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Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis

Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis
Literature review current through: Jan 2024.
This topic last updated: Feb 24, 2023.

INTRODUCTION — Systemic sclerosis (SSc) can be complicated by pulmonary arterial hypertension (PAH). SSc-associated PAH (SSc-PAH) belongs to group 1 PAH (table 1) and has similar characteristics with other types of PAH (eg, idiopathic or hereditary PAH, PAH due to human immunodeficiency virus [HIV] or drugs). In SSc patients, pulmonary hypertension (PH) can also be due to left-sided heart disease (ie, group 2 PH) or interstitial lung disease (group 3 PH), and not infrequently pulmonary veno-occlusive disease (PVOD), which is an unusual form of pulmonary hypertension, affecting both pre- and postcapillary pulmonary vessels, that is also classified as group 1 PAH (group 1.4).

The treatment and prognosis of SSc-PAH is reviewed here, while the treatment of group 2 and group 3 PH as well as PVOD are discussed separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis" and "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults" and "Treatment and prognosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

CLASSIFICATION OF PULMONARY HYPERTENSION — Pulmonary hypertension is classified into five groups (groups 1 through 5) (table 1) [1]. Group 1 (also known as PAH) has several etiologies including connective tissue diseases (CTD) of which SSc is the most common form in the Western world. Systemic lupus erythematosus is more common as a cause of CTD-PAH in China [2]. SSc-PAH is considered present when PAH exists in a patient who has coexisting SSc, and no alternative cause of the PAH (eg, heritable PAH, HIV, liver disease, or drugs) or pulmonary hypertension (PH; eg, left heart disease, interstitial lung disease) exists [3]. The classification and diagnosis of PH is discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

GENERAL MEASURES — The term "general measures" refers to treatments that are directed at SSc and supportive therapies directed at the complications of PAH (eg, oxygen for respiratory failure, diuretics for right heart failure).

Systemic sclerosis-related (immunosuppressants) — Therapy for SSc should be maximized, although such therapy is unlikely to treat SSc-PAH itself or impact survival. Although there is strong evidence for immune dysregulation and fibrosis in the pathogenesis of SSc and SSc-PAH, there are no effective disease-modifying therapies for SSc.

While observational data suggest that some patients with severe PAH associated with CTD (eg, systemic lupus erythematosus, mixed connective tissue disease) have had dramatic improvement in pulmonary hemodynamics with corticosteroids and/or immunosuppressive therapy, this has not been the case for patients with SSc, where corticosteroids may be contraindicated and PAH is refractory to such therapy [4].

Preliminary data suggest that while rituximab did not result in a significant improvement in six-minute walk test at 24 weeks, an improvement was found at week 48 [5]. Further trials are needed to demonstrate whether rituximab could serve as adjunctive immunotherapy in SSc-PAH.

Treatments targeted at organ-based complications of SSc are reviewed separately. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".)

Pulmonary arterial hypertension-related (supportive therapies) — PAH-related general measures refer to supportive therapies targeted at the complications of PAH. Data to support such general measures have been extrapolated from studies largely performed in patients with idiopathic PAH (IPAH). Similar to patients with IPAH, all patients with SSc-PAH should exercise as tolerated [6], receive routine vaccinations (figure 1), be counseled against smoking (tobacco and marijuana) and pregnancy, and, when indicated, be treated with supportive measures including oxygen (table 2), diuretics, and inotropic agents. Evidence to support this approach in patients with IPAH is discussed separately. (See "Standard immunizations for nonpregnant adults" and "Pneumococcal vaccination in adults" and "The benefits and risks of aerobic exercise" and "Pulmonary rehabilitation" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

However, one general measure, anticoagulation, requires special discussion in patients with SSc-PAH. We do not routinely anticoagulate patients with SSc-PAH, since data suggest no benefit or potential harm in this population [7,8]. Data to support the avoidance of anticoagulation is largely derived from clinical experience and data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). In COMPERA, anticoagulation was associated with an improved three-year survival in patients with IPAH compared with those who had other forms of PAH (mostly CTD-associated PAH; hazard ratio [HR] 0.79, 95% CI 0.66-0.94) [9]. In a post-hoc analysis of those with SSc-PAH there was a statistically nonsignificant trend towards worse survival among those taking anticoagulants compared with patients not on anticoagulant therapy (three-year survival 62 versus 74 percent; HR 1.82, 95% CI 0.94-3.54). Potential harm may be due to gastrointestinal bleeding from telangiectasias and altered intestinal absorption that may potentially lead to erratic anticoagulant levels. As an example, one retrospective study of 198 patients reported that compared with IPAH, CTD-related PAH had a higher bleeding event rate (19 versus 5.4 events per 100 patient-years, respectively) [10]. Although registry studies report that most deaths in SSc patients on anticoagulants are due to progressive disease [9,11], randomized studies are required to accurately assess whether increases in bleeding risk offset the potential benefit of anticoagulation in this population.

In the rare event that anticoagulation is administered (eg, those with low cardiac output from severe right heart failure), it may be reasonable to treat such patients with oral anticoagulants if no contraindications exist. When anticoagulant therapy is administered, we advocate the administration of warfarin targeting a goal international normalized ratio (INR) of 2 to 3 rather than direct oral anticoagulants (DOACs) where the therapeutic level cannot necessarily be guaranteed if absorption is erratic. A multicenter trial comparing the DOAC, apixaban, with placebo is pending [12]. Evidence discussing anticoagulation in IPAH populations is provided separately. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

PULMONARY ARTERIAL HYPERTENSION-DIRECTED THERAPY — PAH-directed therapy refers to treatment targeted at PAH itself (eg, treatments that alter pulmonary vascular tone and/or remodeling). PAH-specific therapy should only be administered in specialized centers by clinicians with expertise in the evaluation and management of patients with pulmonary hypertension. Decisions for the care of patients with SSc-PAH should involve discussion among multi-disciplinary specialties including pulmonary vascular, cardiology, and rheumatology experts, and the patient [13]. Most aspects of treatment are nearly identical to that for idiopathic PAH (IPAH) (table 3 and algorithm 1) with some subtle differences. Similar to patients with IPAH, PAH-directed therapy in patients with SSc is individualized according to the World Health Organization (WHO) functional class (table 4) as well as clinician and patient preference. In these sections we discuss data that are pertinent to treatment of SSc-PAH while data that support treatment of IPAH are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Most of the treatment options for SSc-PAH have been extrapolated from clinical trials performed in patients with PAH (which have typically included about 30 percent of patients with connective tissue disorder (CTD) PAH with the majority of these patients having SSc-PAH) and from limited studies in patients with SSc-PAH, many of which have shown similar benefits. An additional caveat to consider when appraising the evidence in SSc patients is that most trials used the six-minute walk test (6MWT) as the primary outcome. The utility of the 6MWT is limited in SSc patients, since many also have comorbidities such as myositis, arthritis and ischemia that limit the validity of the test [14-16]. In addition, while most randomized trials have included patients with CTD-PAH, studies were limited by a paucity of prespecified SSc-PAH patient subgroup analyses.

WHO functional class I (observation) — WHO functional class I patients (table 4) do not require pharmacologic therapy. However, they should be clinically monitored (eg, every three to six months) for disease progression to a functional level that may warrant therapy. Any coexisting conditions that worsen pulmonary hypertension (PH) should also be treated (eg, obstructive sleep apnea, cardiac disease, interstitial lung disease). (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Pulmonary involvement'.)

WHO functional class II-IV (pharmacotherapy) — Patients with WHO functional class II, III, or IV (table 4) should be referred to a specialized center to be evaluated for PAH-specific pharmacotherapy.

Agent selection — There are several classes of agents (table 3) including nitric oxide (NO)-cyclic guanosine monophosphate (GMP) enhancers (phosphodiesterase inhibitors and guanylate cyclase stimulants), endothelin receptor antagonists (ERAs), and prostacyclin pathway agonists. Shared decision-making by the patient and PAH and rheumatology experts that weighs the risks of adverse effects, drug interactions, and benefits of a specific therapy is critical. For specific interactions, use the drug interactions program included with UpToDate.

In general, with the exception of high-dose calcium channel blockade (CCB), the principles of agent selection mirror those of the IPAH population (table 3 and algorithm 1). In most patients with SSc-PAH who have WHO functional class II and III (table 4), initial combination oral therapy is typically administered while those with class IV symptoms are typically treated with a parenteral prostanoid and a second oral agent from a different class. High-dose CCB therapy is unlikely to be prescribed since vasodilator-responsive PAH is a very rare occurrence in SSc patients (approximately 2 percent) and unlike patients with IPAH, the response is unlikely to be sustained.

Further details regarding agent selection in patients with IPAH are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'WHO functional class II and III or low/intermediate risk (combination oral therapy)' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'WHO functional class IV or high risk (parenteral prostanoid-containing combination regimen)' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Agent options

Combination therapy — Combining agents from two different classes is commonly used in patients with IPAH with smaller studies and sub-group analyses that suggest similar benefits in patients with SSc. A review of clinical trials reported in SSc-PAH patients that combination therapy may be effective, but the ideal combination is unknown [17]. While single agent therapy with a phosphodiesterase inhibitor is well tolerated in patients with WHO functional class II and III (table 4), initial combination oral therapy with oral ambrisentan (an ERA), and oral tadalafil (a phosphodiesterase-5 inhibitor [PDE5I]), is commonly prescribed since it is of proven benefit in PAH [18]. Patients with WHO functional class IV are typically treated with a parenteral prostanoid and a second oral agent from a different class (algorithm 1). When combination therapy is indicated, each drug is started separately to examine efficacy and safety before introducing a second therapy.

Data in SSc-PAH patients that support the use of combination therapy are limited. As examples:

In a randomized trial (AMBITION) of PAH patients that included a small proportion of patients with CTD-PAH, combination therapy with oral ambrisentan (ERA), and oral tadalafil (a PDE5I), resulted in a 50 percent reduction in the rate of clinical worsening in patients with WHO class II and III symptoms (table 4), compared with ambrisentan or tadalafil alone [18]. Two post-hoc analyses of the 216 patients who had CTD-PAH, 118 of whom had SSc-PAH, reported a similar 50 percent reduction in the risk of clinical failure compared with single agent therapy (CTD-PAH: hazard ratio [HR] 0.43, 95% CI 0.24-0.77; SSc-PAH: HR 0.44, 95% CI 0.22-0.89) [19,20].

A prospective, open-label, multicenter trial of 24 patients with SSc-PAH, reported that combining ambrisentan and tadalafil resulted in improved pulmonary vascular resistance, 6MWT, and right ventricular structure and function [21].

A retrospective study (PHAROS) of 98 patients with SSc-PAH, reported that the time to clinical worsening was shorter in patients initially started on single agent therapy with an ERA compared with ERA/PDE5I combined or a PDE5I alone (42 versus 7 versus 7 percent respectively), even after adjustment for commonly accepted prognostic factors (eg, low diffusion) [22].

The ambrisentan and tadalafil upfront combination therapy in SSc-PAH trial (ATPAHSS-O) showed that combination therapy was associated with a significant improvement in both right ventricular and left ventricular function as assessed by cardiac magnetic resonance-derived longitudinal and circumferential strain and strain rate [23]. These improvements were related to improvements in 6MWT, N-terminal pro-brain natriuretic peptide (NTproBNP), and hemodynamics parameters, all established prognostic markers in PAH.

A nonrandomized, retrospective cohort study examined the long-term efficacy and safety of monotherapy versus combination therapy for SSc-PAH [24]. Patients were split up in three groups: monotherapy with ERA or PDE5I versus sequential combination therapy versus upfront combination therapy with ERA/PDE5I. Combination therapy showed better long-term survival rates with sequential combination therapy having the best outcome compared with monotherapy.

A retrospective review of patients in the Spanish Scleroderma Registry reported longer survival among those who were treated with combination therapy compared with monotherapy at one year (96 percent [sequential combination therapy] versus 94 percent [upfront combination therapy] versus 78 percent [monotherapy]) [24].

A meta-analysis of clinical trials using combination therapy oral therapies with endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, and prostaglandin analogs showed that combination treatment resulted in more benefits to exercise capacity and hemodynamic parameters in SSc-PAH patients [25].

Further study into the optimal combination oral therapy for patients with SSc-PAH is needed. The AMBITION trial and data to support upfront combination therapy in patients with PAH, including those in WHO functional class IV are discussed in detail separately.

Nitric oxide-cyclic guanosine monophosphate enhancers — These agents include two families of drugs, the guanylate cyclase stimulant, riociguat, and the PDE5Is, sildenafil, tadalafil, and vardenafil. These are not typically used for patients with WHO functional class IV unless in combination with a parenteral prostanoid but can be used in patients with WHO functional class II and III alone or in combination with agents from a different class. Guanylate cyclase stimulants and PDE5Is cannot be combined since they belong to the same class of agents, thereby increasing the risk of serious adverse effects such as hypotension. Limited data in patients with SSc-PAH describe some benefit with these agents.

Phosphodiesterase type 5 inhibitors — The PDE5Is reduce the catabolism of cyclic guanosine monophosphate (cGMP), enhancing the pulmonary vasodilatation induced by endogenous nitric oxide. Sildenafil and tadalafil are the PDE5Is that have been approved for the treatment of PAH. Vardenafil is not approved for this use yet. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Sildenafil – The effects of sildenafil were demonstrated by a multicenter trial (SUPER-1), which compared three doses of sildenafil (20, 40, or 80 mg three times daily for 12 weeks) to placebo in 278 patients with symptomatic PAH [26]. A subgroup analysis of 84 patients with SSc- or CTD-PAH detected improvement in the 6MWT, WHO functional class, pulmonary artery pressure, and pulmonary vascular resistance [27]. Unlike patients with IPAH, there was no dose-response gradient observed in patients with SSc-PAH. The long-term effectiveness of sildenafil in SSc-associated PAH has not been reported. Thus, in most patients with SSc-PAH, we do not titrate the dose of sildenafil above 20 mg three times per day since not only is efficacy limited, but patients are also more likely to experience side effects including progressive anemia due to slow gastrointestinal bleeding from gastric antral vascular ectasia (GAVE; watermelon stomach), or arterio-venous malformations of the intestine [27].

Tadalafil – The efficacy of tadalafil in the treatment of CTD-PAH has only been evaluated in combination with the selective ERA, ambrisentan, the details of which are discussed separately. (See 'Combination therapy' above.)

Vardenafil – Vardenafil has not been tested in patients with SSc-PAH nor is it approved for use in PH patients.

In patients with WHO functional class II and III, although PDE5Is are typically used in combination with an ERA (most often ambrisentan), ERAs are sometimes less well tolerated and single agent therapy with PDE5Is may be tried before adding an oral prostanoid.

Data to support these agents and their adverse effects in patients with PAH are discussed in detail separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Guanylate cyclase stimulant — Riociguat is a stimulator of soluble guanylate cyclase that improves exercise tolerance in patients with group 1 and group 4 PAH (chronic thromboembolic pulmonary hypertension [CTEPH]) (table 1). There are only limited data regarding the safety and efficacy of riociguat in the treatment of SSc-PAH. In a prespecified subgroup analysis of data derived from two trials investigating the safety and efficacy of riociguat in PAH [28,29], when compared with placebo, the administration of riociguat, in patients with CTD-PAH (most of whom had SSc) resulted in improved 6MWT, WHO functional class, and pulmonary pressures [30]. Efficacy persisted for two years. The two-year survival was similar to those with IPAH (93 percent).

However, in patients with pulmonary hypertension (PH) associated with idiopathic pulmonary fibrosis (IPF; mostly usual interstitial pneumonia [UIP]), riociguat has been shown to be associated with an increased rate of adverse effects and mortality [31,32]. Some patients with SSc have interstitial lung disease, most commonly, fibrotic nonspecific interstitial pneumonia (NSIP). Consequently, this toxicity has not been replicated in SSc patients with PAH. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

Data that discuss the treatment with and adverse effects of riociguat in patients IPAH and CTEPH are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis" and "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy" and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Nonvasoreactive patients'.)

Endothelin-1 receptor antagonists — Bosentan and macitentan are nonselective oral agents that inhibit both endothelin-A and endothelin-B receptor signaling. Ambrisentan is an oral selective endothelin-A receptor antagonist. ERAs are not typically used for patients with WHO functional class IV unless in combination with a parenteral prostanoid but can be used in patients with WHO functional class II and III alone or in combination with agents from a different class.

Bosentan – Limited evidence from case series supports a beneficial effect from bosentan in SSc-PAH, although the response may be less than that in IPAH:

In a multicenter trial (BREATHE-1) 213 patients with PAH (approximately 30 percent of whom had SSc- or systemic lupus erythematosus [SLE] associated PAH) were randomly assigned to receive bosentan or placebo [33]. The patients with SSc- or SLE-associated PAH who received bosentan had a modest increase in their 6MWT by 3 meters, compared with a decrease of 40 meters (mean difference 43 meters) in those who received placebo. In comparison, patients with IPAH who received bosentan had an increase in their 6MWT of 46 meters, while those who received placebo had a decrease of 5 meters (mean difference 51 meters). Patients with SSc- or SLE-PAH who received bosentan also had delayed progression to clinical worsening compared with those treated with placebo.

In a study of 53 patients who had PAH associated with either SSc- or scleroderma spectrum disorder, bosentan therapy was associated with a 48-week survival of 92 percent [34]. This exceeds that of historical controls, which had estimated two-year survival rates of only 50 percent [35,36].

Macitentan – A multicenter trial (SERAPHIN) randomly assigned 250 patients with PAH (a small number had SSc) to receive macitentan or placebo [37]. Macitentan significantly reduced mortality and morbidity in this event-driven trial but no post-hoc analysis of patients with CTD- or SSc-PAH was performed. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Ambrisentan – Limited evidence suggests that ambrisentan may be beneficial in patients with SSc-PAH, although the response may be less than that in IPAH. The toxicity of ambrisentan, demonstrated in patients with IPF [38], has not been replicated in patients with SSc-PAH. This trial is discussed separately. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Endothelin receptor antagonists'.)

Two multicenter trials (ARIES-1 and ARIES-2) randomly assigned 394 patients with PAH (that included a small number of patients with CTD-PAH) to receive either ambrisentan or placebo [39]. The 6MWT improved among all patients at 12 weeks, including patients with SSc- or other CTD-PAH. However, those with SSc- or CTD-PAH had a more modest response (mean difference 15 to 23 meters) when compared to patients with IPAH (mean difference 50 to 60 meters). The poorer therapeutic response of SSc-associated PAH, compared with other types of PAH, may reflect the multisystemic nature of SSc as well as the presence of other SSc-associated cardiopulmonary diseases (eg, SSc-interstitial lung disease, veno-occlusive disease, and cardiac disease) [40].

Data to support ERA therapy in patients with PAH and adverse effects of ERAs are discussed in detail separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Prostacyclin pathway agonists — The prostacyclin pathway agonists are primary pulmonary vasodilators. Formulations include parenteral epoprostenol, parenteral or inhaled treprostinil and iloprost, and the oral agent, selexipag. Limited data in patients with SSc-PAH have shown improvement in pulmonary hemodynamics, functional class, exercise capacity, and possibly survival with prostacyclin pathway agonists. With the exception of oral selexipag, which may be administered to patients with WHO functional class II and III, these agents (epoprostenol, treprostinil, iloprost) are often reserved for patients with WHO functional class IV and for those who need a bridge to lung transplantation.

Epoprostenol – Limited studies illustrate the short-term and long-term efficacy of epoprostenol in SSC-PAH:

The short-term efficacy of continuous intravenous epoprostenol in SSc-PAH was marginal as demonstrated in a randomized trial of 111 patients [41]. The mean pulmonary artery pressure decreased 10 percent among patients treated with epoprostenol, compared with an increase of 2 percent among those who received placebo. In addition, epoprostenol therapy decreased pulmonary vascular resistance, increased cardiac output, and improved the functional class. However, requirements for frequent mixing and dealing with ice packs may be particularly challenging for patients with sclerodactyly and Raynaud’s phenomenon.

The long-term benefits of continuous intravenous epoprostenol in SSc-PAH are uncertain due to methodological limitations of the relevant studies. An analysis of data from the original epoprostenol trial above [41] and its open-label extension study found one-, two-, three-, and four-year survival rates of 71, 52, 48, and 48 percent, respectively, among patients with SSc-associated PAH [42]. These survival rates are better than those of historical controls.

Studies that support the use of this agent in patients with PAH are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Treprostinil – Treprostinil is a temperature-stable prostacyclin analogue [43]. In a randomized trial that compared a subcutaneous infusion of treprostinil with placebo, a subgroup analysis of 90 patients with SSc- or CTD-PAH found that treprostinil was associated with modest improvements in 6MWT (mean difference 25 meters), dyspnea, cardiac index, and pulmonary vascular resistance [44]. Inhaled treprostinil is now FDA-approved for interstitial lung disease associated PH (group 3) based on the results of a trial that showed improved 6MWT compared with placebo with this therapy. This trial is discussed in detail separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis", section on 'Interstitial lung disease'.)

Studies that support the use of this agent in patients with PAH are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Iloprost – The effect of iloprost, an inhaled prostacyclin analogue, was demonstrated by an open-label, uncontrolled trial of five patients with SSc-PAH that reported an increased 6MWT (85 meters) at six months [45] Studies that support the use of this agent in patients with PAH are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Selexipag – Selexipag is an oral selective non-prostanoid prostacyclin receptor (IP receptor) agonist that results in vasodilation of the pulmonary vascular bed. One major randomized trial (GRIPHON) of patients with PAH and WHO functional class II and III (table 4), one-third of whom had CTD-PAH, reported reduced hospitalizations and disease progression with selexipag therapy [46]. Responses among those with IPAH and SSc-PAH appeared to be similar in a subgroup post-hoc analysis of this trial [47]. Detailed discussion of GRIPHON is provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Agents of limited benefit

High-dose calcium channel blockers — Unlike patients with IPAH who may have a positive vasoreactivity test, patients with SSc-PAH are not typically treated with high-dose CCB vasodilator therapy. However, SSc-PAH patients often are treated with low-dose CCB for Raynaud phenomenon. The impact of such low-dose CCB therapy in these patients is unknown but unlikely to be significant. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Pharmacologic measures'.)

High-dose CCB therapy is not administered in SSc-PAH based upon the observation that although effective in a small number of IPAH patients (approximately 7 percent of IPAH patients are vasoreactive), SSc-PAH patients are generally much less likely to display an acute vasodilator response (approximately 2 percent) and even when a vasodilator response is demonstrated, it is rarely sustained. Consequently, vasodilator challenge is not recommended in this population. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Calcium channel blockers (trial)' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients'.)

Refractory disease

Right to left shunts — Case reports suggest that shunts (eg, atrial septostomy) are appropriate as a bridge to lung transplantation in those with severe symptomatic SSc-PAH that is refractory to combination therapy [48-50]. This option is discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Right-to-left shunt'.)

Lung transplantation — Lung transplantation remains an option for suitable operative candidates who have severe symptoms due to SSc-PAH and have failed to respond to a systemic prostanoid, either alone or in combination with other agents. (See "Lung transplantation: General guidelines for recipient selection".)

The morbidity and mortality of lung transplantation in patients with SSc-PAH does not appear to be significantly different from that of adults undergoing lung transplantation for other reasons [51-53]. This was illustrated by a retrospective study of 14 patients with SSc-PAH who had undergone lung transplantation [51]. The two-year survival rate was 64 to 71 percent [54]. In another retrospective study of 90 patients with SSc who underwent lung transplantation (for PAH or interstitial lung disease), survival rates at one, three, and five years were 81, 68, and 61 percent, respectively, similar to those without SSc undergoing lung transplantation. However, data suggested that female sex and PAH in combination was associated with a lower survival.

Aspiration-related damage to the allograft from SSc involvement of the esophagus (ie, severe motility and gastroesophageal reflux) and renal disease from SSc are pre-and post-transplantation concerns that may affect transplantation candidacy and require specific management (eg, surgical correction prior to transplant and nutritional supplementation with feeding tubes for 6 to 12 months following transplantation).

Further details regarding lung transplantation are provided separately. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection" and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Lung transplantation'.)

PROGNOSIS — PAH is an independent risk factor for mortality among patients with SSc [55-58], and the severity of PAH predicts mortality in those with SSc-PAH [56,59,60]. Data from cohort analyses suggest that, although survival from SSc–PAH may have improved in the era of PAH-directed therapy, it is worse than that for idiopathic PAH (IPAH), particularly when there are components of pulmonary hypertension associated with interstitial lung disease (ILD) [56,61-66].

Mortality — Studies that report actual mortality rates include the following:

A 2013 meta-analysis of 22 studies representing a total of 2244 patients with SSc–PAH reported pooled one-, two-, and three-year survival rates of 81, 64, and 52 percent, respectively [56]. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

A prospective registry of 131 patients with SSc-PAH (PHAROS) reported one-, two-, and three-year survival rates of 93, 88, and 75 percent, respectively [59], higher when compared with rates reported in the above meta-analysis [56].

A meta-analysis of 11 studies reported a lower survival rate in patients with connective tissue disease-associated PH (mostly SSc patients) compared with other PAH patients (survival rate 62 versus 72 percent at three years) [67].

Whether survival is improving due to the impact of PAH-specific therapies is unclear since data are conflicting:

Studies suggesting no change in the survival following the introduction of PAH-directed therapies (after 2002) include:

One meta-analysis of 22 studies, performed between 1960 and 2012, showed no change in survival over time [56].

A 14-year observational study (1996 to 2010) of patients with PAH (idiopathic and SSc-related) reported that rates in those with SSc remained unchanged even in the modern era of oral vasodilator therapy (after 2002) [64].

Studies suggesting improved survival in the PAH-directed therapy era include [7,59,65-68]:

A prospective cohort study conducted at a single center found that out of 504 SSc patients diagnosed with pulmonary hypertension, those diagnosed between 2010 and 2021 had a median transplant-free survival that was nearly four years longer than those diagnosed between 1999 and 2010 [66]. However, no difference in survival was found for patients with group 2 or 3 SSc-PH. Earlier detection and better therapeutic management appear to have contributed to this better outcome.

Studies from SSc centers focusing on early identification, including PHAROS, performed during the era of PAH-specific vasodilator therapies, reported improved survival at one year (93 to 94 percent), two years (88 to 89 percent), and three years (73 to 75 percent) when compared with previously published studies [7,59]. The long term outcome of the PHAROS registry showed a five-year survival of 63 percent significantly better than other studies of patients with SSc-PAH [65].

A prospective cohort study of 92 patients with SSc-PAH reported that compared with patients treated prior to 2002, patients treated after 2002 had an improved two-year survival (71 versus 47 percent) [68].

The prognosis of patients with SSc-PAH is worse than that of patients with IPAH [56,63,64]. For example, one retrospective cohort study of 91 patients found lower survival rates in patients with SSc-PAH compared to those with IPAH at one year (87 versus 91 percent), two years (64 versus 88 percent), and three years (64 versus 78 percent) [63]. Registry data from 804 patients with PAH (REVEAL) reported lower three-year survival rates in patients with SSc-PAH compared with non-SSc-associated PAH (61 versus 81 percent) [69]. The reason for the worse prognosis in SSc-PAH may relate to an altered response of the right ventricle (RV) to increased afterload in patients with SSc, as evidenced by higher serum levels of N-terminal brain natriuretic peptide (NT-BNP, an index of ventricular strain) and reduced RV contractility when compared with patients with IPAH as well as the multisystem nature of the disease, and perhaps a poorer response to therapy [55,63,70].

The prognosis of patients with SSc-PAH is better than that of patients with SSc-pulmonary hypertension (PH) who have associated interstitial lung disease (SSc ILD-PH). A prospective cohort study of 59 patients with SSc-PAH and SSc ILD-PH reported a worse two-year survival in SSc ILD-PH (46 versus 79 percent) [61]. Most of the deaths among the patients with SSc ILD-PH were due to respiratory failure, whereas most of the deaths among patients with SSc-PAH were due to right heart failure [61]. Similar results were reported in a retrospective cohort study of 97 patients with SSc, which found a lower three-year survival in those with SSc ILD-PH compared with patients with SSc-PAH (47 versus 71 percent) [62].

Predictors — Several predictors of mortality have been reported including the following:

Indicators of severe PAH or right heart failure (eg, higher baseline mean pulmonary artery pressures, high right atrial pressures >20 mmHg, high pulmonary vascular resistance >32 Wood units, low cardiac index, low systolic blood pressure ≤110 mmHg) [56]

Low diffusing capacity for carbon monoxide (DLCO; eg, <50 percent predicted) [56,59,60,69,71,72]

Male gender [56,59,69,71,72]

Age >60 years [56,59,69]

Poor exercise capacity (World Health Organization [WHO] functional class IV; six-minute walk test <165 meters) [56,59,69,71,72]

Pericardial effusions [56,72]

Anti-U1 ribonucleoprotein (RNP) negative status [73]

Similar to patients with non-SSc-PAH, serial risk assessment using a multi-modality approach appears to be a better tool for predicting prognosis than a single initial assessment [74-76]. Two studies that have focused exclusively on SSc-PAH determined that an abbreviated version of the European Cardiology Society/European Respiratory Society (ECS/ERS) guideline risk assessment is accurate in predicting survival in newly diagnosed SSc-PAH [74,75]. In patients considered as low risk, one-year mortality rates estimated by the abbreviated ECS/ERS criteria in patients with SSC-PAH corresponded very closely to the one-year mortality rates estimated from the full version of the ERS/ECS risk assessment criteria. The risk stratification according to the average score achieved also proved to be valid during follow-up assessment. However, less than a third of patients had a low-risk profile and both studies were retrospective and based on registry information obtained prospectively. Another study that evaluated the REVEAL risk score (figure 2) in patients with SSc-PAH reported that it had good discrimination comparable to that in the model development cohort [76]. However, calibration was poor, particularly in the highest risk groups. These studies suggest that multi-modality scores are not as useful in SSC-PAH compared with PAH due to other causes, especially in high-risk patients (table 5). Nonetheless, we suggest that similar to non-SSc-PAH patients, an individualized multimodality approach that may involve the REVEAL or ECS/ERS score may be used for estimating prognosis in SSc-PAH patients, understanding that such prognostic tools may not be as accurate in this population, particularly for patients considered to be high risk. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Baseline risk assessment'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

Classification – Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) belongs to group 1 PAH (table 1). SSc-PAH shares similar characteristics with other types of PAH (eg, idiopathic or hereditary PAH, PAH due to HIV or drugs) and should not be confused with other groups of pulmonary hypertension (PH) that can occur in patients with SSc due to left-sided heart disease (ie, group 2 PH), interstitial lung disease (group 3 PH), or pulmonary veno-occlusive disease. (See 'Introduction' above and 'Classification of pulmonary hypertension' above.)

General measures – Disease-modifying therapy for SSc is unlikely to impact pulmonary hemodynamics or survival due to SSc-PAH. Patients with SSc-PAH should exercise as tolerated, receive routine vaccinations, be counseled against smoking (tobacco and marijuana) and pregnancy, and when indicated, be treated with supportive measures including oxygen, diuretic, and digoxin therapy. We do not routinely anticoagulate patients with SSc-PAH, since data suggest no benefit or even potential harm in this population. (See 'General measures' above.)

PAH-specific therapy – PAH-specific therapy is targeted at altering pulmonary vascular tone and remodeling. It should only be administered by clinicians with expertise in the evaluation and management of patients with pulmonary hypertension.

Most aspects (including the indications) of PAH-specific therapy for patients with SSc-PAH are identical to those for patients with other types of PAH (table 3 and algorithm 1). In most cases, patients with World Health Organization (WHO) functional class II and III symptoms (table 4) are typically treated with upfront combination oral therapy (eg, ambrisentan and tadalafil) while those with WHO functional class IV are generally treated with a parenteral prostanoid and a second oral agent from a different class. This strategy is based upon data extrapolated from major PAH trials that included a small proportion of patients with SSc-PAH as well as from observational studies in patients with SSc-PAH. (See 'Pulmonary arterial hypertension-directed therapy' above and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Definition'.)

With the exception of calcium channel blocker (CCB) therapy, agent selection is similar to that in patients with other types of PAH. High-dose CCB therapy is not typically administered since few patients are vasoreactive and even in those who are vasoreactive, a hemodynamic response is rarely sustained. However, low-dose therapy for the treatment of Raynaud phenomenon is appropriate (See 'High-dose calcium channel blockers' above.)

Prognosis – PAH is an independent risk factor for mortality among patients with SSc, and the severity of PAH predicts mortality in patients with SSc-PAH. Although survival from SSc–PAH may have improved in the era of PAH-directed therapy, it is worse than that for idiopathic PAH (with perhaps the exception of upfront therapy with a combination of ambrisentan and tadalafil), particularly when there are components of PH associated with interstitial lung disease. (See 'Prognosis' above.)

  1. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019; 53.
  2. Zhang N, Li M, Qian J, et al. Pulmonary arterial hypertension in systemic lupus erythematosus based on a CSTAR-PAH study: Baseline characteristics and risk factors. Int J Rheum Dis 2019; 22:921.
  3. Rodríguez-Roisin R, Krowka MJ, Hervé P, et al. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 2004; 24:861.
  4. Sanchez O, Sitbon O, Jaïs X, et al. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest 2006; 130:182.
  5. Zamanian RT, Badesch D, Chung L, et al. Safety and Efficacy of B-Cell Depletion with Rituximab for the Treatment of Systemic Sclerosis-associated Pulmonary Arterial Hypertension: A Multicenter, Double-Blind, Randomized, Placebo-controlled Trial. Am J Respir Crit Care Med 2021; 204:209.
  6. Grünig E, Maier F, Ehlken N, et al. Exercise training in pulmonary arterial hypertension associated with connective tissue diseases. Arthritis Res Ther 2012; 14:R148.
  7. Ngian GS, Stevens W, Prior D, et al. Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study. Arthritis Res Ther 2012; 14:R213.
  8. Johnson SR, Granton JT, Tomlinson GA, et al. Warfarin in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment for uncommon disease. J Rheumatol 2012; 39:276.
  9. Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation 2014; 129:57.
  10. Henkens IR, Hazenoot T, Boonstra A, et al. Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension. Eur Respir J 2013; 41:872.
  11. Preston IR, Roberts KE, Miller DP, et al. Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Circulation 2015; 132:2403.
  12. Calderone A, Stevens W, Prior D, et al. Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol. BMJ Open 2016; 6:e011028.
  13. Fernández-Codina A, Walker KM, Pope JE, Scleroderma Algorithm Group. Treatment Algorithms for Systemic Sclerosis According to Experts. Arthritis Rheumatol 2018; 70:1820.
  14. Impens AJ, Wangkaew S, Seibold JR. The 6-minute walk test in scleroderma--how measuring everything measures nothing. Rheumatology (Oxford) 2008; 47 Suppl 5:v68.
  15. Kowal-Bielecka O, Avouac J, Pittrow D, et al. Echocardiography as an outcome measure in scleroderma-related pulmonary arterial hypertension: a systematic literature analysis by the EPOSS group. J Rheumatol 2010; 37:105.
  16. Vandecasteele E, Melsens K, De Keyser F, et al. A prospective, longitudinal study evaluating the baseline six-minute walk test as an individual reference value in systemic sclerosis patients. Clin Exp Rheumatol 2018; 36 Suppl 113:95.
  17. Johnson SR, Brode SK, Mielniczuk LM, Granton JT. Dual therapy in IPAH and SSc-PAH. A qualitative systematic review. Respir Med 2012; 106:730.
  18. Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med 2015; 373:834.
  19. Coghlan JG, Galiè N, Barberà JA, et al. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial. Ann Rheum Dis 2017; 76:1219.
  20. Matucci-Cerinic M, Bruni C, Allanore Y, et al. Systemic sclerosis and the COVID-19 pandemic: World Scleroderma Foundation preliminary advice for patient management. Ann Rheum Dis 2020; 79:724.
  21. Hassoun PM, Zamanian RT, Damico R, et al. Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2015; 192:1102.
  22. Lammi MR, Mathai SC, Saketkoo LA, et al. Association Between Initial Oral Therapy and Outcomes in Systemic Sclerosis-Related Pulmonary Arterial Hypertension. Arthritis Rheumatol 2016; 68:740.
  23. Sato T, Ambale-Venkatesh B, Lima JAC, et al. The impact of ambrisentan and tadalafil upfront combination therapy on cardiac function in scleroderma associated pulmonary arterial hypertension patients: cardiac magnetic resonance feature tracking study. Pulm Circ 2018; 8:2045893217748307.
  24. Pestaña-Fernández M, Rubio-Rivas M, Tolosa-Vilella C, et al. Longterm Efficacy and Safety of Monotherapy versus Combination Therapy in Systemic Sclerosis-associated Pulmonary Arterial Hypertension: A Retrospective RESCLE Registry Study. J Rheumatol 2020; 47:89.
  25. Lei Y, Zhang X, Lin H, et al. The effects of oral treatment for systemic sclerosis related pulmonary arterial hypertension: A systematic review and meta-analysis. Mod Rheumatol 2021; 31:151.
  26. Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353:2148.
  27. Badesch DB, Hill NS, Burgess G, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol 2007; 34:2417.
  28. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369:330.
  29. Ghofrani HA, Grimminger F, Grünig E, et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med 2016; 4:361.
  30. Humbert M, Coghlan JG, Ghofrani HA, et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis 2017; 76:422.
  31. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/06/news_detail_002558.jsp&mid=WC0b01ac058004d5c1.
  32. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/59816a-eng.php.
  33. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346:896.
  34. Denton CP, Pope JE, Peter HH, et al. Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases. Ann Rheum Dis 2008; 67:1222.
  35. Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 1996; 35:989.
  36. Kawut SM, Taichman DB, Archer-Chicko CL, et al. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 2003; 123:344.
  37. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369:809.
  38. Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med 2013; 158:641.
  39. Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008; 117:3010.
  40. Günther S, Jaïs X, Maitre S, et al. Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis Rheum 2012; 64:2995.
  41. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132:425.
  42. Badesch DB, McGoon MD, Barst RJ, et al. Longterm survival among patients with scleroderma-associated pulmonary arterial hypertension treated with intravenous epoprostenol. J Rheumatol 2009; 36:2244.
  43. Voswinckel R, Reichenberger F, Gall H, et al. Metered dose inhaler delivery of treprostinil for the treatment of pulmonary hypertension. Pulm Pharmacol Ther 2009; 22:50.
  44. Oudiz RJ, Schilz RJ, Barst RJ, et al. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest 2004; 126:420.
  45. Launay D, Hachulla E, Hatron PY, et al. Aerosolized iloprost in CREST syndrome related pulmonary hypertension. J Rheumatol 2001; 28:2252.
  46. Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2015; 373:2522.
  47. Gaine S, Chin K, Coghlan G, et al. Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. Eur Respir J 2017; 50.
  48. Kuhn BT, Javed U, Armstrong EJ, et al. Balloon dilation atrial septostomy for advanced pulmonary hypertension in patients on prostanoid therapy. Catheter Cardiovasc Interv 2015; 85:1066.
  49. O'Loughlin AJ, Keogh A, Muller DW. Insertion of a fenestrated Amplatzer atrial septostomy device for severe pulmonary hypertension. Heart Lung Circ 2006; 15:275.
  50. Allcock RJ, O'Sullivan JJ, Corris PA. Palliation of systemic sclerosis-associated pulmonary hypertension by atrial septostomy. Arthritis Rheum 2001; 44:1660.
  51. Schachna L, Medsger TA Jr, Dauber JH, et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum 2006; 54:3954.
  52. Pradère P, Tudorache I, Magnusson J, et al. Lung transplantation for scleroderma lung disease: An international, multicenter, observational cohort study. J Heart Lung Transplant 2018; 37:903.
  53. Bernstein EJ, Peterson ER, Sell JL, et al. Survival of adults with systemic sclerosis following lung transplantation: a nationwide cohort study. Arthritis Rheumatol 2015; 67:1314.
  54. Saggar R, Khanna D, Furst DE, et al. Systemic sclerosis and bilateral lung transplantation: a single centre experience. Eur Respir J 2010; 36:893.
  55. Mathai SC, Bueso M, Hummers LK, et al. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J 2010; 35:95.
  56. Lefèvre G, Dauchet L, Hachulla E, et al. Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum 2013; 65:2412.
  57. Fischer A, Bull TM, Steen VD. Practical approach to screening for scleroderma-associated pulmonary arterial hypertension. Arthritis Care Res (Hoboken) 2012; 64:303.
  58. Hachulla E, Carpentier P, Gressin V, et al. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinérAIR-Sclérodermie study. Rheumatology (Oxford) 2009; 48:304.
  59. Chung L, Domsic RT, Lingala B, et al. Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken) 2014; 66:489.
  60. Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003; 62:1088.
  61. Mathai SC, Hummers LK, Champion HC, et al. Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: impact of interstitial lung disease. Arthritis Rheum 2009; 60:569.
  62. Launay D, Humbert M, Berezne A, et al. Clinical characteristics and survival in systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease. Chest 2011; 140:1016.
  63. Fisher MR, Mathai SC, Champion HC, et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum 2006; 54:3043.
  64. Rubenfire M, Huffman MD, Krishnan S, et al. Survival in systemic sclerosis with pulmonary arterial hypertension has not improved in the modern era. Chest 2013; 144:1282.
  65. Kolstad KD, Li S, Steen V, et al. 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; 154:862.
  66. Hassan HJ, Naranjo M, Ayoub N, et al. Improved Survival for Patients with Systemic Sclerosis-associated Pulmonary Arterial Hypertension: The Johns Hopkins Registry. Am J Respir Crit Care Med 2023; 207:312.
  67. Khanna D, Zhao C, Saggar R, et al. Long-Term Outcomes in Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension in the Modern Treatment Era: Meta-Analyses of Randomized, Controlled Trials and Observational Registries. Arthritis Rheumatol 2021; 73:837.
  68. Williams MH, Das C, Handler CE, et al. Systemic sclerosis associated pulmonary hypertension: improved survival in the current era. Heart 2006; 92:926.
  69. 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; 146:1494.
  70. Tedford RJ, Mudd JO, Girgis RE, et al. Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circ Heart Fail 2013; 6:953.
  71. 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; 77:128.
  72. Hsu VM, Chung L, Hummers LK, et al. Risk Factors for Mortality and Cardiopulmonary Hospitalization in Systemic Sclerosis Patients At Risk for Pulmonary Hypertension, in the PHAROS Registry. J Rheumatol 2019; 46:176.
  73. Sobanski V, Giovannelli J, Lynch BM, et al. Characteristics and Survival of Anti-U1 RNP Antibody-Positive Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension. Arthritis Rheumatol 2016; 68:484.
  74. Weatherald J, Boucly A, Launay D, et al. Haemodynamics and serial risk assessment in systemic sclerosis associated pulmonary arterial hypertension. Eur Respir J 2018; 52.
  75. Mercurio V, Diab N, Peloquin G, et al. Risk assessment in scleroderma patients with newly diagnosed pulmonary arterial hypertension: application of the ESC/ERS risk prediction model. Eur Respir J 2018; 52.
  76. Mullin CJ, Khair RM, Damico RL, et al. Validation of the REVEAL Prognostic Equation and Risk Score Calculator in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension. Arthritis Rheumatol 2019; 71:1691.
Topic 8256 Version 34.0

References

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