Scleroderma

Kait Arefiev, David F. Fiorentino, and Lorinda Chung
Division of Immunology and Rheumatology, Departments of Dermatology and Medicine, Stanford University School of Medicine, Palo Alto VA Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA
Received 2 June 2011; Accepted 17 August 2011

Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs and widespread vasculopathy. Raynaud’s phenomenon (RP) is often the first manifestation of SSc, frequently preceding the onset of cutaneous sclerosis by several years particularly in patients with limited disease, and eventually occurs in 95% of patients with SSc.

Vasospasm of the digital arteries leads to the three characteristic phases of pallor, cyanosis, then erythema correlating with reduced blood flow, total loss of oxygen supply, and reperfusion. Episodes of RP are usually triggered by cold exposure or stress and can be associated with numbness and pain, resulting in significant disability.

Recurrent episodes of ischemia-reperfusion injury and the subsequent generation of reactive oxygen species can result in ischemic damage to distal tissue sites. Digital ulcers (DUs) are necrotic lesions that occur either at distal aspects of digits (fingers or toes) or over bony prominences and occur in up to 50% of patients with limited or diffuse cutaneous SSc. These lesions are exquisitely painful, heal slowly, and interfere with activities of daily living often leading to substantial functional disability. Other complications associated with DU include scarring with loss of distal tissue, infection that can lead to osteomyelitis, and progression to gangrene requiring amputation.

DUs that develop at distal aspects of digits are thought to be related to recurrent ischemia from various processes, including vasospasm from RP, thrombosis of digital arteries, calcinosis, and structural microvascular changes related to the underlying SSc. Recurrent trauma, particularly in patients with joint contractures, also contributes to the development of DU in patients with SSc.

Ulcerations on the lower extremities proximal to the feet can occur in patients with SSc who likely have macrovascular disease as well. Current treatments for both RP and DU consist of vasodilators including calcium channel blockers (CCBs), alpha-adrenergic inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and nitroglycerin analogues. These medications are moderately effective in reducing the severity of RP in a portion of SSc patients [9], but typically do not lead to substantial benefit in terms of the healing and prevention of DU.

With the availability of powerful vasodilator therapies for the treatment of pulmonary arterial hypertension (PAH), options for the treatment of severe RP, DU, and progressive digital ischemia have increased. Prostacyclin analogues have been shown to accelerate the healing of DU, however, those agents found to be effective thus far require intravenous or subcutaneous delivery. Small studies have indicated that oral phosphodiesterase-5 inhibitors (PDE-5-I) are effective in reducing the severity of RP and promoting the healing of DU.

Large multicenter randomized controlled studies are underway to further evaluate the efficacy of PDE-5-I in the treatment of RP and DU. Several studies have evaluated the efficacy of targeting the vasoconstrictor endothelin-1 (ET-1) for the treatment of RP and/or DU. The purpose of this paper is to summarize the published studies evaluating endothelin receptor antagonists (ETRA) in the treatment of RP and/or ischemic DU associated with SSc.

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