Is Pulmonary Arterial Hypertension Really a Late Complication of Systemic Sclerosis?

doi:10.1378/chest.08-3042

Chest

Volume 136, Issue 5, November 2009, Pages 1211-1219

https://doi.org/10.1378/chest.08-3042 Get rights and content

Background

Pulmonary arterial hypertension (PAH) is a frequent cause of morbidity and mortality in patients with systemic sclerosis (SSc). PAH is generally considered to be a late complication of limited cutaneous SSc. This study identified and investigated a subset of SSc patients with early-onset PAH.

Methods

Clinical and hemodynamic data at the time of diagnosis were collected retrospectively for 78 consecutive patients with PAH associated with SSc. PAH diagnosed within 5 years of the first non-Raynaud phenomenon symptom of SSc was considered to be an early-onset complication. PAH diagnosed > 5 years following SSc diagnosis was considered to be a late complication.

Results

PAH occurred a mean (± SD) duration of 6.3 ± 6.6 years after the diagnosis of SSc (median delay, 4.0 years; 95% CI, 2.88 to 6.0 years). Early-onset PAH was diagnosed in 43 patients (55.1%), and late-onset PAH was diagnosed in 35 patients (44.9%). Patients with early-onset PAH were older at SSc diagnosis than patients with late-onset PAH (mean age, 58.0 ± 12.5 vs 46.6 ± 12.9 years, respectively; p = 0.0002). No differences in age at the time of PAH diagnosis, or in SSc subtype (limited vs diffuse; anticentromere vs anti-Scl70 antibodies), were observed between onset subgroups. At diagnosis, early-onset PAH was more severe than late-onset PAH, with a lower cardiac index (2.4 ± 0.6 vs 2.8 ± 0.6 L/min/m², respectively; p = 0.005) and greater total pulmonary resistance (1,708 ± 777 vs 1,341 ± 530 dyne · s · cm⁻⁵/m², respectively; p = 0.02). Mortality at 3 and 5 years was comparable between subgroups.

Conclusions

In contrast to the expected scenario, early-onset PAH occurred in approximately half of SSc patients. Early-onset PAH was as frequent among patients with diffuse SSc as those with limited SSc. Annual screening for PAH should be implemented immediately after SSc diagnosis for all patients.

Section snippets

Study Centers and Population

This retrospective study was conducted at three centers in France with expertise in the management of PAH associated with SSc (Antoine Béclère Hospital, Clamart; Huriez Hospital, Lille; and Cochin Hospital, Paris). Patients were classified as having SSc according to Masy,⁷ and as having lcSSc or dcSSc according to LeRoy et al.⁸ The SSc subtype definition was based on cutaneous fibrosis both at the time of SSc diagnosis and during the follow-up period. All consecutive patients with lcSSc or dcSSc

Results

Data from 78 consecutive patients with SSc and PAH were obtained from Béclère Hospital, Clamart (n = 43), Huriez Hospital, Lille (n = 24), and Cochin Hospital, Paris (n = 11). Table 1 presents the clinical and hemodynamic data, including the mean duration of SSc at PAH diagnosis. Only 3 of the 78 patients received diagnoses of PAH only during exercise.

At PAH diagnosis, 83% of patients presented with severe dyspnea (NYHA functional class III and IV). Dyspnea was not a novel finding in all

Discussion

PAH is generally considered to be a late-onset complication of lcSSc.⁶ In our patient population, PAH diagnosis occurred a mean duration of 6.0 ± 6.6 years after the first non-Raynaud phenomenon symptom of SSc in patients with lcSSc, and after 7.1 ± 6.6 years in patients with dcSSc. Previous reports1, 11, 12 of the duration between the diagnosis of SSc and the onset of PAH vary according to the study, ranging from 9.08 ± 6.6 years¹¹ to 14 ± 5 years.¹ The large ranges and SDs observed in these

French PAH-SSc Network Investigators

Hôpital Antoine-Béclère, Clamart: Marc Humbert, Xavier Jaïs, Florence Parent, Gérald Simonneau, Olivier Sitbon, and Azzedine Yaici. Hôpital Claude Huriez, Lille: Hilaire Charlanne, Pascal de Groote, Eric Hachulla, Pierre-Yves Hatron, Marc Lambert, Nicolas Lamblin, David Launay, Hélène Maillard, Viviane Queyrel, and Sandrine Morell-Dubois. Hôpital Cochin, Paris: Alice Berezné, Loïc Guillevin, and Luc Mouthon.

Acknowledgments

Author contributions: Drs. Hachulla, Launay, Clerson, and Humbert contributed to the study design. Drs. Hachulla, Launay, Mouthon, Sitbon, Berezne, Guillevin, Hatron, Simonneau, and Humbert contributed to the acquisition of data. Drs. Hachulla, Launay, Clerson, and Humbert contributed to the analysis and interpretation of the data. Drs. Hachulla, Launay, Clerson, and Humbert contributed to manuscript preparation. Dr. Clerson contributed to the statistical analysis.

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Pulmonary hypertension in connective tissue diseases: What every CTD specialist should know – but is afraid to ask!
2024, Revue de Medecine Interne
Pulmonary hypertension (PH) is a possible complication of connective tissue diseases (CTDs), especially systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). It is defined by an elevation of the mean pulmonary arterial pressure above 20 mmHg documented during a right heart catheterization (RHC). Due to their multiorgan involvement, CTDs can induce PH by several mechanisms, that are sometimes intricated: pulmonary vasculopathy (group 1) affecting arterioles (pulmonary arterial hypertension, PAH) and possibly venules (pulmonary veno-occlusive-like disease), left-heart disease (group 2), chronic lung disease (group 3) and/or chronic thromboembolic PH (group 4). PH suspicion is often raised by clinical manifestations (dyspnea, fatigue), echocardiographic data (increased peak tricuspid regurgitation velocity), isolated decrease in DLCO in pulmonary function tests, and/or unexplained elevation of BNP/NT-proBNP. Its formal diagnosis always requires a hemodynamic confirmation by RHC. Strategies for PH screening and RHC referral have been extensively investigated for SSc-PAH but data are lacking in other CTDs. Therapeutic management of PH depends of the underlying mechanism(s): PAH-approved therapies in group 1 PH (with possible use of immunosuppressants, especially in case of SLE or MCTD); management of an underlying left-heart disease in group 2 PH; management of an underlying chronic lung disease in group 3 PH; anticoagulation, pulmonary endartectomy, PAH-approved therapies and/or balloon pulmonary angioplasty in group 4 PH. Regular follow-up is mandatory in all CTD-PH patients.
L’hypertension pulmonaire (HTP) est une complication rare des connectivites, notamment de la sclérodermie systémique (SSc), du lupus érythémateux systémique et de la connectivite mixte. Elle se définit par une élévation de la pression artérielle pulmonaire moyenne ≥ 20 mmHg documentée par un cathétérisme cardiaque droit. Du fait de leur nature systémique, les connectivites peuvent induire une HTP par différents mécanismes, parfois intriqués : vasculopathie pulmonaire (groupe 1 de la classification de l’HTP) affectant les artérioles (hypertension artérielle pulmonaire, HTAP) et possiblement les veinules (ex-maladie veino-occlusive pulmonaire), cardiopathie gauche (groupe 2), maladie respiratoire chronique (groupe 3) ou maladie thromboembolique chronique (groupe 4). L’existence d’une HTP peut être suspectée par la clinique (dyspnée, asthénie), l’échographie cardiaque (élévation de la vitesse de la fuite tricuspide), une baisse isolée de la DLCO lors des épreuves fonctionnelles respiratoires, une élévation du BNP/NT-pro-BNP. Son diagnostic nécessite toujours une confirmation hémodynamique par cathétérisme cardiaque droit. Plusieurs stratégies de dépistage ont été étudiées dans l’HTAP associée à la SSc, mais peu de données sont disponibles dans les autres connectivites. La prise en charge thérapeutique de l’HTP dépend du(es) mécanisme(s) en cause : traitement spécifique en cas d’HTP de groupe 1 (avec discussion d’une immunosuppression en cas de lupus ou de connectivite mixte) ; traitement de la cardiopathie gauche en cas d’HTP de groupe 2 ; traitement de la maladie respiratoire chronique en cas d’HTP du groupe 3 ; anticoagulation, traitement vasodilatateur, endartériectomie et/ou angioplastie pulmonaire en cas d’HTP du groupe 4. Un suivi régulier est indispensable.
Pulmonary Hypertension in Scleroderma– Evaluation and Management
2023, Disease-a-Month
Citation Excerpt :
Scleroderma (SSc) complicated by pulmonary arterial hypertension (PAH) has an alarming prognosis and contributes 30% of mortality amongst scleroderma patients.70 Approximately 50 % of patients with SSc are evolving to PAH, so it's quite plausible to have a routine annual screening in patients with SSc.71 Patients with SSc associated with PAH are at higher risk of mortality compared to patients with idiopathic PAH with a 1-year survival rate of 55% and 84% respectively.65
Pulmonary Arterial Hypertension (PAH) is a clinical syndrome consisting of physiologic/hemodynamic criteria that are a consequence of several etiologies. Systemic Sclerosis (SSc), one of the most common causes of PAH, is an autoimmune disorder of the connective tissue leading to fibrosis that involves the skin, gastrointestinal tract, lungs, heart, kidney etc. SSc has an annual prevalence of one to five cases for every 1000 individuals and nearly 15 percent of all cases develop PAH.
At its core, Pulmonary hypertension (PH) in SSc is an obliterative vasculopathy in small to medium-sized pulmonary arterioles. A host of other local and systemic mechanisms operate in concert to gradually alter the hemodynamics resulting in elevated pulmonary vascular resistance and thus right ventricular afterload. A diagnosis of PAH in SSc is virtually a death sentence, with studies reporting a mortality rate of 50 per cent in the 3 years of diagnosis. Therefore, developing and implementing a robust screening and diagnosis protocol is crucial in the fight against this pervasive disease.
This review aims to summarize the current literature of PAH in SSc, with a special focus on the screening and diagnosis protocols, newer treatment options and prognostic indicators for the same.
Screening for pulmonary arterial hypertension in systemic sclerosis: A systematic literature review.
2020, European Journal of Internal Medicine
Citation Excerpt :
In Systemic Sclerosis (SSc), PAH remains one of the main determinants of mortality in about 8–12% of patients [1,2]. Several studies conducted on large cohorts have highlighted that all SSc patients carry a certain risk, although variable, to develop PAH [3]. Moreover, it is well recognized that even with the same hemodynamic conditions, SSc-PAH patients have a worst outcome as compared to those with the idiopathic form (IPAH) [4], possibly related to a more prominent maladaptive remodeling of the right ventricle (RV) [5].
Pulmonary arterial hypertension (PAH) carries a high morbidity and mortality burden in Systemic Sclerosis (SSc). Therefore, PAH screening and early detection are pivotal. A systematic literature review (SLR) to search for all screening tools and modalities for SSc-PAH was performed in reference to right heart catheterization as diagnostic gold standard. Papers from 2 previously published SLRs and derived from a systematic search on Pubmed, EMBASE, Web of Science for papers published from 03/10/2017 to 31/12/2018 were manually included. A total of 199 papers were reviewed and 32 were extracted, with a low bias risk according to QUADAS2. Echocardiography, pulmonary function tests, clinical features and serum biomarkers were the most frequently tools used for screening, with different parameters combined in a variable fashion, as single item or as part of composite algorithms. Among the composite algorithms, the DETECT score, ESC/ERS 2009 or 2015 guidelines, ASIG and ITINER-air algorithms were the most commonly used in a wide range of patients. In different cohorts, DETECT and ASIG showed higher sensitivity and negative predictive value than ESC/ERS 2009. In conclusion, the literature shows echocardiography as the leading screening tool for SSc-PAH. In particular, systolic pulmonary arterial pressure (sPAP) and tricuspid regurgitation velocity (TRV), both as single items or part of composite algorithms, including also serum biomarkers, clinical and functional items, are the most frequent parameters evaluated.
Prevalence of auto-antibodies associated to pulmonary arterial hypertension in scleroderma – A review
2018, Autoimmunity Reviews
The prevalence of auto-antibodies associated to pulmonary arterial hypertension in scleroderma patients was reviewed, based on reports cited in two major scientific databases.
Data were collected on the following types of antibodies: antinuclear, anti-double-stranded DNA, anticentromere, anti-CENP-A, anti-CENP-B, anti-bicaudal D2, anti-nucleolar, anti-Scl-70 (anti-topoisomerase I), anti-topoisomerase II α, anti-RNP, anti-U1RNP, anti-U3RNP, anti-RNA polymerase III, anti-Th/To, anti-histone, antiphospholipid, anti-PmScl, anti-Sm, anti SSA (anti-Ro),anti SSB (La), anti-Ro52 (TRIM 21), anti-Ku, anti-B23, anti-RuvBL1, anti-RuvBL2, anti-fibrin bound tissue plasminogen activator, anti-endothelial cell, anti-phosphatidylserine-prothrombin complex, anti-endothelin-1 type A receptor, anti-angiotensin II type 1 receptor, anti‑carbonic anhydrase II, anti-fibroblast, anti-cyclic citrullinated peptide, anti-4-sulfated N-Acetyl-lactosamine, class I and II anti-human leukocyte antigen.
Auto-antibodies were shown by different authors to be associated to this condition, with different prevalence values for each type of auto-antibody. Antinuclear antibodies, anti-centromere antibodies, antiphospholipid antibodies, anti-U3 RNP antibodies and anti-Th/To antibodies would appear to show a particularly important prevalence in scleroderma patients with pulmonary hypertension, appearing in about 8/10 (antinuclear), 1/ 2 (anti-centromere, anti-phospholipid), and 1/4 (anti-U3RNP, anti-Th/To) of patients.
The available evidence points in the direction of a strong association between auto-immune mechanisms and pulmonary hypertension in the setting of scleroderma.
2013 ACR/EULAR systemic sclerosis classification criteria in patients with associated pulmonary arterial hypertension
2018, Seminars in Arthritis and Rheumatism
To analyze the performance of the 1980 ACR and new 2013 ACR/EULAR criteria for systemic sclerosis (SSc) in cutaneous SSc (lcSSc) patients, especially those affected by lcSSc and pulmonary arterial hypertension (PAH).
All patients with a clinical lcSSc diagnosis from a prospective observational SSc cohort were included. Sociodemographic and disease-related variables were collected, and PAH confirmed by right heart catheterization (RHC). Performance of the 2013 and 1980 SSc criteria was analyzed in terms of clinical diagnosis. Descriptive and between-group analyses were performed as to the fulfillment of criterion sets, including comparison of survival.
Overall, 321 patients were included, 63% of whom fulfilled the 1980 ACR and 93% the 2013 ACR/EULAR criteria. Agreement between both criteria sets proved poor (κ = 0.23). LcSSC patients fulfilling both criterion sets were significantly younger at diagnosis, whilst presenting organ involvement, calcinosis, fingertip digital ulcers, and pitting scars more frequently than those who met the 2013 criteria only. Patients who fulfilled the 2013 but not the 1980 criteria presented a higher degree of ACA positivity and PAH. Nearly 12% of patients developed PAH. Patients who did not meet the 1980 criteria were affected by a milder disease from but demonstrated higher pulmonary vascular resistance and lower cardiac index than those fulfilling both criterion sets. Whereas patients with PAH met the 2013 criteria, only 47% fulfilled the 1980 criteria. Regardless of criterion set fulfillment, high mortality was observed in PAH patients, with no significant between-patient difference based on criterion set.
The new 2013 ARC/EULAR criteria prove more accurate than the former 1980 ACR criteria in identifying and differentiating patients with lcSSc, especially those with associated PAH. Since PAH exhibits a better prognosis if treated early, all SSc patients should undergo PAH screening.
Pulmonary manifestations in Egyptian patients with systemic sclerosis
2018, Egyptian Rheumatologist
To study the occurrence of interstitial lung disease (ILD) and pulmonary hypertension (PH) in a cohort of Egyptian systemic sclerosis (SSc) patients and their relation to clinical variables.
Thirty SSc patients underwent pulmonary function tests (PFTs), plain chest X-ray and chest high-resolution computed tomography to assess parenchymal abnormality and maximum fibrosis score (Fibmax). Transthoracic echocardiography to screen for evidence of pH. Nailfold capillary microscopy examination for recognizing nailfold capillary abnormalities and staging, skin thickness assessment by modified Rodnan's skin score (MRSS).
The mean age of the patients was 40.97 ± 12.63 years; 22 females and 8 males and disease duration was 9.65 ± 8.18 years. 17(56.7%) patients had diffuse cutaneous systemic sclerosis (dcSSc) and 13(43.3%) localized cutaneous (lcSSc). All patients showed restriction in the PFTs. ILD was present in 83% and PH in 17%; ground-glass opacity in 83.3%, septal thickening in 56.7%, honeycombing in 43.3%, bronchiolectasis in 23.3% and consolidations in 20% of the patients. ILD was significantly more in dcSSc than in lcSSc (p = 0.025). PH was present in 29.4% of the dcSSc patients but in none of the lcSSc patients. MRSS was significantly higher in patients with pulmonary affection than those without (p = 0.016) and in patients with ILD and PH than those with ILD alone. A significant correlation was found between the Fibmax and MRSS (r = 0.87, p < 0.0001). Predictors of ILD were disease duration >11 years, forced vital capacity (FVC) <80%, and MRSS > 20.
ILD is a frequent finding and PH is common in SSc patients especially the dcSSc subtypes. Disease duration, decline in FVC and increased skin thickness are associated with an increased risk of ILD.

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The work was performed in France at Béclère Hospital, Clamart; Huriez Hospital, Lille; and Cochin Hospital, Paris.

Funding/Support: This study was supported by a research grant from Actelion Pharmaceuticals France.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

^*: A list of the French PAH-SSc Network Investigators is located in the Appendix.

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Chest

Original ResearchPulmonary HypertensionIs Pulmonary Arterial Hypertension Really a Late Complication of Systemic Sclerosis?

Background

Methods

Results

Conclusions

Section snippets

Study Centers and Population

Results

Discussion

French PAH-SSc Network Investigators

Acknowledgments

Original Research
Pulmonary Hypertension
Is Pulmonary Arterial Hypertension Really a Late Complication of Systemic Sclerosis?