Pulmonary arterial hypertension (PAH) related to systemic sclerosis (SSc, scleroderma) is a leading cause of death and disease-related morbidity yet paradoxically is the only complication of disease which has been studied adequately to allow regulatory approval and licensing of specific therapies. PAH (WHO Group 1) is defined by right heart catheterization (RHC) as a mean pulmonary artery pressure ≥ 25 mm Hg in the presence of a normal pulmonary capillary wedge pressure (PCWP) and the absence of significant levels of parenchymal lung disease. However, recent studies have demonstrated frequent elevations of PCWP in response to exercise or fluid challenge during right heart catheterization suggesting that left ventricular diastolic dysfunction or WHO Group 2 type disease is an important confounder. Many WHO Group 1 SSc patients have at least mild parenchymal lung disease and patients with longstanding stable moderate parenchymal disease develop PH as a late feature. WHO Group 3 disease implying microvascular disruption and pulmonary veno-occlusive disorder(PVOD)confound ease of disease categorization. Mixed etiology may be the rule not the exception in SSc.
Emerging data suggest markedly improved outcomes associated with early recognition and therapy. Reliance on echocardiography and symptoms alone leads to missed diagnosis in many such subjects. Ancillary testing including measures of pulmonary diffusing capacity or myocardial stress (NT-proBNP assay) become central to screening strategies as does measure of serum uric acid. High resolution chest tomography helps to identify PVOD and to assess the contribution of parenchymal disease whereas ventilation –perfusion radionuclide studies help to exclude thromboembolic disease. Although not yet field validated, the DETECT algorithm suggests that early mild disease can be detected whilst missing only 4% of PAH by employing pulmonary function testing, EKG and echocardiography with assays of NT-proBNP, anticentromere antibody and serum uric acid (see Denton CP et al, EULAR 2013).
The majority of randomized controlled trials are of short duration and focused on exercise capacity and quality of life outcomes. SSc has been an under-represented population which further undermines the power of these trials to measure other potential SSc related benefit (Raynaud, digital ulcers, gastrointestinal motility). Thus reliable data on durability of benefit and on therapeutic efficiency are sorely lacking. In the absence of direct drug to drug comparisons, consensus on drug of choice, applications of combined therapy and benefits of “goal-directed” therapy remain unclear in the SSc population.
Newer animal models suggest the capacity to foster vascular deremodeling either through antagonism of leukotriene B4 or inhibition of c-abl signaling pathways. Testing our ability to measure disease reversal or to even effectively perform the appropriate trials will require enhanced efforts at aggressive screening and earlier and more frequent use of right heart catheterization. The rheumatologist is the central caregiver in a situation of progressive lung disease wherein outcome is dictated by cardiac status and response. clinical disease features. All data point to the need for vigilance and aggressiveness in diagnostic testing.
Disclosure of Interest J. Seibold Shareholder of: Sapientia, Pacific Therapeutics, Consultant for: Actelion, Aries, Bayer, Boehringer-Ingelheim, Celgene, DART, Eiger, Eiccose, FibroGen, Genentech, Novartis, Pfizer, Sanofi-Aventis, Sigma Tau, Speakers bureau: United Therapeutics