What Is the Best Noninvasive Treatment for Digital Ulcers Due to Raynaud's Phenomenon in Scleroderma?

Robert Fox, MD

Disclosures

November 17, 2005

Question

In your experience, what is the best noninvasive treatment for digital ulcers due to Raynaud's phenomenon (RP) in scleroderma?

Luisa Landaeta, MD

Response from Robert Fox, MD

Background

In a majority of scleroderma patients, progressive systemic sclerosis (PSS) and cold-induced skin color changes (or RP) typically include blanching followed by cyanosis and then reactive hyperemia. Prolonged ischemia may lead to necrotic lesions (ulcers) or digital amputation. Once ulcers are present, they represent a difficult problem. The specific question referred to noninvasive (nonsurgical) approaches.

In general, pharmacologic therapy is necessary in addition to the commonly employed measures for RP prevention discussed below. Therapy typically includes oral calcium channel blockers, other vasodilators, sympatholytic agents, and prostaglandins. In the PSS patient, additional therapies have been suggested, including prostaglandins (by intravenous infusion), endothelin inhibitors, and the serotonin uptake inhibitor fluoxetine. Unfortunately, therapy remains unsatisfactory in many patients with ulcers due to RP.

Comment

The management of the ulcers due to RP must include simple measures such as avoidance of cold, stress, nicotine, caffeine, and sympathomimetic decongestant medications (eg, pseudoephedrine).[1]

Calcium channel blockers such as nifedipine, amlodipine, diltiazem, felodipine, nisoldipine, and isradipine have been reported to be effective in RP (although they have not been reported effective in the healing of digital ulcers) in the absence of other agents.[2] Unfortunately, PSS patients with secondary RP are less likely to benefit from calcium channel blockers compared with those with primary RP. Surprisingly, calcium channel blockers differ in their vasodilating potency in RP. In one report, verapamil was ineffective at doses of 40-80 mg 4 times daily in a group of PSS patients with severe RP. In addition, nicardipine was not effective in one study and only minimally different from placebo in another.

In addition to calcium channel blockers, other vasoactive drugs have been tried for the treatment of severe RP and digital ulcers.[3] These include direct vasodilators such as nitroglycerin, nitroprusside, hydralazine, papaverine, minoxidil, niacin, and topical agents, including nitric oxide (via a generating system), hexyl nicotinate, ethyl nicotinate, and thurfyl salicylate. Unfortunately for the PSS patient with digital ulcers, the treatment with these vasodilating agents is frequently limited by side effects. However, patients who cannot tolerate or fail to respond adequately to a calcium channel blocker can try another vasodilator alone or in combination, as individual responses may be idiosyncratic.

A variety of sympatholytic drugs have been used, including methyldopa, reserpine (which has been given intra-arterially), and prazosin. Sympatholytic agents may be helpful for the acute treatment of RP, but their effect tends to lessen with time and they often have intolerable side effects. There is no evidence that their use provides any advantage to that of a calcium channel blocker alone.

The intravascular administration of some of these agents has been used in the treatment of refractory ischemia in RP. Intra-arterial or intravenous phentolamine and intra-arterial reserpine have been advocated for an acute ischemic event that is not responding to oral vasodilators or other measures. However, there are few controlled data to provide guidance on their usage in this setting. Furthermore, although intra-arterial reserpine may reverse acute vasospasm, a controlled trial found that long-term benefit was no better than placebo.

During the past decade, several studies have examined the efficacy of treatment of severe refractory RP and ischemic digital ulcers with intravenous preparations of prostaglandin E1 (PGE1),[4] prostacyclin (PGI2), and iloprost (a PGI2 analog).[5] There are case reports of benefit for refractory skin ulcers with the infusion of PGE1 at a rate of 6-10 ng/kg per minute for a period of 72 hours. However, a multicenter placebo-controlled study using alprostadil (PGE1, which is available in the United States for maintaining ductus arteriosus patency) failed to show a significant clinical benefit in 55 patients with either primary RP or scleroderma. Infusion of a more stable form of PGE1-alpha, named PGE1 alpha-cyclodextrin, via a peripheral vein, reduced the frequency of attacks in 24 women with limited or diffuse scleroderma in an open-label uncontrolled trial. Results of randomized and blinded trials of this agent will be needed to adequately assess its efficacy, but the ease of peripheral venous administration is an advantage over unconjugated PGE1. A controlled trial evaluated the efficacy of iloprost given intravenously (0.5-2.0 ng/kg per min for 6 hours on 5 successive days) to 131 patients with RP secondary to scleroderma; short-term palliation of severe RP was achieved. The mean weekly attack rate fell by 39% and the Raynaud severity score decreased by 35% in the patients treated with iloprost compared with 22% and 20%, respectively, in the group receiving placebo. Intravenous iloprost is not available in the United States. Another study compared intravenous iloprost with oral nifedipine in RP associated with scleroderma. Both drugs were found to be equally effective. Iloprost was used for therapy in 30 patients with scleroderma with maintenance infusions every 3 weeks for a median of 3 years following an initial cycle infusion of 5 days. Healing of digital ulcers and a subjective decrease in RP was reported in this long-term uncontrolled study. Published studies of PGI2 (prostacyclin) in RP have reported benefits following the intravenous infusion rate of 7.5-10 ng/kg per minute for three 5-hour periods. The short-term benefit is similar to that reported with iloprost.

PGI2 (epoprostenol) is now approved in the United States for treatment of primary pulmonary hypertension via a continuous-pump intravenous infusion. This method of delivery of PGI2 has now been studied in pulmonary hypertension secondary to scleroderma. Among patients in the randomized trial for pulmonary hypertension, there was a favorable -- but statistically insignificant -- difference in the severity of RP; fewer new digital ulcers developed in the epoprostenol-treated patients.

A study of oral iloprost did not show benefit over placebo.[6] Preparations of other oral prostaglandins are available for study in Japan, Europe, and the United States. Mixed results have thus far been obtained in studies evaluating their efficacy in RP: One study found that misoprostol (an oral preparation of PGE1) did not reverse cold-induced vasospasm; however, another report found that limaprost (another oral PGEI analog) increased peak digital blood velocity in patients with systemic lupus erythematosus and mixed connective disease, but not scleroderma. Cicaprost, a synthetic prostacyclin analog, reduced the severity of RP in one study. Oral beraprost, another prostacyclin analog, was no more beneficial than placebo in one study, but a nonsignificant trend for benefit was observed in a second prospective report. Oral iloprost was studied in 2 placebo-controlled trials of patients with scleroderma. Oral iloprost was no better than placebo for the management of RP. Treprostinil, a prostacyclin analogue that can be delivered by subcutaneous infusion, was reported effective in a single case study.[7] Treprostinil is approved in the United States only for treatment of primary pulmonary hypertension.

A role for prostaglandins in the management of severe RP appears possible by continuous infusions; however, the effectiveness of an oral or subcutaneous delivery requires further study.

An uncontrolled study with serotonin reuptake inhibitors (such as fluoxetine, 20 mg/day) suggests that such agents may be beneficial in RP. In another short-term, open-label study of 53 patients (approximately half of whom had primary RP), the patients were randomly assigned to treatment with fluoxetine (20 mg per day) or nifedipine (40 mg per day). The severity and frequency of RP decreased in both groups during 2 weeks of treatment, significantly so in those receiving fluoxetine.

Angiotensin-converting enzyme (ACE) inhibitors may be helpful in improving local blood flow in RP by increasing kinins. The role of ACE inhibitors in severe RP is not well studied. One placebo-controlled trial that included patients with primary RP or scleroderma found that the angiotensin receptor blocker losartan reduced the severity and frequency of attacks. In addition, an uncontrolled study of captopril showed improvement in patients with primary RP, but not in those with scleroderma.[8] A double-blind crossover trial of L-arginine was given in an effort to enhance endogenous nitric oxide production in patients with primary RP. No benefit was seen at 28 days.

There are several newer agents in trial, including a neuropeptide calcitonin gene-related peptide (CGRP), a thromboxane A2 inhibitor (sildenafil, and an endothelin inhibitor (bosentan).

Because the neuropeptide CGRP may be present in lower concentrations in the sensory nerves in patients with RP, CGRP has been evaluated as possible therapy. In one study of patients with severe RP, intravenous CGRP improved hand and digital blood flow, skin temperature, and hand rewarming compared with saline; in addition, all ulcers healed in 4 of 5 patients.

Inhibitors of thromboxane A2, a major vasoconstrictor produced by platelets, have been disappointing in the treatment of RP. Sildenafil and other phosphodiesterase inhibitors are being used for improvement of the peripheral and pulmonary circulation.[9]

Although no formal studies for the treatment of RP are reported, there is increasing interest in these agents. Bosentan, an inhibitor of endothelin-1 (a potent vasoconstrictor), is being used for the treatment of pulmonary hypertension. A trial in scleroderma reported a reduction of new digital ulcers compared with placebo in patients treated with bosentan. Further studies are needed to determine whether bosentan or another endothelin antagonist will be helpful for complicated cases with secondary RP.

The herbal supplement ginkgo biloba was studied in primary RP for 10 weeks in a double-blind, placebo-controlled trial. This study found a reduction in the number of attacks by 56% in the active drug group compared with 27% in the placebo group, a statistically significant difference.

Summary

In summary, agents that indirectly cause vasodilation may be useful in patients with RP, but there is no convincing evidence that they are better than calcium channel blockers alone. More studies are needed to define their exact role.

Comments

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