CTD-PAH: an updated practical approach to screening,diagnosis,and management

Abstract

Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a progressive and high-risk subtype of PAH, with outcomes generally worse than those seen in idiopathic PAH. Early recognition and treatment are essential for improving survival, yet early-stage CTD-PAH remains challenging to identify, particularly for non-specialist clinicians. The 2022 ESC/ERS guidelines introduced several key updates that support an earlier diagnosis and more targeted management. These include a revised echocardiographic threshold for pulmonary hypertension probability (tricuspid regurgitation velocity >2.8 m/s), a lowered hemodynamic definition of PAH (mean pulmonary artery pressure >20 mmHg and pulmonary vascular resistance >2 WU), and a preference for annual screening using the DETECT algorithm in asymptomatic systemic sclerosis (SSc) patients. Additionally, novel therapeutic targets such as the activin/TGF-β pathway have been incorporated into updated treatment algorithms. Although CTD-PAH remains associated with worse outcomes than idiopathic PAH, recent advances in screening, risk assessment, and targeted therapies have begun to improve the trajectory of the disease. Early detection, personalized treatment, and comprehensive care are now key to transforming this high-risk condition into a more manageable one.

Keywords

auto-immunity connective tissue disease pulmonary arterial hypertension

Introduction

Pulmonary arterial hypertension (PAH) is a progressive condition characterized by increased pulmonary artery pressure and elevated pulmonary vascular resistance (PVR), leading to right ventricular (RV) failure. Historically, PAH was associated with poor survival; however, over recent decades, advances in pulmonary vasodilator therapies have improved patient outcomes, extending life expectancy and enhancing quality of life across both physical and symptom-related domains.^1–5 PAH is classified into five groups by the World Health Organization (WHO), with WHO Group I encompassing various PAH causes, including connective tissue disease (CTD)-associated PAH (CTD-PAH; Table 1).⁶ CTD-PAH is a complex condition observed in patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), primary Sjögren’s disease, and idiopathic inflammatory myopathies (IIMs), each with unique pathophysiologies and management challenges. While rheumatoid arthritis (RA) was previously considered a potential cause of PAH, the current evidence does not strongly support an association between RA and PAH development.⁷ CTD-PAH is currently associated with worse outcomes than idiopathic PAH. However, recent advances in screening, risk assessment, and targeted therapies have begun to improve the trajectory of the disease.^8,9 Here, a comprehensive yet focused overview of CTD-PAH is provided for nonexpert clinicians, offering key insights into its diagnosis and management for patients with each disease while highlighting recent updates.

Table 1.

World Health Organization (WHO) groups of pulmonary hypertension (PH).

1 Pulmonary arterial hypertension (PAH)
Idiopathic PAH (IPAH) 1.1.1 Nonresponders at vasoreactivity testing 1.1.2 Acute responders at vasoreactivity testing
1.2 Heritable PAH (HPAH)
1.3 Drug/toxin-associated PAH (DPAH)
1.4 PAH associated with other medical conditions 1.4.1 Connective tissue disease 1.4.2 Human immunodeficiency virus infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis
1.5 PAH with features of venous/capillary involvement
1.6 Persistent PH of newborn (PPHN)
2 PH associated with left heart disease
2.1 Heart failure 2.1.1 with a preserved ejection fraction 2.1.2 with a reduced or mildly reduced ejection fraction 2.2 Valvular heart disease 2.3 Congenital/acquired
3 PH associated with lung diseases and/or hypoxia
3.1 Obstructive lung disease or emphysema 3.2 Restrictive lung disease 3.3 Lung disease with mixed restrictive/obstructive pattern 3.4 Hypoventilation syndromes 3.5 Hypoxia without lung disease (e.g., high altitude) 3.6 Developmental lung disorders
4 PH associated with pulmonary artery obstructions
4.1 Chronic thromboembolic PH 4.2 Other pulmonary artery obstructions
5 PH with unclear and/or multifactorial mechanisms
5.1 Hematological disorders 5.2 Systemic disorders 5.3 Metabolic disorders 5.4 Chronic renal failure with or without hemodialysis 5.5 Pulmonary tumor thrombotic micro-angiopathy 5.6 Fibrosing mediastinitis

Scleroderma and PAH

SSc, also known as scleroderma, is a complex and heterogeneous auto-immune disorder characterized by endothelial dysfunction, fibroblast dysregulation, and an abnormal immune response, resulting in progressive skin and internal organ fibrosis. SSc can be classified into limited or diffuse forms, depending on the extent of skin involvement.¹⁰ However, SSc extends beyond the skin, affecting vital organs such as the heart, lungs, gastrointestinal organs, and kidneys, where its progression can cause severe complications and significant morbidity.

Cardiac involvement in patients with SSc is common, with an estimated prevalence of clinically overt disease ranging from 7% to 39%.¹¹ Pulmonary involvement is equally prominent, with interstitial lung disease (ILD) observed in more than 90% of patients during autopsy.¹² ILD and PAH are the leading causes of morbidity and mortality in SSc patients. Notably, women are disproportionately affected by CTD-PAH, including SSc-PAH, reflecting the overall sex bias seen in auto-immune diseases.¹³

SSc patients are susceptible to developing PH across all five WHO PH groups (Table 1).¹⁴ Within WHO Group 1, SSc-PAH results from the direct involvement of the pulmonary arteries, with a subset of patients developing pulmonary veno-occlusive disease (PVOD), a rare and challenging form of PAH that further complicates management. In addition to Group 1 PAH, SSc can contribute to PH through multiple mechanisms. SSc may lead to left-sided heart dysfunction, resulting in heart failure with a preserved or reduced ejection fraction (HFpEF or HFrEF, respectively), which falls under Group 2 PH. Additionally, SSc-related ILD can contribute to PH through Group 3 mechanisms. The above are the more frequently encountered subtypes in clinical practice. Less common PH subtypes in SSc include chronic thromboembolic PH (CTEPH; Group 4), reflecting the heightened thrombotic risk associated with SSc. In addition, SSc-related end-stage renal disease may be accompanied by PH classified under Group 5.

Among the predictors of the PAH risk is the presence of telangiectasias. Shah and colleagues reported a strong association between increased telangiectasias in SSc patients and pulmonary vascular disease, suggesting that telangiectasias may serve as a potential marker for the PAH risk.¹⁵

In addition, the antibody profile of SSc patients provides valuable insights into the PAH risk stratification. Anti-U3 RNP and anticentromere antibody positivity are associated with a greater risk of developing PAH.¹⁶ Conversely, anti-U1 RNP-positive patients who develop PAH tend to have better outcomes than those who are negative for this antibody (Table 2).¹⁷

Table 2.

Summary of the prevalence, risk factors, and prognostic markers of CTD-PAH.

CTD	Prevalence	PH WHO groups	Factors associated with PAH	Factors associated with shorter survival	Good prognostic markers	References
SSc	8%–14%	1, 2, 3, 4, or 5	Limited SSc + Anticentromere Ab + Anti-U3 RNP ↑Telangiectasias	Age > 50 years Male sex Lower GFR &0x002B;HLA DRw6 and HLA DRw52 Lung disease	+ Anti-U1 RNP	14,18,19
SLE	0.1%–2%	1, 2, 3, 4, or 5	Raynaud’s phenomenon Digital vasculitis High disease activity + Anti-U1 RNP Anticardiolipin IgG Ab ↑Uric acid	Thrombocytopenia Thrombosis Pulmonary vasculitis Raynaud’s phenomenon Anticardiolipin Ab	Younger age ↑DLCO	18,20
MCTD	1%–3%	1	ILD Pericarditis Thrombocytopenia +Anti-Sm antibodies		Younger age↑DLCO	21
Sjogren’sdisease	0.2%	1	Young age↓Sicca manifestations+ Anti-U1 RNP+ Anti-SSB Ab	↑Damage index		22
IIMs	0.3%	1 or 3	DMSkin involvementPeripheral micro-angiopathy+ Anti-SSA Ab			23

Ab, antibody; anticentromere Ab, anticentromere antibody; anti-Sm antibodies, anti-Smith antibodies; anti-SSA Ab, anti-Sjögren’s syndrome-related antigen A antibody; anti-SSB Ab, anti-Sjögren’s syndrome-related antigen B antibody; anti-U1 RNP, anti-U1 ribonucleoprotein antibody; anti-U3 RNP, anti-U3 ribonucleoprotein antibody; anticardiolipin IgG Ab, anticardiolipin immunoglobulin G antibody; DLCO, diffuse capacity of the lungs for carbon monoxide; DM, dermatomyositis; GFR, glomerular filtration rate; HLA, human leukocyte antigen; IIMs, Idiopathic inflammatory myopathies; ILD, interstitial lung disease; MCTD, mixed connective tissue disease; PAH, pulmonary arterial hypertension; PH WHO, pulmonary hypertension World Health Organization classification; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

Despite advances in PAH management, the outcomes of SSc-PAH patients remain worse than those of patients with other forms of CTD-PAH or idiopathic PAH (IPAH).^16,24,25 Poor prognostic factors for SSc-PAH include an age >50 years, male sex, comorbid heart or lung disease, advanced New York Heart Association (NYHA) functional class (FC) III/IV status, and RV failure. However, outcomes have improved over time.^26,27 In 1996, patients with SSc-PAH had a median survival of 1 year, but the outcomes improved. From 1999–2010 to 2010–2021, the 5-year transplantation-free survival rose from 37% to 60%, with the median survival increasing to 4–8 years.^8,9 However, similar gains have not been observed in patients with PH caused by lung or heart disease (WHO Groups 2 and 3), and survival remains worse for SSc patients with respiratory-associated PH.^8,9

Systemic lupus erythematosus and PAH

SLE is a chronic auto-immune disease that can affect nearly any organ system, and patients present with a wide spectrum of clinical manifestations. SLE patients commonly experience arthritis or arthralgias, mucocutaneous lesions, alopecia, oral ulcers, Raynaud’s phenomenon, nephritis, gastrointestinal symptoms, neuropsychiatric disturbances, and hematological abnormalities.²⁸ Pulmonary involvement occurs in 50%–70% of SLE patients, with PAH being one of the most concerning complications.²⁹ Cardiovascular disease is also common in SLE patients. The prevalence of heart failure in SLE patients is estimated to range from 1% to 10%, similar to that in SSc-PAH patients.¹⁴

PAH in SLE is a heterogeneous condition with distinct mechanisms. One subset is linked to antiphospholipid antibody syndrome (APS)-related thrombosis and CTEPH, another to SSc-like vasculopathy with anti-RNP positivity, and a third to immune-mediated vasculitis, which may be reversible with immunosuppression.²⁷

Several clinical and laboratory findings are strongly associated with PAH development in SLE patients. Raynaud’s phenomenon, digital vasculitis, pericardial effusion, and anti-U1 RNP and anticardiolipin IgG antibody positivity have all been linked to the PAH risk in observational studies.^27,30–33 High pulmonary pressures on echocardiography have been observed in patients with longer disease durations, pericarditis, peripheral nervous system involvement, and anti-Sm and anticardiolipin antibody positivity (Table 2).³⁴ Interestingly, an elevated pulmonary pressure is more common in patients of African descent, highlighting the potential role of genetic or environmental factors.³⁰

Clustering analyses have provided further insights into auto-antibody patterns in SLE patients, typically revealing 3–5 distinct clusters.³⁵ One cluster often features patients with high disease activity, characterized by elevated anti-dsDNA antibody titers and a higher vasculitis incidence (vasculitic type). Another cluster includes patients with low disease activity but severe PAH (vasculopathic type), whereas a third cluster features patients with antiphospholipid antibodies, who are at increased risk of thromboembolic events.^35,36 The overall 5-year survival rate for SLE-related PAH patients ranges from approximately 60% to 85%.²⁹

Mixed connective tissue disease and PAH

MCTD has clinical features that overlap with those of several CTDs, including SSc, SLE, RA, and PM/DM. MCTD is distinguished by anti-U1 RNP antibody positivity, which is one of the diagnostic criteria.^21,37 Nearly any organ system can be affected by MCTD, although severe renal and central nervous system involvement is uncommon.³⁸

PAH in MCTD patients is more likely to fall under WHO Group 1 than Group 3 (Table 2).³⁹ Compared with MCTD patients without PAH, patients with MCTD-PAH tend to have more severe organ involvement and higher anti-U1 RNP titers. Interestingly, in a study by Vegh and colleagues, all PAH cases developed in MCTD patients at least 3 years after the MCTD diagnosis.⁴⁰ Survival rates for patients with MCTD-PAH are generally favorable compared with those for patients with SSc-PAH, with 1-, 3-, and 5-year survival rates of 96.6%, 70.2%, and 59.3%, respectively, according to the COMPERA registry.⁴¹ A 2023 meta-analysis further indicated that factors such as ILD, age, and sex have minimal impacts on the survival of MCTD-PAH patients.

Sjögren’s disease and PAH

Sjögren’s disease is a systemic auto-immune disease that primarily affects the lacrimal and salivary glands, leading to dry eyes and mouth. It can occur as a primary condition or secondary to other CTDs, such as SLE or RA.⁴² Although cardiac involvement is rare in patients with Sjögren’s disease, PAH can occur, particularly in those with primary Sjögren’s disease.²³ PH in patients with Sjögren’s disease is typically associated with either PAH (WHO Group 1) or Group 3 PH due to lung disease, such as ILD, which affects 9%–20% of patients with Sjögren’s disease.^22,43

Although Sjögren’s-associated PAH is relatively rare, with a reported prevalence of 0.2%, it has been associated with the presence of antinuclear antibodies, anti-Ro/SSA antibodies, anti-RNP antibodies, rheumatoid factor, and hypergammaglobulinemia (Table 2).⁴⁴ The prognosis of patients with Sjögren’s-associated PAH is generally poor, with survival rates of 73% at 1 year and 66% at 3 years. However, a multicenter study in China revealed higher survival rates, with rates of 94%, 88.8%, and 79% at 1, 3, and 5 years, respectively, indicating that the outcomes may vary significantly by region. In this cohort, a low cardiac index and a high damage index, a scoring tool that quantifies cumulative, irreversible organ damage in Sjögren’s syndrome, were associated with worse outcomes.^22,45

Idiopathic inflammatory myopathies and PAH

IIMs, including dermatomyositis (DM) and polymyositis (PM), are a group of auto-immune diseases characterized by immune-mediated muscle damage.⁴⁶ These conditions are associated with PH, particularly when combined with chronic respiratory conditions (WHO Group 3 PH; Table 1). IIMs are also associated with antisynthetase syndrome, which can lead to significant lung disease and subsequent PH (WHO Group 3).

PAH is less common in IIM patients than in those with other CTDs, but when it does occur, it is often linked to DM, skin involvement, and anti-SSA antibody positivity.⁶ Interestingly, survival rates are better for patients with IIM-associated PAH than for those with other forms of CTD-PAH.²³ Data from the UK registry suggest that IIM-PAH patients have a 100% survival rate at 1 and 3 years, a stark contrast to the poorer outcomes observed for SSc-PAH patients.⁴⁷

Screening and diagnosis

Early PAH detection in CTD patients is crucial for improving outcomes. According to the updated ESC/ERS guidelines, an annual evaluation for PAH is recommended for asymptomatic patients with SSc and may be considered for patients with CTD with overlapping features of SSc, using a combination of clinical features, echocardiography, PFTs, and NT-proBNP to select patients with SSc for RHC (Figure 1).⁶

Figure 1.

Algorithm for screening and diagnosing PAH in SSc patients.

Another screening method that has been used is the DETECT algorithm, which is recommended for screening adults with SSc who have had the disease for >3 years, with a forced vital capacity (FVC) of ⩾40% and a diffusing capacity for carbon monoxide (DLCO) <60% to identify asymptomatic PAH patients.^39–42 Coghlan and colleagues reported that the DETECT algorithm has 96% sensitivity, with a false-negative rate of only 4%, compared with a 29% missed diagnosis rate when echocardiographic screening thresholds alone are used.

For symptomatic SSc patients who experience exertional shortness of breath, fatigue, syncope, or palpitations, echocardiography serves as the initial diagnostic method. If the tricuspid regurgitation velocity (TRV) exceeds 2.8 m/s on an echocardiogram, RHC is advised due to an increased PAH risk (Figure 1).

If the findings are normal, further investigations should focus on identifying other potential causes, such as lung or heart disease. However, if no alternative cause is found and the symptoms persist, RHC should be considered, even if the echocardiography findings are unremarkable.⁶

A CTD-PAH diagnosis requires confirmation by RHC, which reveals the following: mPAP > 20 mmHg, pulmonary artery wedge pressure (PAWP) ⩽15 mmHg, and PVR > 2 WU. After diagnosis, risk stratification via validated tools (e.g., the REVEAL risk score or the European three-strata model) is essential to guide therapy.^22,39

Management and challenges

CTD-PAH management has advanced significantly in recent years, driven by improvements in risk stratification and targeted therapy development. Traditionally, treatment has focused on three key pathways: endothelin-1, nitric oxide, and prostacyclin (Figure 2). However, the addition of a fourth pathway targeting the activin/TGF-β signaling axis represents a significant breakthrough, addressing PAH proliferative mechanisms. Currently, treatments span all four pulmonary vasodilator pathways, with 15 available medications in various formulations, including oral, inhaled, subcutaneous, and intravenous formulations.⁴⁸

Figure 2.

Available pulmonary vasodilator pathways, treatments, and their basic mechanisms.

The ESC/ERS guideline recommends performing an initial risk stratification at diagnosis, using validated risk assessment tools to classify patients into low-, intermediate-, or high-risk categories, as shown in the three-strata model outlined in Figure 3.³⁹ For those classified as low- to intermediate-risk, first-line oral therapy—typically a combination of phosphodiesterase type 5 (PDE5) inhibitors and endothelin receptor antagonists (ERAs)—is advised.³⁹ This approach is supported by findings from the AMBITION trial, in which 41% of CTD-PAH patients received combination therapy. The trial demonstrated a significantly lower risk of clinical failure among patients whose first-line treatment was dual ambrisentan and tadalafil therapy than among those who received either agent alone.⁴⁹ A post hoc analysis of the AMBITION trial further revealed that CTD-PAH patients experienced a prolonged time to clinical worsening and increased 6-minute walking distance (6MWD) with initial PDE5 inhibitor and ERA therapy, similar to IPAH patients. These findings reinforce the current consensus recommendations advocating for a standardized treatment approach, applying the same therapeutic algorithm to CTD-PAH as to other PAH subtypes.⁵⁰

Figure 3.

Suggested 2024 treatment algorithm for PAH from the 7th world symposium on pulmonary hypertension.

During follow-up, further stratification into low-, intermediate–low-, intermediate–high-, and high-risk groups based on the NYHA FC, 6MWD, and NT-proBNP levels is advised.³⁹

In intermediate–low-risk patients, according to the GRIPHON study, adding selexipag may be considered.⁵¹ The CTD-PAH patients composed the second-largest group after the IPAH patients in this study. Compared with the placebo, selexipag was associated with a reduced risk of the primary composite endpoint (death or PAH-related complications), including patients on stable background therapy.⁵¹ Additionally, switching from PDE5 inhibitors (PDE5is) to riociguat may be an option, as supported by evidence from the REPLACE trial, which included 111 patients in the riociguat group that consisted of a slightly greater number of PAH-CTD patients (24 [22%] vs 19 [17%]) than the PDE5i group.⁵² The trial resulted in a significant clinical improvement—as measured by the NYHA FC, 6MWD, and NT-proBNP levels—without clinical worsening at 24 weeks after transitioning to riociguat.⁵² For high-risk patients, parenteral prostacyclin therapy remains the most effective treatment available, with strong evidence supporting its role in reducing mortality, particularly when administered in the intravenous form.⁵³ The 2024 World Symposium on PH introduced significant updates by simplifying the initial risk assessment of patients to at a high risk or not and recommending Sotatercept, an activin signaling inhibitor, for all intermediate–low to high-risk patients during follow-up (Figure 3).⁴⁸ This update marked a notable advancement in CTD-PAH treatment.^5,48,54 Sotatercept increased the exercise capacity by ⩾40 m for patients on stable background therapy, as shown in the STELLER trial, which included 29 (17.8%) CTD-PAH patients.⁵ A post hoc analysis of the trial revealed improvements in heart function, hemodynamics, and NT-proBNP levels.⁵⁵ In addition, the ZENITH trial was a phase III, randomized, placebo-controlled study evaluating Sotatercept in high-risk PAH patients, including 48 (27.9%) with CTD-PAH. Patients (WHO FC III/IV, REVEAL Lite 2 ⩾9) received Sotatercept or placebo every 21 days alongside stable dual or triple therapy. Sotatercept reduced the risk of the composite primary endpoint (death, transplant, or PAH-related hospitalization) by 76%, leading to early trial termination due to efficacy.⁵⁶ Although subgroup results for CTD-PAH were not separately reported, their inclusion and stratification support the relevance of findings to this population.

It is not uncommon to encounter patients with CTD complicated by ILD and PH. For these patients, there is fortunately an effective treatment option. The INCREASE trial demonstrated that inhaled treprostinil significantly improves exercise capacity, as measured by the 6MWT, and reduces NT-proBNP levels in patients with PH associated with ILD, including patients with CTD-ILD.⁵⁷ Based on these findings, the FDA approved inhaled treprostinil in 2021 for this indication, making it the only pulmonary vasodilator with proven efficacy in Group 3 PH, and an important treatment option for patients with CTD-PAH and lung involvement.

Regarding immunosuppression, Yasuoka et al.⁵⁸ retrospectively evaluated its role in CTD-PAH, including patients with SLE, MCTD, and primary Sjögren’s disease. A short-term treatment response, defined as improvement in NYHA FC at 3 months, was observed in 53% of patients. Independent predictors of response included a simultaneous diagnosis of PAH with CTD and the use of immunosuppressive therapy—most notably intravenous cyclophosphamide in combination with glucocorticoids.⁵⁸ Given the auto-immune nature of CTD-PAH, these findings highlight that immunosuppressive therapy may play a crucial role in certain subsets of patients. In particular, patients with SLE-PAH or MCTD-PAH may derive clinical benefit from a combination of glucocorticoids and cyclophosphamide, especially in the context of less advanced PAH.^58–61 However, the survival benefits of intensive immunosuppression remain uncertain, largely due to the limited number of trials. Preclinical studies in rats have suggested a potential benefit of mycophenolate mofetil in PAH through its anti-inflammatory and anti-proliferative effects.^62,63 In humans, multiple studies have demonstrated its efficacy in both renal and non-renal manifestations of SLE.⁶⁴ However, specific data regarding its role in SLE-associated PAH are lacking, with evidence limited to case reports.⁶⁵ In a 2025 retrospective study, Rodolfi et al.⁶⁶ reported that early initiation of immunosuppression within 5 years of SSc diagnosis did not delay PAH development or improve survival. However, when analyzing individual immunosuppressants, mycophenolate mofetil was associated with a lower risk of PAH (OR 0.12, 95% CI 0.01–0.98; p = 0.048), whereas hydroxychloroquine use was linked to reduced mortality (HR 0.04, 95% CI 0.06–0.37; p = 0.004).⁶⁶ Collectively, these data suggest that while certain CTD subsets such as SLE-PAH and MCTD-PAH may respond favorably to immunosuppression, SSc-PAH follows a different trajectory, with limited evidence showing benefit from such therapy. Accordingly, a proactive, multimodal approach that integrates immunosuppressive, anti-inflammatory, and vasodilator therapies is often advocated.^67–69 Nevertheless, immunosuppressive therapy is not recommended for SSc-PAH, as underscored by the findings of Zamanian et al.,⁷⁰ who demonstrated that B-cell depletion with rituximab was safe but did not improve outcomes compared with placebo in patients with SSc-PAH.

CTD-PAH management extends beyond disease severity, with challenges such as a poor vasodilator response, medication intolerance from GI involvement, and prevalent neuropsychiatric symptoms.^71,72 These complexities demand a personalized, multidisciplinary approach. Future research should explore the role of immunosuppression in curing CTD-PAH beyond SSc, focusing on the optimal timing and predictors of the treatment response. Identifying reliable biomarkers—through auto-immune markers, multiomics, and advanced imaging—could refine patient selection and personalize therapy.

Conclusion

Although CTD-PAH remains associated with worse outcomes than idiopathic PAH, recent advances in screening, risk assessment, and targeted therapies have begun to improve the trajectory of the disease. Early detection, personalized treatment, and comprehensive care are now key to transforming this high-risk condition into a more manageable one.

Footnotes

Acknowledgements

All figures included in this manuscript were created by the authors using BioRender and/or Venngage.

Declarations

ORCID iDs

Noura Alturaif

Fatima K. Alduraibi

References

Galie

Palazzini

Manes

Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J 2010; 31: 2080–2086.

Pepke-Zaba

Gilbert

Collings

, et al. Sildenafil improves health-related quality of life in patients with pulmonary arterial hypertension. Chest 2008; 133: 183–189.

Mehta

Sastry

BKS

Souza

, et al. Macitentan improves health-related quality of life for patients with pulmonary arterial hypertension. Chest 2017; 151: 106–118.

Hirashiki

Adachi

Okumura

, et al. Medium-term health-related quality of life in patients with pulmonary arterial hypertension treated with goal-oriented sequential combination therapy based on exercise capacity. Health Qual Life Outcomes 2019; 17: 103.

Hoeper

Badesch

Ghofrani

, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med 2023; 388: 1478–1490.

Humbert

Kovacs

Hoeper

, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2023; 61: 2200879.

Montani

Henry

O’Connell

, et al. Association between rheumatoid arthritis and pulmonary hypertension: data from the French pulmonary hypertension registry. Respiration 2018; 95: 244–250.

Chen

Quan

Qian

, et al. 10-year survival of pulmonary arterial hypertension associated with connective tissue disease: insights from a multicentre PAH registry. Rheumatology 2023; 62: 3555–3564.

Xanthouli

Improved survival for patients with systemic sclerosis–associated pulmonary arterial hypertension: for real?

Am J Respir Crit Care Med 2023; 207: 238–240.

10.

Volkmann

Andréasson

Smith

Systemic sclerosis. Lancet 2023; 401: 304–318.

11.

Nadel

Taborska

, et al. Heart involvement in patients with systemic sclerosis—what have we learned about it in the last 5 years. Rheumatol Int 2024; 44: 1823–1836.

12.

Fan

Bender

Shi

, et al. Incidence and prevalence of systemic sclerosis and systemic sclerosis with interstitial lung disease in the United States. J Manag Care Spec Pharm 2020; 26: 1539–1547.

13.

Shapiro

Traiger

Turner

, et al. Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Chest 2012; 141: 363–373.

14.

Khangoora

Bernstein

King

, et al. Connective tissue disease-associated pulmonary hypertension: a comprehensive review. Pulm Circ 2023; 13: e12276.

15.

Shah

Wigley

Hummers

LK.

Telangiectases in scleroderma: a potential clinical marker of pulmonary arterial hypertension. J Rheumatol 2010; 37: 98–104.

16.

Bazan

Mensah

Rudkovskaia

, et al. Pulmonary arterial hypertension in the setting of scleroderma is different than in the setting of lupus: a review. Respir Med 2018; 134: 42–46.

17.

Sobanski

Giovannelli

Lynch

, et al. Characteristics and survival of anti–U1 RNP antibody–positive patients with connective tissue disease–associated pulmonary arterial hypertension. Arthritis Rheumatol 2016; 68: 484–493.

18.

MacGregor

AJ.

Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology 2001; 40: 453–459.

19.

Langevitz

Buskila

Gladman

, et al. HLA alleles in systemic sclerosis: association with pulmonary hypertension and outcome. Rheumatology 1992; 31: 609–613.

20.

Lian

Chen

Wang

, et al. Clinical features and independent predictors of pulmonary arterial hypertension in systemic lupus erythematosus. Rheumatol Int 2012; 32: 1727–1731.

21.

Chaigne

Chevalier

Boucly

, et al. In-depth characterization of pulmonary arterial hypertension in mixed connective tissue disease: a French national multicentre study. Rheumatology 2023; 62: 3261–3267.

22.

Wang

, et al. Pulmonary arterial hypertension associated with primary Sjögren’s syndrome: a multicentre cohort study from China. Eur Respir J 2020; 56: 1902157.

23.

Sanges

Yelnik

Sitbon

, et al. Pulmonary arterial hypertension in idiopathic inflammatory myopathies. Medicine 2016; 95: e4911.

24.

Naranjo

Hassoun

PM.

Systemic sclerosis-associated pulmonary hypertension: spectrum and impact. Diagnostics 2021; 11: 911.

25.

Favoino

Prete

Liakouli

, et al. Idiopathic and connective tissue disease-associated pulmonary arterial hypertension (PAH): similarities, differences and the role of autoimmunity. Autoimmun Rev 2024; 23: 103514.

26.

Chung

Farber

Benza

, et al. Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest 2014; 146: 1494–1504.

27.

Johnson

Granton

JT.

Pulmonary hypertension in systemic sclerosis and systemic lupus erythematosus. Eur Respir Rev 2011; 20: 277–286.

28.

Siegel

Sammaritano

LR.

Systemic lupus erythematosus. JAMA 2024; 331: 1480.

29.

Parperis

Velidakis

Khattab

, et al. Systemic lupus erythematosus and pulmonary hypertension. Int J Mol Sci 2023; 24: 5085.

30.

Foïs

Le Guern

Dupuy

, et al. Noninvasive assessment of systolic pulmonary artery pressure in systemic lupus erythematosus: retrospective analysis of 93 patients. Clin Exp Rheumatol 2010; 28: 836–841.

31.

Simonson

Schiller

Petri

, et al. Pulmonary hypertension in systemic lupus erythematosus. J Rheumatol 1989; 16: 918–925.

32.

Asherson

Higenbottam

Dinh Xuan

, et al. Pulmonary hypertension in a lupus clinic: experience with twenty-four patients. J Rheumatol 1990; 17: 1292–1298.

33.

Asherson

Hackett

Gharavi

, et al. Pulmonary hypertension in systemic lupus erythematosus: a report of three cases. J Rheumatol 1986; 13: 416–420.

34.

Foïs

Sitbon

Systemic lupus erythematosus-associated PAH: is targeting inflammation the key to success?

Eur Respir Rev 2011; 20: 218–219.

35.

Dai

Zhang

, et al. Clinical characteristics and prognosis in systemic lupus erythematosus-associated pulmonary arterial hypertension based on consensus clustering and risk prediction model. Arthritis Res Ther 2023; 25: 155.

36.

Baisya

Devarasetti

Murthy

GSR

, et al. Autoantibody clustering in systemic lupus erythematosus–associated pulmonary arterial hypertension. Indian J Cardiovasc Dis Women 2021; 6: 100–105.

37.

John

Sadiq

George

, et al. Clinical and immunological profile of mixed connective tissue disease and a comparison of four diagnostic criteria. Int J Rheumatol 2020; 2020: 1–6.

38.

Lundberg

IE.

The prognosis of mixed connective tissue disease. Rheum Dis Clin N Am 2005; 31: 535–547.

39.

Hassan

Hozayen

Mustafa

, et al. The prevalence of pulmonary arterial hypertension in patients with mixed connective tissue disease: a systematic review and meta-analysis. Clin Exp Rheumatol 2023; 41(11): 2301–2311.

40.

Vegh

Szodoray

Kappelmayer

, et al. Clinical and immunoserological characteristics of mixed connective tissue disease associated with pulmonary arterial hypertension. Scand J Immunol 2006; 64: 69–76.

41.

Distler

Ofner

Huscher

, et al. Treatment strategies and survival of patients with connective tissue disease and pulmonary arterial hypertension: a COMPERA analysis. Rheumatology 2024; 63: 1139–1146.

42.

Zhan

Zhang

Lin

, et al. Pathogenesis and treatment of Sjogren’s syndrome: review and update. Front Immunol 2023; 14: 1127417.

43.

Flament

Bigot

Chaigne

, et al. Pulmonary manifestations of Sjögren’s syndrome. Eur Respir Rev 2016; 25: 110–123.

44.

Launay

Hachulla

Hatron

, et al. Pulmonary arterial hypertension: a rare complication of primary Sjögren syndrome. Medicine 2007; 86: 299–315.

45.

Barry

Sutcliffe

Isenberg

, et al. The Sjogren’s syndrome damage index–a damage index for use in clinical trials and observational studies in primary Sjogren’s syndrome. Rheumatology 2008; 47: 1193–1198.

46.

Lundberg

Fujimoto

Vencovsky

, et al. Idiopathic inflammatory myopathies. Nat Rev Dis Primers 2021; 7: 86.

47.

Condliffe

Kiely

Peacock

, et al. Connective tissue disease–associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 2009; 179: 151–157.

48.

Chin

Gaine

Gerges

, et al. Treatment algorithm for pulmonary arterial hypertension. Eur Respir J 2024; 64: 2401325.

49.

Galiè

Barberà

Frost

, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015; 373: 834–844.

50.

Kuwana

Blair

Takahashi

, et al. Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis. Ann Rheum Dis 2020; 79: 626–634.

51.

Sitbon

Channick

Chin

, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 2015; 373: 2522–2533.

52.

Hoeper

Al-Hiti

Benza

, et al. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. Lancet Respir Med 2021; 9: 573–584.

53.

Barst

Rubin

Long

, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334: 296–301.

54.

Cascino

Sahay

Moles

, et al. A new day has come: sotatercept for the treatment of pulmonary arterial hypertension. J Heart Lung Transplant 2025; 44: 1–10.

55.

Souza

Badesch

Ghofrani

, et al. Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial. Eur Respir J 2023; 62: 2301107.

56.

Humbert

McLaughlin

Badesch

, et al. Sotatercept in patients with pulmonary arterial hypertension at high risk for death. N Engl J Med 2025; 392: 1987–2000.

57.

Waxman

Restrepo-Jaramillo

Thenappan

, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med 2021; 384: 325–334.

58.

Yasuoka

Shirai

Tamura

, et al. Predictors of favorable responses to immunosuppressive treatment in pulmonary arterial hypertension associated with connective tissue disease. Circ J 2018; 82: 546–554.

59.

Kommireddy

Bhyravavajhala

Kurimeti

, et al. Pulmonary arterial hypertension in systemic lupus erythematosus may benefit by addition of immunosuppression to vasodilator therapy: an observational study. Rheumatology 2015; 54: 1673–1679.

60.

Jiang

Wang

Jin

, et al. Targeted treatment strategy for patients with severe pulmonary hypertension secondary to connective tissue diseases. Rheumatol Autoimmun 2023; 3: 157–165.

61.

Tanaka

Harigai

Tanaka

, et al. Pulmonary hypertension in systemic lupus erythematosus: evaluation of clinical characteristics and response to immunosuppressive treatment. J Rheumatol 2002; 29: 282–287.

62.

Suzuki

Takahashi

Morimoto

, et al. Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats. Biochem Biophys Res Commun 2006; 349: 781–788.

63.

Zheng

Zhang

, et al. The effects and mechanisms of mycophenolate mofetil on pulmonary arterial hypertension in rats. Rheumatol Int 2010; 30: 341–348.

64.

Tselios

Gladman

, et al. Mycophenolate mofetil in nonrenal manifestations of systemic lupus erythematosus: an observational cohort study. J Rheumatol 2016; 43: 552–558.

65.

Nawata

Nagayasu

Fujita

, et al. Severe pulmonary arterial hypertension and interstitial pneumonia related to systemic lupus erythematosus successfully treated with mycophenolate mofetil: a novel case report. Lupus 2020; 29: 1955–1960.

66.

Rodolfi

CCM

Bejerano

AMR

, et al. Impact of immunosuppression on development and outcome of systemic sclerosis-associated pulmonary arterial hypertension. Clin Exp Rheumatol 2025; 43: 1492–1498.

67.

Sanchez

Sitbon

Jaïs

, et al. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest 2006; 130: 182–189.

68.

Jais

Launay

Yaici

, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease–associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum 2008; 58: 521–531.

69.

Miyamichi-Yamamoto

Fukumoto

Sugimura

, et al. Intensive immunosuppressive therapy improves pulmonary hemodynamics and long-term prognosis in patients with pulmonary arterial hypertension associated with connective tissue disease. Circ J 2011; 75: 2668–2674.

70.

Zamanian

Badesch

Chung

, 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: 209–221.

71.

Johnson

Granton

Tomlinson

, 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: 276–285.

72.

Rhee

Gabler

Sangani

, et al. Comparison of treatment response in idiopathic and connective tissue disease–associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2015; 192: 1111–1117.