Endothelin-1 Receptor Blockers Again Shown to Be Ineffective in Treating Skin Fibrosis

Endothelin-1 Receptor Blockers Again Shown to Be Ineffective in Treating Skin Fibrosis

Bosentan and other drugs belonging to the group of endothelin-1 receptor blockers showed promise in preclinical fibrosis models, but delivered disappointing results in clinical trials. Now, a real-life observational study adds to the setback, with this group of drugs showing no effect on skin fibrosis in scleroderma.

Endothelin-1 receptor blockers are approved for the treatment of pulmonary arterial hypertension, a condition often linked to fibrotic disease. Early studies also showed that endothelin might be involved in scleroderma pathogenesis, since patients have high levels of the factor in serum, and that it might be involved in fibrotic development.

Clinical studies of the drug in patients with scleroderma have, however, produced equivocal results. Some studies yielded positive outcomes, reporting that bosentan reduced digital ulcers in scleroderma, and a small trial, including only 10 patients, noted beneficial effects on skin fibrosis after treatment. A clinical trial of bosentan in interstitial lung disease linked to systemic sclerosis, however, did not show any effect of the drug on lung fibrosis.

To get a clearer picture of the role of this drug class in scleroderma patients, a research group from the University Hospital Zurich, Switzerland, analyzed data from patients included in Eustar — the European Scleroderma Trials and Research group.

The study, Effect of endothelin-1 receptor antagonists on skin fibrosis in scleroderma patients from the EUSTAR database, included 75 patients treated with various endothelin-1 receptor blockers, and 969 control patients who did not receive the treatment. Bosentan (brand name, Tracleer) was the most frequently used endothelin-1 receptor blocker, with 68  patients receiving the drug.

Results, published in the Journal of Scleroderma and Related Disorders, showed no difference between the groups when researchers measured the extent of skin fibrosis progression. In subgroup analyses, researchers looked only at patients with diffuse, extended systemic sclerosis, and still did not observe any difference between the treated and untreated groups. A comparison between patients with diffuse disease showing moderately advanced skin fibrosis at study start and untreated patients also yielded no meaningful results.

Taken together, the evidence of clinical studies so far do not support the hypothesis that endothelin-1 receptor blockers are useful in managing fibrosis, and the search for better treatment options may need to focus on other targets.

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