Introduction

Autoimmune connective tissues diseases (CTD) refer to a heterogeneous group of conditions characterized by immune dysfunction, leading to end organ damage due to inflammation, endothelial dysfunction, and fibrosis. Clinical observational registries have been invaluable in describing real-life patients, treatment patterns, and prognostic outcomes of an otherwise rare and diverse group of conditions that can be complicated by pulmonary arterial hypertension (PAH), which is associated with significant morbidity and mortality. Although CTD-PAH will be described more broadly, the focus of this study is on systemic sclerosis-related PAH (SSc-PAH) as the leading cause of CTD-PAH worldwide, thereby providing a unique window to various aspects of pulmonary hypertension assessment and management.

Updated classification of pulmonary hypertension

Pulmonary hypertension (PH) refers to a hemodynamic and pathophysiological state defined by an increase in mean pulmonary artery pressure (PAP) ≥ 25 mmHg at rest as assessed by right heart catheterization (RHC), and is further subclassified according to the pulmonary artery wedge pressure (PAWP) into precapillary (PAWP ≤ 15 mmHg) or postcapillary PH (PAWP > 15 mmHg) . In general, precapillary PH develops in the setting of pulmonary vascular diseases, where obstructive remodeling of the pulmonary arteries results in elevated pulmonary vascular resistance (PVR). By contrast, postcapillary PH develops due to passive transmission of elevated PAWP without necessarily an increase in PVR.

As PH can be the consequence of different clinical conditions, the current PH classification has been further divided into key groups determined according to shared pathophysiology and approach to therapy ( Table 1 ) . Clinical groups included in precapillary PH are PAH (group 1), PH due to lung diseases (group 3), chronic thromboembolic PH (group 4), and PH with unclear and/or multifactorial mechanisms (group 5), while postcapillary PH chiefly comprises PH due to left heart disease (group 2).

Updated classification of pulmonary hypertension

Pulmonary hypertension (PH) refers to a hemodynamic and pathophysiological state defined by an increase in mean pulmonary artery pressure (PAP) ≥ 25 mmHg at rest as assessed by right heart catheterization (RHC), and is further subclassified according to the pulmonary artery wedge pressure (PAWP) into precapillary (PAWP ≤ 15 mmHg) or postcapillary PH (PAWP > 15 mmHg) . In general, precapillary PH develops in the setting of pulmonary vascular diseases, where obstructive remodeling of the pulmonary arteries results in elevated pulmonary vascular resistance (PVR). By contrast, postcapillary PH develops due to passive transmission of elevated PAWP without necessarily an increase in PVR.

As PH can be the consequence of different clinical conditions, the current PH classification has been further divided into key groups determined according to shared pathophysiology and approach to therapy ( Table 1 ) . Clinical groups included in precapillary PH are PAH (group 1), PH due to lung diseases (group 3), chronic thromboembolic PH (group 4), and PH with unclear and/or multifactorial mechanisms (group 5), while postcapillary PH chiefly comprises PH due to left heart disease (group 2).

Epidemiology of CTD-PAH

Registry data have shown that CTD-PAH is the second leading cause of PAH (∼25% of all cases), next to idiopathic PAH (∼46%) . SSc-PAH accounts for almost 75% of cases of CTD-PAH; the remaining, in order of decreasing frequency, are due to systemic lupus erythematosus (SLE, 8–19%), mixed connective tissue disease (MCTD, 8–9%), rheumatoid arthritis (RA, 3–5%), dermatomyositis/polymyositis (DM/PM, 4%), undifferentiated connective tissue disease (2%), and Sjogren’s syndrome (1%) .

Approximately 1 in 10 SSc patients will develop PAH in his/her lifetime. However, much less is known about the true incidence of SSc-PAH, with one longitudinal observational study reporting an incidence rate of 0.61 cases per 100 patients years, in 384 SSc patients with no “high risk” features for PH assessed noninvasively over a mean period of 41.03 ± 5.66 months . This relatively low incidence increases considerably among patients with significant “high risk” factors for PH (systolic PAP at transthoracic echocardiography (TTC) > 40 mmHg and/or diffusing capacity for carbon monoxide (DLCO) < 55% predicted and/or forced vital capacity (FVC)/DLCO ratio > 1.6), with a recent study reporting the frequency of PH in this population to be 10% at 2 years, 13% at 3 years, and 25% at 5 years . Data on the prevalence of PAH in CTDs other than SSc are much less reliable because of the lack of RHC-based studies, but prevalence rates using RHC have been reported in SLE (0.005–9.3%) .

Survival in CTD-PAH: poorer than iPAH

In the vast majority of patients, SSc-PAH is a progressive disease associated with significant mortality. In a recent large systematic study, inclusive of 17 studies and 2011 SSc patients with PAH, 1-, 2-, and 3-year pooled survival rates were reported at 82% (95% CI 79–85%), 67% (95% CI 63–72%), and 56% (95% CI 51–61%), respectively .

The poor prognosis of SSc-PAH patients compared to patients with iPAH has been recognized in a number of studies. In the REVEAL registry, 641 patients with CTD-PAH (including 399 patients with SSc-PAH) were compared with 1251 patients with iPAH, and were shown to have a lower 1-year survival rate (86% vs. 93%, p < 0.0001) and freedom from hospitalization rate (67% vs. 73%, p = 0.03) at 1 year, despite the CTD-PAH group having better pulmonary hemodynamics and right ventricular function on echocardiography than the iPAH group . The CTD-PAH group also had a higher prevalence of pericardial effusion, higher brain natriuretic peptide (BNP) levels (432.8 ± 789.1 vs. 245.6 ± 427.2 pg/mL, p < 0.0001), lower 6-min walk distances (6 MWDs, 300.5 ± 118.0 vs. 329.4 ± 134.7 m, p = 0.01), and lower DLCO levels (44.9 ± 18.0% vs. 63.6% ± 22.1% predicted, p < 0.0001). Compared with the more broad CTD-PAH group, the SSc-PAH subgroup had a lower 1-year survival rate (82% in SSc-PAH vs. 94% in SLE-PAH, 88% in MCTD-PAH, and 96% in RA-PAH).

Importantly, survival rates in SSc-PAH appear to have improved in recent years due to the focus on screening for and early detection of PAH, emergence of evidence-based therapies and treatment strategies, and establishment of centers with expertise in SSc and PAH. The Australian Scleroderma Cohort Study (ASCS) is a prospective, multicenter study of risk and prognostic factors for cardiopulmonary outcomes in SSc and MCTD, in which an early detection algorithm is applied; reported 1- and 3-year survival rates in the CTD-PAH group were 94% and 73%, respectively . Similarly, in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry, 131 SSc patients with incident PAH, who were followed for a mean ± SD of 2.0 ± 1.4 years, had 1-, 2-, and 3-year cumulative survival rates of 93%, 88%, and 75%, respectively . While it is often difficult to directly compare different cohorts due to confounders (unknown or difficult to statistically correct for such as regulations that govern access to treatment/therapeutic strategies, disease trajectory, or patient adherence), it seems likely that these increased survival rates compared to previously reported SSc cohorts are attributable to screening and early detection .

In the large Pittsburgh and EUSTAR registries, SSc-PAH was the second leading cause of SSc-related mortality, next to interstitial lung disease (ILD) . In the ASCS, pulmonary disease (PAH and/or ILD) accounted for approximately 75% of SSc-related deaths and almost half of all deaths in 4 years of follow-up . SSc-PAH has been shown to be an independent predictor of mortality, conferring a twofold increased risk of death (HR 2.018, 95% CI: 1.440–2.827, p < 0.001) in the EUSTAR registry and a sevenfold increased risk of mortality (HR 7.246, 95%CI: 4.000–13.158, p < 0.0001) in the large French ItinerAIR Sclerodermie Study . The combination of ILD and PH predicts a particularly grim prognosis, with 1-, 2-, and 3-year survival rates of 77% (95% CI 70–83%), 48% (95% CI 40–55%), and 35% (95% CI 24–47%), respectively .

Several important predictors of increased mortality have been identified in SSc-PAH, including an advanced functional class of impairment at diagnosis, worse hemodynamic profile at diagnosis (increased mPAP, mean right atrial pressure and PVR, and reduced cardiac index (CI)), age > 60 years, male sex, a pericardial effusion at diagnosis, and severely impaired DLCO . These factors emphasize the clinical imperative to reduce the time to diagnosis and commencement of effective therapies. They also provide a rationale for closer monitoring of patients in poor prognostic groups, including repeated hemodynamic assessments, rapid escalation of therapy (including dual and triple therapy combinations), and enrollment in clinical trials of novel therapies and/or treatment strategies.

Diagnostic evaluation of pulmonary hypertension in CTD

The diagnostic evaluation of a patient with suspected PH requires a systematic approach to (1) confirm the presence of PH via invasive hemodynamic assessment with RHC; (2) determine the main mechanism(s) contributing PH according to the clinical classification; and (3) evaluate severity of the disease based on the degree of functional and hemodynamic impairment. Table 2 describes the key investigations that should be performed in a CTD patient presenting with suspected PH.

SSc is a particularly instructive and challenging prototype CTD for PH, as SSc patients are at risk of multiple potential causes of pulmonary hypertension, and different causes can coexist in the same SSc patient, posing diagnostic and management challenges. The most common cause is PAH (group 1) followed by PH due to left heart disease (group 2) and PH due to lung disease (group 3), with uncommon but underrecognized causes including PH due to pulmonary veno-occlusive disease (PVOD, group 1) and PH due to chronic thromboembolic disease (CTEPH, group 4) patients. In clinical practice, a systematic evaluation of these possibilities is vital to determine the relative contribution of one or more of these causes in managing a particular patient. A multidisciplinary approach is recommended given the complexities involved in the evaluation of PH in CTD .

PAH, or group 1 PH, is a clinical condition characterized by restricted flow through the pulmonary circulation, where the primary disease process is due to a vasculopathy affecting the small pulmonary arteries. The disease process is characterized by progressive remodeling of the small pulmonary arteries due to proliferation of vascular cells, leading to luminal obstruction of vessels and elevation of PVR . It is diagnosed by finding precapillary PH at RHC with a PVR > 3 Wood Units (WU) in the absence of significant lung disease and chronic thromboembolic disease.

PH secondary to left heart disease affects up to 12% of SSc patients, and is diagnosed by the finding of postcapillary PH at RHC (PAWP > 15 mmHg) . The underlying pathogenesis often reflects primary myocardial fibrosis, which is a common, but often occult process in SSc. Alternatively, left heart disease can be related to the presence of traditional risk factors for left heart dysfunction such as older age, hypertension, smoking, or renal disease .

In general, lung disease-associated PH is due to ILD in CTD, and refers to the RHC finding of precapillary PH coupled with significant ILD; significant ILD in PAH trials has been variably defined according to the extent of involvement on high-resolution computed tomography (HRCT) of the chest (usually more than mild) together with lung function testing abnormalities (TLC < 70% or FVC < 60–70%) . Importantly, only a small proportion of patients with severe ILD will actually develop PH, which is fortunate given the grim prognosis of this group . It seems likely that in a disease like SSc, a true pulmonary vasculopathy (group 1) may coexist with significant ILD, making further research into this group important.

Finally, PH due to PVOD is probably underrecognized in CTD, particularly in the setting of SSc . PVOD needs particular mention, since differentiating PVOD from PAH can be clinically challenging and PAH-specific therapy tends to be tolerated poorly by patients with PVOD. The vasculopathy of PVOD is characterized by preferential involvement of small pulmonary veins together with patchy capillary proliferation , in contrast to the predominant involvement of small pulmonary arteries in PAH. However, the invasive hemodynamic features of PAH and PVOD are indistinguishable, as both are characterized by precapillary PH at RHC . Chest HRCT is the investigation most likely to reveal underlying PVOD, and is characterized by the triad of mediastinal lymphadenopathy, smooth interlobular septal thickening, and centrilobular ground glass opacities . In addition to HRCT signs, a very low DLCO and severe hypoxemia are other features suspicious of PVOD . Features suggestive of PVOD have been found in as many as two-thirds of patients who are classified as “SSc-PAH” based on postmortem histological examination . The high prevalence of veno-occlusive disease in SSc may explain, in part, the refractoriness to targeted PAH therapy in some patients. The importance of identifying PVOD as the cause for precapillary PH depends on the fact that PAH therapy can actually precipitate severe pulmonary edema .

CTEPH can occur in CTD, particularly in the setting of antiphospholipid syndrome. Although less common in SSc, the diagnosis of CTEPH needs to be excluded in all patients with precapillary PH. In CTEPH, organized thrombi result in luminal occlusion of the more proximal pulmonary arteries . It is important to identify this condition, as it can be potentially cured surgically .

In CTDs other than SSc, the pathogenesis of PH varies according to the underlying CTD. In SLE, pulmonary vasculitis and thromboembolic disease are seen relatively more commonly. In the inflammatory myositis conditions, the extent of ILD seems to be the main contributor to PH, although higher rates of acute thromboembolism have also been noted. Relatively little is known about the pathogenesis of PH in RA.

Early detection and screening for PAH in SSc

Reliance on the development of symptoms such as exertional dyspnea is insensitive for the early diagnosis of PAH, and is often confounded by other manifestations of CTD such as musculoskeletal disease or anemia . Given the high lifetime risk of developing PAH in SSc, the current availability of efficacious drug therapies, and the progressive nature of SSc-PAH, systematic screening for PAH has been currently recommended by professional bodies worldwide for patients with SSc or SSc-spectrum disorders . At present, screening has not been routinely offered to other CTD subtypes, given the low overall frequency of PAH outside the setting of SSc.

Longitudinal observational studies embedded within clinical practice have provided important insights as well as evidence that systematic screening for SSc-PAH can be associated with improved outcomes. A French study showed that SSc patients who had PAH diagnosed via a screening program had milder disease and improved long-term survival compared with those who were diagnosed via routine clinical care. In this study, a systematic and structured screening program using TTE was offered to all patients with SSc, regardless of symptoms. Patients with a peak tricuspid regurgitation jet velocity of >3 m/s or a peak tricuspid regurgitation jet velocity of 2.5–3 m/s accompanied by unexplained dyspnea underwent RHC to confirm the presence of PAH. The group that underwent systematic TTE-based screening was then compared to a control group who had PAH detected via standard clinical care. The screening cohort had significantly less severe PAH at diagnosis as measured by the New York Heart Association (NYHA) functional class (50.0% vs. 12.5% in class I or II; p = 0.036) and pulmonary hemodynamics (PVR index: 734 ± 486 vs. 1299 ± 428 dyn s m ⁻⁵ m ² ; p = 0.01). Importantly, major improvements in survival rates were observed in patients who were diagnosed through the screening program compared with those who were provided routine care. The 1-, 3-, 5-, and 8-year survival rates in the screening cohort were 100%, 81%, 73%, and 64% versus 75%, 31%, 25%, and 17%, respectively ( p = 0.0037) in the routine care cohort, allowing for the fact that lead time bias is difficult to exclude.

Although TTE remains the most widely used noninvasive modality to screen for PAH, other noninvasive markers have also showed their utility for the detection of SSc-PAH. These include lung function parameters and biomarkers of ventricular dysfunction. A low DLCO is associated with the presence of current PAH and can also predict the occurrence of future PAH in SSc patients without ILD . Patients with SSc-PAH typically have moderate-to-severe reduction in DLCO at the time of diagnosis, and the French ItinerAIR study found that a predicted DLCO of <60% was associated with a markedly increased probability of PAH (OR 9.23, 95%CI 2.73–31.15) . The Pittsburgh Scleroderma Databank showed that a reduction and/or progressive fall in DLCO could be documented 4–5 years before the diagnosis of SSc-PAH . Because DLCO is influenced by lung volumes, pulmonary vascular disease usually results in a disproportionate reduction in DLCO compared with lung volumes. Therefore, FVC/DLCO ratio [or DLCO/VA (alveolar volume)] has been postulated to be a refined lung function parameter to indicate the presence of pulmonary vasculopathy in SSc-PAH .

B-type natriuretic peptide is released from ventricular myocytes in response to increased wall tension, and has been shown to be a useful and widely available biomarker for the presence of SSc-PAH. In patients with established PAH, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) correlates with the severity of pulmonary vascular disease and the degree of right ventricular dysfunction . Screening studies have documented varying NT-pro-BNP cutoff values (210–395 pg/mL) for the optimal detection of SSc-PAH , with the acknowledgment that these thresholds may potentially miss patients with very mild disease and normal right ventricular function, as NT-pro-BNP is a surrogate marker of ventricular strain. In clinical practice, NT-pro-BNP levels can also be elevated due to conditions other than PAH such as left ventricular dysfunction and advanced renal insufficiency , which can also complicate SSc.