Keywords
Pulmonary arterial hypertension, pulmonary hypertension, systemic sclerosis
Introduction
Systemic sclerosis (SSc) is a systemic rheumatic disease characterized by autoimmunity, vascular injury, and unchecked collagen synthesis leading to fibrosis of the skin and internal organs1,2. Based on the extent of skin fibrosis, SSc has been classified as either limited cutaneous or diffuse cutaneous phenotype3, with diffuse cutaneous SSc characterized by earlier and more frequent internal organ involvement4. The term “systemic sclerosis sine scleroderma” is sometimes used to refer to SSc with visceral organ involvement in the absence of cutaneous manifestation5,6.
One major complication of SSc is pulmonary arterial hypertension (PAH). Historically, PAH has been quoted as one of the leading causes of death in patients with SSc7–11. PAH represents group 1 pulmonary hypertension (PH) in the World Health Organization (WHO) classification system, characterized by elevated mean pulmonary arterial pressure (mPAP) ≥25 mmHg with elevated pulmonary vascular resistance (PVR) ≥3 Wood units and normal pulmonary capillary wedge pressure (PCWP) ≤15 mmHg in the absence of etiologies known to cause other groups (2–5) of PH12. More recently, mPAP >20 mmHg has been proposed as a new definition of precapillary PH, which includes PAH13. Approximately 10% of SSc patients (under the original definition) are affected by PAH10,14–16, and a similar prevalence was re-demonstrated in a recent study17. While SSc-associated PAH (SSc-PAH) comprises a major proportion of PAH registries18, less is known about its incidence, with one study reporting 0.61 cases per 100 patient-years19.
SSc-PAH, which can complicate both limited and diffuse cutaneous subtypes of SSc19,20, suffers from a particularly poor prognosis. The presence of PAH predicts early death in SSc21,22, and mortality associated with SSc-PAH is higher than that seen in other PH groups and even other subtypes of PAH23. Multiple studies demonstrated poorer survival in SSc-PAH compared to idiopathic PAH (IPAH) despite less pronounced hemodynamic derangement23–29. A recent retrospective study of 375 patients showed similar findings (median survival of 3 years in SSc-PAH versus 7.8 years in IPAH), and the difference in mortality was attributed to older age and more pronounced gas exchange impairment in SSc-PAH30. Another plausible explanation for the high mortality in SSc-PAH is reduced contractility of the right ventricle (RV). A number of retrospective studies have consistently documented more impaired RV systolic function in SSc-PAH compared to that in IPAH for a given RV afterload31,32, and the RV function appears to improve with PAH-targeted therapy in IPAH but not in SSc-PAH33. SSc-PAH is associated with worse outcomes and higher mortality, even when compared to other connective tissue disease-related PAH (CTD-PAH), suggesting that SSc-PAH represents a unique phenotype that perhaps should be managed differently to other subgroups of CTD-PAH10,25,34.
The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial was a recently published randomized double-blind multicenter study that compared upfront ambrisentan and tadalafil combination therapy to monotherapy in 500 treatment-naïve participants with WHO functional class II–III PAH35. Clinical failure (defined as death, hospitalization for PAH, progression of disease, or unsatisfactory clinical response) was observed in 18% of those receiving the combination treatment compared to 31% of monotherapy recipients (hazard ratio of 0.50). After 24 weeks of intervention, the combination therapy was associated with improvements in secondary outcomes, including the 6-minute walk distance and N-terminal pro-brain natriuretic peptide levels, compared to pooled monotherapy. Other recent studies suggest that PAH-targeted therapy, such as the ambrisentan and tadalafil combination treatment, riociguat, and selexipag, likely confers clinical benefit in the subgroup of CTD-PAH patients36–38. The optimal medical therapy for the subset of SSc-PAH patients, however, is less defined39, as demonstrated by the SSc-PAH-associated mortality that remains high22,40 and largely unchanged over time29,34,41,42. For instance, a recent study from the REVEAL registry (the Registry to Evaluate Early and Long-term PAH Disease Management) demonstrated that 5-year mortality in subjects newly diagnosed with SSc-PAH can be as high as 60%41. Despite improved understanding of predictors of mortality in SSc-PAH34,43,44 and the development of new prognostic models specifically validated in SSc-PAH cohorts45–47, clinical outcomes of SSc-PAH remain rather disappointing48.
Innate heterogeneity of pulmonary hypertension in systemic sclerosis
The poor clinical outcome and suboptimal response to treatment observed in SSc-PAH likely reflect the various phenotypes of PH that can coexist in SSc, precluding straightforward identification of those SSc patients with isolated PAH (Table 1)49. SSc is often complicated by fibrotic interstitial lung disease (ILD)50–52, more commonly in diffuse cutaneous SSc than in limited cutaneous SSc53. The fibrotic ILD can be further complicated by neuromuscular weakness and chronic aspiration54, contributing to the development of hypoxemia-induced (WHO group 3) PH. Unselected use of PAH-specific therapy with vasodilatory effect in the presence of ILD can exacerbate ventilation–perfusion (V/Q) mismatch, resulting in aggravation of hypoxemia and secondary PH55.
Table 1. Mechanisms of pulmonary hypertension in systemic sclerosis.
World Health Organization group | Mechanism of pulmonary hypertension |
---|
1 | • Connective tissue disease-associated pulmonary arterial hypertension • Portopulmonary hypertension |
1′ | • Pulmonary veno-occlusive disease • Pulmonary capillary hemangiomatosis |
2 | • Myocardial fibrosis • Accelerated atherosclerosis • Kidney failure |
3 | • Interstitial lung disease (combined pulmonary fibrosis and emphysema) |
4 | • Venous thromboembolism/chronic thromboembolic pulmonary hypertension (antiphospholipid antibodies) |
One form of ILD increasingly recognized in SSc is combined pulmonary fibrosis and emphysema (CPFE)56–58. Although smoking history places SSc patients at a higher risk of developing CPFE59, it is also observed in never-smokers and those with minimal tobacco history57. A significant portion of SSc patients with CPFE go on to develop PH60, illustrated by a recent study demonstrating a higher incidence of precapillary PH and higher mortality in 36 SSc-CPFE patients compared to 72 SSc-ILD patients without emphysema59. Emphysema in CPFE can cause an additional reduction in carbon monoxide diffusing capacity (DLCO) and lung volume pseudo-normalization, and these physiologic consequences of CPFE can potentially compromise the diagnostic accuracy of PH in SSc patients with fibrotic ILD57.
Under-recognized pulmonary venous hypertension in SSc is also believed to underlie the poor response to treatment and high mortality seen in SSc-PAH. Pathologic studies of lung tissues from SSc-PAH patients demonstrate fibrosis of veins and venules resulting in pulmonary veno-occlusive disease (PVOD)-like changes (WHO group 1)61,62. In patients with SSc-PAH, the presence of computed tomography findings suggestive of PVOD has been associated with pulmonary edema in response to vasodilator therapy and worse clinical outcomes63,64. Even more rarely, patients with SSc can suffer from pulmonary capillary hemangiomatosis (PCH), a disease that is now thought to be related to PVOD in its etiology65. Other unrelated mechanisms by which SSc causes post-capillary PH and precipitates pulmonary edema include myocardial fibrosis66–68 and ischemic heart disease due to accelerated atherosclerosis (WHO group 2)69,70. Subtle left ventricular diastolic dysfunction due to occult fibrosis of the myocardium may not be apparent and become unmasked with fluid challenge during cardiac catheterization71.
Many studies have also documented the increased risk of venous thromboembolism (VTE) in SSc, which predisposes the patient to developing chronic thromboembolic PH (CTEPH, WHO group 4)72–74. There is an increased prevalence of antiphospholipid antibodies in SSc, although it remains unclear whether these antibodies represent the autoimmune nature of SSc-PAH, under-recognition of CTEPH, or both75–78. SSc is also associated with primary biliary cholangitis, which may subsequently produce portopulmonary hypertension79,80. These various phenotypes of PH often coexist in SSc, and they underscore the difficulty in selecting the right patient population who will benefit from PAH-targeted therapy or even anticoagulation.
Pulmonary arterial hypertension-targeted therapy in systemic sclerosis patients with concurrent interstitial lung disease and precapillary pulmonary hypertension
The role of PAH-targeted therapy in SSc patients with both ILD and precapillary PH represents a major area of uncertainty and interest to both clinicians and researchers. SSc often involves ILD50–53, and the presence of concurrent ILD is associated with increased mortality in SSc patients with precapillary PH10,42,81–83. While PAH-specific drugs may alleviate the increased PVR resulting from pulmonary arteriopathy of SSc, the often-coexisting ILD in this patient population has raised the concern of exacerbating V/Q mismatch as more blood flows to the non-ventilated parts of the lungs55. As a result, there has been uncertainty regarding the tolerability of PAH-targeted therapy in SSc-associated precapillary PH owing to the high prevalence of concurrent ILD. Contrary to this historical perspective, however, two recent studies illustrate that PAH-targeted therapy may be well tolerated in the presence of ILD.
As previously mentioned, the AMBITION trial was a randomized double-blind study that demonstrated that the upfront combination therapy with ambrisentan and tadalafil protected treatment-naïve PAH patients from clinical worsening compared to monotherapy35. A recent post hoc analysis of the AMBITION trial showed that the combination PAH-targeted therapy conferred similar clinical benefit in the subgroup of SSc-PAH patients36. Of the 118 subjects with SSc-PAH, clinical failure (defined as death, hospitalization for PAH, progression of disease, or unsatisfactory clinical response) was seen in 21% of those receiving the combination treatment compared to 40% of monotherapy recipients (hazard ratio of 0.44 with 56% risk reduction). In the SSc-PAH subgroup, the combination therapy led to significantly improved outcomes compared to what had been previously reported in the general SSc-PAH patient population. While the AMBITION trial specifically targeted subjects with PAH, it is notable that the participants were allowed to have mild to moderate lung disease (total lung capacity [TLC] ≥60% of predicted normal, forced expiratory volume in 1 second [FEV1] ≥55% of predicted normal)35. Therefore, it is probable that a substantial portion of the SSc-PAH subgroup had some degree of ILD or even SSc-ILD-PH, although the presence of severe ILD would have been unlikely given that the average TLC was 90% of predicted36. The subgroup analysis did not investigate the effect of the combination therapy on hypoxemia and gas exchange; however, the study suggests PAH-targeted therapy with vasodilatory effect can be well tolerated in SSc-PAH patients with concurrent non-severe ILD, and it may be unnecessary to exclude a modest degree of ILD prior to trialing PAH-targeted therapy.
A more recent single-center cohort study evaluated response to PAH-targeted therapy in 29 SSc patients who had both right heart catheterization-proven PH and ILD visualized on high-resolution computed tomography of the chest84. The ILDs in these patients were physiologically mild (forced vital capacity [FVC] 70.3% predicted, TLC 84.7% predicted, DLCO 43.1% predicted), followed either nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) pattern, and affected >20% of the lungs in 65.5% (19 of 29) of cases. The majority of the participants had mild (mPAP 25–35 mmHg) or moderate (mPAP 35–45 mmHg) PH, and six of the 29 had post-capillary PH with PCWP >15 mmHg. A total of 24 of the 29 patients were treated with PAH-targeted therapy, and they tolerated a single, dual, or triple-agent PAH regimen well. Importantly, the PAH-targeted treatment did not worsen V/Q mismatching, again supporting the notion that PAH-specific therapy can be safely used in SSc patients with non-severe ILD. Given the non-randomized nature of this evidence, however, more robust, large-scale, randomized studies are needed before firm conclusions and generalized clinical applications can be made.
Soluble guanylate cyclase stimulators in systemic sclerosis associated with pulmonary arterial hypertension
Soluble guanylate cyclase (sGC) stimulators, another class of PAH-targeted drugs, have recently gained interest for their potential use in SSc-PAH. In addition to vasodilation, sGC stimulation and a resultant increase in the cyclic guanosine monophosphate level produce an antifibrotic effect by inhibiting non-canonical TGF-β signaling pathways85. In mice, the sGC stimulator BAY 41-2272 prevented and reversed skin fibrosis86. Similarly, riociguat, another sGC stimulator in clinical use, was shown to be effective against skin and gastrointestinal tract fibrosis in multiple mouse models, with its antifibrotic effect more pronounced than that of sildenafil87.
Since SSc is characterized by fibrosis as well as vasculopathy, sGC stimulators with both antifibrotic and vasodilatory effects are considered promising candidates for the treatment of SSc-PAH. Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial (PATENT)-1 was a double-blind randomized international study that established the efficacy of riociguat in PAH patients, which was extended to PATENT-2 for the assessment of long-term effects of riociguat88,89. A recent subgroup analysis of the two trials demonstrated in SSc-PAH patients that riociguat was associated with improvement in cardiac index and reduction in PVR at 12 weeks, and possibly with an increase in the 6-minute walk distance compared to placebo37. Another case series described three patients whose SSc-PAH improved after phosphodiesterase-5 inhibitors were replaced with riociguat90. It remains uncertain, however, whether the antifibrotic effect of riociguat confers additional clinical benefit specific to SSc-PAH.
Despite these seemingly favorable outcomes, the safety and tolerability of riociguat in SSc-PAH patients with concurrent ILD are unclear. In a pilot study of 22 patients with concurrent ILD (TLC >30% of predicted) and treatment-naïve precapillary PH, the use of riociguat was associated with lower PVR and higher cardiac output, suggesting riociguat can safely provide similar hemodynamic benefit in patients with SSc-ILD-PH91. However, in a recently published multicenter randomized trial, Riociguat for Idiopathic Interstitial Pneumonia-Associated Pulmonary Hypertension (RISE-IIP), riociguat was associated with harm and increased mortality in patients with precapillary PH and idiopathic (therefore non-CTD) ILD (mean TLC 66% of predicted)92. While RISE-IIP did not involve SSc or other CTD patients, the demonstrated negative impact of riociguat in patients with significant lung disease will likely deter future attempts to prospectively investigate sGC stimulation in SSc-ILD-PH, barring new, convincing observational data favoring its use in this patient population. Lastly, given that riociguat is effective in CTEPH93 and SSc patients are predisposed to VTE, another interesting question regards the potential role of sGC stimulation in SSc patients affected by CTEPH.
Conclusion
PAH-targeted therapy appears to be well tolerated and beneficial in SSc-PAH patients with its safety further questioned in the coexistence of ILD. Challenges still remain in choosing the patient population best suited for PAH-specific medications. The distinction between SSc-PAH with ILD (WHO group 1) and SSc-ILD-PH with increased PVR (WHO group 3) is arbitrary and remains undefined. Similarly, the severity of ILD beyond which PAH-targeted therapy becomes harmful is unknown, and this threshold may in part depend on the type of ILD, patient demographics, and other comorbidities. Each SSc patient with PAH or ILD-PH may develop varying degrees of other confounding complications that can independently cause PH (e.g. myocardial fibrosis or PVOD-like changes) either before or even during PAH-targeted treatment, precluding reliable patient selection and accurate response assessment. For example, it is likely prudent to avoid indiscriminate use of PAH-targeted therapy in the presence of significant left-sided heart failure in order to prevent the potential precipitation of pulmonary edema. Furthermore, how rigorously and frequently SSc patients with established PH should be screened for other associated causes of PH is unclear. High-quality, randomized trial-based data are lacking, partially owing to the rarity of the disease.
Novel therapeutic approaches may clarify the unresolved treatment strategies in this patient population. Inhaled PAH-targeted therapy has the theoretical advantage of improving perfusion only in the well-ventilated areas of the lungs, thereby preventing worsened V/Q mismatch that may be seen with systemic administration of the medication. Based on this hypothesis, an ongoing clinical trial (NCT02630316) looks at the role of inhaled treprostinil in ILD-PH patients, the results of which may be applicable to SSc patients with concurrent precapillary PH and ILD. Early evidence suggests the possibility of using gene expression profiling to predict clinical course and monitor response to PAH-targeted therapy in SSc patients, although more data are needed until clinical applicability can be reached94–96. While we await answers to the aforementioned questions, the decision to implement PAH-targeted therapy in SSc will have to remain individualized, incorporating both the clinician’s experience and the patient’s values.
Abbreviations
AMBITION, Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension; CPFE, combined pulmonary fibrosis and emphysema; CTD, connective tissue disease; CTD-PAH, connective tissue disease-related pulmonary arterial hypertension; CTEPH, chronic thromboembolic pulmonary hypertension; DLCO, carbon monoxide diffusing capacity; ILD, interstitial lung disease; IPAH, idiopathic pulmonary arterial hypertension; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PATENT, Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVOD, pulmonary veno-occlusive disease; PVR, pulmonary vascular resistance; RISE-IIP, Riociguat for Idiopathic Interstitial Pneumonia-Associated Pulmonary Hypertension; RV, right ventricle; sGC, soluble guanylate cyclase; SSc, systemic sclerosis; SSc-PAH, systemic sclerosis-associated pulmonary arterial hypertension; TLC, total lung capacity; V/Q, ventilation–perfusion; VTE, venous thromboembolism; WHO, World Health Organization.
F1000 recommendedReferences
- 1.
Tamby MC, Chanseaud Y, Guillevin L, et al.:
New insights into the pathogenesis of systemic sclerosis.
Autoimmun Rev.
2003; 2(3): 152–7. PubMed Abstract
| Publisher Full Text
- 2.
Varga J:
Systemic sclerosis: An update.
Bull NYU Hosp Jt Dis.
2008; 66(3): 198–202. PubMed Abstract
- 3.
LeRoy EC, Medsger TA Jr:
Criteria for the classification of early systemic sclerosis.
J Rheumatol.
2001; 28(7): 1573–6. PubMed Abstract
- 4.
Medsger TA Jr:
Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well-being.
Rheum Dis Clin North Am.
2003; 29(2): 255–73, vi. PubMed Abstract
- 5.
Poormoghim H, Lucas M, Fertig N, et al.:
Systemic sclerosis sine scleroderma: Demographic, clinical, and serologic features and survival in forty-eight patients.
Arthritis Rheum.
2000; 43(2): 444–51. PubMed Abstract
| Publisher Full Text
- 6.
Hachulla E, Launay D:
Diagnosis and classification of systemic sclerosis.
Clin Rev Allergy Immunol.
2011; 40(2): 78–83. PubMed Abstract
| Publisher Full Text
- 7.
Steen VD, Medsger TA:
Changes in causes of death in systemic sclerosis, 1972-2002.
Ann Rheum Dis.
2007; 66(7): 940–4. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 8.
Tyndall AJ, Bannert B, Vonk M, et al.:
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): 1809–15. PubMed Abstract
| Publisher Full Text
- 9.
Hachulla E, Carpentier P, Gressin V, et al.:
Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinérAIR-Sclérodermie study.
Rheumatology (Oxford).
2009; 48(3): 304–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 10.
Condliffe R, Kiely DG, Peacock AJ, et al.:
Connective Tissue Disease-associated Pulmonary Arterial Hypertension in the Modern Treatment Era.
Am J Respir Crit Care Med.
2009; 179(2): 151–7. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 11.
Launay D, Sitbon O, Hachulla E, et al.:
Survival in systemic sclerosis-associated pulmonary arterial hypertension in the modern management era.
Ann Rheum Dis.
2013; 72(12): 1940–6. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 12.
Galiè N, Humbert M, Vachiery J, et al.:
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). Eur Respir J 2015; 46: 903-975.
Eur Respir J.
2015; 46(6): 1855–6. PubMed Abstract
| Publisher Full Text
- 13.
Simonneau G, Montani D, Celermajer DS, et al.:
Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
Eur Respir J.
2019; 53(1): pii: 1801913. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 14.
Avouac J, Airò P, Meune C, et al.:
Prevalence of Pulmonary Hypertension in Systemic Sclerosis in European Caucasians and Metaanalysis of 5 Studies.
J Rheumatol.
2010; 37(11): 2290–8. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 15.
Hachulla E, Gressin V, Guillevin L, et al.:
Early detection of pulmonary arterial hypertension in systemic sclerosis: A French nationwide prospective multicenter study.
Arthritis Rheum.
2005; 52(12): 3792–800. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 16.
Mukerjee D, St George D, Coleiro B, et al.:
Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: Application of a registry approach.
Ann Rheum Dis.
2003; 62(11): 1088–93. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 17.
Morrisroe K, Stevens W, Sahhar J, et al.:
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. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 18.
McGoon MD, Benza RL, Escribano-Subias P, et al.:
Pulmonary arterial hypertension: epidemiology and registries.
J Am Coll Cardiol.
2013; 62(25 Suppl): D51–D59. PubMed Abstract
| Publisher Full Text
- 19.
Hachulla E, de Groote P, Gressin V, et al.:
The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France.
Arthritis Rheum.
2009; 60(6): 1831–9. PubMed Abstract
| Publisher Full Text
- 20.
Pokeerbux MR, Giovannelli J, Dauchet L, et al.:
Survival and prognosis factors in systemic sclerosis: Data of a French multicenter cohort, systematic review, and meta-analysis of the literature.
Arthritis Res Ther.
2019; 21(1): 86. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 21.
Hao Y, Hudson M, Baron M, et al.:
Early Mortality in a Multinational Systemic Sclerosis Inception Cohort.
Arthritis Rheumatol.
2017; 69(5): 1067–77. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 22.
Morrisroe K, Stevens W, Huq M, et al.:
Survival and quality of life in incident systemic sclerosis-related pulmonary arterial hypertension.
Arthritis Res Ther.
2017; 19(1): 122. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 23.
Hurdman J, Condliffe R, Elliot CA, et al.:
ASPIRE registry: Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre.
Eur Respir J.
2012; 39(4): 945–55. PubMed Abstract
| Publisher Full Text
- 24.
Kawut SM, Taichman DB, Archer-Chicko CL, et al.:
Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis.
Chest.
2003; 123(2): 344–50. PubMed Abstract
| Publisher Full Text
- 25.
Chung L, Liu J, Parsons L, et al.:
Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: Identifying systemic sclerosis as a unique phenotype.
Chest.
2010; 138(6): 1383–94. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 26.
Clements PJ, Tan M, McLaughlin VV, et al.:
The pulmonary arterial hypertension quality enhancement research initiative: Comparison of patients with idiopathic PAH to patients with systemic sclerosis-associated PAH.
Ann Rheum Dis.
2012; 71(2): 249–52. PubMed Abstract
| Publisher Full Text
- 27.
Fisher MR, Mathai SC, Champion HC, et al.:
Clinical differences between idiopathic and scleroderma-related pulmonary hypertension.
Arthritis Rheum.
2006; 54(9): 3043–50. PubMed Abstract
| Publisher Full Text
- 28.
Ramjug S, Hussain N, Hurdman J, et al.:
Long-term outcomes of domiciliary intravenous iloprost in idiopathic and connective tissue disease-associated pulmonary arterial hypertension.
Respirology.
2017; 22(2): 372–7. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 29.
Rubenfire M, Huffman MD, Krishnan S, et al.:
Survival in Systemic Sclerosis With Pulmonary Arterial Hypertension Has Not Improved in the Modern Era.
Chest.
2013; 144(4): 1282–90. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 30.
Ramjug S, Hussain N, Hurdman J, et al.:
Idiopathic and Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: A Comparison of Demographic, Hemodynamic, and MRI Characteristics and Outcomes.
Chest.
2017; 152(1): 92–102. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 31.
Overbeek MJ, Lankhaar JW, Westerhof N, et al.:
Right ventricular contractility in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension.
Eur Respir J.
2008; 31(6): 1160–6. PubMed Abstract
| Publisher Full Text
- 32.
Tedford RJ, Mudd JO, Girgis RE, et al.:
Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension.
Circ Heart Fail.
2013; 6(5): 953–63. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 33.
Argula RG, Karwa A, Lauer A, et al.:
Differences in Right Ventricular Functional Changes during Treatment between Systemic Sclerosis-associated Pulmonary Arterial Hypertension and Idiopathic Pulmonary Arterial Hypertension.
Ann Am Thorac Soc .
2017; 14(5): 682–689. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 34.
Chung L, Farber HW, Benza R, et al.:
Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry.
Chest.
2014; 146(6): 1494–504. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 35.
Galiè N, Barberà JA, Frost AE, et al.:
Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension.
N Engl J Med.
2015; 373(9): 834–44. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 36.
Coghlan JG, Galiè N, Barberà JA, et al.:
Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.
Ann Rheum Dis.
2017; 76(7): 1219–27. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 37.
Humbert M, Coghlan JG, Ghofrani HA, et al.:
Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2.
Ann Rheum Dis.
2017; 76(2): 422–6. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 38.
Gaine S, Chin K, Coghlan G, et al.:
Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension.
Eur Respir J.
2017; 50(2): pii: 1602493. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 39.
Lammi MR, Mathai SC, Saketkoo LA, et al.:
Association Between Initial Oral Therapy and Outcomes in Systemic Sclerosis-Related Pulmonary Arterial Hypertension.
Arthritis Rheumatol.
2016; 68(3): 740–8. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 40.
Hesselstrand R, Wildt M, Ekmehag B, et al.:
Survival in patients with pulmonary arterial hypertension associated with systemic sclerosis from a Swedish single centre: prognosis still poor and prediction difficult.
Scand J Rheumatol.
2010; 40(2): 127–32. PubMed Abstract
| Publisher Full Text
- 41.
Farber HW, Miller DP, Poms AD, et al.:
Five-Year outcomes of patients enrolled in the REVEAL Registry.
Chest.
2015; 148(4): 1043–54. PubMed Abstract
| Publisher Full Text
- 42.
Lefèvre G, Dauchet L, Hachulla E, et al.:
Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis.
Arthritis Rheum.
2013; 65(9): 2412–23. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 43.
Chung L, Domsic RT, Lingala B, et al.:
Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry.
Arthritis Care Res (Hoboken).
2014; 66(3): 489–95. PubMed Abstract
| Publisher Full Text
- 44.
Kolstad KD, Li S, Steen V, et al.:
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): 862–71. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 45.
Mullin CJ, Khair RM, Damico RL, et al.:
Validation of the REVEAL Prognostic Equation and Risk Score Calculator in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.
Arthritis Rheumatol.
2019; 71(10): 1691–700. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 46.
Mercurio V, Diab N, Peloquin G, et al.:
Risk assessment in scleroderma patients with newly diagnosed pulmonary arterial hypertension: application of the ESC/ERS risk prediction model.
Eur Respir J.
2018; 52(4): pii: 1800497. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 47.
Weatherald J, Boucly A, Launay D, et al.:
Haemodynamics and serial risk assessment in systemic sclerosis associated pulmonary arterial hypertension.
Eur Respir J.
2018; 52(4): pii: 1800678. PubMed Abstract
| Publisher Full Text
- 48.
Olsson KM, Hoeper MM:
Risk assessment in patients with systemic sclerosis and pulmonary arterial hypertension.
Eur Respir J.
2018; 52(4): pii: 1801745. PubMed Abstract
| Publisher Full Text
- 49.
Launay D, Sobanski V, Hachulla E, et al.:
Pulmonary hypertension in systemic sclerosis: different phenotypes.
Eur Respir Rev.
2017; 26(145): pii: 170056. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 50.
Steen VD, Conte C, Owens GR, et al.:
Severe restrictive lung disease in systemic sclerosis.
Arthritis Rheum.
1994; 37(9): 1283–9. PubMed Abstract
| Publisher Full Text
- 51.
Schurawitzki H, Stiglbauer R, Graninger W, et al.:
Interstitial lung disease in progressive systemic sclerosis: high-resolution CT versus radiography.
Radiology.
1990; 176(3): 755–9. PubMed Abstract
| Publisher Full Text
- 52.
Launay D, Remy-Jardin M, Michon-Pasturel U, et al.:
High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis.
J Rheumatol.
2006; 33(9): 1789–801. PubMed Abstract
- 53.
Nihtyanova SI, Schreiber BE, Ong VH, et al.:
Prediction of pulmonary complications and long-term survival in systemic sclerosis.
Arthritis Rheumatol.
2014; 66(6): 1625–35. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 54.
Le Pavec J, Launay D, Mathai SC, et al.:
Scleroderma lung disease.
Clin Rev Allergy Immunol .
2011; 40(2): 104–16. PubMed Abstract
| Publisher Full Text
- 55.
Le Pavec J, Girgis RE, Lechtzin N, et al.:
Systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease: impact of pulmonary arterial hypertension therapies.
Arthritis Rheum.
2011; 63(8): 2456–64. PubMed Abstract
| Publisher Full Text
- 56.
Cottin V, Nunes H, Brillet PY, et al.:
Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity.
Eur Respir J.
2005; 26(4): 586–93. PubMed Abstract
| Publisher Full Text
- 57.
Antoniou KM, Margaritopoulos GA, Goh NS, et al.:
Combined Pulmonary Fibrosis and Emphysema in Scleroderma-Related Lung Disease Has a Major Confounding Effect on Lung Physiology and Screening for Pulmonary Hypertension.
Arthritis Rheumatol.
2016; 68(4): 1004–12. PubMed Abstract
| Publisher Full Text
- 58.
Cottin V, Cordier JF:
Combined pulmonary fibrosis and emphysema in connective tissue disease.
Curr Opin Pulm Med.
2012; 18(5): 418–27. PubMed Abstract
| Publisher Full Text
- 59.
Champtiaux N, Cottin V, Chassagnon G, et al.:
Combined pulmonary fibrosis and emphysema in systemic sclerosis: A syndrome associated with heavy morbidity and mortality.
Semin Arthritis Rheum.
2019; 49(1): 98–104. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 60.
Cottin V, Nunes H, Mouthon L, et al.:
Combined pulmonary fibrosis and emphysema syndrome in connective tissue disease.
Arthritis Rheum.
2011; 63(1): 295–304. PubMed Abstract
| Publisher Full Text
- 61.
Dorfmüller P, Humbert M, Perros F, et al.:
Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases.
Hum Pathol.
2007; 38(6): 893–902. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 62.
Overbeek MJ, Vonk MC, Boonstra A, et al.:
Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: A distinctive vasculopathy.
Eur Respir J.
2009; 34(2): 371–9. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 63.
Günther S, Jaïs X, Maitre S, et al.:
Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension.
Arthritis Rheum.
2012; 64(9): 2995–3005. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 64.
Connolly MJ, Abdullah S, Ridout DA, et al.:
Prognostic significance of computed tomography criteria for pulmonary veno-occlusive disease in systemic sclerosis-pulmonary arterial hypertension.
Rheumatology (Oxford).
2017; 56(12): 2197–2203. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 65.
McGuire F, Kennelly T, Tillack T, et al.:
Pulmonary capillary hemangiomatosis associated with CREST syndrome: a case report and review of the literature.
Respiration.
2010; 80(5): 435–8. PubMed Abstract
| Publisher Full Text
- 66.
Follansbee WP, Miller TR, Curtiss EI, et al.:
A controlled clinicopathologic study of myocardial fibrosis in systemic sclerosis (scleroderma).
J Rheumatol.
1990; 17(5): 656–62. PubMed Abstract
- 67.
Hachulla AL, Launay D, Gaxotte V, et al.:
Cardiac magnetic resonance imaging in systemic sclerosis: A cross-sectional observational study of 52 patients.
Ann Rheum Dis.
2009; 68(12): 1878–84. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 68.
Bourji KI, Kelemen BW, Mathai SC, et al.:
Poor survival in patients with scleroderma and pulmonary hypertension due to heart failure with preserved ejection fraction.
Pulm Circ.
2017; 7(2): 409–20. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 69.
Chu SY, Chen YJ, Liu CJ, et al.:
Increased risk of acute myocardial infarction in systemic sclerosis: A nationwide population-based study.
Am J Med.
2013; 126(11): 982–8. PubMed Abstract
| Publisher Full Text
- 70.
Au K, Singh MK, Bodukam V, et al.:
Atherosclerosis in systemic sclerosis: A systematic review and meta-analysis.
Arthritis Rheum.
2011; 63(7): 2078–90. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 71.
Fox BD, Shimony A, Langleben D, et al.:
High prevalence of occult left heart disease in scleroderma-pulmonary hypertension.
Eur Respir J.
2013; 42(4): 1083–91. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 72.
Schoenfeld SR, Choi HK, Sayre EC, et al.:
Risk of Pulmonary Embolism and Deep Venous Thrombosis in Systemic Sclerosis: A General Population-Based Study.
Arthritis Care Res (Hoboken).
2016; 68(2): 246–53. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 73.
Ungprasert P, Srivali N, Kittanamongkolchai W:
Systemic sclerosis and risk of venous thromboembolism: A systematic review and meta-analysis.
Mod Rheumatol.
2015; 25(6): 893–7. PubMed Abstract
| Publisher Full Text
- 74.
Chung WS, Lin CL, Sung FC, et al.:
Systemic sclerosis increases the risks of deep vein thrombosis and pulmonary thromboembolism: A nationwide cohort study.
Rheumatology (Oxford).
2014; 53(9): 1639–45. PubMed Abstract
| Publisher Full Text
- 75.
Morrisroe KB, Stevens W, Nandurkar H, et al.:
The association of antiphospholipid antibodies with cardiopulmonary manifestations of systemic sclerosis.
Clin Exp Rheumatol.
2014; 32(6 Suppl 86): S-133–7. PubMed Abstract
- 76.
Merashli M, Alves J, Ames PRJ:
Clinical relevance of antiphospholipid antibodies in systemic sclerosis: A systematic review and meta-analysis.
Semin Arthritis Rheum.
2017; 46(5): 615–624. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 77.
Sanna G, Bertolaccini ML, Mameli A, et al.:
Antiphospholipid antibodies in patients with scleroderma: Prevalence and clinical significance.
Ann Rheum Dis.
2005; 64(12): 1795–6. PubMed Abstract
| Publisher Full Text
| Free Full Text
- 78.
Nunes JPL, Cunha AC, Meirinhos T, et al.:
Prevalence of auto-antibodies associated to pulmonary arterial hypertension in scleroderma - A review.
Autoimmun Rev.
2018; 17(12): 1186–1201. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 79.
Zheng B, Vincent C, Fritzler MJ, et al.:
Prevalence of Systemic Sclerosis in Primary Biliary Cholangitis Using the New ACR/EULAR Classification Criteria.
J Rheumatol.
2017; 44(1): 33–9. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 80.
Ohira H, Watanabe H:
Pathophysiology and recent findings of primary biliary cirrhosis complicated by systemic sclerosis.
Hepatol Res.
2014; 44(4): 377–83. PubMed Abstract
| Publisher Full Text
- 81.
Michelfelder M, Becker M, Riedlinger A, et al.:
Interstitial lung disease increases mortality in systemic sclerosis patients with pulmonary arterial hypertension without affecting hemodynamics and exercise capacity.
Clin Rheumatol.
2017; 36(2): 381–390. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 82.
Volkmann ER, Saggar R, Khanna D, et al.:
Improved transplant-free survival in patients with systemic sclerosis-associated pulmonary hypertension and Interstitial lung disease.
Arthritis Rheumatol.
2014; 66(7): 1900–8. PubMed Abstract
| Publisher Full Text
- 83.
Goh NS, Desai SR, Veeraraghavan S, et al.:
Interstitial Lung Disease in Systemic Sclerosis: a simple staging system.
Am J Respir Crit Care Med.
2008; 177(11): 1248–54. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 84.
Young A, Vummidi D, Visovatti S, et al.:
Prevalence, Treatment, and Outcomes of Coexistent Pulmonary Hypertension and Interstitial Lung Disease in Systemic Sclerosis.
Arthritis Rheumatology.
2019; 71(8): 1339–49. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 85.
Beyer C, Zenzmaier C, Palumbo-Zerr K, et al.:
Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling.
Ann Rheum Dis.
2015; 74(7): 1408–16. PubMed Abstract
| Publisher Full Text
- 86.
Beyer C, Reich N, Schindler SC, et al.:
Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis.
Ann Rheum Dis.
2012; 71(6): 1019–26. PubMed Abstract
| Publisher Full Text
- 87.
Dees C, Beyer C, Distler A, et al.:
Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies.
Ann Rheum Dis.
2015; 74(8): 1621–5. PubMed Abstract
| Publisher Full Text
- 88.
Ghofrani HA, Galiè N, Grimminger F, et al.:
Riociguat for the treatment of pulmonary arterial hypertension.
N Engl J Med.
2013; 369(4): 330–40. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 89.
Rubin LJ, Galie N, Grimminger F, et al.:
Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2).
Eur Respir J.
2015; 45(5): 1303–1313. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 90.
Raina A, Benza RL, Farber HW:
Replacing a phosphodiesterase-5 inhibitor with riociguat in patients with connective tissue disease-associated pulmonary arterial hypertension: A case series.
Pulm Circ.
2017; 7(3): 741–6. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 91.
Hoeper MM, Halank M, Wilkens H, et al.:
Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial.
Eur Respir J.
2013; 41(4): 853–60. PubMed Abstract
| Publisher Full Text
- 92.
Nathan SD, Behr J, Collard HR, et al.:
Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study.
Lancet Respir Med.
2019; 7(9): 780–790. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 93.
Ghofrani HA, D'Armini AM, Grimminger F, et al.:
Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.
N Engl J Med.
2013; 369(4): 319–29. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 94.
Cheong FY, Gower AC, Farber HW:
Changes in gene expression profiles in patients with pulmonary arterial hypertension associated with scleroderma treated with tadalafil.
Semin Arthritis Rheum.
2017; 46(4): 465–472. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
- 95.
Moll M, Christmann RB, Zhang Y, et al.:
Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease.
J Scleroderma Relat Disord.
2018; 3(3): 242–248. PubMed Abstract
| Publisher Full Text
| Free Full Text
| F1000 Recommendation
- 96.
Bossini-Castillo L, Campillo-Davó D, López-Isac E, et al.:
An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis.
J Rheumatol.
2017; 44(10): 1453–1457. PubMed Abstract
| Publisher Full Text
| F1000 Recommendation
Comments on this article Comments (0)