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Kang, E.H. Pulmonary Manifestations and Rheumatic Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/8349 (accessed on 15 December 2025).
Kang EH. Pulmonary Manifestations and Rheumatic Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/8349. Accessed December 15, 2025.
Kang, Eun Ha. "Pulmonary Manifestations and Rheumatic Diseases" Encyclopedia, https://encyclopedia.pub/entry/8349 (accessed December 15, 2025).
Kang, E.H. (2021, March 30). Pulmonary Manifestations and Rheumatic Diseases. In Encyclopedia. https://encyclopedia.pub/entry/8349
Kang, Eun Ha. "Pulmonary Manifestations and Rheumatic Diseases." Encyclopedia. Web. 30 March, 2021.
Pulmonary Manifestations and Rheumatic Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/ph14030251

Among the diverse forms of lung involvement, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are two important conditions in patients with rheumatic diseases that are associated with significant morbidity and mortality. The management of ILD and PAH is challenging because the current treatment often provides only limited patient survival benefits. Such challenges derive from their common pathogenic mechanisms, where not only the inflammatory processes of immune cells but also the fibrotic and proliferative processes of nonimmune cells play critical roles in disease progression, making immunosuppressive therapy less effective. Recently, updated treatment strategies adopting targeted agents have been introduced with promising results in clinical trials for ILD ad PAH.

rheumatic interstitial lung disease pulmonary arterial hypertension targeted therapy

1. Introduction

Lung involvement is common in patients with rheumatic diseases (RDs), causing substantial morbidity and mortality in these patients. Individual RDs tend to be associated with a characteristic lung disease pattern where the key structure of the injury, as well as the critical cells and cytokines involved, are different [1].

Among the diverse forms of lung involvement, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the two most important manifestations in patients with RD, leading to grave prognoses [2]. Of note, rheumatoid arthritis (RA), myositis, and systemic sclerosis (SSc) are the major systemic RDs, in which a significant proportion of the patients develop and die from ILD and/or PAH. However, recent advances in pharmacologic interventions have been shown to delay the disease progression of these lung conditions and also improve patient survival. In this review, we introduced updated knowledge on the treatment options for ILD and PAH in RDs, focusing on targeted therapies.

2. Interstitial Lung Disease (ILD)

Lung involvement in RDs most commonly takes the form of ILD. In particular, more than two thirds of the patients exhibit ILD in SSc and myositis [3][4]. Clinically symptomatic ILD is less frequent in RA than SSc and myositis, found only in about 10% of the patients [5]. However, the associated morbidity and mortality are never less. RD-associated ILD (RD-ILD) can be classified as usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD), lymphoid interstitial pneumonia (LIP) and others, according to the radiologic and/or pathologic–morphologic patterns presented by the revised 2013 American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias [6]. In RDs, the two most predominant types of ILDs are NISP and UIP [1]. While the prognosis is similar between RD-NISP and idiopathic NSIP, the prognosis of the RD-UIP other than RA-UIP is better than that of idiopathic UIP or idiopathic pulmonary fibrosis (IPF) [7].

2.1. Rheumatoid Arthritis Associated ILD (RA-ILD)

Potential targets of the lung injury in RA include almost all components of the lung structures. Thus, lung injury associated with RA encompasses a wide spectrum of disorders such as parenchymal (ILD), airway (bronchiectasis or bronchiolitis), pleural (pleurisy), and vascular diseases. Among them, ILD is most common.

2.1.1. Clinical Features of RA-ILD

Approximately 10% of RA patients suffer clinically significant RA-ILD [5], with 8–9 times the lifetime risk of ILD development among RA patients compared to that of the general population (7.7% vs. 0.9%, respectively) [8]. Thirty-four percent of RA-ILD was found to occur within one year of RA diagnosis [9] and the risk of RA-ILD increases with RA duration and autoantibody (rheumatoid factor and/or anticitrullinated protein antibody) titers [10][11].

Unlike other RD-ILDs in which NSIP is the most prevalent histopathologic pattern, up to half of the RA-ILD cases show the UIP pattern, with NSIP as the second most common pattern [1]. With a heterogeneous progression rate across individuals, symptoms of RA-ILD usually progress over time once clinically present. The UIP patterns tend to demonstrate extensive disease at baseline and more rapid pulmonary function decline during follow-up, thus are associated with a worse prognosis [1][12]. The mortality of the patients with RA-ILD was as high as three times that of the patients with RA alone, with more than one third of RA-ILD patients being dead at five-years after ILD diagnosis [8][9].

Although it is considered that the natural progression of RA-ILD is heterogeneous, as in IPF, and a subgroup of those whose lung function progressively declines would show a grave prognosis, the exact natural history of RA-ILD is not fully known, particularly regarding acute exacerbation. In addition to the chronic lung function loss, acute exacerbation is another cause of the mortality associated with RA-ILD. However, a substantial proportion of patients with RA-ILD would suffer mixed patterns.

Acute exacerbation is a fatal condition characterized by a rapidly progressive respiratory failure. It has been well recognized not only in IPF and NSIP [6], but also in RD-ILD, particularly RA-ILD [13]. The radiographic characteristics of the acute exacerbation are defined as ground-glass opacities (GGOs) or consolidations newly overlaid on the background reticular abnormalities. Two thirds of RA-ILD patients with acute exacerbation died during the initial episode, causing a 2.5-fold increased mortality among RA-ILD patients [14]. The risk factors for the acute exacerbation of RA-ILD include UIP histology, old age, and methotrexate (MTX) use [14]. In IPF, more advanced lung fibrosis is also known as a reliable risk factor of the acute exacerbation [15].

2.1.2. Pharmacologic Treatment of RA-ILD

Unfortunately, there have been no randomized controlled trials (RCTs) for RA-ILD and the EULAR and ACR recommendations do not specify how to treat RA-ILD yet [16][17]. In general, physicians either adopt the treatment strategies against the corresponding pattern of idiopathic interstitial pneumonia or practice empirical therapies with immunosuppressives. However, due to the heterogeneous clinical behaviors of RA-ILD, the treatment goal is hard to define: treatment to achieve recovery versus treatment to stabilize or slow progression. In the case of acute exacerbation, most therapies are immunosuppressants with potent anti-inflammatory effects, assuming reversibility of the lesions, while in case of chronic progression, the antifibrotic approach will take the priority [2]. Therefore, physicians need to understand the dominant pathogenic mechanism underlying the clinical behavior of individual cases of RA-ILD, which can vary at different time points even in the same patient.

2.2. Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD)

The pulmonary manifestations of SSc can be both direct and indirect. The former category includes parenchymal (ILD) and vascular diseases (PAH) and the latter includes aspiration due to gastroesophageal reflux associated with esophageal sphincter fibrosis.

2.2.1. Clinical Features of SSc-ILD

The key pathophysiology of SSc encompasses a triad of immune activation, vasculopathy, and fibrosis. Due to fibrosis and vasculopathy, the lung involvement of SSc most often manifests as ILD and/or PAH. ILD develops more frequently in the diffuse than limited cutaneous subset, particularly in the presence of antitopoisomerase I antibodies. SSc-specific anti-U3 RNP and anti-Th/To are also associated with SSc-ILD [18].

As many as 90% of SSc patients show ILD [3]. Among 3656 SSc patients from the European Scleroderma Trials and Research group, ILD was observed by plain chest radiography in approximately half of the patients with the diffuse cutaneous SSc and in one third of the patients with the limited cutaneous SSc [19]. Regarding severity, moderate (FVC of 50–75%) to severe (FVC < 50%) restrictive lung disease was found in 40% of SSc patients [20]. The pulmonary function of SSc-ILD patients mostly declines during the first several years after the onset of non-Raynaud’s symptoms, but the progression rate of decline is best predicted by the baseline severity of the lung function or fibrosis [1]. A greater impairment at baseline predicts more progression in the future. Further, there are a significant proportion of patients not treated without progression [21], suggesting that the clinical course of SSc-ILD is variable [22].

The predominant histologic pattern of SSc-ILD is NSIP based on biopsy and/or HRCT [1][3][23]. However, the histologic pattern does not affect the clinical outcome of SSc-ILD [1][7][23]. Because fibrosis is the main histologic finding other than inflammation, even GGO represents fine reticulation and is rarely reversed but replaced later by overt fibrotic findings such as reticulation or honeycombing [24][25].

The mortality of SSc patients showed an overall three-fold increased standardized mortality ratio compared to the general population [26]: the survival of SSc patients was 74.9% at 5 years and 62.5% at 10 years from the diagnosis, with the mortality risk in the presence of ILD being 2.9-fold compared to in the absence of ILD [26].

2.2.2. Pharmacologic Treatment of SSc-ILD

The lung function of SSc patients with FVC of ≥80% at baseline rarely declines [22]. Thus, symptomatic patients are the primary target of treatments, particularly those whose ILD is moderate-to-severe or shows progression. The recent European consensus statements presented an agreement on screening of ILD for all SSc patients at baseline particularly in the presence of risk factors (diffuse cutaneous subset, antitopoisomerase antibody, low DLCO) preferably by HRCT but also with pulmonary function test (PFT) and clinical assessment as supporting tools [27]. The statements recommend treatment for all severe cases defined by PFT or HRCT, and for those who progress based on clinical assessment, HRCT, and/or PFT. However, the statements did not specify the threshold to define severe ILD or when to initiate or escalate treatment. Those who have symptoms that are progressively deteriorating (newly developed functional class II and more), whose FVC and/or DLCO decline is large enough (≥10% and ≥15%, respectively) [28][29], or whose FVC or DLCO is severe enough to justify treatment-related adverse events (refer to the inclusion criteria for Scleroderma Lung Study or SENSCIS trial below) [30][31][32] would be reasonable candidates to initiate or escalate treatment.

2.3. Myositis Associated Interstitial Lung Disease (Myositis-ILD)

As in SSc, the pulmonary manifestations of myositis can be categorized as direct and indirect. The direct involvements are mostly ILD. The indirect involvements consist of aspiration pneumonia due to pharyngeal muscle weakness and hypoventilation due to respiratory muscle weakness [33].

2.3.1. Clinical Course of Myositis-ILD

A majority of myositis-associated lung involvement manifests as ILD. Unlike in SSc, isolated PAH is rare in myositis [34]. ILD manifests early in the course of myositis, often found at the time of diagnosis [4][35][36]. Being prevalent in up to two thirds of myositis patients [4][36], more than 90% of myositis patients develop ILD in the presence of antiaminoacyl tRNA synthetase (ARS) antibody [37]. The clinical course of myositis-ILD is diverse but distinguished from SSc-ILD in that as many as 20% of myositis-ILD cases manifest as a rapidly progressive form that challenges successful treatment [36]. This contrasts with SSc-ILD, where fibrosis is the hallmark of the disease, causing more chronic progression. Such difference indicates that inflammatory process is a dominant process in myositis-ILD, generally in proportion to symptom deterioration rate, and culminates in the rapidly progressive form in which respiratory failure can occur even within days [38][39].

While NSIP is most common for myositis-ILD in general [1], DAD is more common in case of the rapidly progressive type [37]. The rapidly progressive ILD tends to cluster in patients with either classic DM or amyopathic dermatomyositis than polymyositis, particularly in the presence of antimelanoma differentiation-associated gene 5 (anti-MDA5) [40]. Myositis-ILD of the rapidly progressive type is refractory to treatment leading to a high mortality [39].

The treatment response of myositis-ILD follows the underlying histological pattern [36][41][42]. OP is well treated by steroids alone, whereas DAD and UIP respond poorly even to combination therapy [36][41]. The treatment response of NSIP depends upon the degree of inflammation compared to fibrosis [42]. Biomarker studies showed that high serum levels of ferritin, IL-18, or soluble CD206 (macrophage mannose receptor) were associated with a poor treatment response among patients with anti-MDA5-positive ILD [43][44].

2.3.2. Pharmacologic Treatment of Myositis-ILD

Due to the rarity of the disease and the heterogeneous clinical subsets within the disease, the treatment of myositis-ILD most often relies upon empirical therapy consisting of steroids combined with conventional immunosuppressives such as CYC, cyclosporine, or MMF without sufficient data supported by RCTs [1]. Even more limited are the data for targeted treatments. A recent Japanese study showed that the initial combination treatment with high dose steroid, tacrolimus, and CYC with or without plasmapheresis was associated with a better response in anti-MDA5-positive ILD patients compared to step-up therapy from initial high-dose steroids [45]. This finding also put emphasis on the early aggressive treatment for anti-MDA5-positive, rapidly progressive ILD. Moreover, a Spanish expert group agreed that anti-MDA5-positive ILD should be similarly treated [46]. Of note, despite the disease-specific anti-MDA5 autoantibody, successful treatment with rituximab has only been anecdotally reported [47].

2.4. Future Treatment Strategies for Rheumatic Disease Associated Interstitial Lung Disease

Nintedanib and pirfenidone slow but do not halt the progression of IPF. Thus, interest in the combination of the two drugs is growing, but more data are needed on the safety and efficacy of combination therapy. There are a few studies that showed relatively acceptable tolerability and safety of the two drugs combined for a short-term period (12~24 weeks) [48][49]: the combination was completed in two thirds of patients despite a higher adverse event rate compared to the single drug treatment. However, there have yet to be large randomized controlled trials assessing whether combination therapy has increased efficacy compared to treatment with a single antifibrotic drug.

Several clinical trials evaluating the efficacy of the new drugs on pulmonary outcomes are underway. The ISABELA 1 and 2 trials are now ongoing to examine the effect of autotaxin inhibitor GB-0998 among patients with IPF (ClinicalTrials.gov number, NCT03711162; NCT03733444) [50]. A phase 2 RCT of bortezomib plus MMF versus MMF alone on patients with SSc-ILD is currently ongoing (ClinicalTrials.gov number, NCT02370693). Romilkimab, a monoclonal antibody targeting IL-4 and IL-13, showed efficacy after 24 weeks on skin fibrosis associated with diffuse SSc under background immunosuppressive agents in a phase 2 pilot study [51]. However, it failed to show benefits in the of IPF after 52 weeks [52]. Guselkumab (monoclonal antibody that blocks IL-23) is under investigation in SSc patients with skin fibrosis as the primary outcome of and lung function as one of the secondary outcomes (ClinicalTrials.gov number, NCT04683029).

3. Pulmonary Arterial Hypertension (PAH)

Abnormal proliferation, vasoconstriction, and thrombosis of the pulmonary vasculature are the main pathogenic mechanisms of PAH. Right heart catheterization (RHC) is the gold standard to diagnose PAH using the criteria of a mean pulmonary arterial pressure of ≥25 mmHg and a pulmonary capillary wedge pressure of ≤15 mmHg [53].

3.1. Systemic Sclerosis Associated Pulmonary Arterial Hypertension (SSc-PAH)

Not only isolated PAH but also PH secondary to either left heart dysfunction or ILD progression can occur in SSc, either separately or in combination. The SSc-PAH shows a unique phenotype of PAH with a worst prognosis compared to idiopathic or non-SSc RD- PAH [54][55].

3.1.1. Clinical Features of SSc-PAH

The mortality risk of SSc patients increases by 3-fold in the presence of PAH, showing PAH is a deadly complication of SSc patients [56]. Therefore, patients should be screened for PAH based on symptoms, echocardiography, and DLCO patterns and undergo RHC if identified as high-risk [57][58]. With RHC, SSc-PAH was found in approximately 10% of these high-risk candidates. The limited rather than the diffuse cutaneous subset shows a higher prevalence of SSc-PAH, which was observed in up to half of the patients with CREST syndrome [59]. It was reported that 50% of SSc-PAH occurs within five years from the first non-Raynaud phenomenon symptom with the mean interval from SSc diagnosis to PAH occurrence of 6.3 years [60].

Like those with idiopathic PAH, patients with SSc-PAH are either clinically silent or show only nonspecific symptoms until their disease is advanced. Therefore, active surveillance is the key to early intervention, which indeed led to better survival compared to passive identification [61]. In SSc patients, male sex, old age, overt vasculopathy such as telangiectasia and digital ulcers, anticentromere or anti-U3 RNP antibodies, and the limited cutaneous subset (e.g., CREST syndrome) were identified as risk factors for PAH [62]. However, both the sensitivity and the specificity of these risk factors are limited. Other findings suggestive of PAH include elevated levels of the N-terminal probrain natriuretic peptide (NT-proBNP) or disproportionately low DLCO [63][64]. In particular, echocardiographic measures are one of the important screening tools to identify candidates for RHC. For example, a tricuspid regurgitation (TR) velocity of ≥2.5 m/s is considered one of the findings highly suggestive of PAH [65]. However, the sensitivity at this TR velocity threshold is limited, missing 20% of the mild PAH patients [65][66]. DETECT is a multidimensional algorithm to identify SSc patients at a high risk of PAH, used as the active surveillance strategy to avoid the delayed diagnosis of PAH [1][65]. Among 57 DETECT enrollees with SSc-PAH, 44% progressed during a median follow-up of 12.6 months [67]. The factors associated with progression were male gender, disproportionately low DLCO, and poor functional capacity. A more simplified and practical algorithm proposed in 2013 to initially screen SSc patients uses PFT, echocardiography, and NT-proBNP for referral for RHC [68] (Table 1).

Table 1. Screening algorithm for SSc-PAH proposed in 2013 a.

  Quality of Evidence
All patients with SSc should be screened for PAH Moderate
Initial screening evaluation in patients with SSc or SSc-spectrum disorders  
► Pulmonary function test (PFT) with diffusion capacity of carbon monoxide (DLCO) High
► Transthoracic echocardiography (TTE) High
► N-terminal probrain natriuretic peptide (NT-proBNP) Moderate
► DETECT algorithm if DLCO% < 60% and >3 years disease duration from non-RP Moderate
Recommendations for right heart catheterization for SSc or SSc-spectrum disorders  
Screening method Parameter cut-off Signs/symptoms requirement b  
PFT c FVC/DLCO ratio > 1.6 and/or DLCO < 60% Yes High
  FVC/DLCO ratio > 1.6 and/or DLCO < 60% plusNT-proBNP > 2 x upper limit of normal No High
TTE TR velocity Yes High
  2.5–2.8 m/s No High
  >2.8 m/s No High
  Cavity enlargements irrespective of TR velocityRA major dimension > 53 mm orRV mid-cavity dimension > 35 mm    
Composite Meets DETECT algorithm with DLCO% < 60% and >3 years of disease duration No Moderate

a Cited and modified from “Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension” by Khanna D, et al. Arthritis Rheum 2013; 65: 3194–3201 [68]. b Symptoms: dyspnea upon rest or exercise, fatigue, presyncope/syncope, chest pain, palpitations, dizziness, lightheadedness. Signs: loud pulmonic sound, peripheral edema. c Without overt systolic dysfunction, greater than grade I diastolic dysfunction, greater than mild mitral or aortic valve disease, or evidence of PAH in echocardiography. DLCO = diffusion capacity of carbon monoxide; FVC = forced vital capacity; NT-proBNP = N-terminal probrain natriuretic peptide; PAH = pulmonary arterial hypertension; PFT = pulmonary function test; RA = right atrium; RV = right ventricle; SSc = systemic sclerosis; TTE = transthoracic echocardiography.

In a recent prospective observational study, 93 SSc-ILD patients were screened and underwent RHC following the above 2013 algorithm. Of these, 31.2% were found to have RHC-proven PAH, and the survival rate was 91% at three years [69]. This improved survival is striking compared to the exceptionally grave prognosis (survival of 39% at three years) previously reported for SSc patients with coexisting ILD and PAH [70]. Based on this finding, the poor prognosis of SSc-PAH patients compared to patients with idiopathic or PAH of other rheumatic diseases could be due to delayed diagnosis and treatment [54][55], and early treatment is paramount for better survival.

3.1.2. Pharmacological Treatment of SSc-PAH

Treatment with Conventional Agents

Immunosuppression against the hyperimmune state of SSc is never sufficient to stop SSc-PAH progression due to fibrotic and proliferative pathways driven by nonimmune cells. An acute vasoreactive response is observed in 10% of the patients with RD-PAH, but the response to calcium channel blockers beyond 3–4 months is preserved in less than 1% of these patients [71].

Treatment with Targeted Agents and Risk Stratification

Although the autoimmune process may be the fundamental mechanism orchestrating the initiation and progression of RD-PAH, its downstream effects involve nonimmune components as well, leading to pulmonary vascular remodeling. In particular, the treatment effect of anti-inflammatory agents is limited in lung diseases associated with SSc, indicating that noninflammatory pathways play a dominant role. In PAH, endothelial dysfunction due to abnormally regulated vasoactive and/or proliferative mediators induces vascular constriction and remodeling. Currently, three pathways important in endothelial function are targeted by PAH treatments, endothelin-1, nitric oxide (NO), and prostacyclin pathways [72]. Endothelin receptor antagonist (ERA), phosphodiesterase 5 inhibitor (PDE5i), and soluble guanylate cyclase (sGC) stimulator, which potentiate the effect of nitric oxide (NO), as well as prostacyclin analogs (PCA), are commercially available (Table 2).

Table 2. Efficacy of drug monotherapy for group 1 PAH according to WHO functional class a.

  Class b-Level c
WHO-FC II WHO-FC III WHO-FC IV
ERA Ambrisentan I A I A IIb C
Bosentan I A I A IIb C
Macitentan I B I B IIb C
PDE5i Sildenafil I A I A IIb C
Tadalafil I B I B IIb C
Vardenafil IIb B IIb B IIb C
sGC stimulator Riociguat I B I B IIb C
PCA Epoprostenol Intravenous ‒ ‒ I A I A
Iloprost Inhaled ‒ ‒ I B IIb C
Intravenous ‒ ‒ IIa C IIb C
Treprostinil Subcutaneous ‒ ‒ I B IIb C
Inhaled ‒ ‒ I B IIb C
Intravenous ‒ ‒ IIa C IIb C
Oral ‒ ‒ IIb B ‒ ‒
Beraprost ‒ ‒ IIb IIb ‒ ‒
Selexipag [oral] I B I B ‒ ‒

a Cited and modified from “2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension” by Galiè N et al. Eur Heart J. 2016; 37:67–119 [66], b Class of recommendation, c level of evidence, ERA = endothelin receptor antagonist; PDE5i = phosphodiesterase 5 inhibitor; sGC = soluble guanylate cyclase; PAH = pulmonary arterial hypertension; PCA = prostacyclin analog or receptor antagonist; WHO = World Health Organization; FC = functional class.

According to the 2017 EULAR recommendations [73], ERA (ambrisentan, bosentan, and macitentan), PDE5i (sildenafil and tadalafil), and an sGC stimulator (riociguats) are considered the first-line options for treating SSc-PAH based on high-quality RCTs that showed improvement in exercise capacity, the time to clinical worsening (defined as a composite of death, hospitalization, and disease progression), and/or PAH-related hemodynamics in heterogeneous patients with PAH including RD-PAH. These studies were not powered to show the independent efficacy of the SSc-PAH subgroup, but the EULAR recommendations are based on the extrapolation of the high-quality RCT results. In the subgroup analyses, the direction of the results was not different between patients with idiopathic PAH and RD-PAH. In the idiopathic PAH, significant improvements in exercise capacity and reductions in mortality (pooled effect, 44% reduction; p < 0.041) by these treatments were demonstrated [74].

A high-quality RCT showed that continuous intravenous epoprostenol (a prostacyclin analog) administration improved exercise capacity, functional class, and hemodynamics in patients with SSc-PAH [75]. The administration of continuous intravenous epoprostenol requires an indwelling central venous catheter and abrupt cessation of the drug may cause PAH rebound that can be fatal. Thus, the EULAR recommendations suggest that this treatment should be considered for severe SSc-PAH of class III and IV [73]. In addition to epoprostenol, other PCAs (iloprost and treprostinil) showed similar results in high-quality RCTs on heterogeneous patients with PAH including RD-PAH and are also approved for the treatment of PAH including RD-PAH [73]. Although not commented in EULAR recommendations, selexipag, an oral selective prostacyclin IP receptor agonist, has shown efficacy in the phase 3 GRIPHON trial of reducing the risk of a primary composite endpoint of morbidity and mortality by 40% and 41% in PAH and RD-PAH (majority, SSc-PAH), respectively [76][77]. Selexipag is the only oral prostacyclin receptor agonist that showed a reduction of morbidity and mortality in a RCT.

In addition to the application of individual drugs that target each corresponding pathway, the advancements in recent treatment strategies include the risk assessment of PAH patients and linking the baseline severity of PAH to the subsequent treatment intensity or escalation [66][72]. According to the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines [66], a multiparametric approach should be considered to stratify patients into low-, intermediate- or high-risk groups for 1-year mortality using clinical (clinical signs of right heart failure, the progression of symptoms, and syncope), functional class (WHO or NYHA class), exercise (6-min walking distance and cardiopulmonary exercise testing), biochemical (NT-proBNP), and echocardiographic/hemodynamic parameters (Table 3).

Table 3. 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the risk assessment of patients with PAH a.

Parameters of Prognosis

 Estimated 1-Year Mortality
Low Risk < 5% Low Risk < 5% Low Risk < 5%
Clinical signs of right heart failure Absent Absent Present
Progression of symptoms No Slow Rapid
Syncope No Occasional syncope b Repeated syncope c
WHO functional class I, II III IV
6MWD >440 m 165–440 m <165 m
Cardiopulmonary exercise testing Peak VO2 > 15 mL/min/kg (>65% predicted)
VE/VCO2 slope < 36		 Peak VO2 >15 mL/min/kg
(35–65% predicted)
VE/VCO2 slope < 36		 Peak VO2 <11 mL/min/kg
(<35% predicted)
VE/VCO2 slope ≥ 45
NT-proBNP levels BNP < 50 ng/L
NT-proBNP < 300 ng/L		 BNP 50–300 ng/L
NT-proBNP 300–1400 ng/L		 BNP >300 ng/L
NT-proBNP > 1400 ng/L
Imaging (echocardiography, CMR imaging) RA area <18 cm2
No pericardial effusion		 VE/VCO2 slope < 36 RA area > 26 cm2
pericardial effusion
Hemodynamics RAP < 8 mmHg
CI ≥ 2.5 L/min/m2
SvO2 > 65%		 RAP 8–14 mmHg
CI 2.0–2.4 L/min/m2
SvO2 60–65%		 RAP > 14 mmHg
CI < 2.0 L/min/m2
SvO2 < 60%

a Cited and modified from “2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension” Galiè N, et al. Eur Heart J. 2016;37:67–119 [66]. b Occasional syncope during brisk or heavy exercise, or occasional orthostatic syncope in an otherwise stable patient. c Repeated episodes of syncope even with little or regular physical activity. 6MWD = 6-min walking distance; BNP = brain natriuretic peptide; CI = cardiac index; CMR = cardiac magnetic resonance; NT-proBNP = N-terminal probrain natriuretic peptide; PAH = pulmonary arterial hypertension; RA = right atrium; RAP = right atrial pressure; SvO2 = mixed venous oxygen saturation; VE/VCO2 = ventilatory equivalents for carbon dioxide; VO2 = oxygen consumption; WHO = World Health Organization.

Another important feature of the 2015 ESC/ERS guidelines for PAH is the endorsement of pre-emptive combination therapy targeting different endothelial pathways, particularly for high-risk patients [66]. The most compelling evidence for such strategy came from the recent AMBITION trial where a 50% reduction in the composite endpoint of clinical failure events at 24 weeks was seen from treatment with the upfront combination of ambrisentan and tadalafil compared to either drug alone in patients with PAH and RD-PAH [78]. Similarly, the add-on effect of a study drug (either macitentan, selexipag, or riociguat) was observed in other RCTs when combined with a background PAH treatment using a different class [76][79][80], also endorsing sequential combination therapy. Similar evidence for upfront or initial combination or sequential combination therapy was also observed in patients with RD-PAH including SSc-PAH [77][81][82]. The 2015 ESC/ERS guidelines also depict a treatment algorithm that recommends treatment escalation (double to triple, maximal medical therapy including intravenous PCA) when the reassessment in 3–6 months shows an insufficient response such as residual intermediate- or high-risk status [66]. However, the evidence for the benefits of combination therapy remains to be replicated, specifically for SSc-PAH in future studies.

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