What Is PAH-CTD?

PAH Introduction

Pulmonary arterial hypertension (PAH, WHO Group I) is a progressive syndrome resulting from restricted blood flow through the pulmonary arterial circulation, which leads to reduced cardiac output, right heart failure, and ultimately, death.1 PAH subgroups include idiopathic PAH, heritable PAH, drug- or toxin-induced PAH, and associated PAH. Associated PAH may be linked with a number of diseases or conditions, including connective tissue disease (CTD).2

Prevalence of PAH-SSc

PAH associated with connective tissue disease (PAH-CTD) is the second most prevalent type of PAH (after idiopathic PAH) in the US and Europe,3 affecting 0.5% to 15% of patients with CTD.4 Although PAH-CTD can affect patients of all races, among people in the National Biological Sample and Data Repository for PAH (PAH Biobank), African American patients were 2.5 times more likely to have PAH-CTD than patients of other races.5* PAH may be a serious complication of CTD such as systemic sclerosis (SSc, or scleroderma), mixed CTD, and systemic lupus erythematosus (SLE).6,7

PAH-CTD associations6
PAH-CTD associations chart PAH-CTD associations chart

While SLE and rheumatoid arthritis are among the most common CTDs, PAH occurs most 
frequently in SSc, with 74% of PAH-CTD cases being diagnosed in patients with SSc.6

≈100,000 people living with SSc in the United States8
5% to 12% of patients with SSc will develop PAH3
44% of patients with PAH-SSc in the DETECT study with follow-up data (25/57) progressed during a short time (median observation time, 12.6 months)9†
You can help make the connection between CTD and the risk of PAH earlier using noninvasive tests—see how the DETECT algorithm can help identify patients with SSc in need of right heart catheterization.10 Learn More >

PAH-SSc and Racial Disparities

As mentioned above, PAH-CTD may disproportionately occur in African Americans compared with other races.5 That disparity may persist in PAH-SSc:

One study from 2003 found that 48% (n=130) OF AFRICAN AMERICANS IN A SCLERODERMA CENTER HAD PAH, compared with 39% OVERALL (n=709)11

Another study from 2014 reported that AFRICAN AMERICAN PATIENTS (n=29) HAD GREATER DISEASE SEVERITY AT PAH-SSc DIAGNOSIS, including worse Functional Class, right ventricular function, NT-proBNP and 6-minute walk distance THAN EUROPEAN AMERICAN PATIENTS (n=131)12‡

The PAH-SSc Link

SSc is a chronic, inflammatory, autoimmune disease characterized by endothelial dysfunction and microvascular disease.13-15 This baseline inflammation and endothelial dysfunction contributes to the development of associated PAH, followed by vasoconstriction and vascular remodeling and eventual right heart failure.6,13 While earlier-stage PAH is characterized by smooth muscle hypertrophy and vasoconstriction, proliferative features predominate in later stages.16 It is in this stage of progression that most patients with PAH-SSc are diagnosed, reducing effectiveness of vasodilator treatment and carrying a worse prognosis.16-18

Diagram showing pathoggenesis of PAH

PATHOGENESIS OF PAH16

Diagram showing vasoconstriction and advanced vascular lesion
Figure reproduced with permission from [JAMA. 2000;284(24):3160-3168.]. Copyright ©2000 American Medical Association. All rights reserved.

Delays in PAH-SSc Diagnosis

Patients with SSc can develop PAH at any time, but experience a median delay in diagnosis of 4 years.19 The following chart is an example for illustrative purposes only to portray the delay in diagnosis of PAH-SSc that a patient may experience. In some patients with SSc, median time to diagnosis of SSc after Raynaud’s phenomenon onset was 2.8 years.20 Additionally, median time to diagnosis of PAH in patients with SSc was 4 years.19

Delay in PAH-SSc diagnosis19,20

4-year chart showing PAH-CTD diagnosis to detection
Learn about annual screenings for PAH in patients with SSc.3 Find Out What the Guidelines Say >

Symptoms and Risk Factors

Awareness of symptoms and predictive risk factors can help identify PAH in patients with SSc. Misdiagnosis and delayed diagnosis may be attributed to the nonspecific nature of the presenting symptoms.21,22

Symptoms of PAH-SSc13

  • Dyspnea
  • Syncope
  • Orthostasis
  • Fatigue
  • Chest pain

Regular screening followed by diagnostic right heart catheterization is required to consistently detect PAH-SSc.23

Risk factors for PAH-SSc24,25

Time-Related Risk Factors

  • Older age at scleroderma onset
  • Long-standing disease

Co-Existing Conditions

  • Limited cutaneous scleroderma
  • Cutaneous telangiectasias
  • Severe digital ischemia
  • Severe Raynaud’s phenomenon

Diagnostic Results

  • Nucleolar pattern of antinuclear antibodies
  • Anticentromere antibodies
  • Declining or isolated low Dlco
*This 2017 study of racial and ethnic differences in PAH included 1837 White, African American, and Hispanic patients enrolled in the National Biological Sample and Data Repository for PAH (PAH Biobank).5
DETECT was a global cross-sectional study involving 62 experienced centers. DETECT was funded and supported by Actelion Pharmaceuticals Ltd. 488 patients with SSc enrolled between 2008 and 2011, and nearly 1 in 5 (18.7%, 87/466) were found to have PAH. Disease progression was defined as FC worsening, combination therapy for PAH, PAH-related hospitalization, or death.9,10
Racial classification was based on self-report. Hispanic patients (2% of 131) were considered together with White patients within the group of European Americans for simplicity.12
Dlco=diffusing capacity of the lungs for carbon monoxide; FC=Functional Class; NT-proBNP=N-terminal pro-brain natriuretic peptide; PAH-SSc=pulmonary arterial hypertension associated with systemic sclerosis; WHO=World Health Organization.
References: 1. Lai Y-C, Potoka KC, Champion HC, Mora AL, Gladwin MT. Pulmonary arterial hypertension: the clinical syndrome. Circ Res. 2014;115(1):115-130. 2. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. 3. Galiè N, Humbert M, Vachiéry J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2015;46(4):903-975. 4. Khanna D, Gladue H, Channick R, et al. Recommendations for screening and detection of connective-tissue disease associated pulmonary arterial hypertension. Arthritis Rheum. 2013;65(12):3194-3201. 5. Al-Naamani N, Paulus JK, Roberts KE, et al. Racial and ethnic differences in pulmonary arterial hypertension. Pulm Circ. 2017;7(4):793-796. 6. Zanatta E, Polito P, Famoso G, et al. Pulmonary arterial hypertension in connective tissue disorders: pathophysiology and treatment. Exp Biol Med. 2019;244(2):120-131. 7. Chung L, Farber HW, Benza R, et al. Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. CHEST. 2014;146(6):1494-1504. 8. Varga J. Systemic sclerosis (scleroderma) and related disorders. In: Fauci AS, Kasper DL, Longo DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. McGraw-Hill; 2008:2096-2106. 9. Mihai C, Antic M, Dobrota R, et al. Factors associated with disease progression in early-diagnosed pulmonary arterial hypertension associated with systemic sclerosis: longitudinal data from the DETECT cohort. Ann Rheum Dis. 2018;77(1):128-132. 10. Coghlan JG, Denton CP, Grünig E, et al; DETECT study group. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73(7):1340-1349. 11. Schachna L, Wigley FM, Chang B, White B, Wise RA, Gelber AC. Age and risk of pulmonary arterial hypertension in scleroderma. CHEST. 2003;124(6):2098-2104. 12. Blanco I, Mathai S, Shafiq M, et al. Severity of systemic sclerosis-associated pulmonary arterial hypertension in African Americans. Medicine (Baltimore). 2014;93(5):177-185. 13. Chaisson NF, Hassoun PM. Systemic sclerosis-associated pulmonary arterial hypertension. CHEST. 2013;144(4):1346-1356. 14. Kelemen BW, Mathai SC, Tedford RJ, et al. Right ventricular remodeling in idiopathic and scleroderma-associated pulmonary arterial hypertension: two distinct phenotypes. Pulm Circ. 2015;5(2):327-334. 15. Mathai SC, Hassoun PM. Pulmonary arterial hypertension in connective tissue diseases. Heart Fail Clin. 2012;8(3):413-425. 16. Gaine S. Pulmonary hypertension. JAMA. 2000;284(24):3160-3168. 17. Condliffe R, Kiely DG, Peacock AJ, et al. Connective tissue disease–associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med. 2009;179(2):151-157. 18. Vachiéry J-L, Coghlan G. Screening for pulmonary arterial hypertension in systemic sclerosis. Eur Respir Rev. 2009;18(113):162-169. 19. Hachulla E, Launay D, Mouthon L, et al; French PAH-SSc Network. Is pulmonary arterial hypertension really a late complication of systemic sclerosis? CHEST. 2009;136(5):1211-1219. 20. Delisle VC, Hudson M, Baron M, Thombs BD; The Canadian Scleroderma Research Group. Sex and time to diagnosis in systemic sclerosis: an updated analysis of 1,129 patients from the Canadian scleroderma research group registry. Clin Exp Rheumatol. 2014;32(6 suppl 86):S10-S14. 21. Mandras SA, Ventura HO, Corris PA. Breaking down the barriers: why the delay in referral for pulmonary arterial hypertension? Ochsner J. 2016;16(3):257-262. 22. Vachiéry J-L, Gaine S. Challenges in the diagnosis and treatment of pulmonary arterial hypertension. Eur Respir Rev. 2012;21(126):313-320. 23. Denton CP, Hachulla E. Risk factors associated with pulmonary arterial hypertension in patients with systemic sclerosis and implications for screening. Eur Respir Rev. 2011;20(122):270-276. 24. Yaqub A, Chung L. Epidemiology and risk factors for pulmonary hypertension in systemic sclerosis. Curr Rheumatol Rep. 2013;15(1):302. 25. Fischer A, Bull TM, Steen VD. Practical approach to screening for scleroderma-associated pulmonary arterial hypertension. Arthritis Care Res (Hoboken). 2012;64(3):303-310.