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 Table of Contents  
Year : 2017  |  Volume : 12  |  Issue : 6  |  Page : 204-210

Screening and management of pulmonary arterial hypertension in systemic sclerosis

Department of Medicine, University of Scleroderma Program, University of Michigan, Ann Arbor, MI, USA

Date of Web Publication23-Nov-2017

Correspondence Address:
Vivek Nagaraja
Department of Medicine, Division of Rheumatology, University of Michigan, 300 North Ingalls Building, Room 7C27, Ann Arbor, MI 48109-5422
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.219085

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Systemic sclerosis-associated pulmonary hypertension (SSc-PH) and pulmonary arterial (PA) hypertension (SSc-PAH) are well-recognized manifestations. SSc-PH is a hemodynamic observation, and it is important to identify underlying etiology. SSc patients commonly have mixed etiology for SSc-PH due to interstitial lung disease, PAH, and left heart disease. SSc-PAH is associated with high morbidity and mortality. Early detection of PAH through routine screening improves survival in patients with SSc. Right heart catheterization is mandatory to diagnose PAH. SSc-PAH patients should be managed by a multidisciplinary team comprising of rheumatologist, pulmonologist, cardiologist, and physiotherapist. Various pharmacotherapy options to treat SSc-PAH are derived from the idiopathic PAH management. Upfront or sequential combination therapy of PAH-specific drugs seems to confer a clinical benefit compared to monotherapy. Cardiopulmonary rehabilitation should be considered as a part of the management plan. Lung transplantation is a consideration in patients who are not responding to pharmacotherapy. Although the long-term prognosis of SSc-PAH has been historically poor, the landscape is gradually changing with early detection and institution of treatment.

Keywords: Pulmonary arterial hypertension, pulmonary hypertension, systemic sclerosis

How to cite this article:
Nagaraja V, Khanna D. Screening and management of pulmonary arterial hypertension in systemic sclerosis. Indian J Rheumatol 2017;12, Suppl S1:204-10

How to cite this URL:
Nagaraja V, Khanna D. Screening and management of pulmonary arterial hypertension in systemic sclerosis. Indian J Rheumatol [serial online] 2017 [cited 2022 Jun 27];12, Suppl S1:204-10. Available from:

  Introduction Top

Systemic sclerosis (SSc) is characterized by immunologic abnormalities, microvascular dysfunction, and tissue fibrosis,[1] with potential involvement of vital organs including the heart and lungs, resulting in substantial morbidity and mortality. Pulmonary hypertension (PH) is a hemodynamic observation and should lead to identifying underlying cause. Pulmonary arterial (PA) hypertension (PAH) affects approximately 10%–12% of patients with SSc, and the prevalence is 19% in patients with diffusing capacity of the lung for carbon monoxide lower than 60% predicted at the time of diagnosis.[2],[3] The PAH is defined at right heart catheterization (RHC) by a mean PA pressure of ≥25 mmHg with a pulmonary capillary wedge pressure of ≤15 mmHg.[4] Additional criteria may include a normal or reduced cardiac output or a pulmonary vascular resistance of >3 Wood units.[4],[5] PAH is one of the leading causes of morbidity and mortality in SSc patients.[6] In an international inception cohort of SSc patients, PAH accounted for almost 35% of deaths and was also the strongest independent predictor of mortality in this population, despite the use of advanced PAH therapies.[6] Compared to idiopathic PAH (IPAH) patients, those with connective tissue disease (CTD)-related PAH (CTD-PAH) have poor survival.[7] SSc-related PAH (SSc-PAH) has the least favorable prognosis in this subset among CTD-PAH although recent observational studies and long-term follow-up from clinical trials show improving survival.[8] This poor prognosis is likely a result of older age at onset, underlying interstitial lung disease (ILD), and coexistent left heart disease.[7] This review focuses on the management of SSc-PAH.

  Is Early Screening for Pulmonary Arterial Hypertension Beneficial? Top

Given the high mortality associated with SSc-PAH, does active screening and early detection of PAH impact on the survival? In a small group of SSc patients, PAH identified early through an active screening program conferred better survival in comparison to PAH detection through usual clinical care.[9] The survival was associated with PAH diagnosis at an earlier functional class; the screening led to a larger number of patients diagnosed with PAH at functional Class I or II. Conversely, patients in the usual care group were more likely to be in functional Class III and IV, and their 3-year survival was similar to the pretreatment era.[10] This observation is consistent with previous data that has shown that baseline WHO functional Class III and IV as an independent predictor of mortality in SSc patients with isolated PAH.[11] In addition, the US registry of early SSc-PAH (PH Assessment and Recognition of Outcomes in Scleroderma [PHAROS]) showed a better 3-year survival compared with other cohorts within the past 3 years.[12] Based on these data, recommendations for active screening and early detection of PAH in SSc patients have been proposed by different societies.[13] Current guidelines recommend annual screening of all SSc patients (asymptomatic patients) for PAH [Figure 1] and [Table 1].[13],[14],[15],[16] Three different societies recommend annual transthoracic echocardiography and other modalities, such as pulmonary function test, NT-ProBNP, or the DETECT algorithm.[13],[14],[15] It is important to highlight that echocardiography is not the gold standard to diagnose PAH. In the DETECT study (, further, the use of DETECT screening algorithm missed only 4% PAH cases versus 29% based on the 2009 European Society of Cardiology/European Respiratory Society (ESC/ERS) criteria.
Figure 1: Recommendations for pulmonary arterial hypertension screening in systemic sclerosis patients. Symptoms: dyspnea on rest or exercise, fatigue, presyncope/ syncope, chest pain, palpitations, dizziness, lightheadedness attributable to PH, and other conditions such as anemia and ILD are ruled out. Signs: Loud pulmonic sound, peripheral edema. *Right atrial (>53 mm) or ventricular enlargement (>35mm)

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Table 1: Recommendations for pulmonary arterial hypertension screening in patients with systemic sclerosis

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  Diagnosis of Pulmonary Arterial Hypertension: Right Heart Catheterization Is Mandatory for the Diagnosis of Pulmonary Arterial Hypertension Top

Echocardiography is commonly performed to diagnose elevated PA pressure. In addition, it is useful in assessing right atrial and ventricular size and function and assesses left ventricular valvular disease (a secondary cause of PH).[17] The assessment of PA pressure by echocardiography relies on measurement of the tricuspid regurgitant (TR) jet to provide an indirect measurement of the systolic PA pressure (also called estimated right ventricular systolic pressure or [eRVSP]). The absence of this jet does not exclude PH. In the SSc population, an eRVSP of >47 mmHg has 58% sensitivity, 96% specificity, and 93% positive predictive value in diagnosing PAH.[18] Although echocardiography has high specificity for diagnosis advanced PAH, it missed up to 36% with PAH in the DETECT study. Twenty percent of SSc patients with TR jet of <2.5 m/sec (equivalent to 30 mmHg) and 36% of patients with TR jet of <2.8 m/sec (equivalent to 36 mmHg) had PAH by RHC [Table 2].[3] This echocardiography technique of diagnosing PH becomes less reliable with the presence of concomitant lung disease such as ILD. In a study of lung transplant recipients comparing echocardiography with RHC as a diagnostic test for PAH, 52% of pressure estimations were found to be inaccurate (more than 10 mmHg difference compared with measured pressure), and 48% of patients were misclassified as having PH by echocardiography.[19] When PH is suspected in SSc patients, cardiac catheterization is required to establish the presence of PH, make a diagnosis of PAH, measure left heart dynamics (wedge pressure and left ventricular end-diastolic pressure), determine the severity of PH/PAH and prognosticate, exclude congenital heart disease, and perform accurate vasodilator testing.[13],[16] The benefits of RHC in PAH evaluation override the potential risks. In a study of 7,218 RHC procedures, 76 (1.1%) serious adverse events were noted.[20] Most of these events were of mild-to-moderate intensity and resolved either spontaneously or after appropriate intervention. The most frequent complications were related to venous access (e.g., hematoma and pneumothorax), followed by arrhythmias and hypotensive episodes related to vagal reactions or pulmonary vasoreactivity testing. Four fatal events were recorded in association with any of the catheter procedures, resulting in an overall procedure-related mortality of 0.055%.
Table 2: False negativity associated with echocardiographic parameters

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As a clinician, one needs to remember PH in SSc patients can be multifactorial with the coexistence of PAH, PH due to left heart disease, and underlying ILD and requires expertise and input from cardiology and pulmonary to differentiate these. RHC is necessary to exclude PAH and assess PH due to left heart disease.

  Treatment of Pulmonary Arterial Hypertension in Systemic Sclerosis Top

General approach

It is imperative to determine which mechanism is operative since this dictates treatment in the context of a multifaceted disease. It is advisable to refer SSc-PAH patients to a tertiary referral center to enable collaborative, multidisciplinary care involving as team of rheumatologist, cardiologist, pulmonologist, and cardiopulmonary rehabilitation specialist.[15]


Oral anticoagulation has been recommended as an adjunct therapy for IPAH for many decades. This recommendation was based on demonstration of thrombotic lesions in pulmonary arteries of IPAH patients with plexogenic arteriopathy and was thought to result from in situ thrombosis related to pulmonary vessel endothelial damage.[21] Abnormalities in coagulation and fibrinolytic pathways have been documented in IPAH patient.[22] The routine use of oral anticoagulants confers a survival benefit in IPAH patients.[23] On the contrary, data from more recent registry studies conducted in Europe and the United States provided evidence that routine anticoagulation in SSc-PAH may not be beneficial and demonstrated increased risk of death and bleeding, especially from the underlying gastric antral vascular ectasia.[23],[24] Based on these studies, the most recent treatment guidelines from the 2015 ESC/ERS advice against routine anticoagulation for SSc-PAH patients.[15]

Cardiopulmonary rehabilitation

The recent guidelines recommend patients with IPAH to participate in a supervised exercise program such as pulmonary rehabilitation. In a small study of 21 patients with CTD-PAH, of which eight patients had SSc-PAH, the institution of an exercise training program (supervised training in-hospital for 3 weeks and unsupervised program at home for 12 weeks) improved quality of life factors, 6-min walk distance (6MWD), and maximum workload achieved during exercise.[25] Although further data from randomized clinical trials are needed to better define the ideal mode, session duration, and length of exercise intervention program in patients with SSc-PAH, these data support routine supervised exercise for patients with PAH and as such should be incorporated into clinical management early on in the course of disease.

  Pulmonary Arterial Hypertension-Specific Therapy Top

Most of the therapeutic tools for SSc-PAH are derived from clinical trials that have incorporated Group 1 PAH.[15],[26] In general, the treatment of CTD-PAH, including SSc-PAH, is less robust compared to IPAH [26] although post hoc analysis from recent trials (many of them are upfront combination therapy or add-on therapy of 2 PAH-specific therapies) shows similar response in SSc-PAH versus IPAH.

Endothelin receptor antagonists

Endothelin-1 (ET-1) is a potent vasoconstrictor and smooth muscle mitogen. Patients with SSc-PAH have been noted to have high concentrations of ET-1 in their lungs.[27] There are two receptors (endothelin receptor A and B) that are targeted by endothelin receptor antagonists (ERAs). ERAs that have been tested in clinical trials include nonselective dual-action receptor antagonists (bosentan and macitentan) and selective receptor antagonists of endothelin receptor A (ambrisentan and sitaxsentan). Randomized controlled trials involving patients with different forms of PAH, including CTD-PAH, indicate that ERAs (bosentan, ambrisentan, and macitentan) improve exercise capacity and time to clinical worsening in patients with IPAH.[28],[29],[30],[31] Adverse events associated with ERAs in these clinical trials included abnormal liver function tests, peripheral edema, palpitations, headache, chest pain, nasal congestion, and anemia, but the safety profile differed for specific agents. In a recent SSc-PAH patients' subgroup analysis of Prospective Huntington at Risk Observational Study cohort, compared to treatment with a phosphodiesterase type 5 inhibitors (PDE5i) or combination ERA/PDE5i, initial therapy with an ERA was associated with significantly worse 3-year clinical worsening and survival, even after controlling for other prognostic variables.[32] Although a small number of patients (yet, larger compared to other SSc-PAH subgroup analyses) and a retrospective analysis, this finding raises an important question about the initial choice of agents and warrants head-head comparison between therapy options in SSc-PAH patients.

Nitric oxide pathway

Phosphodiesterase type 5 inhibitors

PDE5is slow the degradation of the cyclic guanosine monophosphate (cGMP) and prolong the vasodilatory effect of nitric oxide through the nitric oxide/cGMP pathway. Sildenafil, tadalafil, and vardenafil have shown significant improvements in exercise capacity and time to clinical worsening in three studies including between 23% and 30% CTD-PAH patients.[33],[34],[35] In a subanalysis of SUPER-1, a significant improvement was noticed in 6MWD in 84 CTD-PAH (45% with SSc) in the sildenafil treatment group.[36] Subgroup analysis of PHIRST study showed significant changes in placebo-controlled 6MWD for CTD-PAH using tadalafil 20 and 40 mg.[33] In the SSc-PAH subgroup analysis of PHAROS cohort, PDE5i monotherapy seemed to have better outcomes in terms of time to clinical worsening and survival compared to ERA monotherapy.[32] The most common side effects associated with PDE5i included flushing, dyspepsia, diarrhea, headache, and myalgia.

Soluble guanylate cyclase stimulator

T he soluble guanylate cyclase stimulator riociguat enhances cGMP production. It demonstrated significant improvements in exercise capacity, time to clinical worsening, and hemodynamic parameters in patients with PAH.[37] In patients with CTD-PAH (N = 111, SSc-PAH = 66), riociguat increased mean 6MWD, WHO functional class, pulmonary vascular resistance, and cardiac index versus placebo; these improvements in exercise capacity and functional class persisted at 2 years.[38] Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population. Drug-related serious adverse events included syncope, increased hepatic enzyme levels, dizziness, acute renal failure, and hypotension.[37]

  Prostacyclin Pathway Agonists Top

The drug formulations used to treat PAH include intravenous prostacyclin (epoprostenol), synthetic analogs of prostacyclin (intravenous treprostinil, subcutaneous treprostinil, inhaled treprostinil, and inhaled iloprost), and nonprostanoid prostacyclin receptor agonists (selexipag). In a study involving 111 SSc-PAH patients, continuous intravenous infusion, starting dose 2 ng/kg/min and increased based on clinical symptoms and tolerability in combination with conventional therapy (diuretics, oral anticoagulants, oxygen, and glycosides), improved exercise capacity, functional status and hemodynamic measures in SSc-PAH, compared with conventional therapy.[39] Epoprostenol has a very short half-life and is administered through a permanent indwelling central venous catheter. Consequently, there is a potential for adverse events such as infections, pneumothorax and hemorrhage. Abrupt disruption of intravenous epoprostenol due to these adverse events may lead to life-threatening PAH rebound. Based on overall risk-to-benefit considerations, the experts and guidelines recommend intravenous epoprostenol as the treatment of choice in severe, therapy-resistant SSc-PAH, which are in line with those of recently published guidelines of other societies.[15],[40] Other prostacyclin analogs have also been approved for use in PAH. The data in SSc-PAH subset are lacking. Oral treprostinil monotherapy improves exercise capacity and dyspnea symptoms but has no significant effect on other outcomes such as time to clinical worsening or WHO functional class.[41] Similar benefits are observed with long-term subcutaneous treprostinil with an additional effect on survival.[42] Inhaled treprostinil as an add-on therapy to oral agents such as bosentan or sildenafil in PAH patients is well tolerated and improves exercise capacity and quality of life.[43] Side effects associated with usage of intravenous treprostinil are similar to that reported with intravenous epoprostenol and include headache, jaw pain, diarrhea, abdominal pain, anorexia, vomiting, photosensitivity, cutaneous flushing, and arthralgia as well as the risk of complications associated with continuous infusion through catheter. Subcutaneous infusion of prostanoids is frequently associated with pain at the infusion site. Inhaled prostanoids can result in cough, headache, flushing, nausea, and syncope.[44] Selexipag is an oral selective IP prostacyclin-receptor agonist that is structurally distinct from prostacyclin. In an event-driven study involving PAH patient, the risk of the death or a complication related to PAH was lower among those who received selexipag than among those who received placebo; however, there was no significant difference in mortality between the two groups.[45] A prespecified subgroup analysis of patients with CTD-PAH was also performed. Of the 334 CTD-PAH patients, 170 had SSc-PAH, 82 had systemic lupus erythematosus (SLE)-PAH, and the rest had mixed CTD. In comparison to the overall GRIPHON population, CTD group was slightly older with higher number of females and shorter time since diagnosis. Specifically, SSc patients were more impaired at baseline and had a progressive PAH course. Selexipag reduced the risk of composite morbidity/mortality events in patients with PAH-CTD by 41% (hazard ratio 0.59; 95% confidence interval 0.41–0.85). Interestingly, the treatment effect was consistent irrespective of baseline PAH therapy or CTD subtype.

  Combination Therapies Top

In severe or progressive PAH cases, combination therapy with different PAH-specific drugs should be taken into account. An additional agent may be initiated sequentially or initially (upfront combination). Several randomized controlled trials (RCTs) have studied the efficacy of a combination therapy and included a proportion of CTD-PAH ranging from 18% to 37%.[43],[46],[47],[48] The combination therapy was shown to improve exercise capacity and time to clinical worsening in most of these trials. In the recent COMPASS-2 study (334 PAH of whom 26% had CTD-PAH), addition of bosentan to sildenafil did not demonstrate significant reduction in time to clinical worsening.[48] Ambrisentan and Tadalafil in Patients with PA Hypertension (AMBITION) study demonstrated that up-front combination therapy with tadalafil and ambrisentan was superior to monotherapy with either tadalafil or ambrisentan in treatment-naive patients with PAH in reducing time to clinical worsening (defined as the first occurrence of a composite endpoint of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response).[21] A sub-group analysis in SSc-PAH patients demonstrated that patients were older with a lower 6MWD and less advanced hemodynamics at baseline, than patients with IPAH.[22] The initial combination therapy significantly reduced the relative risk for clinical failure in CTD-PAH and SSc-PAH by 57% and 56%, respectively, a benefit similar to the overall study population.

In summary, upfront combination therapy or sequential combination therapy with careful planned follow-up can lead to better outcomes in clinical trials. This needs to be validated in real-life cohorts.

  Lung Transplantation Top

According to the 2015 ESC/ERS PH Guidelines, SSc should not be considered as a presumptive contraindication for lung transplantation.[15] Indeed, recent studies have suggested that the survival of lung-transplanted SSc patients was similar to other conditions.[49],[50] These guidelines and others have highlighted the need of a multidisciplinary approach before, during, and after the procedure given the multisystem nature of SSc. Indications and contraindications for transplantation have to be adapted to the specificities of SSc with a special focus on digestive (gastroesophageal reflux disease and intestinal disease), cardiac, renal, and cutaneous involvement.

  Other Treatments Top

In the two studies on the use of tyrosine kinase inhibitor (imatinib) in SSc, the results were negative gave negative data both in PAH and in SSc.[51],[52] Two retrospective studies suggested that some SLE or mixed CTD-PAH patients might benefit from an immunosuppressive therapy combining glucocorticoids and cyclophosphamide. To date, there are no data supporting the use of immunosuppressants in SSc-PAH.[53],[54] However, the use of immunosuppressants could still be a perspective in SSc-PAH. Indeed, some SSc-PAH patients have serological hallmarks of mixed CTD or SLE such as anti-U1-ribonucleoprotein (RNP) autoantibodies. In a recent study, anti-U1RNP positivity was even associated with a trend in decreased mortality in SSc-PAH.[55] Immunosuppressive therapy could be appealing in SSc-PAH as it is a systemic autoimmune rheumatic disease. In line with this hypothesis, rituximab is currently assessed in SSc-PAH in a phase 2 trial in the SSc-PAH (NCT01086540).

  Conclusions Top

SSc-PAH continues to be a major cause morbidity and mortality in SSc. The coexistence of ILD increases this risk. Although SSc-PAH has poor survival, early screening and detection appear to improve morbidity and mortality. RHC is necessary to make the diagnosis, assess for severity of PAH, and rule out other causes. Upfront aggressive therapy (based on RCT) and close follow are required for better outcomes. It is vital to understand and determine specific prognostic markers and markers of clinical improvement or worsening in this patient subset. A multidisciplinary approach in expert referral centers is mandatory for SSc-PAH management.


Dr. Khanna was funded by K24 NIH/NIAMS AR063120 and NIH/NIAMS R01AR070470.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Table 1], [Table 2]


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