There are two main pulmonary complications in systemic sclerosis (SSc, scleroderma):
• interstitial lung disease (ILD) that usually results in pulmonary fibrosis, and
• pulmonary arterial hypertension (PAH). PAH is a lethal complication of SSc, but treatment can improve symptoms and survival.1
In an earlier article (Ten Points About ILD), the first of a two-part series, I dealt with the management of ILD. Here, I discuss questions about PAH in SSc including frequency, diagnosis, and treatment.
How common is pulmonary arterial hypertension in systemic sclerosis?
PAH occurs in 15% of SSc in two subsets: diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). The prevalence of the two subsets is about equal, or slightly greater in the latter group.1 Without treatment the expected median survival is only two years.2
ILD, PAH, and cardiomyopathy are the three leading causes of SSc-related mortality.3
Who gets PAH in SSc?
Studies have tried to determine the risk factors for PAH in SSc, but not all papers agree. They may include:
• a positive anti-centromere antibody,
• older age at onset,
• longer disease duration, especially in the limited cutaneous SSc subset,
• low diffusing capacity,
• elevated BNP (brain naturetic peptide), and
• elevated uric acid.4
Risk factors may be different in lcSSc and dcSSc and also in those with PAH associated with significant ILD vs those who have no ILD.
In the DETECT study, right heart catheterization was performed for patients with SSc who did not have known PAH if they had at least three years of disease duration with a diffusing capacity less than 60% predicted and a forced vital capacity of at least 40% predicted.5 An elaborate algorithm was used to determine who should get a screening echocardiogram. The generalizability and utility of this algorithm in usual practice is untested. In general, an annual screening echocardiogram is suggested, with or without pulmonary function tests.
How is SSc PAH diagnosed?
In patients with SSc, the goal is to detect early PAH and to differentiate PAH from other kinds of pulmonary hypertension such as pulmonary venous changes and pulmonary veno-occlusive disease.
• A detailed history of dyspnea is needed, because many patients deny shortness of breath as they accommodate to the slowly progressive pneumonitis. Asking about dyspnea during activities such as carrying parcels, walking outside or walking up a hill, and comparative questions (‘Compared to last year, has there been a change in your ability to do certain activities and if so, why?’) may help to determine whether a patient is symptomatic.
• Usually there is a screening chest X-ray at least once in SSc to see whether there is ILD and also to look for blunted pulmonary arteries or right heart enlargement. (The latter would not be screening but would present in advanced PAH).
• On physical examination, PAH may cause right heart failure (loud P2, elevated JVP, peripheral edema).
• Pulmonary function testing (PFT) can determine whether there is interstitial lung disease, but in SSc a low diffusing capacity (DLCO) may also be suggestive of PAH. A DLCO % predicted less than half of the total lung capacity (TLC) % predicted should raise suspicion of PAH in SSc.6
• Echocardiograms are often performed as annual screens in SSc to detect an elevated pulmonary artery pressure estimated via Doppler where there is tricuspid regurgitation (which is present in most people) and signs of right heart enlargement or failure. The echocardiogram is sensitive but not specific, so if PAH is suspected the diagnostic test is a right heart catheterization. The diagnosis can only be made by right heart catheterization where there is a normal wedge pressure, elevated pulmonary vascular resistance and elevated pulmonary artery pressure. There are standardized measurements for PAH.7
Who should be screened for SSc PAH?
Early detection can improve symptoms, reduce clinical worsening, and likely prolong life by triggering appropriate targeted treatment, so all patients with SSc should be screened. This is especially true for patients with older age at onset and longer disease duration, especially for those in the lcSSc subset who have had the disease for many years.
Does screening for PAH in SSc make a difference?
Annual echocardiograms (with PFT or without) have detected many patients in functional class II (i.e., earlier) with better hemodynamics.4,8,9 Earlier treatment in PAH reduces clinical worsening and achieves better outcomes.10 Detection of PAH may be difficult in SSc, as other complications may limit mobility and patients who are de-conditioned may not remark about dyspnea. The causes of pulmonary hypertension may be complex, including diastolic dysfunction, cardiomyopathy, heart failure, or pulmonary veno-occulsive disease, as well as PAH with or without interstitial lung disease. Thus all SSc patients should be screened regularly in order to detect PAH early.
How should SSc PAH be treated?
Patients with SSc PAH should be referred to an expert PAH center. Guidelines from the European Union League Against Rheumatism (EULAR) recommend PAH treatment with endothelin receptor blockers (bosentan, ambrisentan and soon macicentan), PDE5 inhibitors (sildenafil and tadalafil) and prostacyclins (epoprostenol, trepostinil and in some countries inhaled iloprost).11 Experts often give combination treatment, initiating treatment early (functional class II) and treating to a target such as improved functional class, longer 6-minute walk time, and appropriate changes on repeat right heart catheterization.12
Treatment improves survival, even in cases of severe PAH.13 The value of warfarin in SSc PAH is unknown, and there are increased risks of bleeding if patients have erosive esophagitis or gastric antral vascular ectasia (GAVE). Exercise and treatment of hypoxia with oxygen and of right heart failure with diurectics and possibly digoxin are all useful adjunctive treatments prescribed as needed.
Younger patients with SSc and PAH may be offered lung transplantation, with outcomes similar over time to age-matched patients with idiopathic pulmonary arterial hypertension.14
What about treatment with immune suppressants?
There are no guidelines for treating SSc-associated PAH with immune suppressants. Data do not exist to support guidelines for this, except for some positive case reports. Most experts think that SSc-associated PAH is not likely to respond to currently available immune suppressants.
Should PAH be treated in severe SSc with ILD?
SSc patients with moderate ILD who also have PAH documented by right heart catheterization have a very poor prognosis.6 These patients were excluded from PAH trials; treatment with PAH therapies may not be effective or safe. However, if there is mild ILD and proven PAH, then PAH is treated according to usual guidelines.
The take-home message
• PAH occurs in 15% of patients with SSc. Although survival has improved, it is a lethal complication.
• PAH in SSc should be detected as early as possible because prompt treatment substantially improves outcomes. Regular screening with echocardiography is recommended.
• The diagnosis is made by right heart catheterization.
1. Muangchan C; Canadian Scleroderma Research Group, Baron M, Pope J. The 15% Rule in Scleroderma: The Frequency of Severe Organ Complications in Systemic Sclerosis. A Systematic Review. J Rheumatol. (2013) [Epub ahead of print] PMID: 23858045
2. Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol (1996)35:989-993
3. Steen VD and Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis (2007) 66:940-944. Epub Feb 28, 2007. PMID: 17329309
4. Humbert M, Yaici A, de Groote P, et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum (2011) 63:3522-3530.
5. Coghlan JG, Denton CP, Gronig E, et al on behalf of the DETECT study group. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis (2013) [Epub ahead of print] PMID: 23687283.
6. Steen VD, Lucas M, Fertig N, Medsger TA Jr. Pulmonary arterial hypertension and severe pulmonary fibrosis in systemic sclerosis patients with a nucleolar antibody. J Rheumatol (2007) 34(11):2230-2235. Epub 2007 Oct 15. PMID: 17937469
7. Galie N, Hoeper MM, Humber M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation, European Heart Journal (2009) 30:2493–2537. doi:10.1093/eurheartj/ehp297
8. 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) 52:3792-3800
9. Phung S, Strange G, Chung LP, et al. Prevalence of pulmonary arterial hypertension in an Australian scleroderma population: screening allows for earlier diagnosis. Intern Med J (2009) 10:682-691. doi: 10.1111/j.1445-5994.2008.01823.x. Epub 2008 Nov 3, 2008
10. Hachulla E and Denton CP. Early intervention in pulmonary arterial hypertension associated with systemic sclerosis: an essential component of disease management. Eur Respir Rev (2010) 19:314-320. doi: 10.1183/09059180.00007810
11. Kowal-Bielecka O, Landewé R, Avouac J, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis (2009) 68:620-628. doi: 10.1136/ard.2008.096677. Epub 2009 Jan 15. PMID: 19147617
12. Walker KM and Pope J; participating members of the Scleroderma Clinical Trials Consortium (SCTC); Canadian Scleroderma Research Group (CSRG). Treatment of systemic sclerosis complications: what to use when first-line treatment fails--a consensus of systemic sclerosis experts. Semin Arthritis Rheum (2012) 42:42-55. doi: 10.1016/j.semarthrit.2012.01.003. Epub 2012 Mar 29. PubMed PMID: 22464314
13. Denton CP, Pope JE, Peter HH, et al Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases. Ann Rheum Dis (2008) 67:1222-1228. Epub 2007 Nov 30
14. Sottile PD, Iturbe D, Katsumoto TR, et al Outcomes in systemic sclerosis-related lung disease after lung transplantation. Transplantation (2013) 95:975-980. doi: 10.1097/TP.0b013e3182845f23. PMID: 23545509