An estimated 5% to 12% of patients with systemic sclerosis (SSc) develop pulmonary arterial hypertension (PAH), which is a common cause of increased morbidity and morbidity in this patient population.1 Recent findings have shown a higher risk for death among patients with SSc-associated PAH compared with patients with SSc without PAH (hazard ratio [HR], 2.50; 95% CI, 1.83-3.42; P <.0001) and patients with idiopathic PAH without SSc (median survival, 3 vs 7.8 years, respectively).2,3

Risk factors for PAH in SSc include older age, late disease onset, longer disease duration, and postmenopausal status.4,5 In addition, digital ulcers and increased rates of telangiectasias have been linked to an elevated risk, and pseudotumoral telangiectasias (>5 mm in diameter) increased the odds of precapillary pulmonary hypertension by more than 12-fold, according to a 2016 study (OR, 12.60; 95% CI, 1.68-94.53).6

Pulmonary function test (PFT) parameters that have been found to be predictive of increased risk for PAH in SSc include isolated low diffusing capacity of carbon monoxide (DLCO; <50% predicted), DLCO/alveolar volume (AV) <70%, and reduced DLCO relative to forced vital capacity (FVC%/DLCO% ratio >1.6).1 In 1 study, an increase in right ventricular systolic pressure (RVSP) at a rate of 1 to 1.99 mm Hg/y, 2 to 2.22 mm Hg/y, and >3.0 mm Hg/y was associated with a relative HR for PAH of 1.90 (95% CI, 0.91-3.96), 5.09 (95% CI, 2.53-10.26), and 6.15 (95% CI. 3.58-10.56), respectively, compared with patients with SSc with a stable RVSP.7

Right heart catheterization is the only definitive method of diagnosing PAH. According to current recommendations, all patients with SSc “should be screened for PAH with PFTs, TTE [transthoracic echocardiogram], and NT-proBNP at baseline and at the time of development of any new signs or symptoms[, and] PFTs and TTE should be repeated annually,” wrote the authors of a paper published in Current Rheumatology Reports.1 They noted that adherence to these recommendations is low, however. Less than 50% of rheumatologists were screening patients with SSc of more than 10 years’ disease duration with an annual TTE and PFTs, according to an Australian study from 2017.8

Treatment strategies for SSc-associated PAH range from medications to exercise training to lung transplantation. Improvement in functional status is the primary treatment goal.

To learn more about the risk factors, current screening and treatment strategies, and remaining research needs pertaining to SSc-associated PAH, Rheumatology Advisor interviewed Robert F. Spiera, MD, rheumatologist, researcher, and director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery in New York City.

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Rheumatology Advisor: What is generally known about PAH in SSc?

Dr Spiera: PAH is an important complication of SSc, and 1 of the leading causes of mortality in this disease. Although it occurs in a minority of patients, clinicians must be attentive to it, as it can emerge at any point over the course of the disease and often presents years into the disease, at a point when clinicians and patients may be less vigilant about new organ complications of the disease. World Health Organization (WHO) Class I PAH, which occurs in the absence of significant parenchymal lung disease, is typical, and those patients are often likely to be monitored less closely for cardiopulmonary complications later in the disease course, so vigilance is essential. WHO Class III PAH, of course, can also be seen in patients with significant interstitial lung disease, and that combination portends a particularly poor prognosis.

Rheumatology Advisor: What are some of the risk factors and predictors of PAH in SSc?

Dr Spiera: PAH is a quintessentially vasculopathic feature of SSc and has been associated in some studies with being more likely in patients with other typically vasculopathic (as opposed to fibrotic) disease features, such as a history of digital ulcers or greater numbers of telangiectasias. Patients with limited disease seem to be at higher risk for PAH (WHO Class 1). Other clinical features include later onset of disease and longer disease duration.

Serologically, the presence of anticentromere antibodies and, conversely, the absence of Scl-70 have been associated with an increased risk, which is not surprising, given the disease phenotypes typically associated with those autoantibodies (anticentromere with limited disease and Scl70 with diffuse disease). On routine antinuclear antibody testing, a nucleolar pattern is associated with higher risk. Other, less commonly checked antibodies associated with increased risk include anti-U1RNP and antiphospholipid antibodies.

Rheumatology Advisor: What are standard screening and treatment approaches for PAH in patients with SSc?

Dr Spiera: Ultimately, establishing the diagnosis of PAH requires right heart catheterization. In terms of screening, a good history and physical are important at each visit, in addition to querying patients about exercise intolerance or exertional dyspnea, as well as cardiac auscultation. A number of screening algorithms have been proposed and are being evaluated in observational studies. Obtaining a baseline echocardiogram with Doppler ultrasound and estimation of PA pressure coupled with PFTs (which should include assessment of diffusion capacity, or a disproportionate reduction in DLCO compared with FVC suggests pulmonary vascular disease) are recommended and should be repeated annually, even in the absence of symptoms. Measuring NT-proBNP is suggested at baseline or if new symptoms emerge.

Treatment of SSc-associated PAH uses the same strategies as those used for idiopathic PAH, including vasodilators, endothelin receptor antagonists, prostacyclins, and in many patients, combination therapy. Anticoagulation is not routinely employed, and when doing so, clinicians should be vigilant about the potential presence of gastric antral vascular ectasias (GAVE), which is another vascular manifestation of SSc and can be present in some of these patients. GAVE can result in significant gastrointestinal bleeding in the context of anticoagulation. Adjunctive modalities, including exercise training and supplemental oxygen, are appropriate in some patients.

There is no recognized role of immunomodulation for improving outcomes in SSc-associated PAH, but an ongoing National Institutes of Health-funded clinical trial is assessing whether rituximab may be helpful.

Rheumatology Advisor: What types of biomarkers and therapies are needed to improve outcomes in patients with SSc-associated PAH?

Dr Spiera: At present, there are no reliable biomarkers to identify patients in the earliest stages of developing PAH. If immunomodulation proves to be of value in SSc-associated PAH, early treatment would be rational and would likely improve outcomes, so identifying such biomarkers is important. Identifying and addressing early incipient PAH may even be important with regard to aggressive use of vasodilators and preventing vascular remodeling and damage, but that has yet to be established. Conversely, late detection could result in cardiac damage that is often irreversible.


  1. Sundaram SMChung L. An update on systemic sclerosis-associated pulmonary arterial hypertension: a review of the current literature. Curr Rheumatol Rep. 2018;20(2):10.
  2. Hao Y, Hudson M, Baron M, et al. Early mortality in a multinational systemic sclerosis inception cohort. Arthritis Rheumatol. 2017;69(5):1067-1077.
  3. Ramjug S, Hussain N, Hurdman J, et al. Idiopathic and systemic sclerosis-associated pulmonary arterial hypertension: a comparison of demographic, hemodynamic, and MRI characteristics and outcomes. Chest. 2017;152(1):92-102.
  4. Avouac J, Airo P, Meune C, et al. Prevalence of pulmonary hypertension in systemic sclerosis in European Caucasians and meta-analysis of 5 studies. J Rheumatol. 2010;37(11):2290-2298.
  5. Scorza R, Caronni M, Bazzi S, et al. Post-menopause is the main risk factor for developing isolated pulmonary hypertension in systemic sclerosis. Ann N Y Acad Sci. 2002;966(1):238-246.
  6. Hurabielle C, Avouac J, Lepri G, de Risi T, Kahan A, Allanore Y. Skin telangiectasia and the identification of a subset of systemic sclerosis patients with severe vascular disease. Arthritis Care Res (Hoboken). 2016;68(7):1021-1027.
  7. Shah AA, Chung SE, Wigley FM, Wise RA, Hummers LK. Changes in estimated right ventricular systolic pressure predict mortality and pulmonary hypertension in a cohort of scleroderma patients. Ann Rheum Dis. 2013;72(7):1136-1140.
  8. Morrisroe K, Stevens W, Sahhar J, et al. Epidemiology and disease characteristics of systemic sclerosis-related pulmonary arterial hypertension: results from a real-life screening programme. Arthritis Res Ther. 2017;19(1):42.