SNOWMASS, Colo. – Until further testing confirms or disproves the promise of an oral formulation of treprostinil that is making its way through the developmental pipeline for management of Raynaud’s phenomenon and the ischemic finger, rheumatologists will have to continue to make do with modestly efficacious agents that all are best employed in conjunction with background therapy using a long-acting calcium channel blocker titrated to the maximum tolerated dose.
Dr. Frederick Wigley
Calling the developmental oral treprostinil agent particularly exciting, Dr. Frederick M. Wigley noted that the prostacyclin analogs are highly effective in cases of Raynaud’s with severe digital ischemia, but the ones available now have to be given intravenously, which is costly and inconvenient.
An effective oral prostacyclin would be a major development. The early clinical trials of oral treprostinil have been quite promising, and the drug is now moving into advanced trials for Raynaud’s phenomenon as well as for pulmonary arterial hypertension, according to Dr. Wigley, professor of medicine and director of the scleroderma center at Johns Hopkins University, Baltimore.
However, for now, "the kingpin of our therapy is usually the calcium channel blocker," he observed at a symposium sponsored by the American College of Rheumatology.
He highlighted the agents variously prescribed for Raynaud’s and how they fit into his management strategy – and in some cases, why they do not.
His first-line drug for Raynaud’s and the ischemic finger is amlodipine, at a starting dose of 5 mg that is titrated to 20 mg/day. This typically results in a 35%-40% reduction in patient-rated symptom severity scores, which he characterized as "a modest benefit." In addition, full-dose calcium channel blocker therapy also appears to reduce the incidence of digital ulcers, in Dr. Wigley’s experience.
Other medications often used for Raynaud’s phenomenon include:
• Topical nitrates: This popular therapy improves blood flow in affected fingers, but at the price of headaches and other side effects that many patients find intolerable.
"In my practice, I generally use topical nitrates when I have a patient with one finger that’s in trouble and I’m trying to get a bit of blush to the surface of the skin. It’s a therapy that’s generally not tolerated when used on a daily basis on all the fingers," the rheumatologist said.
• Other topicals: EMLA cream (2.5% lidocaine/2.5% prilocaine in a eutectic mixture) provides numbing as well as vasodilation. "I use it often in patients who have painful fingertips. It’s probably not quite as potent as the topical nitrates," Dr. Wigley said.
Several studies have shown that topical minoxidil is ineffective. Topical niacin is helpful in bringing a blush to ischemic skin, but it doesn’t address deeper ischemic events.
• ACE inhibitors and angiotensin-receptor blockers: ACE inhibitors are famously effective in preventing fatal renal crisis in scleroderma patients, but they don’t reduce the frequency or severity of Raynaud’s episodes, as was demonstrated in a large, randomized, double-blind clinical trial (Arthritis Rheum. 2007;56:3837-46).
In contrast, the angiotensin receptor blocker losartan at 50 mg/day has been shown in a randomized trial to be an effective alternative to calcium channel blocker therapy (Arthritis Rheum. 1999;42:2646-55). However, Dr. Wigley said his own clinical experience has been that losartan’s benefits are milder than with a long-acting calcium channel blocker pushed to the maximum tolerated dose.
• Selective serotonin reuptake inhibitors: Activated platelets in Raynaud’s release serotonin, a vasoconstrictor. In a 53-patient randomized, crossover trial, fluoxetine (Prozac) at 20 mg/day resulted in greater reductions in the frequency, duration, and severity of Raynaud’s attacks compared to baseline than did nifedipine at 40 mg/day (Rheumatology 2001;40:1038-43).
• Alpha adrenergic blockers: Prazosin was once a very popular treatment, but it has given way to the long-acting calcium channel blockers, which are more effective. Prazosin is primarily an alpha-1 inhibitor, and there aren’t a lot of alpha-1 receptors on vascular smooth muscle cells. The alpha-2C receptor is the key player at that site. Selective alpha-2C receptor inhibitors are in development.
• Phosphodiesterase inhibitors: "I must say that I’m generally disappointed with these drugs, and when I use them I do so in conjunction with a calcium channel blocker for their best benefit," Dr. Wigley said.
• Prostaglandins: A Cochrane review of seven clinical trials in patients with Raynaud’s phenomenon and scleroderma concluded that prostacyclin analogs reduced attack frequency and severity, improved digital lesions, and resulted in favorable physician assessments of treatment outcome (Cochrane Database of Syst. Rev., 1998, Issue 2, Art. No. CD000953).
European physicians have pioneered cyclic therapy with intravenous iloprost in patients with severe Raynaud’s, giving it daily, weekly, or monthly during the winter months and less frequently as needed during warmer weather. Dr. Wigley said that he utilizes intravenous epoprostenol as a key part of his approach to patients with an acute digital ischemic crisis.