Early detection of PAH in connective tissue diseases: Why and how?

Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTDs). At the International Conference of Chinese Rheumatologists (ICCR) 2024, Dr Yeon-Ah Lee of the Kyung Hee University, Seoul, South Korea, emphasized the importance of screening and early detection of PAH in patients with CTDs and provided practical guidance for rheumatologists on screening for CTD-PAH, particularly in patients with systemic sclerosis (SSc) and systemic lupus erythematosus (SLE).

Up to 15 percent of CTD patients have PAH

PAH is a life-threatening complication that affects up to 15 percent of patients with CTDs. [Semin Arthritis Rheum 2014;43:536-541]

“Diagnosis of PAH is usually delayed by >2 years,” said Lee. [Chest 2011;140:19- 26] “This delay is primarily due to lack of awareness, nonspecific and mild symptoms [eg, dyspnoea on exertion, fatigue, and syncope during or shortly after exertion], or absence of symptoms in the early stage.” [Eur Heart J 2022;43:3618-3731; Ther Adv Respir Dis 2024;18:17534666231218886]

Screening enables better outcomes

Patients with CTD-PAH have the worst prognosis in the overall PAH population, with a 3-year overall survival (OS) rate of merely 62 percent. [Rev Port Cardiol (Engl Ed) 2018;37:749-757; Arthritis Rheumatol 2021;73:837-847]

Prognosis is even less favourable for patients with SSc-PAH, with a 3-year OS rate of 31 percent when PAH is not actively screened for. In contrast, the 3-year OS rate is markedly improved to 81 percent with active screening. [Arthritis Rheum 2011;63:3522-3530]

“Even a 3-month delay in PAH diagnosis results in a completely different prognosis vs prompt diagnosis within 3 months [logrank p<0.01],” highlighted Lee. (Figure 1) [J Cardiol 2024;83:365-370]

“Our two cases illustrate that outcomes were notably better for patient 1 who received an early diagnosis vs patient 2 who had a delayed diagnosis. Active screening allows detection and treatment of PAH at an early stage [ie, functional class (FC), I/II], subsequently leading to better long-term outcomes,” commented Lee.

Guidelines recommend annual PAH screening in CTDs

The 2022 European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines recommended annual screening of PAH in patients with SSc (class of recommendation, I) and patients with CTD and overlapping SSc features (class of recommendation, IIb). [Eur Heart J 2022;43:3618-731]

Similarly, the Japanese Circulation Society (JCS) guidelines recommended annual screening in CTD patients at high risk of PAH, regardless of presence or absence of symptoms. [Circ J 2019;83:842-945]

Expert panel: 13 risk factors for PAH in SLE

SLE-PAH is the predominant form of CTD-PAH in Asia (China, 49 percent; Korea, 35.8 percent), which differs from Western countries, where SSc-PAH is the most prevalent form (US, 62 percent; UK, 83 percent). [Int J Rheum Dis 2012;15:e80-e89; Eur Respir J 2014;44:963-972; Eur Respir J 2012;39:945-955; Chest 2014;146:1494-1504]

“However, it is still unclear which subgroup of SLE patients should undergo PAH screening,” said Lee. “Therefore, a Delphi panel comprising eight panellists — six rheumatologists and two cardiologists — developed an expert consensus on risk factors for SLE-PAH in the Asia Pacific region.” [ACR Open Rheumatol 2023;5:663-676]

Thirty-three factors were identified from a systematic review, the ESC/ERS guidelines, and expert opinions. Of these, 13 risk factors are considered as important. (Table)

After three rounds of the Delphi panel process, the panellists reached a consensus that seven key serological and clinical factors are important: N-terminal pro-brain natriuretic peptide (NT-proBNP), BNP, anticentromere antibodies, pericardial effusion, DL_CO, TRV, and scleroderma pattern on nailfold capillaroscopy.

“[As illustrated in cases 1 and 2], these factors could be used in developing a screening algorithm to identify SLE patients at high risk of developing PAH, to facilitate early diagnosis,” remarked Lee.

Notably, all panellists agreed that early diagnosis and treatment of SLE-PAH is crucial because it could improve prognosis. “High-risk patients should be identified for annual screening,” said Lee. “SLE patients exhibiting high-risk symptoms such as unexplained progressive dyspnoea and Raynaud’s phenomenon [such as our patient 2] as well as those planning a pregnancy should also be screened for PAH.”

Screening algorithms

In adult patients with SSc, the noninvasive, two-step DETECT screening algorithm is used for identifying SSc-PAH. Depending on the risk score obtained in step 1 and the two additional echocardiographic variables, patients may then be referred for RHC if necessary. (Figure 2) A simpler Australian Scleroderma Interest Group (ASIG) Screening Algorithm, which positions PFTs and NT-proBNP evaluation before echocardiography, is also used to identify PAH in patients with SSc. [Eur Heart J 2022;43:3618-731; Ann Rheum Dis 2014;7:1340-1349; Arthritis Res Ther 2013;15:R193]

Although there is no consensus on optimal PAH screening algorithm for SLE patients, the SOPHIE study aimed to apply the pulmonary hypertension screening algorithm recommended for SSc in Hong Kong Chinese patients with SLE. [ERJ Open Res 2018;4:00135-2017]

Cornerstone of CTD-PAH treatment

The prognosis of SLE-PAH is generally more favourable than SSc-PAH. “One possible reason is that a substantial proportion of patients with SLE-PAH or mixed connective tissue diseases [MCTD]-PAH respond to immunosuppressive therapy,” Lee explained. [Am J Respir Crit Care Med 2009;179:151-157; Chest 2006;130:182-189]

“Notably, both the 2022 ESC/ERS and 2019 JCS guidelines indicate that all cases of CTD-PAH follow the same treatment algorithm as idiopathic PAH [class I recommendation in both guidelines], where PAH-targeted therapies [eg, macitentan, selexipag] are an integral part of treatment,” said Lee. “Combination treatment with PAH-targeted therapy and immunosuppressants is the mainstay for SLE- and MCTD-PAH.” [Eur Heart J 2022;43:3618- 731; Circ J 2019;83:842-945]

Summary

Screening for PAH in patients with CTD is vital for earlier detection and better long-term outcomes. Annual screening for PAH should be provided to CTD patients with SSc, overlapping SSc features, and those at high risk. An Asia-Pacific expert panel recommended screening in SLE patients with dyspnoea or Raynaud’s phenomenon and proposed seven risk factors to be used in a screening algorithm to identify SLE patients at high risk of developing PAH.