Treatment Options For The Cutaneous Manifestations Of Systemic Sclerosis

J. Dutz, MD, FRCPC


Divisions of Dermatology and Rheumatology, Faculty of Medicine, University of British Columbia, Vancouver, Canada

ABSTRACT

Systemic sclerosis is a multisystem disorder with vascular instability as a clinical hallmark. Treatment currently consists of recognition and management of end-organ damage. Dermatologists can assist in the management of these patients by facilitating early diagnosis, and treating cutaneous manifestations such as Raynaud’s phenomenon, cutaneous calcinosis, and digital ulceration. New potentially disease-modifying therapies are now undergoing clinical trials.

Key Words:
systemic sclerosis, scleroderma

Systemic sclerosis (SSc) differs from localized scleroderma in prognosis as well as clinical expression. Patients have acral sclerosis associated with vascular instability in addition to internal organ involvement. They are seen by both rheumatologists and dermatologists, who participate in the management of cutaneous complications of the disease. The extent of skin involvement is quantified by a skin scoring method that correlates involvement with prognosis and is an accurate reflection of skin biopsy thickness.¹ Systemic sclerosis is commonly divided into the limited form (formerly termed CREST) or the diffuse form. Each of these is associated with clinically “silent” complications about which the clinician should be aware. In limited SSc, a significant proportion of patients develop life-threatening pulmonary hypertension. Baseline electrocardiography, echocardiography and pulmonary function testing may identify individuals at risk.^2,3 In generalized SSc, renal hypertensive crisis is the silent threat, and periodic blood pressure monitoring is advised. No therapies have been shown in blinded placebo-controlled trails to improve the overall course of systemic sclerosis.⁴ As a result, the current therapy for SSc is to treat the disease’s complications. The purpose of this article is to review the management of the cutaneous manifestations of this disease.

Clinical Issues Of Relevance To Dermatologists

Sclerodermatous skin is characterized by increased thickness, dryness, hair loss, pigment alteration, telangiectasis and pruritis. In addition, patients with scleroderma may have an increased risk of cancer. A population-based retrospective cohort study identified a standardized incidence ratio of 4.2:1 for nonmelanoma skin cancer.⁵ Treatment of involved skin includes frequent use of emollients and physical protection from temperature extremes and abrasion. The use of antihistamines and the tricyclic antidepressant, doxepin, can alleviate pruritis.

Raynaud’s phenomenon is a triphasic color reaction where the digits turn blue and white in response to cold, followed by a reactive plethora. This is often the presenting sign of SSc and can lead to pain, ulceration and digit loss. Dihydropyridines are the calcium antagonists most often used to treat this because they have some selectivity for smooth muscle.⁶ Nifedipine in a standard formulation (10 mg Po TID),^7,8 or in a sustained release (“retard”) preparation (10-20 mg PO BID), as well as amlodipine, a long acting dyihydropyrolidine⁹ (10 mg PO OD) have been shown to be effective at reducing pain and vasospasm in double blind placebo-controlled trials. Side effects, including headaches, dizziness, ankle swelling, and flushing can be limiting. Nitroglycerin ointment 1% applied TID to digits can be used as an adjunct and has shown efficacy in terms of reduced frequency of attacks and ulceration.¹⁰ Sustained release patches can also lessen the number and severity of attacks.¹⁰ Again, headaches can be a limiting side-effect. In severe Raynaud’s, intravenous iloprost infusion can be used for short-term palliation.¹¹ Oral analogues have, unfortunately, not yet fulfilled their promise.¹² When digital ulceration occurs, low dose acetylsalicylic acid (325 mg OD) can be added.³ Antibiotics and colloid dressings can also be of benefit. Surgical approaches include sympathectomy and limited microsurgical arteriolysis.¹³ Proximal vessel disease should be considered in the presence of digital gangrene, as ulnar artery narrowing has been recognized increasingly in patients with SSc.¹⁴

Cutaneous calcinosis can be the source of both pain and disability in patients with localised SSc. There is no pharmacological treatment that can prevent or reduce calcinosis. Coumadin,¹⁵ colchicine,¹⁶ bisphosphonates,^17,18 and diltiazem have been tried with variable success.¹⁹ Surgical extirpation can be of benefit for larger lesions²⁰ and smaller lesions can be effectively treated with CO2 laser.²¹ Impaired healing is variable, as CO2 laser treatment has been shown to be beneficial for peri-oral rhytids in limited progressive systemic sclerosis.²²

Systemic corticosteroids have been used by dermatologists in the early edematous phase of SSc. A case-controlled study of the use of systemic corticosteroids in SSc suggested an adverse outcome with an odds ratio of 4.37:1 for scleroderma renal crisis.²³ Systemic corticosteroid therapy is, thus, best avoided in patients with SSc. The substitution of other immunosuppressives is suggested for life threatening disease such as myositis, pericarditis or alveolitis.

Table 1: Cutaneous manifestations in systemic sclerosis and possible treatment options.

Possible Treatment Regimens

No therapy has been shown in controlled clinical trials to be truly disease-modifying. The use of D-penicillamine has been supported by both retrospective²⁴ and prospective²⁵ studies. However, a recent double-blind controlled trial showed no difference in outcome between low dose D-penicillamine (125mg on an alternate day basis) and high-dose D-penicillamine (750- 1000mg/day), putting the efficacy of this drug in doubt.²⁶ In a much publicized report on the use of minocycline, only 4 out of 11 patients improved significantly.²⁷ Methotrexate showed promise in a small 24-week randomized double blind trial.²⁸ A larger trial of 70 patients has suggested a trend toward improvement of skin disease, but has not yet been reported in full.²⁹ The recent formulation of guidelines for clinical trials in this disease should allow the determination of the clinical efficacy of these and various new treatment modalities. Recombinant human relaxin is being evaluated and may result in clinically significant skin score improvement.^30,31 A study of autologous stem cell transplantation is also ongoing, with favorable anecdotal experience.³²

Conclusion

Dermatologists should participate in the care of patients with systemic sclerosis. They can facilitate patient entry into ongoing trials by aiding in early diagnosis and can also help in the management of specific cutaneous complications such as Raynaud’s phenomenon, cutaneous malignancy, and cutaneous calcification. As the puzzle of pathogenesis in sclerotic skin disorders is being unraveled, further promising treatments are certain to become part of our clinical armamentarium.

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