Prevalence, risk factors and echocardiographic predictors of pulmonary hypertension in systemic lupus erythematosus: towards a screening protocol

Abstract

Background

Systemic lupus erythematosus (SLE) significantly affects the lungs and heart, and pulmonary hypertension (PH) is a severe manifestation that leads to considerable morbidity and mortality.

Objectives

We aimed to determine the prevalence and risk factors of probable SLE-PH, assess the main echocardiographic predictors and develop a potential screening strategy.

Methods

A prospective single-centre study was conducted on 201 patients with SLE who underwent transthoracic echocardiography. Patients meeting PH criteria were referred for right heart catheterisation (RHC).

Results

Among patients, 88.56% were women, 85.57% were of Spanish origin and 43.78% had structural heart disease. Out of these, 16 (7.96%) had intermediate or high probability criteria for PH according to European Society of Cardiology (ESC) 2022. Six RHCs confirmed PH with a prevalence of 2.99% for SLE-PH and 1.99% for SLE-pulmonary arterial hypertension (PAH).

Key risk factors

Key risk factors included age, cardiorespiratory symptoms, serositis, anti-Ro, cardiac biomarkers and altered pulmonary function tests (PFTs). PH was linked to a higher Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SDI) (mean SDI 4.75 vs 2.05, p<0.001) and increased mortality risk in a 2-year follow-up (12.50% vs 1.08%, p=0.002).

Conclusion

In our cohort, 7.96% of patients with SLE had an intermediate or high PH probability. By RHC, six patients (2.99%) met the ESC/European Respiratory Society criteria for PH and four (1.99%) for PAH. The main risk factors were older age, cardiorespiratory symptoms, serositis, anti-Ro, cardiac biomarkers and altered PFTs. PH was a severe SLE complication, suggesting the need for earlier diagnosis through data-driven screening to reduce associated morbidity and mortality.

Correspondence to Dr Jorge Álvarez Troncoso; [email protected]

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Systemic lupus erythematosus (SLE) significantly impacts the cardiac and pulmonary systems, with pulmonary hypertension (PH) emerging as a severe manifestation. The literature indicates a broad prevalence range (2–20%) of SLE-PH, showcasing a diagnostic gap and necessitating further investigation for improved early detection and management strategies.

WHAT THIS STUDY ADDS

• The study refines the prevalence of PH in patients with SLE to 2.99%, and pulmonary arterial hypertension to 1.99%. Key risk factors are highlighted, and the tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio is underlined as an effective echocardiographic marker for PH, which could significantly aid in better screening and diagnosis processes.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Our findings advocate for a re-evaluation of diagnostic guidelines and a proactive screening approach for PH in patients with SLE. In clinical settings, routine assessment employing the identified echocardiographic markers could become a standardised part of managing patients with SLE, potentially leading to early detection and treatment of PH, thereby improving patient outcomes.

Introduction

Systemic lupus erythematosus (SLE) is a connective tissue disease (CTD) that can affect various organs and systems, including the lungs and heart.¹ Pulmonary hypertension (PH) is a rare but serious complication of SLE associated with significant morbidity and mortality, and it might be the third leading cause of death in patients with SLE.^2–4 PH can be silent, and clinical manifestations are typically absent in the early stage, with a delay of 2–4 years between the onset of symptoms and pulmonary arterial hypertension (PAH) diagnosis.^4–7 The exact mechanism of SLE-PH is still not fully understood but may involve inflammation, vasculitis and thrombosis, and early detection and management of the condition are challenging.⁸

Among the CTDs, systemic sclerosis (SSc) has the highest prevalence of PH, followed by SLE.^{3 9 10} However, the prevalence of SLE-PH varies widely in the literature, ranging from 2% to 20%, and a growing body of evidence suggests that it may be underdiagnosed.^{3 6 10 11}

SLE-PH can manifest as any of the five groups of the National Institute for Health and Care Excellence 2022 classification⁷: group 1 (PAH), group 2 (PH due to left heart disease), group 3 (PH due to lung diseases or hypoxia), group 4 (chronic thromboembolic PH) and group 5 (PH with unclear or multifactorial mechanisms). The classification should be based on the predominant mechanism and may change over time, as the underlying mechanisms can evolve or change.⁷

Despite the increasing recognition of SLE-PH, there is still a lack of consensus on the best approach for diagnosis and management.^{10 11} Therefore, it is essential to understand the underlying mechanisms further and develop new strategies for earlier diagnosis.

The 2022 European guidelines for PH emphasise using right heart catheterisation (RHC) in classifying PH.⁷ RHC provides important haemodynamic data that are crucial in determining the underlying pathophysiology and subtype of the condition.

PH is defined by an increased mean pulmonary arterial pressure (mPAP ≥20 mm Hg) measured by resting RHC. PAH is defined by mPAP ≥20 mm Hg, normal pulmonary artery wedge pressure (PAWP) ≤15 mm Hg and elevated pulmonary vascular resistance (PVR) ≥2 Wood units (WU).⁷

Transthoracic echocardiography (TTE) is the best screening tool for PH due to its wide availability, portability, sensitivity, specificity and cost-effectiveness.^{5 12–14}

Systolic pulmonary arterial pressure (sPAP) measures the pressure in the pulmonary artery during systole, an indirect measure of pulmonary artery pressure.⁷ However, TTE estimates of sPAP show good correlations across patient populations but with only moderate precision individually with RHC.^{15 16} Such imprecision can lead to underestimating and overestimating true sPAP, failure to identify PH or overdiagnosis.¹⁷ A peak tricuspid regurgitation velocity (TRV) of 2.8 m/s may suggest PH; however, the presence or absence of PH cannot be reliably determined by TRV alone.⁷ Thus, the European Society of Cardiology (ESC)⁷ recommends a multiparameter assessment of the TTE probability of PH, including peak TRV together with eight additional echocardiographic signs divided into three main categories (A: the ventricles; B: pulmonary artery; C: inferior vena cava (IVC) and right atrium). Among these, tricuspid annular plane systolic excursion (TAPSE)/sPAP ratio is used in echocardiography to assess right ventricular systolic function and pulmonary artery pressure. The TAPSE/sPAP ratio estimates the relationship between right ventricular systolic function and pulmonary artery pressure and has recently been used to predict the risk of SSc-PH.¹⁷

Our objective was to assess the prevalence of probable SLE-PH (intermediate or high probability according to ESC 2022) and confirmed by RHC and risk factors in our cohort. The secondary objectives were to evaluate the main echocardiographic predictors of PH and evaluate a possible screening strategy for SLE-PH.

Methods

Study population

This was a prospective, single-centre study. From December 2019 to June 2021, consecutive patients with SLE (defined by the American College of Rheumatology/European Alliance of Associations for Rheumatology 2019 classification criteria) who were actively followed up in the Systemic Autoimmune Diseases Unit, Internal Medicine Department of the Hospital Universitario La Paz (HAPLES cohort) were included. Patients who met the classification criteria for mixed CTD (MCTD) were excluded from the study. Patients with concomitant Sjögren’s syndrome or antiphospholipid syndrome were not excluded.

To mitigate potential biases and enhance the study’s validity, the following measures were implemented: the sample was sourced from a specialised SLE unit to minimise selection bias; a prospective design was employed for systematic data collection; standardised protocols were adhered to for all assessments; and statistical adjustments were made for known confounders. Additionally, a sample size of approximately 147 patients with SLE was calculated using a 95% confidence level and a 2.5% margin of error, further adjusted for anticipated attrition.

Assessments of SLE-related measures

Demographic, clinical, analytical, immunological and therapeutic data were evaluated. Disease activity was measured using the SLE Disease Activity Index (SLEDAI). Assessments of SLE-related accrual damage were performed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).^{14 16}

TTE evaluation of SLE

TTE was performed by an expert echocardiographer. Cardiac involvement was defined as the relevant abnormalities (symptomatic or asymptomatic) found in TTE.^{17 18} Suspected PH was defined using the following TTE criteria: sPAP >36 mm Hg, peak TRV >280 cm/s or indirect signs. Patients were classified based on the likelihood of PH using the ESC/European Respiratory Society (ERS) guidelines.⁷

In total, 209 patients fulfilled the inclusion criteria and did not meet any exclusion criteria. However, eight patients did not undergo TTE due to individual circumstances such as refusal to undergo TTE³ or being lost to follow-up,⁵ resulting in a cohort of 201 patients for this study (figure 1). Patients who met the echocardiographic criteria for PH were referred to the PH unit, where individual decisions on performing RHC were made based on clinical practice guidelines available at the time (figure 2).

Figure 1. Inclusion criteria flow chart. ACR/EULAR, American College of Rheumatology/European Alliance of Associations for Rheumatology; SLE, systemic lupus erythematosus; TTE, transthoracic echocardiography.

Figure 2. Flow chart of SLE-PH diagnosis. CpcPH, combined pre-capillary and post-capillary PH; IpcPH, isolated post-capillary PH; PH, pulmonary hypertension; RHC, right heart catheterisation; SLE, systemic lupus erythematosus; TTE, transthoracic echocardiography.

Statistical analysis

Descriptive statistics were used to summarise clinical and demographic variables. Categorical variables are presented as frequencies and percentages (%), whereas continuous variables are presented as means and SDs for normally distributed variables or as medians and IQRs for non-normal variables. The Χ² test was used to analyse categorical variables, and ORs were calculated as a measure of association. Logistic regression models were used to identify variables that influenced the presence of PH (measured using TTE and RHC) and to control for possible confounders or effect modifiers. The CIs were estimated using robust methods. Multivariate analysis was used to determine the independent risk factors associated with the development of SLE-PH. Multivariate logistic regression analysis included variables with p values of <0.1 in the univariate analysis, along with other variables that could potentially influence the development of PH. Results were considered statistically significant at p<0.05. Statistical analysis was performed using statistical software (Wizard Pro for Mac V.2.0.12.).

Results

A total of 201 patients with SLE met the inclusion criteria and underwent TTE. Most patients were women (88.56%) and Spanish (85.57%). The demographic, cardiovascular and immunological characteristics of the patients with SLE are reported in table 1.

Table 1

Demographic and clinical features of patients with SLE

Demographics
Female, n (%)	178 (88.56)
Spanish origin, n (%)	172 (85.57)
Age at SLE diagnosis, mean (SD)	35.07 (±15.43)
Mean follow-up time, mean (SD)	15.59 (±10.56)
Cardiovascular risk factors and events
Hypertension, n (%)	88 (43.78)
Dyslipidaemia, n (%)	75 (37.31)
Diabetes mellitus, n (%)	12 (5.97)
Obesity, n (%)	28 (13.93)
Major adverse cardiovascular events, n (%)	14 (6.97)
Thrombosis, n (%)	30 (14.93)
Polyautoimmunity
Antiphospholipid antibodies carriers, n (%)	92 (45.77)
Antiphospholipid syndrome, n (%)	27 (13.43)
Sjögren’s syndrome, n (%)	22 (10.95)

SLE, systemic lupus erythematosus.

The most frequent SLE manifestations in our cohort were articular (80.10%), cutaneous (62.69%), haematological (31.84%), serositis (23.38%: 16.92% pericarditis and 11.44% pleuritis), lupus nephritis (22.38%), Raynaud’s phenomenon (19.90%) and neuropsychiatric lupus (18.91%). The most frequent cardiorespiratory symptoms were dyspnoea (16.92%), chest pain (13.93%) and cough (10.95%). All patients were positive for antinuclear antibodies (ANA), 63.18% for anti-dsDNA, 27.86% for anti-Ro, 14.93% for anti-Sm and 9.45% for anti-RNP.

Regarding treatment, 91.54% of patients were on hydroxychloroquine and 87.66% were on corticosteroids, although only 8.46% were taking doses greater than 7.5 mg/day during the study. Ninety patients (44.74%) received conventional disease-modifying antirheumatic drug (cDMARD) and 13 (6.47%) received biological disease-modifying antirheumatic drug (bDMARD). Azathioprine (21.89%) was the most used cDMARD, followed by mycophenolate (17.91%), methotrexate (8.46%) and cyclophosphamide (4.98%). The most used bDMARDs were belimumab (4.48%) and rituximab (1.99%), respectively. The mean SLEDAI was 4.89 (±4.79), with 36.32% of patients having an SLEDAI score ≥6. The mean SDI was 2.27 (±2.94), with 72.14% of the patients having an SDI ≥1 and 49.75% having an SDI ≥2.

Regarding TTE findings, 43.78% of patients had structural heart disease. Cardiac involvement included significant valvular heart disease (26.37%), left ventricular hypertrophy (18.41%), pericarditis (16.92%) and myocarditis (1.5%, also confirmed with cardiac MRI). A total of 12.40% (n=25) of the patients met the echocardiographic and clinical criteria for heart failure, according to the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines: 20 patients had heart failure with preserved ejection fraction (left ventricular ejection fraction (LVEF) ≥50%), four heart failure with moderately reduced ejection fraction (LVEF 41–49%) and one heart failure with reduced ejection fraction (≤40%).

PH was suspected in all patients with an sPAP ≥36 mm Hg, TRV >280 m/s or indirect signs. Among the patients with abnormal TTE, 17 (8.46%) had a TRV >280 cm/s, sPAP ≥36 mm Hg or indirect PH criteria. However, only 12 patients were suspected to have PH according to the 2015 ESC/ERS guidelines. According to the 2022 criteria, 16 (7.96%) patients had intermediate or high probability criteria (due to TRV >280 cm/s or other echo PH signs of PH), representing an increase of 33.33% in suspected PH using the new classification criteria (table 2). In addition, the 2015 guidelines divided four patients into probable and eight as possible, while the 2022 guidelines classified 4 as high probability and 12 as intermediate probability. Only one of the four patients classified as probable was a candidate for RHC, whereas three of the four high-probability patients were candidates for RHC. Six RHCs were performed (figure 2), and all had confirmed PH.

Table 2

Patients with an intermediate or high probability of pulmonary hypertension (PH)

ID	sPAP (mm Hg)	TAPSE/sPAP ratio	A	B	C	TTE PH (2022)	RHC	mPAP	PAWP	PVR	Definition	Group
#13	34.6	0.81	0	1	1	Intermediate	No; LVH, HFpEF	–	–	–	–	–
#19	34.6	0.55	1	1	0	Intermediate	No; HFpEF (hypokinesia), death	–	–	–	–	–
#24	39.4	0.56	0	1	0	Intermediate	No; COPD, HFpEF (VHD)	–	–	–	–	–
#29	66.9	0.36	1	1	0	High	No; melanoma	–	–	–	–	–
#31	36.2	0.53	1	1	0	Intermediate	No; LVH, HFpEF	–	–	–	–	–
#87	44.5	0.43	1	1	0	Intermediate	No; lost to follow-up	–	–	–	–	–
#91	52.0	0.39	1	0	0	Intermediate	No; HFpEF (LVH, VHD), death	–	–	–	–	–
#95	42.0	0.36	1	1	0	High	Yes	28	14	3.5	Pre-capillary	1
#117	37.0	0.46	1	0	1	Intermediate	Yes; VHD	25	18	1.88	IpcPH	2
#127	45.0	0.62	0	0	0	Intermediate	No; LVH, HFpEF	–	–	–	–	–
#166	65.0	0.26	1	1	0	High	Yes	45	18	6.4	CpcPH	1 & 2
#167	50.0	0.28	1	0	1	Intermediate	No; ILD, HFpEF (VHD)	–	–	–	–	–
#185	46.0	0.43	1	1	0	High	Yes	56	10	8,8	Pre-capillary	1
#192	35.6	0.48	1	0	1	Intermediate	No; LBBB, HFpEF	–	–	–	–	–
#210	40.8	0.54	0	1	0	Intermediate	Yes	25	11	2,0	Pre-capillary	4
#225	42.5	0.54	0	0	0	Intermediate	Yes	21	8	2,4	Pre-capillary	1

COPD, chronic obstructive pulmonary disease; CpcPH, combined pre-capillary and post-capillary PH; HFpEF, heart failure with preserved ejection fraction; ILD, interstitial lung disease; IpcPH, isolated post-capillary PH; LBBB, left bundle branch block; LVH, left ventricular hypertrophy; mPAP, mean pulmonary arterial pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RHC, right heart catheterisation; sPAP, systolic pulmonary arterial pressure; TAPSE, tricuspid annular plane systolic excursion; TTE, transthoracic echocardiography; VHD, valvular heart disease.

Three RHCs were not performed due to patient conditions (melanoma, loss to follow-up and death), four due to TTE criteria of PH secondary to left heart disease (with a presumably predominant PH in group 2) and one advanced interstitial lung disease (ILD) with concomitant left heart disease. Four patients were diagnosed with pre-capillary PH (three patients from group 1 (PAH) and one from group 4 (chronic thromboembolic PH (CTEPH)), one with isolated post-capillary PH (group 2), and one with combined pre-capillary and post-capillary PH (groups 1 and 2). CTEPH diagnosis was based on thoracic CT pulmonary angiography and ventilation/perfusion scintigraphy findings. The final prevalence of SLE-PH and SLE-PAH by RHC was 2.99% and 1.99%, respectively. The main findings for the RHCs are described in table 3.

Table 3

Data of right heart catheterisation (n=6)

Mean PAP (mm Hg)	33.16±14.11
Systolic PAP (mm Hg)	54.83±23.52
Diastolic PAP (mm Hg)	22.17±13.67
PAWP (mm Hg)	13.16±4.22
PVR (WU)	4.16±2.83
Vasodilator response (%)	0
Pulmonary SaO2 (%)	68.76±5.46
Cardiac output (L/min)	4.65±0.97
Cardiac index (L/min/m2)	2.43±0.38

PAP, pulmonary arterial pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; SaO₂, arterial oxygen saturation; WU, Wood units.

According to the 2015 guidelines, five patients met the PH criteria (mPAP ≥25 mm Hg), and only three met the PAH criteria (mPAP ≥25 mm Hg and PAWP ≤15 mm Hg). However, according to the 2022 ESC/ERS guidelines, six patients met the PH criteria (mPAP >20 mm Hg), and four met the PAH criteria (mPAP >20 mm Hg, PAWP ≤15 mm Hg and PVR >2 WU). The new criteria represent a 20% increase in PH and 33.33% increase in PAH.

We evaluated the risk factors for both suspected (by TTE) and confirmed (by RHC) PH (table 4), as cases of PH confirmed by RHC may exclude patients with group 2 PH (table 4).

Table 4

Risk factors for PH by TTE or by RHC

	Confirmed PH by RHC			Suspected PH by TTE
Characteristics	PH (n=6)	No PH (n=195)	P value	High-intermediate probability (n=16)	Low probability (n=185)	P value	OR (95% CI)
Age ≥50 (years) (%)	50.00	44.10	0.775	81.25	41.08	0.002	6.22 (1.71 to 22.56)
Male sex (%)	0	11.79	0.371	6.25	11.89	0.496	–
Disease duration >10 (years)	100	62.05	0.058	87.50	61.08	0.036	4.46 (0.99 to 20.21)
BMI ≥25 kg/m2 (%)	66.67	44.10	0.274	68.75	42.70	0.044	2.95 (0.99 to 8.84)
Symptomatic (%)	100	27.69	<0.001	75.00	25.95	<0.001	8.56 (2.64 to 27.82)
Dyspnoea (%)	100	14.36	<0.001	75.00	12.43	<0.001	21.13 (6.28 to 71.07)
NYHA III–IV (%)	50.00	2.05	<0.001	31.25	1.08	<0.001	101.25 (14.90 to 688.23)
Chest pain (%)	50.00	12.82	0.010	25.00	12.97	0.183	–
Cough (%)	50.00	9.74	0.002	31.25	9.19	0.007	4.49 (1.40 to 14.46)
Serositis (%)	50.00	22.56	0.118	50.00	21.08	0.009	3.74 (1.32 to 10.61)
Pericarditis (%)	33.33	16.41	0.276	37.50	15.14	0.022	3.36 (1.13 to 9.99)
SDI ≥2 (%)	83.33	48.72	0.016	87.50	46.49	0.002	8.06 (1.78 to 36.46)
Biomarkers
NT-proBNP ≥450 pg/mL (%)	50.00	12.31	0.008	43.75	10.81	<0.001	6.42 (2.16 to 19.11)
usTnI ≥0.04 pg/mL (%)	66.67	10.26	<0.001	37.50	9.73	0.001	5.56 (1.81 to 17.11)
Anti-Ro (%)	66.67	26.67	0.031	50.00	25.94	0.039	2.85 (1.02 to 8.02)
Pulmonary function tests
FVC <80% expected (%)	16.67	1.03	0.002	18.75	0.00	<0.001	10.44 (2.11 to 51.68)
FEV1 <80% expected (%)	33.33	4.62	0.002	25.00	3.78	<0.001	8.48 (2.17 to 33.04)
DLCO <80% expected (%)	33.33	5.13	0.004	25.00	4.32	<0.001	7.38 (1.94 to 28.03)
TLC <80% expected (%)	16.67	2.05	0.024	12.50	1.62	0.007	8.67 (1.34 to 56.23)

BMI, body mass index; DLCO, diffusing capacity of the lungs for carbon monoxide; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PH, pulmonary hypertension; RHC, right heart catheterisation; SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; TLC, total lung capacity; TTE, transthoracic echocardiography; usTnI, ultrasensitive troponin I.

Age and disease duration >10 years were independent risk factors for a higher probability of SLE-PH (p<0.002 and p=0.036, respectively). However, we found no correlation between the male sex and ethnicity. We found that overweight patients (body mass index ≥25 kg/m²) had a higher probability of SLE-PH (p=0.044). We found no statistically significant association between SLE-PH and Raynaud’s phenomenon, telangiectasias or livedo reticularis. Cutaneous, articular, renal, neurological and haematological involvement was unrelated to SLE-PH.

Only serositis (p=0.009), understood as pericarditis, pleuritis or shrinking lungs, was an SLE manifestation associated with an increased risk of PH. Cardiorespiratory symptoms are associated with an increased risk of SLE-PH.

Hypocomplementemia, ANA titres, anti-dsDNA, lupus anticoagulant, anticardiolipin, anti-B2GP1 or anti-prothrombin, anti-Sm, anti-RNP, anti-La, anti-histones and anti-ribosomal P presented no statistical significance. Anti-Ro positivity was associated with an intermediate or high probability of PH (p=0.039), PH confirmed by RHC (p=0.031), pre-capillary PH (p=0.034) and PAH (p=0.005).

The biomarkers N-terminal pro-brain natriuretic peptide (NT-proBNP) and ultrasensitive troponin I (usTnI) were excellent predictors of PH risk. Specifically, the cut-off points of NT-proBNP >450 pg/mL and usTnI >0.04 pg/mL correlated significantly with echocardiographic suspicion of PH and its confirmation by RHC.

Altered pulmonary function tests (PFTs) were associated with an intermediate-high probability of PH (table 4). Altered PFTs were defined as forced vital capacity (FVC) <80% expected, total lung capacity <80%, forced expiratory volume in 1 s (FEV₁) <80% and diffusing capacity of the lungs for carbon monoxide (DLCO) <80% (and DLCO <60%). However, it did not correlate with the expected FEV₁/FVC ratio of <70%. Patients with altered PFTs had a normal CT scan ruling out ILD, except for one case of advanced ILD that also had PH.

The best echocardiographic marker of PH beyond the TRV was the TAPSE/sPAP ratio (p<0.001, OR (95% CI): 129.28 (28.97 to 577.01)). The TAPSE/sPAP cut-off point of <0.55 was the best, with an area under the curve of 0.89. The TAPSE/sPAP ratio was superior to that of the IVC, right atrial area, pulmonary artery acceleration time, main pulmonary artery diameter and isolated TAPSE (all statistically significant). Right ventricular diameters, tissue systolic wave velocity, tissue Tei index and right ventricular shortening fraction were not significant.

Intermediate high-probability PH presented a mean SDI of more than two times higher than low probability (mean SDI 4.75 vs 2.05, respectively, p<0.001). SDI was also higher in patients with RHC-confirmed PH (p=0.013). We did not find a significant correlation between PH and any SLEDAI scores (p=0.431), nor with specific thresholds such as SLEDAI ≥4 (p=0.311), SLEDAI ≥6 (p=0.301) or SLEDAI ≥12 (p=0.308).

Presenting intermediate high-probability PH was correlated with increased mortality risk in the 2-year follow-up period compared with low-probability PH (12.50% vs 1.08%, respectively, p=0.002).

Discussion

This study aimed to evaluate the prevalence of SLE-PH evaluated by TTE and RHC in a Spanish cohort and to identify the risk factors associated with its development.

In most cohorts, the prevalence of SLE-PH is lower than SSc-PH (2–3% vs 7–10%).^{6 10 11 19} However, SLE is almost four to five times more prevalent than SSc; therefore, this complication may be globally relevant.¹¹ SLE is known to be more prevalent and severe in non-Caucasian populations, comprising >50% of all CTD-PH (58.4%) in Asians.^{3 4 6 11 20} Although it has been postulated that there could be a higher prevalence of SLE-PH in Asians, the prevalence in our study is similar to these cohorts: 7.96% of PH by TTE, 2.99% of SLE-PH by RHC and 1.99% of SLE-PAH by RHC.

The prevalence of SLE-PH in European cohorts varies depending on the study population and the diagnostic criteria used, but several studies have reported a relatively high prevalence of SLE-PH in patients with SLE.¹¹ SLE-PH remains a significant complication of SLE in European cohorts, with a prevalence ranging from 2.4% to 10.6%.^{10 11} Clinicians should be aware of the potential for SLE-PH in patients with SLE and closely monitor them for signs and symptoms of the condition. Early diagnosis and treatment of SLE-PH are crucial to prevent potentially life-threatening complications.⁷

Recent SLE-PH studies have used various diagnostic criteria to identify and classify patients with PH.^{2 4 6 21 22} Common criteria include an mPAP ≥25 mm Hg at rest measured by RHC, a TRV velocity ≥280 cm/s measured by TTE and an sPAP of ≥30 or 40 mm Hg measured by TTE. The specific criteria used may vary among studies depending on the research question and study design.^{6 21 22} The lack of homogeneity in the clinical question conditions has different prevalence, results and methods. Recent changes in PH guidelines have led to changes in RHC definition and TTE screening. New guidelines,⁷ compared with previous ones,²³ allow for greater echocardiographic sensitivity, increasing suspicions by more than 20%, but with better risk correlation and better matching of patients who are candidates for RHC.

In our cohort, the primary factors predicting an intermediate-high probability of SLE-PH were age, prolonged follow-up period, being overweight, presence of cardiorespiratory symptoms, serositis, anti-Ro positivity, elevated cardiac biomarkers (NT-proBNP and usTnI) and abnormal PFTs.

On the other hand, it has been postulated that SLE-PH could be related to disease activity and lupus flare, but not acute-phase reactants, anti-dsDNA, complement or SLEDAI correlated with SLE-PH in our cohort.

Unlike other cohorts,^{21 22} we failed to find a correlation with other antibodies such as antiphospholipid, anti-Sm or anti-La. In our study, patients with MCTD (anti-RNP positivity compulsory) were excluded, as they might meet the classification criteria for SLE because the prevalence of PH and the pathophysiology of the disease are different, with greater vasculopathy and greater similarities with SSc. Therefore, the prevalence of anti-RNP positivity may be lower, and no correlation was found between this autoantibody and the risk of SLE-PH.

We did not find a correlation with Raynaud’s phenomenon, vasculitis, cutaneous lupus, or renal or haematological manifestations. However, serositis, specifically pericarditis, seems to be a common risk factor in most series.^{4 6 11 21 22}

Overall, our study adds to the growing body of evidence on SLE-PH risk factors and highlights the importance of monitoring for serositis and cardiorespiratory symptoms in patients with SLE, particularly those older and with longer disease duration. Anti-Ro positivity is also an important and common risk factor, as it may be a marker of more severe SLE disease activity and an increased risk of PAH. Finally, the TAPSE/sPAP ratio is a useful echocardiographic marker for PH, which may have important clinical implications in identifying and monitoring patients with SLE-PH.

Early diagnosis of PH is associated with improved long-term survival.^2–4 Therefore, early detection of PH has been identified as a crucial step in improving the outcome of this devastating condition.⁷ The new PH guidelines recommend an annual evaluation of patients with CTD with overlapping features of SSc. It is evident in SSc (DETECT Study) that a multimodal approach using TTE^{5 7 12 13} and biomarkers is a sensitive, non-invasive tool to identify PH with minimal false negatives. As this was a TTE screening study (not symptom based), asymptomatic or paucisymptomatic patients were diagnosed. The presence of dyspnoea, chest pain and cough should be questioned periodically, as this is a simple and effective way to predict the risk of PH in patients with SLE. However, a diagnosis based exclusively on symptoms is a late diagnosis, with all that implies. Although dyspnoea is a relatively common symptom, a small percentage of patients experience moderate-to-severe exertional dyspnoea. In addition, NT-proBNP and usTnI had a high positive predictive value for heart disease and PH.

The study’s limitations are inherent to a single-centre study. RHC was not performed by protocol, but was individualised according to the standard clinical practice of the PH unit. This may indicate that some patients in presumed group 2 could have other concomitant involvement without relevant therapeutic implications. However, some patients with a high clinical suspicion of PH could not undergo RHC for various reasons, which could have affected the definitive prevalence.

The strengths of this study lie in the fact that this is a large cohort with a protocolised TTE study performed by an expert echocardiographer, with the referral of intermediate-probability or high-probability cases to a PH unit, RHC evaluation and prospective follow-up of 2 years after echocardiography.

Despite being a screening study for SLE-PH, patients with PH had greater accrual damage and higher mortality, as observed in other prospective and retrospective cohorts.^{10 11 21 22} Therefore, since structural heart disease is highly prevalent and PH is associated with high morbidity and mortality, screening based on symptoms, risk factors and biomarkers may be an appropriate strategy to reduce complications (figure 3). Echocardiographic study would be advisable for all symptomatic patients. Our results suggest it might be performed in asymptomatic patients with anti-Ro, serositis or elevated cardiac biomarkers (usTnI or NT-proBNP). In addition, in the presence of suspected PH on TTE, patients should be referred to a multidisciplinary PH unit with expertise in CTD-PH. Although RHC may have some risks, it is the test of choice for the diagnosis of PH. RHC should always be considered to confirm SLE-PH and allow for proper pre-capillary PH treatment.

Figure 3. SLE-PH screening proposal. NT-proBNP, N-terminal pro-brain natriuretic peptide; PFTs, pulmonary function tests; PH, pulmonary hypertension; RHC, right heart catheterisation; SLE, systemic lupus erythematosus; sPAP, systolic pulmonary arterial pressure; TAPSE, tricuspid annular plane systolic excursion; TRV, tricuspid regurgitation velocity; TTE, transthoracic echocardiography; usTnI, ultrasensitive troponin I.

Conclusions

In our cohort of 201 patients with SLE who underwent TTE, 7.96% had an intermediate or high probability of PH. Six patients (2.99%) met the ESC/ERS criteria for PH and four for PAH. The main risk factors for PH are older age, cardiorespiratory symptoms, serositis, anti-Ro, cardiac biomarkers and altered PFTs. TAPSE/sPAP ratio <0.55 was the best echocardiographic marker beyond TRV. PH is a rare but serious complication of SLE and is associated with greater accrual of damage and mortality. Thus, we propose echocardiographic screening based on symptoms and risk factors that could allow better probability stratification, earlier RHC diagnosis and treatment, potentially improving the prognosis of these patients.

We thank the patients whose participation significantly advanced our understanding of lupus.

Data availability statement

Data are available upon reasonable request. Datasets from this study are not publicly available due to privacy and ethical constraints but can be obtained from the corresponding author upon reasonable request.

Ethics statements

Patient consent for publication

Obtained.

Ethics approval

This study involves human participants and was approved by the Ethics Commission of the Hospital Universitario La Paz (PI-3500) and complied with the Declaration of Helsinki. All the participants provided written informed consent.

Footnote

Twitter @joraltron

Contributors JJR-B conceived the study idea. JJR-B, CSA and JAT handled design. JAT and RST performed data gathering. JAT performed execution, analysis and initial drafting. JAT is responsible for the overall content as guarantor. All authors reviewed, approved the final version and agreed to be accountable for the work.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

References

¹ Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019; 78: 736–45. doi:10.1136/annrheumdis-2019-215089

² Zhao J, Wang Y, Wang Q, et al. Clinical characteristics and survival of pulmonary arterial hypertension associated with three major connective tissue diseases: a cohort study in China. Int J Cardiol 2017; 249: 418. doi:10.1016/j.ijcard.2017.06.126

³ McGoon MD, Miller DP. REVEAL: a contemporary US pulmonary arterial hypertension registry. Eur Respir Rev 2012; 21: 8–18. doi:10.1183/09059180.00008211

⁴ Qian J, Wang Y, Huang C, et al. Survival and prognostic factors of systemic lupus erythematosus-associated pulmonary arterial hypertension: a PRISMA-compliant systematic review and meta-analysis. Autoimmun Rev 2016; 15: 250–7. doi:10.1016/j.autrev.2015.11.012

⁵ Schneider M, Pistritto AM, Gerges C, et al. Multi-view approach for the diagnosis of pulmonary hypertension using transthoracic echocardiography. Int J Cardiovasc Imaging 2018; 34: 695–700. doi:10.1007/s10554-017-1279-8

⁶ Xia YK, Tu SH, Hu YH, et al. Pulmonary hypertension in systemic lupus erythematosus: a systematic review and analysis of 642 cases in Chinese population. Rheumatol Int 2013; 33: 1211–7. doi:10.1007/s00296-012-2525-y

⁷ Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2022; 43: 3618–731. doi:10.1093/eurheartj/ehac237

⁸ Yao M, Zhang C, Gao C, et al. Exploration of the shared gene signatures and molecular mechanisms between systemic lupus erythematosus and pulmonary arterial hypertension: evidence from Transcriptome data. Front Immunol 2021; 12: 658341. doi:10.3389/fimmu.2021.658341

⁹ Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D34–41. doi:10.1016/j.jacc.2013.10.029

¹⁰ Dhala A. Pulmonary arterial hypertension in systemic lupus erythematosus: current status and future direction. Clin Dev Immunol 2012; 2012: 854941. doi:10.1155/2012/854941

¹¹ Johnson SR, Granton JT. Pulmonary hypertension in systemic sclerosis and systemic lupus erythematosus. Eur Respir Rev 2011; 20: 277–86. doi:10.1183/09059180.00003811

¹² Augustine DX, Coates-Bradshaw LD, Willis J, et al. Echocardiographic assessment of pulmonary hypertension: a guideline protocol from the British society of echocardiography. Echo Res Pract 2018; 5: G11–24.: ERP-17-0071. doi:10.1530/ERP-17-0071

¹³ Kiely DG, Lawrie A, Humbert M. Screening strategies for pulmonary arterial hypertension. Eur Heart J Suppl 2019; 21: K9–20. doi:10.1093/eurheartj/suz204

¹⁴ Janda S, Shahidi N, Gin K, et al. Diagnostic accuracy of echocardiography for pulmonary hypertension: a systematic review and meta-analysis. Heart 2011; 97: 612–22. doi:10.1136/hrt.2010.212084

¹⁵ Fisher MR, Forfia PR, Chamera E, et al. Accuracy of doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med 2009; 179: 615–21. doi:10.1164/rccm.200811-1691OC

¹⁶ Rich JD, Shah SJ, Swamy RS, et al. Inaccuracy of doppler echocardiographic estimates of pulmonary artery pressures in patients with pulmonary hypertension: implications for clinical practice. Chest 2011; 139: 988–93. doi:10.1378/chest.10-1269

¹⁷ Colalillo A, Grimaldi MC, Vaiarello V, et al. In systemic sclerosis, the TAPSE/sPAP ratio can be used in addition to the DETECT algorithm for pulmonary arterial hypertension diagnosis. Rheumatology 2022; 61: 2450–6. doi:10.1093/rheumatology/keab748

¹⁸ Roberts JD, Forfia PR. Diagnosis and assessment of pulmonary vascular disease by doppler echocardiography. Pulm Circ 2011; 1: 160–81. doi:10.4103/2045-8932.83446

¹⁹ Pérez-Peñate GM, Rúa-Figueroa I, Juliá-Serdá G, et al. Pulmonary arterial hypertension in systemic lupus erythematosus: prevalence and predictors. J Rheumatol 2016; 43: 323–9. doi:10.3899/jrheum.150451

²⁰ Thumboo J, Wee HL. Systemic lupus erythematosus in Asia: is it more common and more severe. APLAR Journal of Rheumatology 2006; 9: 320–6. doi:10.1111/j.1479-8077.2006.00235.x

²¹ Lei Y, Zhang X, Feng Y, et al. Risk factors of pulmonary arterial hypertension in patients with systemic lupus erythematosus. Cardiol Young 2021; 31: 1619–24. doi:10.1017/S1047951121000688

²² Hachulla E, Jais X, Cinquetti G, et al. Pulmonary arterial hypertension associated with systemic lupus erythematosus. Chest 2018; 153: 143–51. doi:10.1016/j.chest.2017.08.014

²³ Galiè N, Humbert M, Vachiery J-L. ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37: 67–119. doi:10.1093/eurheartj/ehv317