Epidemiology and disease characteristics of systemic sclerosis-related pulmonary arterial hypertension: results from a real-life screening programme

The ASCS is a nationwide project wherein patients with SSc are recruited from 13 participating centres across Australia. SSc experts were invited by a core group of rheumatologists to form the Australian Scleroderma Interest Group (ASIG) and to take part in the ASCS through recruitment of patients and collection of data at their centres. Physicians who are not at an ASIG centre and care for patients with SSc are invited to refer patients for the screening service, while ongoing care between screening visits remains their responsibility.

All patients with SSc, defined according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria [25] or Leroy/Medsger criteria [26], and mixed connective tissue disease (MCTD), as originally described by Sharp et al. [27], are eligible for enrolment. Patients provide written informed consent for collection of de-identified data, chart review, and storage of serum and DNA for future studies. All human research ethics committees of the participating sites have approved ASCS.

Comprehensive demographic and disease-related data are collected annually and entered into a custom-made database hosted by St. Vincent’s Hospital Melbourne using a remote secure access token. A log is kept of all users and the database is backed up daily. Logic checks are used to detect errors in data entry and incomplete entries.

Participation in the ASCS mandates annual application of a PAH screening algorithm created by a panel of Australian rheumatologists, cardiologists and respiratory physicians (Fig. 1) based on the European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines [28, 29]. According to Fig. 1, investigations are recommended for symptomatic patients with low probability of PAH, and irrespective of symptoms for patients with moderate or high probability of PAH [30].

If any value falls outside a predetermined range for systolic pulmonary arterial pressure (sPAP) on TTE, diffusing capacity of the lung for carbon monoxide (DLCO) corrected for haemoglobin, and/or forced vital capacity (FVC) according to the screening algorithm, an email to the treating physician is automatically generated, indicating why the alert has been triggered and recommending a course of action. If the physician chooses not to follow the algorithm he/she must justify this decision.

Non-ASIG physicians’ screening practices and adherence to published recommendations for PAH screening [24, 28, 29] were assessed by means of a cross-sectional survey (Additional file 1: Table S1 using survey monkey circulated through the Australian Rheumatology Association following the establishment of ASCS in 2007. The survey addressed existing screening practices based on SSc disease subtype and disease duration (early or late defined as <10 or ≥10 years from the first non-Raynaud’s disease manifestation, respectively), barriers to screening encountered by physicians and suggestions for streamlining screening.

A total of 1636 patients were recruited into ASCS from July 2007 to July 2016 (census date). Recruitment comprised new referrals from general practitioners for comprehensive specialist management, and from rheumatologists requesting the PAH screening service only. The number of patients recruited, relative to the predicted prevalence of SSc in Australia [31, 32] and population data from the Australian Bureau of Statistics [33] were estimated.

Of the 1636 patients, 1243 (75.9%) had been seen within the 18 months before the census date and were considered “current” (Table 1). The period of 18 months was selected to allow for delays in data entry. Patient characteristics and follow-up status are summarised in Table 1.

Patients with limited disease (lcSSc) were older at recruitment than patients with diffuse disease (dcSSc) (58.8 ± 12.2 vs 53.1 ± 13.1 years, p < 0.001) with longer disease duration from first non-Raynaud’s clinical manifestation (12.2 ± 10.8 vs 8.1 ± 8.7 years, p < 0.001). ILD was more prevalent in the patients with dcSSc (40.9% vs 21.1%) but there was no significant difference in the prevalence of PAH (10.1% vs 12.7%, p = 0.40) (Table 2).

In total, 232 patients (14.2%) were diagnosed with pulmonary hypertension (PH). Of these, 194 patients (83.6%) had World Health Organisation (WHO) Group I PAH according to the criteria developed in Nice [34], 15 patients (6.5%) had exercise-induced PH, 18 patients (7.8%) had PH secondary to left ventricular dysfunction (WHO Group 2 PH) and 5 patients (2.2%) had PH secondary to ILD (WHO Group 3 PH). Only patients with WHO Group I PAH were analysed in this study.

At enrollment, 34 (2.1%) patients had previously been diagnosed with PAH and 122 (7.5%) were diagnosed at their first contact with ASCS. Among the latter, 89 (72.9%) had SSc disease duration of ≥4 years and the date of their last TTE was 1.6 ± 4.6 years before enrollment to ASCS, highlighting a lack of adherence to annual PAH screening in the community.

A total of 4326 screening visits were analysed, to determine the success of, and adherence to the PAH screening algorithm (Table 3). Only patients not previously diagnosed with PAH were included. At the first screening visit, sufficient data to apply the screening algorithm were available for 1363 patients. Of these, 101 patients (7.4%) were at high risk of PAH, 121 patients (8.9%) at moderate risk, 358 patients (26.3%) at low risk and 470 patients (34.5%) at no increased risk based on TTE and PFT results. The number of patients with no tricuspid regurgitation (TR) on TTE, and hence inestimable sPAP, was high at 313 (22.9%).

At the first screening visit, 157 of the 580 (27.1%) patients at low (38/358), moderate (36/121), or high (83/101) risk of PAH underwent RHC. WHO Group 1 PAH was diagnosed in 122 patients (8.9% of the cohort), including 4 of 19 (21.0%) patients with a normal TTE and 10 of 24 patients (41.7%) with a missing sPAP on TTE due to lack of a TR jet. The patients in the latter two groups were referred for RHC due to reduced exercise capacity and/reduced DLCO. Only 4% of the patients with no TR were referred for RHC but 36.8% of these were diagnosed with WHO Group 1 PAH. At the physician’s discretion and based on other indicators such as patient symptoms and TTE parameters, patients whose initial RHC was negative for PAH were considered for future RHC.

The screening algorithm correctly identified patients at increased risk of PAH and stratified them by level of risk. The higher the probability of PAH, the more likely PAH was to be identified on RHC (Table 3). A new diagnosis of WHO Group I PAH was made in 160 patients from 4326 (3.7%) screening visits (115/1122 with lcSSc, 32/377 with dcSSc and 10/83 with MCTD), giving a prevalence of PAH of 11.8% (10.3% in lcSSc, 8.5% in dcSSc and 12.0% in MCTD). The annual prevalence of PAH was 1.4% (1.2% in lcSSc, 0.9% in dcSSc, 0.4% in MCTD). All patients were treated with specific PAH therapy.

Patients with PAH were significantly older than patients without PAH (63.1 vs 56.3 years, p < 0.001), had longer disease duration (13.6 vs 10.4 years, p < 0.001) and were in WHO Functional Class III/IV (85.0% vs 21.7%, p < 0.001) (Table 4). Clinical manifestations and autoantibody status are summarised in Table 4.

To assess whether the ASCS screening programme succeeded in detecting PAH at an earlier stage, we divided our PAH cohort into those patients whose PAH was detected on first screening and those whose PAH was detected on the second or subsequent screen (Table 5).

We believe that PAH detected on first screen were likely to be a “delayed diagnosis” in patients who were referred to ASCS due to symptoms or clinical suspicion of PAH, whereas PAH detected on subsequent screens was more likely to be an “incident” PAH identified on earlier screening.

Patients diagnosed with PAH on subsequent screens compared with first screen were more likely to have dcSSc (35.1% vs 15.9%, p = 0.03), be in a better WHO functional class (54.1% vs 75.9% in Class III, 5.4% vs 16.2% in Class IV, p = 0.01) and have less advanced PAH at diagnosis evidenced by lower mPVR (3.8 vs 5.5, p = 0.005), higher mean 6MWD (340.6 vs 295.9, p = 0.05), lower mPAP (32.5 vs 38.2, p = 0.005), and fewer non-trivial pericardial effusions (2.7% vs 16.0%, p = 0.03).

PAH treatment with combination therapy and anticoagulation therapy was prescribed at a similar rate in those diagnosed at subsequent screens (36.8% and 28.9%, respectively) and those diagnosed at first screen (32.1% and 26.8%, respectively). Three-year survival from the time of PAH diagnosis was better in those diagnosed on subsequent screen compared with those diagnosed at first screen as outlined in Fig. 2 (94.7% vs 42.7%, p < 0.001) and mean time to death was longer in those diagnosed with PAH on subsequent screens compared with those diagnosed at first screen (4.7 ± 2.3 vs 2.3 ± 2.3, p < 0.001). PAH was the direct cause of death in 100% of patients diagnosed on subsequent screen and in 92.7% of those diagnosed on first screen (p = 0.40).

ASIG physicians’ adherence to PAH screening guidelines was high with 84.4% of patients undergoing annual screening over a ten-year period. Despite the screening algorithm (Fig. 1) mandating that patients at moderate or high risk of PAH should undergo RHC, only 29.7% (170/572) had RHC. Even among those in the high probability group, only 59.1% of patients underwent RHC. Physician justification for not performing RHC predominantly related to their WHO functional class. In 50.5% of cases, RHC was not performed as the patient was in WHO Functional Class I (31.6%), or Class II (14.7%) or was not dyspnoeic (4.2%). In 18.9% of cases, the physician referred the patient to another specialist for their opinion, most commonly a cardiologist or respiratory physician. In 16.8% of cases, the physician was deterred from arranging RHC due to the presence of mild ILD that they felt accounted for the TTE or PFT result. The remaining justifications included a plan to repeat the TTE and/or PFT at a later date (4.2%), patient refusal to have RHC (2.1%), terminal malignancy (2.1%) and no access to RHC (1.1%).

Of 334 non-ASIG Australian rheumatologists, 52 responded to the survey on screening practices and barriers to screening (Additional file 1: Table S1). The majority (88.9%) reported screening asymptomatic patients for PAH regularly. Just over half of the respondents ordered annual screening for their asymptomatic patients with early SSc (lcSSc 58.9%, dcSSc 52.6%), with even fewer screening annually in late disease (lcSSc 38.5%, dcSSc 43.6%). All respondents (100%) would investigate their patients with symptoms consistent with PAH. In early symptomatic SSc (with breathlessness or reduced exercise tolerance), the majority of respondents would screen on a six-monthly (51.2%) or annual basis (33.6%). In late symptomatic SSc, 38.9% of respondents would screen their patients six-monthly and 41.2% of respondents would screen annually. Alarmingly, 17.5% of respondents would only screen symptomatic patients every two years.

Explanations for not following guidelines for PAH screening included cost of screening (60%) and concerns about how to interpret the results (80%). In order to improve screening, 50% of respondents felt that they required better guidelines for the selection and frequency of screening tests, 44.7% wanted a reminder system, 42.1% wanted guideline simplification but only 31.6% felt that access to an experienced screening centre would be helpful. If reimbursed by Medicare Australia, 76.3% of respondents would consider the use of a blood test such as N-terminal pro B-type natriuretic peptide (NT-pro-BNP) a major advance.