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Vasoprotection in Systemic Sclerosis: New Strategies for Raynaud’s Phenomenon

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 73rd Annual Meeting of the American College of Rheumatology

Philadelphia, Pennsylvania / October 17-21, 2009

Vasculopathy in patients with systemic sclerosis mainly affects small arteries, reducing blood flow and promoting tissue ischemia, which leads to Raynaud’s phenomenon (RP) and digital ulcers. RP is essentially a condition in which there is an inappropriate constriction of blood vessels in the extremities in response to cold or emotional stress. Although approximately 10% of the population without systemic sclerosis are affected by RP, RP in association with systemic sclerosis is typically much more severe and can lead to major complications such as digital ulceration, gangrene and loss of digits. In the setting of systemic sclerosis, RP may also be thought of as a harbinger of more widespread vascular insult.

According to Dr. Fredrick Wigley, Director, Scleroderma Center, Johns Hopkins University, Baltimore, Maryland, “Looked at closely, patients [with systemic sclerosis] who just have Raynaud’s still have nailfold capillary changes suggesting a microvascular insult that is subterranean.” The peripheral vasculature is not the only site of vascular insult but can occur systemically, taking the form of renal crisis in some patients, pulmonary hypertension, cardiac disease, gastrointestinal dysmotility and impotence in men, which is extremely common, Dr. Wigley indicated. Because vascular disease is, in essence, driving processes associated with tissue injury in systemic sclerosis, “vascular protection may indeed have an impact on disease modification,” he told the delegates.

History of Systemic Sclerosis Treatment

The first principle of managing systemic sclerosis is to treat the vasospasm. The most popular agents used in this regard are the calcium channel blockers (CCBs), in particular the dihydropyridine. The CCBs have been shown to reduce the severity of RP but only modestly by about 35%. As pointed out by Dr. Wigley, patients with systemic sclerosis are living longer than in previous decades and speculation is that the CCBs might be providing some protection against internal organ damage even if they only modestly protect against RP. Similarly, prior to the era of widespread ACE inhibitor use, renal crises accounted for about 25% of all deaths in patients with systemic sclerosis. Today, the leading cause of death in patients with systemic sclerosis is pulmonary disease. As Dr. Wigley suggested, it is possible that the ACE inhibitors have provided a degree of protection against renal crises in this patient population, even though they have not been shown to reduce either the frequency or severity of RP.

Researchers have also determined that in the setting of systemic sclerosis, there is an increase in endothelin, a decrease in nitric oxide and a defect in prostaglandin metabolism, all of which set the stage for a vasoconstriction in blood vessels. “It therefore makes sense for us to try and replace each of these elements if we can,” he stated. Indeed, a number of studies have confirmed that prostacyclin analogues do redress some of the vascular manifestations of systemic sclerosis, improving symptoms and lessening the severity of RP as well as digital ulcers. Endothelin receptor inhibitors in turn have been recruited in the treatment of systemic sclerosis, as they have been shown to be upregulated in vascular disease, a logical target for inhibition. Studies to date indicate that the endothelin receptor inhibitors mainly inhibit the formation of new ulcers, but they do not appear to modulate the vasospastic phenomena leading to RP or digital ulcers. Agents such as bosentan are also indicated for the treatment of pulmonary arterial hypertension, as they have been shown to significantly improve survival outcomes in patients with pulmonary manifestations of systemic sclerosis.

Additional Approaches to Vasoprotection

Other approaches to vasoprotection in RP secondary to systemic sclerosis were discussed here by individual investigators, including Prof. Christopher Denton, Professor of Experimental Rheumatology, University College Medical School, London, UK. As researchers have suggested, vasodilators may be variably effective in this setting but tend to be associated with significant side effects. Oral sildenafil and other phosphodiesterase type 5 (PDE-5) inhibitors are an attractive option in patients with RP secondary to systemic sclerosis, as they indirectly increase nitric oxide production by affecting downstream mediators of nitric oxide.

Reducing RP Attacks

Here at the ACR, Prof. Denton described a double-blind, placebo-control randomized trial of 57 patients with RP secondary to limited cutaneous systemic sclerosis (Poster 472).The per-protocol population included 45 patients (sildenafil, n=20; placebo, n=25). They were randomized to either modified-release sildenafil at a dose of 100 mg/day p.o. for three days, followed by the same formulation at 200 mg/day p.o. for 25 days, or placebo.

At baseline, patients reported experiencing at least seven RP attacks per week, with attacks occurring on five or more days per week. After a median duration of 29 days, patients randomized to the active therapy arm had a mean of 44% fewer attacks per week compared to placebo controls, who had a mean 18.1% reduction in weekly attacks (P=0.034 for the per-protocol population). Decreases in the Raynaud’s Condition Score and total duration of attacks were also greater for patients in the PDE-5 arm relative to baseline than placebo controls; the difference between the two groups did not reach statistical significance. Changes in the Raynaud’s pain score relative to baseline were similar in both groups as well.

The most frequent treatment-emergent adverse events (AEs) were headache and dyspepsia, the majority being mild or moderate. As Prof. Denton noted, patients with systemic sclerosis tend to experience a lot of gastrointestinal side effects, including dyspepsia, which are manifestations of the disease and most patients would receive anti-reflux medications routinely as part of their standard care.

“I think what we can say is that these findings are encouraging in what is a difficult group of patients with RP secondary to scleroderma where, in addition to spasm of blood vessels, you probably have narrowed blood vessels as well and yet we were still able to improve things,” indicated Prof. Denton. He remarked that given sildenafil is indicated for the treatment of pulmonary arterial hypertension in Canada, there might well be a link between the benefits from treatment seen in this patient population and those with different vascular complications arising from the same disease process.

Statins and Systemic Sclerosis

It is well established that the statins have benefits that go beyond lipid-lowering. In another study presented here by Dr. Masataka Kuwana, Keio University School of Medicine, Tokyo, Japan, he and investigators carried out a 24-month, open-label trial evaluating the effect of atorvastatin on vascular symptoms in patients with vascular manifestations of systemic sclerosis. Patients received atorvastatin 10 mg/day for 24 months.

Of the eight patients who completed the trial, there were significant reductions in the Raynaud’s condition score (P=0.01) as well as patient assessment by visual analogue scale (P=0.0003). Three patients had digital ulcers at study entry and among this small group of subjects, the mean number of new digital ulcers dropped to 3.3 per year at 12 months and 2.7 per year at two years from a baseline mean of 4.7 ulcers per year. “There has been minimal success in treating vascular manifestations of systemic sclerosis with non-selective vasodilators, so new treatment strategies are needed,” the authors stated. They added that because the statins improve endothelial function, they have the potential to improve vascular manifestations of this challenging disease.

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