BALTIMORE — Scleroderma patients should have yearly screening for pulmonary arterial hypertension, Dr. Kwas Huston said at a conference on rheumatic diseases sponsored by Johns Hopkins University.
At Johns Hopkins' Scleroderma Center, all patients undergo annual screening for pulmonary arterial hypertension (PAH) with pulmonary function testing (PFT) and two-dimensional echocardiography. Asymptomatic patients with mild changes and right ventricular systolic pressure (RVSP) less than 40 mm Hg are rescreened at 6 months. Symptomatic patients with signs and/or abnormal two-dimensional echocardiography (RVSP greater than 40 mm Hg) undergo right heart catheterization to confirm the diagnosis.
“We now have treatments we didn't have 5 or 10 years ago. … The evaluation is important to identify pulmonary hypertension and for prognosis,” said Dr. Huston, of the division of rheumatology at Johns Hopkins.
In the UNCOVER study published by Dr. Huston's group, 122 of 791 patients with scleroderma and mixed connective tissue disease seen in 50 community rheumatology practices had an existing diagnosis of PAH. But when the remaining 669 patients without a diagnosis of PAH subsequently underwent echocardiography, 89 had previously unrecognized PAH, for a total prevalence of 27% (Arthritis Rheum. 2005;52;2125–32).
Increased age at the onset of scleroderma is a major risk factor for PAH. Data from one study suggest that PAH risk increases 52% for every 10 years of age at disease onset, and that patients aged 60 and older have over twice the risk of younger patients (Chest 2003;124:2098–104). Other risk factors include severe Raynaud's phenomenon, low pulmonary diffusing capacity, calcinosis, Raynaud's disease, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome, he said.
PFT is useful for identifying PAH and for determining prognosis. In 71 scleroderma patients followed for a mean of 5 years, those with a carbon monoxide diffusing capacity (DLCO) of 40% or less had a 9% survival at 5 years, versus 75% among those with DLCO above 40% (Am. J. Med. 1984;77:1027–34). Pulmonary pressures were not measured in that study, but mortality is thought to be attributed to PAH, Dr. Huston noted.
The DLCO is also a useful predictor of who will develop PAH. In a retrospective case-control study of 212 scleroderma patients, the mean DLCO among the 106 with PAH was 52% of predicted 4.5 years prior to the PAH diagnosis, compared with 80% of predicted among the other 106 scleroderma patients who did not develop PAH (Arthritis Rheum. 2003;48:516–22).
Echocardiography is a useful companion screening tool. It had a sensitivity of 90% and specificity of 75% for identifying patients who had PAH on catheterization in a study of 33 scleroderma patients in whom clinical assessment, including ECG, chest x-ray, pulmonary function tests, and high-resolution computed tomography, raised suspicion of PAH (Br. J. Rheumatol. 1997;36:239–43). Echocardiography missed just two patients, both with pulmonary arterial systolic pressures (PASP) in the 30s. All patients with PASP above 40 mm Hg by echocardiography had abnormal pressures on catheterization.
As with PFT, echocardiography adds prognostic value. Increased mortality was tied to higher initial reading and with rising pressures in a study of 930 scleroderma patients, in whom mortality was 20% at 20 months among those with a single pressure of 30 mm Hg or greater. Rapid rises occurred more frequently in limited than in diffuse scleroderma (Rheumatology [Oxford]:2001;40:453–9).
In a study of 794 patients followed for 4 years, 3-year survival was inversely proportionate to mean PASP, from 75% among those with PASP under 32 mm Hg to 61% for 32–44 mm Hg, to 33% for pressures above 45 mm Hg (Ann. Rheum. Dis. 2003;62:1088–93).
Data support echocardiography and PFT for screening scleroderma, but Dr. Huston said areas of uncertainty include the role of exercise echocardiography in identifying patients with elevated right heart pressures on exercise but normal at rest, and the significance of a low-normal RVSP or low DLCO with normal echocardiography.
Flawed Drugs Still Give Hope
While five of the approved medications for treating pulmonary arterial hypertension offer patients hope that was unavailable a few years ago, each has drawbacks, Dr. Huston cautioned. (For the newest approval, see story below.)
The five medications are three prostanoids (epoprostenol, treprostinil, and inhaled lipoprost), an endothelin antagonist (bosentan) and the phosphodiesterase inhibitor sildenafil. Each was approved by the Food and Drug Administration after short-term randomized controlled trials, usually lasting 12–16 weeks. “We don't know what to expect in the long term,” Dr. Huston said.
The only drug to show a survival benefit was epoprostenol. Trials for the other drugs did not include enough patients to assess the drug's effect on mortality, and instead, used surrogate end points, like results of the 6-minute walk test or dyspnea questionnaires. Moreover, the large trials included patients with multiple causes of PAH, including scleroderma and lupus, groups that may not be comparable.