Endothelin inhibitors
Endothelin inhibitors also may play a role in vascular protection. Endothelin is secreted in scleroderma and is a potent vasoconstrictor. Endothelin inhibition has been shown to have benefit for pulmonary hypertension, but unlike in primary pulmonary hypertension, it does not appear to affect long-term survival in patients with scleroderma. However, endothelin inhibitors have some transient benefit in scleroderma patients with respect to measures of walking and pulmonary vascular resistance.
"It makes sense, because endothelin is a stimulant, not only for the vasoconstrictive pathway (by blocking nitric oxide), but it also stimulates proliferation of smooth muscle," he said.
In a controlled trial, bosentan was associated with fewer digital ulcers when compared with placebo, and also was associated with improvement in subjective hand function (Arthritis Rheum. 2004;50:3985-93). There was no benefit for Raynaud’s attack rate or duration of attack, so based on this trial the treatment was approved in Europe only for scleroderma patients with recurrent digital ulcers.
A study of another endothelin inhibitor – macitentan – was terminated for lack of benefit for digital ulcers, but a subanalysis of the patients showed an evolution of new ulcers in those who had been receiving active treatment, compared with those who had been receiving placebo, so there may be some benefit that the study design did not quite show, he said.
Angiotensin II type 1 receptor blockers
Angiotensin receptor blockers (ARBs) that block angiotensin 1 – and thereby decrease the angiotensin hormone’s signal to increase levels of the fibrosis-promoting transforming growth factor beta – have been shown to have dramatic effect for the vascular disease in Marfan’s syndrome. Marfan’s syndrome involves a fibrotic reaction similar to that seen in scleroderma.
"So it’s possible that using an ARB would be helpful," Dr. Wigley said.
In an uncontrolled trial in the United Kingdom, losartan at 50 mg was comparable or better than was nifedipine at 40 mg for treating Raynaud’s phenomenon, so losartan may be an option for those who don’t respond to or can’t tolerate nifedipine, he said.
Tyrosine kinase and Rho-kinase inhibitors
Tyrosine kinase and Rho-kinase inhibitors have also been evaluated for the treatment of pulmonary hypertension. Tyrosine kinase inhibitors were associated with dramatic reversal of disease, but are limited by cardiac toxicity. Rho-kinase inhibitors "make sense biologically" because of the role of the RhoA/Rho kinase pathway in regulating numerous pathologic processes including vasoconstriction, vascular remodeling, and fibrosis, Dr. Wigley said.
One Rho-kinase inhibitor – fasudil – is approved for use in Japan, and an inhaled formulation is currently being studied for pulmonary hypertension.
Stem cells
Studies in Japan of human mesenchymal stem cells suggest that bone-marrow-derived stem cells injected directly into the skin of patients with digital ulcers leads to improvement in the ulcers over time.
"There was no control group, so it’s not clear that the treatment was the reason for the benefit, but it is an interesting concept. Instead of stimulating the bone marrow to get stem cells, why not just inject them into the skin," he said.
These are just some of the approaches being looked at to provide vascular protection in patients with scleroderma, said Dr. Wigley, who also reviewed approaches for managing vasospasm, hypoxia, and superoxide injury, and vascular occlusion.
"I hope [these approaches] will stimulate your interest in looking at what may happen in the future," he said.
Dr. Wigley disclosed that he lectures, conducts research, and/or serves as a consultant for Actelion, CSL Behring, Hoffman-La Roche, KineMed, MedImmune, Novartis, Sanofi-Aventis, and United Therapeutics.