Introduction

Pulmonary hypertension (PH) is a disorder associated with multiple clinical conditions and confers a poor prognosis.¹ Left heart disease and pulmonary disorders are the most common causes of PH all over the world.² Patients with connective tissue diseases (CTDs) are at particular risk for the development of PH.³ Although any type of PH can occur in the course of CTDs, pulmonary arterial hypertension (PAH) is the leading cause of PH in systemic sclerosis (SSc) and is also common in other CTDs such as mixed connective tissue disorder (MCTD) and systemic lupus erythematosus (SLE).⁴ The PAH is characterized by increased pulmonary vascular resistance (PVR) due to the remodeling of pulmonary vasculature, which eventually leads to progressive right ventricular failure and death if untreated.⁵ The prognosis of PAH has improved significantly after the widespread use of specific treatments.⁶ Despite similar responses to treatment, the prognosis of connective tissue disease–associated PAH (CTD-PAH) is significantly worse compared to idiopathic PAH and a 3-year mortality rate is reported about 50% in SSc-associated PAH (SSc-PAH).⁷

Right heart catheterization (RHC) is mandatory for the diagnosis of PH. According to current hemodynamic criteria, PH is defined as an elevated mean pulmonary artery pressure (mPAP >20 mm Hg) at rest.¹ The PAH is hemodynamically characterized by increased PVR >2 WU and normal pulmonary capillary wedge pressure (≤15 mm Hg) in the absence of other causes of precapillary PH, such as chronic thromboembolic PH (CTEPH) and PH associated with lung diseases.¹ The symptoms of PAH are non-specific, with progressive dyspnea being the most common.⁸ Additional symptoms may include fatigue, palpitations, syncope, chest pain, and hemoptysis.⁸ Co-existing conditions such as interstitial lung disease (ILD) and left ventricular diastolic dysfunction (LVDD) may also contribute to these non-specific symptoms in patients with CTD. Thus, the differential diagnosis of PAH is challenging in CTDs, and most of the patients have symptoms and advanced disease at the time of diagnosis.⁹ Early detection through screening, ideally before symptom onset, may allow for early intervention and contribute to improved outcomes. The RHC is not considered an appropriate screening test for PH and PAH due to its invasive nature, highlighting the necessity for the development and utilization of noninvasive methods.

Screening is defined as the detection of a disease in an at-risk population before the development of symptoms.¹⁰ To be considered suitable for screening, a disease should be prevalent, have an early pre-symptomatic period and there must be evidence that early intervention improves outcomes. Additionally, the test used in screening should be noninvasive, easily accessible, reproducible and have high sensitivity and specificity.¹¹ The PAH is rare in the general population (with an estimated prevalence of 48-55 cases per million); therefore, population-wide screening is not feasible and practical.¹² However, the high prevalence of PAH in SSc (7%-19%) may justify systematic screening in this high-risk group.¹³ The PAH accounts for 30% of SSc-related deaths indicating that it is a major complication of SSc.¹⁴ Furthermore, evidence suggests that SSc-PAH patients diagnosed via screening have less functional and hemodynamic impairment at diagnosis and better survival rates.¹⁵ Recent SSc-PAH registries employing PAH screening have reported 3-year survival rates of approximately 75%.¹⁶ Although lead-time bias cannot be completely excluded, these findings suggest that early diagnosis may improve prognosis in SSc-PAH. However, the prevalence of PAH in other CTDs is much lower than SSc, and the potential benefit of screening in these populations remains uncertain.

Several methods including cardiac and thoracic imaging, blood biomarkers, pulmonary function tests and composite algorithms have been used for PH screening in patients with CTDs. This study aimed to provide a literature review on the performance of these methods for PH and present multidisciplinary consensus-based recommendations and an algorithm for screening and early detection of PH in patients with CTDs for physicians in Türkiye who are involved in the routine care of this patient group.

Methods

The consensus group was composed of 10 rheumatologists, 4 cardiologists and 3 pulmonologists. Research questions were formulated by 2 authors (A.S. and A.A.), and the systematic literature review (SLR) team (B.F.Y., M.E.Y., D.T.K., M.E., B.D.D., S.A., Y.Y.) conducted an extensive search in the PubMed database for studies published up to January 1, 2024. The search terms used and the flow diagram illustrating the study selection process are provided in the Supplementary Appendix. Only original studies written in English that met the following criteria were included: 1) diagnosis of PH and/or PAH was confirmed by RHC and 2) provided data on the performance of the relevant methods in detecting PH and/or PAH. The patient population of interest consisted of individuals with CTDs, including SSc, SLE, MCTD, and Sjogren’s syndrome. The diagnostic and screening methods evaluated included electrocardiography (ECG), transthoracic echocardiography (TTE), cardiac magnetic resonance imaging (MRI), natriuretic peptides (brain natriuretic peptide (BNP) and N terminal pro BNP (NT-proBNP)), chest X-ray, chest computed tomography (CT), pulmonary function tests (spirometry and diffusion capacity for carbon monoxide [DLCO]), 6-minute walk test (6MWT), and composite screening algorithms. The performance of these methods in detecting PH and/or PAH was assessed based on sensitivity, specificity, and positive predictive values (PPVs)/negative predictive values (NPVs). Results of the literature review were summarized by the SLR team in order to inform the consensus group (Supplementary Table 1). The draft recommendations were formulated and sent to the members of the consensus group via email. Group members voted on the draft recommendations by indicating whether they agreed or disagreed with each item. Each final recommendation required ≥70% agreement to be approved. The quality of evidence (high, moderate, low, and very low) and strength of recommendations (strong or conditional) were determined using the GRADE approach.^17,18 In addition, an algorithm for screening and early detection of PH for patients with SSc and other CTDs exhibiting overlap features of SSc tailored to the specific conditions of Türkiye was developed and approved by all members of the consensus group. Artificial intelligence–assisted technologies were not used in the production of this submitted work.

Results

The literature search identified 7864 publications and 33 articles were included after title, abstract, and full-text evaluation. Among the included studies, 31 involved only patients with SSc, whereas 2 studies included a small number of patients with MCTD, SLE, Sjogren’s syndrome, rheumatoid arthritis and undifferentiated CTD (UCTD), in addition to SSc patients (Supplementary Table 1; article no 10 and 15). The hemodynamic definitions of PH and PAH, the cutoff values used for diagnostic methods and the symptom status of patients varied across the studies.

Echocardiography

Transthoracic echocardiography is one of the most widely used methods for PH screening in CTDs and is recommended for annual screening in SSc patients by international PH guidelines.¹⁹ Echocardiography can estimate systolic pulmonary artery pressure (sPAP) using tricuspid regurgitation velocity (TRV) and provides information about other signs suggesting PH, such as right ventricular enlargement, increased pulmonary artery diameter, interventricular septal flattening, reduced right ventricular outflow tract acceleration time, and tricuspid annular plane systolic excursion (TAPSE) (Table 1).¹ However, a significant limitation of echocardiography is that TRV is not detectable in all patients due to inadequate Doppler signal.²⁰ In SSc patients, studies have reported the sensitivity of different cutoff values for tricuspid gradient (TG) and estimated sPAP in detecting PH, precapillary PH, or PAH as 47%-100%, with a specificity of 70%-100%.^21-26 In a study including a heterogeneous group of patients with CTD, Rajaram et al²⁷ found that TG ≥ 40 mm Hg on echocardiography had a sensitivity of 86%, specificity of 82%, PPV of 91%, and NPV of 72% for detecting PAH.

In early stages of pulmonary vascular disease, patients with SSc with normal hemodynamic findings at rest may display an abnormal hemodynamic response in exercise. However, such a response does not necessarily indicate pulmonary vascular disease and may also occur in the presence of other conditions such as LVDD.^28,29 In SSc patients with reassuring resting echocardiographic findings, TRV measurement during dobutamine and exercise stress echocardiography showed sensitivity of 80% and 90% and specificity of 84% and 80%, respectively, for detecting PAH.^30,31 Suzuki et al³² also demonstrated that exercise echocardiography had superior sensitivity (93% vs. 79%) and specificity (90% vs. 76%) compared to resting echocardiography for detecting PAH in patients with CTDs.

Natriuretic Peptides

Increased myocardial wall stress in PH results in the release of natriuretic peptides from cardiomyocytes.³³ Several studies have investigated the diagnostic, predictive, and prognostic value of increased natriuretic peptides, particularly in SSc-PAH.³⁴ However, serum levels of natriuretic peptides may remain normal in the early stages of PAH, which limits their utility for early diagnosis. Additionally, some other factors such as age, gender, body weight, and renal function can affect their serum levels.³³ In the reviewed studies, different cutoff values for BNP had a sensitivity of 60%-85% and a specificity of 35%-87% in detecting PH or PAH in patients with SSc.^35,36 Different cutoff values of serum NT-proBNP levels were reported to have a sensitivity of 45%-92%, a specificity of 90%-100%, and a negative predictive value of 56%-93% for detecting PH or PAH in patients with SSc.^36-38

Electrocardiography

Common ECG findings associated with PH include right axis deviation, increased P wave amplitude (P pulmonale), and right bundle branch block.³⁹ Since these changes reflect advanced disease with increased right ventricular wall tension and hypertrophy, ECG is often normal in the early stage of PH. The sensitivity and specificity of different ECG findings for detecting PH or PAH have been reported to be between 44%-73% and 67%-97%, respectively^35,40-42 in patients with SSc.

Chest X-ray

Enlargement of the pulmonary arteries and right heart chambers are chest x-ray findings suggesting PH. Unfortunately, these findings are often absent in early-stage disease, thus a normal chest x-ray does not exclude PH.⁴³ A study of 49 SSc patients by Ungerer et al⁴² reported a sensitivity of 25% for right descending pulmonary artery enlargement, with a specificity and positive predictive value of 100% in detecting PAH.

Pulmonary Function Tests

A disproportionate reduction in carbon monoxide diffusing capacity (DLCO) with a relatively preserved forced vital capacity (FVC) can be observed in SSc-PAH.⁴⁴ Most SSc patients have DLCO levels below 60% at the diagnosis of PAH; however, decrease in DLCO begins several years prior to diagnosis.^45,46 In addition, other conditions such as ILD may also lead to decrease in DLCO in patients with SSc, which limits its specificity for PAH. Sensitivity and specificity of different cutoff values of DLCO for detecting PH or PAH in SSc patients ranged from 39%-100% and 86%-100%, respectively.^21,26,38,42 A sensitivity of 64%-100% and specificity of 32%-96% was reported for the FVC/DLCO ratio in detecting PH or PAH across the reviewed studies.^26,32,35,38 Sivova et al⁴⁷ suggested that the pulmonary capillary blood volume (Vcap) component of DLCO had better diagnostic performance than DLCO and the FVC/DLCO ratio for detecting precapillary PH in SSc patients with ILD; thus, partitioning of DLCO in this patient group may be beneficial. In another study, a formula derived using peripheral oxygen saturation and DLCO showed a sensitivity above 90% in detecting PH in SSc patients with equivocal findings in TTE, which indicates PFTs may be used as a complementary tool to echocardiography.⁴⁸

Chest Computed Tomography

Chest CT findings suggesting the presence of PH include enlargement of pulmonary arteries and right ventricle, increased pulmonary artery-to-aorta diameter ratio and lung perfusion changes.⁴³ Condliffe et al²⁴ reported that pulmonary artery-to-aorta diameter ratio (dPa/dAo) >1 and right ventricle to left ventricle diameter ratio (dRV/dLV) >1 both have sensitivities around 80% for detecting PH in SSc patients. They also demonstrated that a composite index incorporating dPa/dAo and dRV/dLV has higher sensitivity (89%) with a specificity of 89%.²⁴ Another study showed a sensitivity of 65% and specificity of 67% for increased right ventricular wall thickness (>3.5 mm) in detecting PAH in patients with CTDs.²⁷

Cardiac Magnetic Resonance Imaging

Cardiac MRI allows both morphological and functional assessments of cardiac structures and pulmonary arteries. It provides valuable information for diagnosing PH, risk stratification, and prognostication.⁴⁹ The advantages of cardiac MRI are that it is noninvasive, does not contain ionizing radiation, and is highly reproducible. Its limitations include high cost, limited accessibility, and longer examination time. Pulmonary artery-to-aorta diameter ratio, ventricular mass index (VMI), pulmonary artery velocity, and pulmonary artery distensibility are some parameters used for PAH detection in cardiac MRI.⁴⁹ In a study including SSc patients, a VMI >0.56 showed 100% sensitivity and 70% specificity in detecting PH.²⁵ Rajaram et al²⁷ reported 85% sensitivity and 82% specificity for VMI >0.45 and 80% sensitivity and 78% specificity for pulmonary artery distensibility <15% for PAH diagnosis in patients with CTDs. In another study, Hsu et al²² reported a moderate sensitivity (68% and 57%) and specificity (57% for both) for pulmonary artery diameter and maximum pulmonary artery velocity in detecting PH in SSc patients. A case-control study showed that both right ventricular free wall GLS (RVFW GLS) and right ventricular ejection fraction (RVEF) measured by cardiac MRI have high sensitivity (84% and 95%) and specificity (77% and 84%) in detecting SSc-PAH.⁵⁰

6-Minute Walk Test

6-minute walk test (6MWT) is widely used to assess exercise capacity in patients with PH. However, it may be affected by other conditions such as ILD, LVDD, and musculoskeletal involvement in patients with CTDs, limiting its specificity for PH.⁵¹ Gadre et al⁵² reported that a DIBOSA (distance walked in 6 minutes, Borg dyspnea index, and saturation of oxygen at 6 minutes) score of 0 or 1 in 6MWT had a sensitivity of 100% and a specificity of 36.3% for detecting PH in patients with SSc.

Composite Screening Algorithms

Since individual use of each method has disadvantages, combinations of different tests such as ECG, echocardiography, CT, and pulmonary function tests have been used in several studies to improve performance in detecting PH. These studies have reported sensitivity of 87%-100%, with specificity between 48% and 92% in detecting SSc-PH or SSc-PAH.^24,35,53-57 Gladue et al⁵³ demonstrated that combining echocardiographic right ventricular systolic pressure (RVSP) and pulmonary function test parameters (DLCO and FVC/DLCO ratio) has better sensitivity and NPV for detecting PAH compared to individual use of each method.

The prospective, multicenter DETECT study enrolled a SSc population enriched for PAH (DLCO < 60% and disease duration > 3 years), and RHC was systematically performed in all patients.⁵⁶ Among participants, 64% were in WHO functional class I or II. The study proposed a 2-step algorithm to identify patients who should undergo RHC. In step 1, the included parameters were FVC/DLCO ratio, presence of telangiectasia, anti-centromere antibody positivity, serum uric acid and NT-proBNP levels, and right axis deviation on ECG. Step 2 consisted of 2 echocardiographic parameters: right atrial area and TRV. The algorithm demonstrated a sensitivity of 96%, specificity of 48%, PPV of 35%, and NPV of 98% for detecting PAH. Subsequent single-center studies confirmed that the DETECT algorithm has higher sensitivity and NPV than echocardiographic evaluation alone, even in patients with DLCO ≥ 60%.^58,59 However, a recent post-hoc analysis of the original DETECT cohort revealed a decrease in sensitivity when the current hemodynamic criteria were applied.⁶⁰ The high referral (62%) and false-positive rates of the DETECT algorithm have led to further research to improve its specificity and PPV. Santaniello et al⁶¹ showed that adding cardiopulmonary exercise test (CPET) to the DETECT algorithm improved its specificity (77.8%) and PPV (63%) without affecting the sensitivity. Similarly, Colalillo et al⁶² demonstrated that combining TAPSE/sPAP ratio with the DETECT algorithm increased the PPV from 31% to 62%.

In a study of 49 SSc patients who underwent RHC, Thakkar et al⁵⁷ proposed the ASIG screening model, which combines NT-proBNP and pulmonary function test results. The algorithm demonstrated a sensitivity of 94.1%, specificity of 54.5%, PPV of 61.5%, and NPV of 92.3%. This “first-tier” algorithm suggests that if either of 2 components is present (DLCO <70% predicted with FVC/DLCO ≥ 1.8 AND/OR NT-proBNP > 210 pg/mL), the patient should undergo further evaluation with TTE, high-resolution CT, ventilation-perfusion (V/Q) scanning, and 6MWT; and RHC should be performed in cases suspected of PAH. Further investigation for PAH is unnecessary in patients where both components are absent.

In a comparison of the DETECT, ASIG, and 2009 ESC/ERS algorithms for PAH screening in SSc patients, Hao et al⁶³ reported that both DETECT and ASIG algorithms had higher sensitivity (100% for both) than the ESC/ERS (96.3%) algorithm. The ASIG algorithm had higher specificity (54.5% vs. 35.3%) and PPV (60% vs. 55.1%) and a lower referral rate compared to the DETECT algorithm. In another study, Vandecasteele et al⁶⁴ compared the DETECT algorithm with the 2009 and 2015 ESC/ERS echocardiographic screening algorithms. All 3 algorithms captured all PAH patients, though DETECT had the highest referral rate (30%) and lowest PPV (6%). Interestingly, the DETECT algorithm more frequently recommended RHC (93%) than the 2009 and 2015 algorithms (29% and 71%, respectively) in patients with mean pulmonary artery pressure (mPAP) between 21 and 24 mm Hg.

Consensus-based recommendations and algorithm for screening and early detection of PH in patients with CTD are illustrated in Table 2 and Figure 1.

Discussion

Review of the literature revealed that various noninvasive diagnostic methods have been evaluated for detecting PH or PAH in patients with SSc while data is limited for other CTDs. Most of the conducted studies included symptomatic patients with an increased risk of PH rather than a true screening population (asymptomatic or mildly symptomatic individuals). With the exception of 1 study, most did not systematically perform RHC, and therefore predictive values of relevant methods for PAH may not be accurately determined.

Unfortunately, current methods other than DLCO do not have the capability to identify patients with PAH prior to the elevation of pulmonary artery pressure. However, as mentioned above, DLCO levels begin to decline years before the diagnosis of PAH, and it is not clear how these patients should be followed. As a result, very early diagnosis of PAH does not seem to be achievable using current methods, underscoring the need for reliable biomarkers. There are several promising circulating biomarkers that have shown acceptable performance in the identification of CTD-PAH such as asymmetric dimethylarginine, growth differentiation factor-15, follistatin-like 3, and midkine; however, they need to be validated in large patient cohorts before being implemented in routine clinical practice.⁶⁵

Echocardiography is the most commonly used method for PH screening in patients with CTD and allows for direct estimation of pulmonary artery pressure. Echocardiography can also identify other conditions such as valvular heart disease and left ventricular dysfunction, which may contribute to the development of PH. Most of the composite algorithms utilize echocardiography to determine patients at high risk for PH or PAH, prior to RHC. In Türkiye, studies investigating PH in CTDs have mostly used echocardiography as the diagnostic tool and reported the frequency of PH as 19%, 1.8%-8.2%, and 23.4% in SSc, SLE, and Sjögren’s syndrome, respectively, indicating that these patients are at increased risk for the development of PH.^66-69 In a survey conducted among rheumatologists in Türkiye, echocardiography was reported as the most frequently used method for PH screening in patients with CTDs. Approximately 80% of respondents indicated that echocardiographic evaluation is performed within one month of ordering at their respective centers.⁷⁰ The fact that the age at diagnosis of SSc-PAH is lower in Türkiye than previously reported registries suggests that screening methods are easily accessible in the Turkish healthcare system.⁷¹ It is believed that each country needs to define appropriate screening strategies by considering its unique healthcare resources along with accessibility and cost of screening methods. In addition, the preferences of healthcare professionals involved in the routine care of patients are also of importance. Consequently, the consensus group developed an algorithm that prioritizes echocardiography for screening and early detection of PH in patients with SSc and other CTDs exhibiting overlap features of SSc, while also identifying circumstances where alternative screening methods to echocardiography would be appropriate. Although a literature review on CPET was not performed, CPET was incorporated into the proposed algorithm. Despite its complexity and the fact that it can only be performed in a limited number of centers in Türkiye, CPET may provide valuable data in identifying both the presence and underlying etiology of PH in selected patients.⁷² The suggested algorithm has been designed for physicians practicing in Türkiye, and its applicability to other countries may vary based on their regulations and healthcare resources.

The optimal frequency of PAH screening in patients with CTDs remains uncertain. Some studies suggest that the identification of SSc patients with very low probability of PAH based on symptoms, DLCO, and NT-proBNP, may eliminate the need for annual echocardiographic screening in this population.⁵⁵ Findings from the Australian scleroderma study cohort revealed that the majority of patients were diagnosed with PAH at the initial screening; however, those diagnosed on subsequent annual screenings had more favorable functional capacity and hemodynamic parameters.⁷³ Considering the high mortality rate of PAH, it is recommended that annual screening for PAH in patients with SSc and other CTDs with overlap SSc features of SSc, though evidence supporting this strategy is limited.

Due to the time frame used in the literature review, the included studies mostly used the previous hemodynamic cutoff values for mPAP and PVR. Recent studies suggest that the sensitivity of the DETECT algorithm may be lower in identifying SSc-PAH according to the new haemodynamic definition.^60,74 A prospective study conducted in Türkiye also demonstrated that the sensitivity of the ESC/ERS, DETECT, and ASIG algorithms for detecting PAH in patients with SSc decreased when revised hemodynamic criteria were applied.⁶⁶ This underscores the need for validated diagnostic algorithms tailored to the updated hemodynamic criteria. Feasibility and benefit of screening PH is controversial in CTDs other than SSc. Although these patients are clearly at increased risk of PH development, data about PH screening is quite limited. Thus, evaluation of CTD patients without overlap features of SSc for PH is recommended only if they have symptoms or signs suggesting PH. In patients with CTD exhibiting SSc features, the same algorithm used for SSc patients can be applied for the detection of PH.

In conclusion, an updated literature review was provided along with consensus-based recommendations for screening and early diagnosis of PH in CTDs. An algorithm incorporating patients’ symptom status and different diagnostic methods was also proposed for clinical use by physicians in Turkiye. Future validation of this algorithm in large prospective patient cohorts would be valuable for evaluating its applicability and effectiveness.

Supplementary Materials

Footnotes

Informed Consent: This work is a manuscript review and consensus statement; therefore, it does not involve any patient data.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept – A.S., A.A.; Design – A.S., D.T.K., M.E., Y.Y., A.A.; Supervision – A.A.; Resources – A.S., A.A.; Materials – A.S., A.A.; Data Collection and/or Processing – A.S., D.T.K., M.E., M.E.Y., B.F.Y., B.D.D., S.A., Y.Y.; Analysis and/or Interpretation – A.S., A.A., D.T.K., M.E., Y.Y., M.E.Y., B.F.Y., B.D.D., S.A.; Literature Search – A.S., D.T.K., M.E., M.E.Y., B.F.Y., B.D.D., S.A., Y.Y.; Writing – A.S., A.A.; Critical Review – D.T.K., M.E., M.E.Y., B.F.Y., B.D.D., S.A., Y.Y., M.İ., O.K., U.N.K., Z.P.Ö., B.A., G.O., B.M., S.K.

Declaration of Interests: The authors have no conflicts of interest to declare.

References

1. Humbert M, Kovacs G, Hoeper MM. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2023;61(1):2200879-.
2. Hoeper MM, Humbert M, Souza R. A global view of pulmonary hypertension. Lancet Respir Med. 2016;4(4):306-322.
3. Lau EMT, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol. 2017;14(10):603-614.
4. Condliffe R, Kiely DG, Peacock AJ. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med. 2009;179(2):151-157.
5. Hassoun PM. Pulmonary arterial hypertension. N Engl J Med. 2021;385(25):2361-2376.
6. Humbert M, Sitbon O, Guignabert C. Treatment of pulmonary arterial hypertension: recent progress and a look to the future. Lancet Respir Med. 2023;11(9):804-819.
7. Fisher MR, Mathai SC, Champion HC. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum. 2006;54(9):3043-3050.
8. Mocumbi A, Humbert M, Saxena A. Pulmonary hypertension. Nat Rev Dis Primers. 2024;10(1):1-.
9. Weatherald J, Boucly A, Launay D. Haemodynamics and serial risk assessment in systemic sclerosis associated pulmonary arterial hypertension. Eur Respir J. 2018;52(4):1800678-.
10. Wald NJ. The definition of screening. J Med Screen. 2001;8(1):1-.
11. Aggarwal R, Ranganathan P, Pramesh CS. Research studies on screening tests. Perspect Clin Res. 2022;13(3):168-171.
12. Leber L, Beaudet A, Muller A. Epidemiology of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: identification of the most accurate estimates from a systematic literature review. Pulm Circ. 2021;11(1):2045894020977300-.
13. Weatherald J, Montani D, Jevnikar M, Jaïs X, Savale L, Humbert M. Screening for pulmonary arterial hypertension in systemic sclerosis. Eur Respir Rev. 2019;28(153):190023-.
14. Tyndall AJ, Bannert B, Vonk M. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809-1815.
15. Humbert M, Yaici A, de Groote P. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum. 2011;63(11):3522-3530.
16. Kolstad KD, Li S, Steen V, Chung L. Long-term outcomes in systemic sclerosis-associated pulmonary arterial hypertension from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry (PHAROS). Chest. 2018;154(4):862-871.
17. Guyatt G, Oxman AD, Akl EA. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383-394.
18. Schünemann HB, Guyatt G, Oxman A. . GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations. 2013;():-.
19. Galiè N, Humbert M, Vachiery JL. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119.
20. Gladue H, Altorok N, Townsend W, McLaughlin V, Khanna D. Screening and diagnostic modalities for connective tissue disease-associated pulmonary arterial hypertension: a systematic review. Semin Arthritis Rheum. 2014;43(4):536-541.
21. Mukerjee D, St George D, Knight C. Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis. Rheumatol (Oxf Engl). 2004;43(4):461-466.
22. Hsu VM, Moreyra AE, Wilson AC. Assessment of pulmonary arterial hypertension in patients with systemic sclerosis: comparison of noninvasive tests with results of right-heart catheterization. J Rheumatol. 2008;35(3):458-465.
23. Kooranifar S, Naghshin R, Sezavar SH, Hajsadeghi S, Talebzadeh SM. Diagnostic value of chest spiral CT scan and Doppler echocardiography compared to right heart catheterization to predict pulmonary arterial hypertension in patients with scleroderma. Acta Biomed. 2021;92(1):e2021074-.
24. Condliffe R, Radon M, Hurdman J. CT pulmonary angiography combined with echocardiography in suspected systemic sclerosis-associated pulmonary arterial hypertension. Rheumatol (Oxf Engl). 2011;50(8):1480-1486.
25. Hagger D, Condliffe R, Woodhouse N. Ventricular mass index correlates with pulmonary artery pressure and predicts survival in suspected systemic sclerosis-associated pulmonary arterial hypertension. Rheumatol (Oxf Engl). 2009;48(9):1137-1142.
26. Yoneda K, Takahashi S, Nakayama K, Iwahashi M, Emoto N, Kumagai S. Combination of echocardiography and pulmonary function tests could predict no complication of pulmonary hypertension during 5 years in patients with systemic sclerosis. Int J Rheum Dis. 2023;26(3):493-500.
27. Rajaram S, Swift AJ, Capener D. Comparison of the diagnostic utility of cardiac magnetic resonance imaging, computed tomography, and echocardiography in assessment of suspected pulmonary arterial hypertension in patients with connective tissue disease. J Rheumatol. 2012;39(6):1265-1274.
28. Saggar R, Khanna D, Furst DE. Exercise-induced pulmonary hypertension associated with systemic sclerosis: four distinct entities. Arthritis Rheum. 2010;62(12):3741-3750.
29. Steen V, Chou M, Shanmugam V, Mathias M, Kuru T, Morrissey R. Exercise-induced pulmonary arterial hypertension in patients with systemic sclerosis. Chest. 2008;134(1):146-151.
30. Rallidis LS, Papangelopoulou K, Makavos G, Varounis C, Anthi A, Orfanos SE. Low-dose dobutamine stress echocardiography for the early detection of pulmonary arterial hypertension in selected patients with systemic sclerosis whose resting echocardiography is non-diagnostic for pulmonary hypertension. J Clin Med. 2021;10(17):3972-.
31. Rallidis LS, Papangelopoulou K, Anthi A. The Role of exercise Doppler echocardiography to unmask pulmonary arterial hypertension in selected patients with systemic sclerosis and equivocal baseline echocardiographic values for pulmonary hypertension. Diagnostics (Basel). 2021;11(7):1200-.
32. Suzuki K, Akashi YJ, Manabe M. Simple exercise echocardiography using a Master’s two-step test for early detection of pulmonary arterial hypertension. J Cardiol. 2013;62(3):176-182.
33. Lewis RA, Durrington C, Condliffe R, Kiely DG. BNP/NT-proBNP in pulmonary arterial hypertension: time for point-of-care testing?. Eur Respir Rev. 2020;29(156):200009-.
34. Dimitroulas T, Giannakoulas G, Karvounis H, Gatzoulis MA, Settas L. Natriuretic peptides in systemic sclerosis-related pulmonary arterial hypertension. Semin Arthritis Rheum. 2010;39(4):278-284.
35. Ninagawa K, Kato M, Nakamura H. Reduced diffusing capacity for carbon monoxide predicts borderline pulmonary arterial pressure in patients with systemic sclerosis. Rheumatol Int. 2019;39(11):1883-1887.
36. Cavagna L, Caporali R, Klersy C. Comparison of brain natriuretic peptide (BNP) and NT-proBNP in screening for pulmonary arterial hypertension in patients with systemic sclerosis. J Rheumatol. 2010;37(10):2064-2070.
37. Williams MH, Handler CE, Akram R. Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur Heart J. 2006;27(12):1485-1494.
38. Thakkar V, Stevens WM, Prior D. N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: a case-control study. Arthritis Res Ther. 2012;14(3):R143-.
39. Ley L, Höltgen R, Bogossian H, Ghofrani HA, Bandorski D. Electrocardiogram in patients with pulmonary hypertension. J Electrocardiol. 2023;79():24-29.
40. Couperus LE, Vliegen HW, Henkens IR. Electrocardiographic detection of pulmonary hypertension in patients with systemic sclerosis using the ventricular gradient. J Electrocardiol. 2016;49(1):60-68.
41. Wokhlu N, Hsu VM, Wilson A, Moreyra AE, Shindler D. P-wave amplitude and pulmonary artery pressure in scleroderma. J Electrocardiol. 2006;39(4):385-388.
42. Ungerer RG, Tashkin DP, Furst D. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med. 1983;75(1):65-74.
43. Ascha M, Renapurkar RD, Tonelli AR. A review of imaging modalities in pulmonary hypertension. Ann Thorac Med. 2017;12(2):61-73.
44. Steen VD, Graham G, Conte C, Owens G, Medsger TA. Isolated diffusing capacity reduction in systemic sclerosis. Arthritis Rheum. 1992;35(7):765-770.
45. Hachulla E, Gressin V, Guillevin L. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum. 2005;52(12):3792-3800.
46. Steen V, Medsger TA. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003;48(2):516-522.
47. Sivova N, Launay D, Wémeau-Stervinou L. Relevance of partitioning DLCO to detect pulmonary hypertension in systemic sclerosis. PLoS One. 2013;8(10):e78001-.
48. Schreiber BE, Valerio CJ, Keir GJ. Improving the detection of pulmonary hypertension in systemic sclerosis using pulmonary function tests. Arthritis Rheum. 2011;63(11):3531-3539.
49. Broncano J, Bhalla S, Gutierrez FR. Cardiac MRI in pulmonary hypertension: from magnet to bedside. RadioGraphics. 2020;40(4):982-1002.
50. Lindholm A, Hesselstrand R, Rådegran G, Arheden H, Ostenfeld E. Decreased biventricular longitudinal strain in patients with systemic sclerosis is mainly caused by pulmonary hypertension and not by systemic sclerosis per se. Clin Physiol Funct Imaging. 2019;39(3):215-225.
51. Garin MC, Highland KB, Silver RM, Strange C. Limitations to the 6-minute walk test in interstitial lung disease and pulmonary hypertension in scleroderma. J Rheumatol. 2009;36(2):330-336.
52. Gadre A, Ghattas C, Han X, Wang X, Minai O, Highland KB. Six-minute walk test as a predictor of diagnosis, disease severity, and clinical outcomes in scleroderma-associated pulmonary hypertension: the DIBOSA study. Lung. 2017;195(5):529-536.
53. Gladue H, Steen V, Allanore Y. Combination of echocardiographic and pulmonary function test measures improves sensitivity for diagnosis of systemic sclerosis-associated pulmonary arterial hypertension: analysis of 2 cohorts. J Rheumatol. 2013;40(10):1706-1711.
54. Lui JK, Gillmeyer KR, Sangani RA. A multimodal prediction model for diagnosing pulmonary hypertension in systemic sclerosis. Arthritis Care Res (Hoboken). 2023;75(7):1462-1468.
55. Semalulu T, Rudski L, Huynh T. An evidence-based strategy to screen for pulmonary arterial hypertension in systemic sclerosis. Semin Arthritis Rheum. 2020;50(6):1421-1427.
56. Coghlan JG, Denton CP, Grünig E. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73(7):1340-1349.
57. Thakkar V, Stevens W, Prior D. The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study. Arthritis Res Ther. 2013;15(6):R193-.
58. Young A, Moles VM, Jaafar S. Performance of the DETECT algorithm for pulmonary hypertension screening in a systemic sclerosis cohort. Arthritis Rheumatol. 2021;73(9):1731-1737.
59. Guillén-Del Castillo A, Callejas-Moraga EL, García G. High sensitivity and negative predictive value of the DETECT algorithm for an early diagnosis of pulmonary arterial hypertension in systemic sclerosis: application in a single center. Arthritis Res Ther. 2017;19(1):135-.
60. Distler O, Bonderman D, Coghlan JG. Performance of DETECT pulmonary arterial hypertension algorithm according to the hemodynamic definition of pulmonary arterial hypertension in the 2022 European Society of Cardiology and the European Respiratory Society guidelines. Arthritis Rheumatol. 2024;76(5):777-782.
61. Santaniello A, Casella R, Vicenzi M. Cardiopulmonary exercise testing in a combined screening approach to individuate pulmonary arterial hypertension in systemic sclerosis. Rheumatol (Oxf Engl). 2020;59(7):1581-1586.
62. Colalillo A, Grimaldi MC, Vaiarello V. In systemic sclerosis, the TAPSE/sPAP ratio can be used in addition to the DETECT algorithm for pulmonary arterial hypertension diagnosis. Rheumatol (Oxf Engl). 2022;61(6):2450-2456.
63. Hao Y, Thakkar V, Stevens W. A comparison of the predictive accuracy of three screening models for pulmonary arterial hypertension in systemic sclerosis. Arthritis Res Ther. 2015;17(1):7-.
64. Vandecasteele E, Drieghe B, Melsens K. Screening for pulmonary arterial hypertension in an unselected prospective systemic sclerosis cohort. Eur Respir J. 2017;49(5):1602275-.
65. Moccaldi B, De Michieli L, Binda M. Serum biomarkers in connective tissue disease-associated pulmonary arterial hypertension. Int J Mol Sci. 2023;24(4):4178-.
66. Erdogan M, Kilickiran Avci B, Ebren C. Screening for pulmonary arterial hypertension in patients with systemic sclerosis in the era of new pulmonary arterial hypertension definitions. Clin Exp Rheumatol. 2024;42(8):1590-1597.
67. Cefle A, Inanc M, Sayarlioglu M. Pulmonary hypertension in systemic lupus erythematosus: relationship with antiphospholipid antibodies and severe disease outcome. Rheumatol Int. 2011;31(2):183-189.
68. Akdogan A, Kilic L, Dogan I. Pulmonary hypertension in systemic lupus erythematosus: pulmonary thromboembolism is the leading cause. J Clin Rheumatol. 2013;19(8):421-425.
69. Kobak S, Kalkan S, Kirilmaz B, Orman M, Ercan E. Pulmonary arterial hypertension in patients with primary Sjögren’s syndrome. Autoimmune Dis. 2014;2014():710401-.
70. Fırlatan B, Sarı A, Karadağ DT. Ulusal Romatoloji. Ocak. 2025;S1():94-.
71. Sarı A, Satış H, Ayan G. Survival in systemic sclerosis associated pulmonary arterial hypertension in the current treatment era-results from a nationwide study. Clin Rheumatol. 2024;43(6):1919-1925.
72. Dmytriiev K, Stickland MK, Weatherald J. Cardiopulmonary exercise testing in pulmonary hypertension. Heart Fail Clin. 2025;21(1):51-61.
73. Morrisroe K, Stevens W, Sahhar J. Epidemiology and disease characteristics of systemic sclerosis-related pulmonary arterial hypertension: results from a real-life screening programme. Arthritis Res Ther. 2017;19(1):42-.
74. Ito T, Nakai T, Kidoguchi G. Effectiveness of DETECT algorithm in Japanese systemic sclerosis patients with old or new hemodynamic definition of pulmonary arterial hypertension. Arthritis Rheumatol. 2020;72(Suppl 10):-.