NEW YORK — The marked decrease in mortality relating to renal crisis in patients with scleroderma because of the widespread use of ACE inhibitors has been accompanied by a huge increase in deaths from lung disease.
“Current treatment of scleroderma lags far behind some of the great successes we have seen in other rheumatic diseases. It has the highest mortality, with a 10-year survival of only 55%,” Dr. John Varga said at a rheumatology meeting sponsored by New York University.
Immunosuppressive therapies have been largely ineffective in scleroderma. “Steroids don't work and are probably contraindicated, and experience with methotrexate and the tumor necrosis factor inhibitors has not been very positive,” he said.
However, “we have learned a great deal about what happens with scleroderma vasculopathy,” said Dr. Varga, professor of medicine at Northwestern University, Chicago.
The most important vasculopathy in scleroderma is pulmonary arterial hypertension (PAH), Dr. Varga said. “This has always been the case, but until 2 decades ago we didn't even know how to recognize it, and because there was essentially no treatment, there was very little interest in trying to study it,” he said.
PAH develops in approximately 10%–20% of patients with scleroderma, and often manifests late in the disease. “Survival is abysmal,” he said, and although newer treatments currently in use may change this, the survival data are not yet available. In any case, because PAH is such a serious and prevalent complication, it is important for clinical rheumatologists to screen for it and to do so early, he said.
The most common screening study is Doppler echocardiography, which is easily reproducible, noninvasive, and relatively inexpensive. However, this test has many false positives and false negatives and cannot differentiate PAH from pulmonary vascular hypertension, for which the treatment is very different. Right heart catheterization is needed for anyone with suspected PAH or rapidly falling diffusing capacity, according to Dr. Varga.
Better understanding of the key signaling pathways in PAH, such as the endothelin pathway, has led to the development and approval of agents such as bosentan, sildenafil, and ambrisentan. Currently there is considerable interest in combination therapy and goal-directed therapy, in which specific target goals and time frames are set and, if not met, the drug dosages are increased.
There also is good evidence now that cyclophosphamide (Cytoxan) slows interstitial lung disease, as was shown in the Scleroderma Lung Study. In that trial, 158 patients with alveolitis were randomized to cyclophosphamide or placebo and followed for 12 months. Those on standard therapy showed marked decline in lung function, while disease stabilized among those on the active treatment (Arthritis Rheum. 2007;56:1676–84).
Small but significant benefits were seen on skin scores, and some improvements were reported on the health assessment questionnaire as well as on the symptom of breathlessness—which was very important for the patients, said Dr. Varga, who participated in the trial.
“These results were encouraging, although there was debate as to whether the risk of Cytoxan was worth these fairly modest benefits,” he said.
Further follow-up found that benefits of cyclophosphamide on forced vital capacity continued through 18 months, but thereafter began to wane and was lost at two years. “Perhaps these patients should have a second treatment,” he suggested.
Targeting the pathways and mediators involved in fibrosis is another new and exciting area of research and clinical development, Dr. Varga said.
One profibrotic mediator of interest is transforming growth factor β (TGF-β), which is a ubiquitous growth factor with pleiotropic effects that act through the Smad pathway.
Small molecules have been developed that specifically block this pathway; in animal models they look promising, but no clinical data are yet available.
Good evidence from the Scleroderma Lung Study shows Cytoxan slows interstitial lung disease. DR. VARGA