J. Dutz, MD, FRCPC
Divisions of Dermatology and Rheumatology, Faculty of Medicine, University of British Columbia, Vancouver, Canada
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.
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.
|SSc Cuntaneous Manifestations||Possible Treatment/Dose||Side Effects|
Tried with variable success:
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
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.
- Furst DE, Clements PJ, Steen VD, et al. The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis. J Rheumatol 25(1):84-8 (1998 Jan).
- White B. Clinical approach to scleroderma. Semin Cutan Med Surg 17(3):213-8 (1998 Sep).
- Kerin K, Yost JH. Advances in the diagnosis and management of sclerodermarelated vascular complications. Compr Ther 24(11-12):574-81 (1998 Nov-Dec).
- Herrick AL. Advances in treatment of systemic sclerosis. Lancet 352(9144):1874-5 (1998 Dec).
- Rosenthal AK, McLaughlin JK, Gridley G, Nyren O. Incidence of cancer among patients with systemic sclerosis. Cancer 76(5):910-4 (1995 Sep).
- Sturgill MG, Seibold JR. Rational use of calcium-channel antagonists in Raynaud’s phenomenon. Curr Opin Rheumatol 10(6):584-8 (1998 Nov).
- Smith CD, McKendry RJ. Controlled trial of nifedipine in the treatment of Raynaud’s phenomenon. Lancet 2(8311):1299-301 (1982 Dec).
- Rademaker M, Cooke ED, Almond NE, et al. Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud’s phenomenon in patients with systemic sclerosis: a double blind randomised study. BMJ 298(6673):561-4 (1989 Mar).
- La Civita L, Pitaro N, Rossi M, et al. Amlodipine in the treatment of Raynaud’s phenomenon [letter]. Br J Rheumatol 32(6):524-5 (1993 Jun).
- Franks AG Jr. Topical glyceryl trinitrate as adjunctive treatment in Raynaud’s disease. Lancet 1(8263):76-7 (1982 Jan).
- Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebocontrolled, double-blind study. Ann Intern Med 120(3):199-206 (1994 Feb).
- Wigley FM, Korn JH, Csuka ME, et al. Oral iloprost treatment in patients with Raynaud’s phenomenon secondary to systemic sclerosis: a multicenter, placebocontrolled, double-blind study. Arthritis Rheum 41(4):670-7 (1998 Apr).
- Tham S, Grossman JA. Limited microsurgical arteriolysis for complications of digital vasospasm. J Hand Surg [Br] 22(3):359-61 (1997 Jun).
- Stafford L, Englert H, Gover J, Bertouch J. Distribution of macrovascular disease in scleroderma. Ann Rheum Dis 57(8):476-9 (1998 Aug).
- Yoshida S, Torikai K. The effects of warfarin on calcinosis in a patient with systemic sclerosis. J Rheumatol 20(7):1233-5 (1993 Jul).
- Fuchs D, Fruchter L, Fishel B, Holtzman M, Yaron M. Colchicine suppression of local inflammation due to calcinosis in dermatomyositis and progressive systemic sclerosis. Clin Rheumatol 5(4):527-30 (1986 Dec).
- Metzger AL, Singer FR, Bluestone R, Pearson CM. Failure of disodium etidronate in calcinosis due to dermatomyositis and scleroderma. N Engl J Med 291(24):1294-6 (1974 Dec).
- Rabens SF, Bethune JE. Disodium etidronate therapy for dystrophic cutaneous calcification. Arch Dermatol 111(3):357-61 (1975 Mar).
- Vayssairat M, Hidouche D, Abdoucheli-Baudot N, Gaitz JP. Clinical significance of subcutaneous calcinosis in patients with systemic sclerosis. Does diltiazem induce its regression? Ann Rheum Dis 57(4):252-4 (1998 Apr).
- Neumeister M, Murray K. Calcinosis of the hand in scleroderma: a case report. Can J Plast Surg 7(5):241-244 (1999 Sep/Oct).
- Bottomley WW, Goodfield MJ, Sheehan-Dare RA. Digital calcification in systemic sclerosis: effective treatment with good tissue preservation using the carbon dioxide laser. Br J Dermatol 135(2):302-4 (1996 Aug).
- Apfelberg DB, Varga J, Greenbaum SS. Carbon dioxide laser resurfacing of perioral rhytids in scleroderma patients. Dermatol Surg 24(5):517-9 (1998 May).
- Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 41(9):1613-9 (1998 Sep).
- Steen VD, Medsger TA Jr, Rodnan GP. D-Penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis. Ann Intern Med 97(5):652-9 (1982 Nov).
- Jimenez SA, Sigal SH. A 15-year prospective study of treatment of rapidly progressive systemic sclerosis with D-penicillamine. J Rheumatol 18(10):1496-503 (1991 Oct).
- Clements PJ, Furst DE, Wong WK, et al. High-dose versus low-dose Dpenicillamine in early diffuse systemic sclerosis: analysis of a two-year, doubleblind, randomized, controlled clinical trial. Arthritis Rheum 42(6):1194-203 (1999 Jun).
- Le CH, Morales A, Trentham DE. Minocycline in early diffuse scleroderma. Lancet 352(9142):1755-6 (1998 Nov).
- van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol 35(4):364-72 (1996 Apr).
- Pope J, Bellamy N, Seibold J. A randomized controlled trial of methotrexate versus placebo in early diffuse scleroderma: preliminary analysis. Arthrtis Rheum 41 (suppl):S102 (abstr.) (1998).
- Seibold JR, Clements PJ, Furst DE, et al. Safety and pharmacokinetics of recombinant human relaxin in systemic sclerosis. J Rheumatol 25(2):302-7 (1998 Feb).
- Seibold JR, Korn JH, Simms R, et al. Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 132(11):871-9 (2000 Jun).
- Martini A, Maccario R, Ravelli A, et al. Marked and sustained improvement two years after autologous stem cell transplantation in a girl with systemic sclerosis. Arthritis Rheum 42(4):807-11 (1999 Apr).