PAH-Associated Connective Tissue Diseases: A Case for Separating SSc, SLE

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PAH-associated systemic sclerosis and systemic lupus erythematosus have different therapeutic recommendations and patient characteristics, and thus should not be treated as one disease.
PAH-associated systemic sclerosis and systemic lupus erythematosus have different therapeutic recommendations and patient characteristics, and thus should not be treated as one disease.

Connective tissue diseases (CTD) in pulmonary arterial hypertension (PAH) have long been regarded as one syndrome.1 Emerging evidence, however, suggests that two of the most prevalent CTDs, systemic sclerosis (SSc) and systemic lupus erythematosus (SLE), should be regarded as separate diseases due to their different etiologies, prognoses, and therapeutic responses.1

In part because of their rarity, the diseases had been combined into a single category because it is difficult to recruit adequate numbers for trial purposes. In an interview with Pulmonology Advisor, pulmonologist Wassim Fares, MD, MSc, senior director of clinical science at Actelion Clinical Research in Cherry Hill, New Jersey, explained that it is misleading “that both SLE and SSc are lumped into a single category, ‘connective tissue disease associated PAH,' without appreciating the major differences between these 2 diseases.”

How the CTDs Differ in PAH

While the prevalence of SLE is estimated at 20 to200 per 100,000 adults in the United States, it represents a relatively small percentage in the PAH population, approximately 1% to 5%.1 SSc, however, has a smaller prevalence in the United States population, approximately 20 to 30 per 100,000 adults, but it represents 7% to 12% of patients with PAH.1

Patients with SSc tend to develop PAH at an older age, 60 to 65, whereas patients with SLE develop PAH at a younger age, approximately 40 to 45.1 The disease progression is also divergent: SSc-PAH is progressive and patients do not respond to immunosuppressants. The comorbid condition has a poor 3-year survival rate of 50% to 60%.1 On the other hand, the SLE-PAH 3-year survival rate is 75% to 85%, and some patients do respond to immunosuppressant therapy.1

PAH itself has a range of outcomes, with the World Health Organization/New York Heart Association functional classifications from I to IV that characterize patients' health status as no impairment to severe symptoms with physical limitations.2 Managing comorbid PAH-SSc or PAH-SLE is about striking a delicate balance because therapy that is beneficial in SSc may be deleterious in PAH. “One of the biggest misconceptions may be that controlling inflammation with steroids and, occasionally, with methotrexate, which is essential for patients with SSc, may provoke development of hypertension directly or via renal complications,” said Viktor Semenov, a PhD fellow in the internal medicine department at Dnipropetrovsk Medical Academy in Dnipro, Ukraine, in an interview with Pulmonology Advisor. “Finding a balance of dosage and duration of anti-inflammatory treatment is challenging.”

Systemic Sclerosis

If not diagnosed properly and early, SSc-PAH can be fatal.3 The multinational 3-year longitudinal DETECT study sought to determine what factors contributed to disease progression and poor outcomes in 57 patients (median age, 61; 28.6% men) with comorbid SSc-PAH and confirmed by right-sided heart catheterization.3 At the median 12.6-month follow-up, the DETECT algorithm found disease progression in 43.9% of patients. Drivers significantly associated with disease progression included male sex, high forced vital capacity %/carbon monoxide lung diffusion capacity (DLCO) % ratio, low DLCO, and a high Borg Dyspnea Index score at baseline.3  

“The DETECT algorithm can identify patients with SSc at high risk for PAH much more accurately than previous approaches,” noted rheumatologist Oliver Distler, MD, from the University Hospital Zurich in Switzerland, in an interview with Pulmonology Advisor. “This leads to the diagnosis of [PAH] at much earlier stages.”

A recent study suggested that SSc can be further divided into diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc) to better guide treatment and predict outcomes.4 Semenov and colleagues sought to characterize 148 patients (median age, 47) with SSc. Although both groups of patients with SSc had some hypertension, other laboratory values and clinical signs differentiated the patient categories. For example, skin lesions and pulmonary fibrosis were more likely to occur in patients with dcSSc than in patients with lcSSc. Individuals who had hypertension at SSc diagnosis tended to be older than patients who did not have hypertension.4

“The most important question is to determine the origin of PAH,” noted lead investigator Viktor Semenov. “Our previous investigations showed us that age and elevated markers of inflammation have [a] powerful impact on hypertension development.”

Systemic Lupus Erythematosus

Although the precise mechanism of SLE-mediated PAH is not fully understood, evidence has shown that controlling the inflammation of SLE benefits SLE-PAH.1 Moreover, patients with SLE-PAH have shown an improvement in symptoms with combination treatments that reduce the hemodynamic measures of mean PA pressure, cardiac index, and pulmonary vascular resistance.1

“There is much more variability in the course of SLE-associated PAH than a scleroderma-associated PAH,” said Dr Fares. “There is typically no PAH response to immunosuppressants in scleroderma-associated PAH, while there may be a response at times in SLE-associated PAH, especially in the setting of a lupus flare. Their underlying pathophysiology is not the same despite some overlap, and their long-term clinical outcomes are different as well.”

Rheumatologist Dr Distler agreed: “One of the major open questions is the correct classification of the specific form of [PAH] in the [CTDs]. Because of the coexisting comorbidities, correct classification into class I [PAH] or class II and III [PH] associated with cardiac disease or interstitial lung disease is often very challenging. Clear definitions and classification criteria must be provided.”

Summary & Clinical Applicability

Comorbid CTDs in PAH have vastly different prognoses and therapies, and thus should be categorized separately.  Although SSc and SLE are autoimmune diseases, treating inflammation in SLE can be beneficial, but this is not helpful in controlling SSc.

Limitations & Disclosures



  1. Bazan IS, Mensah KA, Rudkovskaia AA, et al. Pulmonary arterial hypertension in the setting of scleroderma is different than in the setting of lupus: a review. Respir Med. 2018;134:42-46.
  2. Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017;50(2). pii: 1700889.
  3. Mihai C, Antic M, Dobrota R, et al. Factors associated with disease progression in early-diagnosed pulmonary arterial hypertension associated with systemic sclerosis: longitudinal data from the DETECT cohort. Ann Rheum Dis. 2018;77(1):128-132.
  4. Semenov V, Kuryata O, Lysunets T. Clinical pattern of systemic sclerosis in Central Ukraine. Association between clinical manifestations of systemic sclerosis and hypertension. Reumatologia. 2018;56(1):24-30.
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