390/jcm10215115

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sato T, Hatano M, Iwasaki Y, Maki H, Saito A, Minatsuki S, Inaba T, Amiya E, Fujio K, Watanabe M, Yamamoto K, Komuro I (2018) Prevalence of primary Sjögren’s syndrome in patients undergoing evaluation for pulmonary arterial hypertension. PLoS ONE 13(5):e0197297. https://doi.org/10.1371/journal.pone.0197297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Heper G, Polat M, Yetkin E, Senen K (2010) Cardiac findings in Behçet’s patients. Int J Dermatol 49(5):574–578. https://doi.org/10.1111/j.1365-4632.2010.04424.x

    Article  PubMed  Google Scholar 

  40. Espinosa G, Blanco I, Antón JM, Sánchez M, Macchiarini P, Barberà JA (2010) Chronic thromboembolic pulmonary hypertension in Behçet’s disease: effectiveness of endarterectomy. Clin Exp Rheumatol 28(4 Suppl 60):S79-81

    PubMed  Google Scholar 

  41. Yıldızeli ŞO, Yanartaş M, Taş S, Direskeneli H, Mutlu B, Ceyhan B, Yıldızeli B (2018) Outcomes of patients with Behçet’s syndrome after pulmonary endarterectomy. Thorac Cardiovasc Surg 66(2):187–192. https://doi.org/10.1055/s-0037-1604411

    Article  PubMed  Google Scholar 

  42. Narváez J, Mora-Limiñana M, Ros I, Ibañez M, Valldeperas J, Crémer D, Nolla JM, Juan-Mas A (2019) Pulmonary arterial hypertension in adult-onset Still’s disease: a case series and systematic review of the literature. Semin Arthritis Rheum 9(1):162–170. https://doi.org/10.1016/j.semarthrit.2018.11.007

    Article  Google Scholar 

  43. Lefèvre G, Dauchet L, Hachulla E, Montani D, Sobanski V, Lambert M, Hatron PY, Humbert M, Launay D (2013) Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum 65(9):2412–2423. https://doi.org/10.1002/art.38029

    Article  PubMed  Google Scholar 

  44. Jais X, Launay D, Yaici A, Le Pavec J, Tchérakian C, Sitbon O, Simonneau G, Humbert M (2008) Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum 58(2):521–531. https://doi.org/10.1002/art.23303

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology, Faculty of Medicine, Department of Internal Medicine, Eskişehir Osmangazi University, 26480, Eskişehir, Turkey

    Döndü Üsküdar Cansu & Cengiz Korkmaz

Authors
  1. Döndü Üsküdar Cansu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cengiz Korkmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DUC conceived the study; DUC collected the data; DUC and CK wrote the first draft of the manuscript; DUC and CK revised the manuscript. All authors read and approved the final version before submission.

Corresponding author

Correspondence to Döndü Üsküdar Cansu.

Ethics declarations

Consent for publication

Not applicable.

Disclosures

None.

Disclaimer

No part of this review, including ideas, text, and tables, is copied or published elsewhere in any language.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cansu, D.Ü., Korkmaz, C. Pulmonary hypertension in connective tissue diseases: epidemiology, pathogenesis, and treatment. Clin Rheumatol (2022). https://doi.org/10.1007/s10067-022-06446-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10067-022-06446-y

Keywords

  • Connective tissue disease
  • Pulmonary hypertension
  • Rheumatic disease
  • Rheumatology