Research Article

Longitudinal Risk Phenotyping in Incident Systemic Sclerosis-associated Pulmonary Arterial Hypertension (SSc-PAH): An Unsupervised Cluster Analysis of the PHAROS Registry

Samuel H Friedman*, Jacob Williams, Madison Hyer2, Nicholas Fox, Viswanathan Ramakrishnan, Matthew R Lammi, Virginia D Steen and Rahul G Argula

Published: 15 March, 2024 | Volume 8 - Issue 1 | Pages: 015-022

Background: Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is characterized by pulmonary arterial remodeling resulting in right ventricular failure and death if untreated. Despite therapeutic advances, there is survival variability within the SSc-PAH population. The aim of this study was to delineate high-risk subgroups of SSc-PAH using readily available clinical parameters.
Methods: We analyzed data from the PHAROS database, a prospective observational registry of incident SSc-PAH patients. Latent class modeling was performed based on trends in 6MWD over time. We compared survival between the clusters regarding baseline clinical parameters and changes in these parameters over time.
Results: We identified four unique groups within 103 patients meeting our inclusion criteria, based on trajectories of 6MWD. Patients in Cluster 4 exhibited a decline in 6MWD over time and had the worst prognosis with a median survival of 3 years. Patients in Cluster 3, with the lowest baseline 6MWD, were associated with lower median survival (5 years) when compared to Clusters 1 and 2 (> 9 and 7 years, respectively), despite an improvement in 6MWD over time. There were no meaningful changes in SF-36 and WHO functional class between the clusters, but BNP trended higher over time in the higher-risk clusters. 
Conclusion: We identified high-risk subsets of SSc-PAH characterized by significantly worse survival. Incident SSc-PAH patients with a decline in 6MWD over time or low baseline 6MWD had worse survival when compared to SSc-PAH patients who demonstrated relatively stable or mild reduction in 6MWD over time.

Read Full Article HTML DOI: 10.29328/journal.jprr.1001053 Cite this Article Read Full Article PDF


  1. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017 Oct 7;390(10103):1685-1699. doi: 10.1016/S0140-6736(17)30933-9. Epub 2017 Apr 13. PMID: 28413064.
  2. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007 Jul;66(7):940-4. doi: 10.1136/ard.2006.066068. Epub 2007 Feb 28. PMID: 17329309; PMCID: PMC1955114.
  3. Chaisson NF, Hassoun PM. Systemic sclerosis-associated pulmonary arterial hypertension. Chest. 2013 Oct;144(4):1346-1356. doi: 10.1378/chest.12-2396. PMID: 24081346; PMCID: PMC3787920.
  4. Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M. A USA-based registry for pulmonary arterial hypertension: 1982-2006. Eur Respir J. 2007 Dec;30(6):1103-10. doi: 10.1183/09031936.00042107. Epub 2007 Sep 5. PMID: 17804449.
  5. 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. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006 May 1;173(9):1023-30. doi: 10.1164/rccm.200510-1668OC. Epub 2006 Feb 2. PMID: 16456139.
  6. 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. Update of screening and diagnostic modalities for connective tissue disease-associated pulmonary arterial hypertension. Semin Arthritis Rheum. 2019 Jun;48(6):1059-1067. doi: 10.1016/j.semarthrit.2018.10.010. Epub 2018 Oct 14. PMID: 30415942; PMCID: PMC7155785.
  7. Schoenfeld SR, Castelino FV. Evaluation and management approaches for scleroderma lung disease. Ther Adv Respir Dis. 2017 Aug;11(8):327-340. doi: 10.1177/1753465817713680. Epub 2017 Jun 16. PMID: 28621173; PMCID: PMC5933653.
  8. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004 Sep 30;351(14):1425-36. doi: 10.1056/NEJMra040291. PMID: 15459304.
  9. Rhee RL, Gabler NB, Sangani S, Praestgaard A, Merkel PA, Kawut SM. Comparison of Treatment Response in Idiopathic and Connective Tissue Disease-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2015 Nov 1;192(9):1111-7. doi: 10.1164/rccm.201507-1456OC. PMID: 26291092; PMCID: PMC4642205.
  10. Rubenfire M, Huffman MD, Krishnan S, Seibold JR, Schiopu E, McLaughlin VV. Survival in systemic sclerosis with pulmonary arterial hypertension has not improved in the modern era. Chest. 2013 Oct;144(4):1282-1290. doi: 10.1378/chest.12-0653. PMID: 23744060.
  11. Hinchcliff M, Fischer A, Schiopu E, Steen VD; PHAROS Investigators. Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS): baseline characteristics and description of study population. J Rheumatol. 2011 Oct;38(10):2172-9. doi: 10.3899/jrheum.101243. Epub 2011 Aug 15. PMID: 21844142; PMCID: PMC3230328.
  12. Kolstad KD, Li S, Steen V, Chung L; PHAROS Investigators. Long-Term Outcomes in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension From the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry (PHAROS). Chest. 2018 Oct;154(4):862-871. doi: 10.1016/j.chest.2018.05.002. Epub 2018 May 16. PMID: 29777655; PMCID: PMC6207791.
  13. Ramjug S, Hussain N, Hurdman J, Billings C, Charalampopoulos A, Elliot CA, Kiely DG, Sabroe I, Rajaram S, Swift AJ, Condliffe R. Idiopathic and Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: A Comparison of Demographic, Hemodynamic, and MRI Characteristics and Outcomes. Chest. 2017 Jul;152(1):92-102. doi: 10.1016/j.chest.2017.02.010. Epub 2017 Feb 20. PMID: 28223154.
  14. Morrisroe K, Stevens W, Huq M, Prior D, Sahhar J, Ngian GS, Celermajer D, Zochling J, Proudman S, Nikpour M; Australian Scleroderma Interest Group (ASIG). Survival and quality of life in incident systemic sclerosis-related pulmonary arterial hypertension. Arthritis Res Ther. 2017 Jun 2;19(1):122. doi: 10.1186/s13075-017-1341-x. PMID: 28576149; PMCID: PMC5457656.
  15. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon MD. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010 Feb;137(2):376-87. doi: 10.1378/chest.09-1140. Epub 2009 Oct 16. PMID: 19837821.
  16. Benza RL, Gomberg-Maitland M, Elliott CG, Farber HW, Foreman AJ, Frost AE, McGoon MD, Pasta DJ, Selej M, Burger CD, Frantz RP. Predicting Survival in Patients With Pulmonary Arterial Hypertension: The REVEAL Risk Score Calculator 2.0 and Comparison With ESC/ERS-Based Risk Assessment Strategies. Chest. 2019 Aug;156(2):323-337. doi: 10.1016/j.chest.2019.02.004. Epub 2019 Feb 14. PMID: 30772387.
  17. Mullin CJ, Khair RM, Damico RL, Kolb TM, Hummers LK, Hassoun PM, Steen VD, Mathai SC; PHAROS Investigators. Validation of the REVEAL Prognostic Equation and Risk Score Calculator in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension. Arthritis Rheumatol. 2019 Oct;71(10):1691-1700. doi: 10.1002/art.40918. Epub 2019 Aug 26. PMID: 31066998.
  18. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf 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. 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. 2016 Jan 1;37(1):67-119. doi: 10.1093/eurheartj/ehv317. Epub 2015 Aug 29. PMID: 26320113.
  19. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019 Jan 24;53(1):1801913. doi: 10.1183/13993003.01913-2018. PMID: 30545968; PMCID: PMC6351336.
  20. Weller BE, Bowen NK, Faubert SJ. Latent Class Analysis: A Guide to Best Practice. Journal of Black Psychology. 2020; 46(4):287-311.
  21. Demir R, Küçükoğlu MS. Six-minute walk test in pulmonary arterial hypertension. Anatol J Cardiol. 2015 Mar;15(3):249-54. doi: 10.5152/akd.2015.5834. PMID: 25880178; PMCID: PMC5337064.
  22. Moutchia J, McClelland RL, Al-Naamani N, Appleby DH, Blank K, Grinnan D, Holmes JH, Mathai SC, Minhas J, Ventetuolo CE, Zamanian RT, Kawut SM. Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2023 Apr 15;207(8):1070-1079. doi: 10.1164/rccm.202208-1547OC. PMID: 36629737; PMCID: PMC10112451.
  23. Steen VD, Medsger TA Jr. The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum. 1997 Nov;40(11):1984-91. doi: 10.1002/art.1780401110. PMID: 9365087.
  24. Rizzi M, Radovanovic D, Santus P, Airoldi A, Frassanito F, Vanni S, Cristiano A, Sarzi-Puttini P, Atzeni F. Usefulness of six-minute walk test in systemic sclerosis. Clin Exp Rheumatol. 2018 Jul-Aug;36 Suppl 113(4):161-167. Epub 2018 Sep 7. PMID: 30277863.
  25. Vandecasteele E, Melsens K, De Keyser F, De Pauw M, Deschepper E, Decuman S, Piette Y, Thevissen K, Brusselle G, Smith V. A prospective, longitudinal study evaluating the baseline six-minute walk test as an individual reference value in systemic sclerosis patients. Clin Exp Rheumatol. 2018 Jul-Aug;36 Suppl 113(4):95-101. Epub 2018 Aug 28. PMID: 30183593.
  26. Gabler NB, French B, Strom BL, Palevsky HI, Taichman DB, Kawut SM, Halpern SD. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012 Jul 17;126(3):349-56. doi: 10.1161/CIRCULATIONAHA.112.105890. Epub 2012 Jun 13. PMID: 22696079; PMCID: PMC4237273.
  27. Fritz JS, Blair C, Oudiz RJ, Dufton C, Olschewski H, Despain D, Gillies H, Kawut SM. Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension. Chest. 2013 Feb 1;143(2):315-323. doi: 10.1378/chest.12-0270. PMID: 22814814; PMCID: PMC4694187.
  28. Groepenhoff H, Vonk-Noordegraaf A, van de Veerdonk MC, Boonstra A, Westerhof N, Bogaard HJ. Prognostic relevance of changes in exercise test variables in pulmonary arterial hypertension. PLoS One. 2013 Sep 5;8(9):e72013. doi: 10.1371/journal.pone.0072013. PMID: 24039732; PMCID: PMC3764059.
  29. Launay D, Sobanski V, Hachulla E, Humbert M. Pulmonary hypertension in systemic sclerosis: different phenotypes. Eur Respir Rev. 2017 Sep 27;26(145):170056. doi: 10.1183/16000617.0056-2017. PMID: 28954767; PMCID: PMC9488608.
  30. Lammi MR, Saketkoo LA, Gordon JK, Steen VD. Changes in hemodynamic classification over time are common in systemic sclerosis-associated pulmonary hypertension: insights from the PHAROS cohort. Pulm Circ. 2018 Apr-Jun;8(2):2045893218757404. doi: 10.1177/2045893218757404. PMID: 29468935; PMCID: PMC5826006.
  31. Naeije R, Badagliacca R. The overloaded right heart and ventricular interdependence. Cardiovasc Res. 2017 Oct 1;113(12):1474-1485. doi: 10.1093/cvr/cvx160. PMID: 28957537.
  32. Badesch DB, Champion HC, Gomez Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S55-S66. doi: 10.1016/j.jacc.2009.04.011. PMID: 19555859.
  33. 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, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237. Erratum in: Eur Heart J. 2023 Apr 17;44(15):1312. PMID: 36017548.


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