Scleroderma: Preventing Complications and Reducing Morbidity
The therapeutic goals for scleroderma can often be met with pharmacologic treatment.
The therapeutic goals for scleroderma can often be met with pharmacologic treatment.
Scleroderma—the Greek word for hard skin and also called systemic sclerosis (SSc)—affects 75,000 to 100,000 people in the United States in varying degrees.1,2 This multisystem autoimmune connective tissue disorder predisposes patients to excess collagen formation and chronic inflammatory infiltration. It’s still not clear how patients develop SSc; they may have a genetic predisposition, or perhaps an environmental exposure or a psychological or mechanical stressor induces the pathology.1,3,4 Subsequent immunologic and vascular changes lead to SSc’s most obvious symptom, skin induration (thickening and fibrosis), and to degenerative changes in many organs (eg, heart, lungs, kidneys, gastrointestinal [GI] tract). Patients usually receive a diagnosis when they are 30 to 50 years of age, and women are affected 4 to 9 times more often than men.2,3
Since 1980, clinicians have used the American Rheumatism Association Preliminary Clinical Criteria for Systemic Sclerosis (updated in 2001) to diagnose SSc (Online Table 1).2,5,6 SSc’s first clinical sign is usually Raynaud’s phenomenon—a bilateral, episodic reaction of the fingers, toes, and/or nose due to arterial vasospasm. Patients may have Raynaud’s phenomenon for years before fibrosis starts,3,7 so clinicians should monitor patients with Raynaud’s closely. Based on skin involvement, experts classify SSc into limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc).8,9 In lcSSc, sclerosis is generally confined to the hands, forearms, face, and neck.5 In dsSSc, severe esophageal dysfunction is the most common visceral complication. Chest, abdomen, shoulder, and/or upper arm involvement are common in dcSSc, as are disease complications.5 Most SSc patients die of lung involvement (eg, pulmonary fibrosis, interstitial lung disease), with an average survival of 12 years after diagnosis.3,8,9
Table 1: American Rheumatism Association Preliminary Clinical Criteria for Systemic Sclerosis
Diagnosis requires either the major criterion or 2 minor criteria
Major criterion: proximal scleroderma
Supporting an lcSSc diagnosis:
· Immunologic testing (antinuclear antibodies are present in about 90% to 95% of affected patients)
· Confirmed Raynaud’s phenomenon
· Abnormal nail fold capillary patterns and/or
· SSc-specific autoantibodies for diagnosis of lcSSc
· Digital sclerodactyly
· Pitting scars or loss of substance in the finger pads
· Bibasilar pulmonary fibrosis
Supporting a dcSSc diagnosis:
· The criteria for lcSSc plus the presence of proximal cutaneous changes
Adapted from references 2, 5, and 6.
Lifestyle modifications may alleviate some of SSc’s signs and symptoms. Interventions designed for Raynaud’s—protecting fingers and toes from trauma and cold temperatures, and staying warm—may prevent damage. Patients should avoid vitamin C doses >1000 mg per day, as they stimulate collagen formation and enhance its deposition. To maintain mobility and reduce contractures, exercise and physical and/or occupational therapy are critical. Patients with GI involvement may need to eat small, frequent meals rather than larger meals. Patients with SSc must keep digital ulcers dry and clean and avoid skin contact with potential corrosives and abrasives.1,10
Patients with SSc ideally need ongoing individualized care from a rheumatologist, especially if dcSSc and visceral organ involvement develop. The goals of therapy—preventing complications and reducing morbidity—can often be met with pharmacologic treatment despite a lack of FDA-approved therapies specific to SSc.
All SSc patients should use topical moisturizers. Topical corticosteroids (eg, triamcinolone) may help prevent progression and improve scleroderma affecting the scalp and forehead.6,11 If pruritus is a problem, histamine1 or histamine2 blockers, tricyclic antidepressants, and/or trazodone may help.6,12,13
Dihydropyridine calcium channel blockers (usually oral nifedipine) are first-line therapy to reduce the severity and frequency of SSc-related digital vasculopathy. Patients with severe Raynaud’s phenomenon or active digital ulcers may respond to vasodilation using intravenous (IV) prostanoids (usually iloprost).6,12,13
An increasingly important drug used for managing SSc is bosentan, which may reduce the frequency of new digital ulcers in patients who fail therapy with calcium channel blockers and/or prostanoids; bosentan does not improve healing. Bosentan is also strongly recommended in patients with SSc-associated pulmonary arterial hypertension (PAH); research indicates that the drug maintains exercise capacity and improves survival. Sildenafil may also improve SSc-associated PAH; in severe cases, IV epoprostenol may be used.6,12-14
If patients develop SSc-associated renal crisis, angiotensin-converting enzyme (ACE) inhibitors are renoprotective and control blood pressure effectively in SSc patients. ACE inhibitors should not be prescribed prophylactically, as they may result in poorer patient outcomes.6,12,13,15
Proton pump inhibitors can prevent gastroesophageal reflux, esophageal ulcers, and strictures. Laxatives may be needed if constipation is a concern. Prokinetic agents (eg, octreotide, cisapride) may help SSc patients with symptomatic motility disturbances, including dysphagia. Some SSc patients develop malabsorption secondary to bacterial overgrowth; experts recommend rotating antibiotics in these patients.16-18
Treating the Underlying Pathology
Corticosteroids, which have immunosuppressant and anti-inflammatory properties, are common therapies. Oral prednisone may be used to treat arthralgias and myalgias for short durations to avoid long-term complications, including osteoporosis, glucose abnormalities, ocular disorders, and weight gain. Prednisone in doses >40 mg per day is associated with increased risk of scleroderma renal crisis; alternative analgesics (eg, nonsteroidal anti-inflammatory drugs, acetaminophen) are preferred if they are effective.11,12
Vitamin D analogues—oral calcitriol and topical calcipotriene ointment19—affect keratinocyte differentiation and proliferation. Calcitriol in doses of 0.5 to 0.75 mcg daily also inhibits fibroblast proliferation, collagen synthesis, and, possibly, T-lymphocyte activation, leading to better joint mobility and skin extensibility after 3 to 7 months of treatment.20,21
Immunosuppressants have also been used for treating SSc, with mixed results. Clinicians have described the use of methotrexate with or without concomitant corticosteroids: significant benefit was seen in treating resistant and active lcSSc, with no serious adverse reactions reported after 3 to 6 months of treatment.22,23 One randomized, placebo-controlled, double-blind study of 29 SSc patients receiving weekly methotrexate injections found that skin induration and handgrip strength improved at 6 months of treatment. Methotrexate use requires close monitoring of a patient’s complete blood count (CBC), platelet count, liver function, blood urea nitrogen concentration, creatinine level, and estimated glomerular filtration rate.24
Researchers have determined that the interleukin-2 (IL-2) level is elevated in early SSc, suggesting that the IL-2 antagonist cyclosporine might help. Small studies have found that cyclosporine decreases skin induration but doesn’t affect pulmonary or cardiac involvement. The potential for nephrotoxicity limits its use, especially at high doses (>3 mg/kg/day). Cyclosporine also requires hypertension and bone marrow suppression monitoring, and has significant drug interactions.25 Recent studies indicate that mycophenolate mofetil may be a promising alternative to cyclophosphamide.26-28
D-penicillamine, an antifibrotic chelating agent, affects collagen cross-linkages. An early study found improved degree and extent of skin thickness, significantly reduced rate of new visceral organ involvement, and significantly improved 5-year cumulative survival rate after 38 months of follow-up. A later multicenter, double-blind, randomized clinical trial found that using more than 125 mg every other day resulted in no additional improvement, but significantly more adverse events, including proteinuria.25,29
Colchicine may disrupt collagen synthesis, reduce fibroblast proliferation, promote collagenase activity, and reduce inflammation. Generally well tolerated, colchicine appears to improve skin elasticity, mouth opening, finger motility, and dysphagia.30 Monitoring includes CBC as well as liver and renal function tests.
Other agents have been examined in small studies (Table 214,25,29,30-35). Additional studies are needed to ensure that the agents are effective and the benefits outweigh the risks.25
Patients with SSc often have serious, complex complications. Pharmacists’ drug expertise is critical for these patients, who often take many drugs. Pharmacists may find it challenging to screen patients for drug interactions and to help patients understand the risks and benefits of various drugs. Patients require close monitoring for adverse events.
Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy.
- Chifflot H, Fautzi, Sordet C, et al. Incidence and prevalence of systemic sclerosis: a systematic literature review.
- Scleroderma (systemic sclerosis). American College of Rheumatology website. www.rheumatology.org/practice/clinical/patients/diseases_and_conditions/scleroderma.asp. Accessed March 4, 2014.
- Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360:1989-2003.
- Hui KK, Johnston MF, Brodsky M, et al. Scleroderma, stress and CAM utilization. Evid Based Complement Alternat Med. 2009;6:503-506.
- LeRoy EC, Medsger TA. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28:1573-1576.
- Subcommittee for Scleroderma Criteria of American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980;23:581-590.
- Charles C, Clements P, Furst DA. Systemic sclerosis: hypothesis-driven treatment strategies. Lancet. 2006;367:1683-1691.
- Rocco VK, Hurd ER. Scleroderma and scleroderma-like disorders. Semin Arthritis Rheum. 1996;16:22-69.
- White B, Bauer EA, Goldsmith LA, et al. Guidelines for clinical trials in systemic sclerosis (scleroderma). Disease-modifying interventions. The American College of Rheumatology Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis. Arthritis Rheum. 1995;38:351-360.
- Sapadin AN, Fleischmajer R. Treatment of scleroderma. Arch Dermatol. 2002;138:99-105.
- 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. 1998;41:1613-1619.
- Walker KM, Pope J. Expert agreement on EULAR/EUSTAR recommendations for the management of systemic sclerosis. J Rheumatol. 2011;38:1326-1328.
- Kowal-Bielecka O, Landewe R, Avouac J, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009;68:620-628.
- Oldfield V, Lyseng-Williamson KA. Bosentan: a review of its use in pulmonary arterial hypertension and systemic sclerosis. Am J Cardiovasc Drugs. 2006;6:189-208.
- Penn H, Denton CP. Diagnosis, management and prevention of scleroderma renal disease. Curr Opin Rheumatol. 2008;20:692-696.
- Hani C, Soudah MD, Hasler WL, Owyang C. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med. 1991;325:1461-1467.
- Kahan A, Chaussade S, Gaudric M, et al. The effect of cisapride on gastro-oesophageal dysfunction in systemic sclerosis: a controlled manometric study. Br J Clin Pharmacol. 1991;31:683-687.
- Sjogren RW. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum. 1994;37:1265-1282.
- Cunningham BB, Landells ID, Langman C, et al. Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol. 1998;39:211-215.
- Elst EF, Van Suijlekom-Smit LW, Oranje AP. Treatment of linear scleroderma with oral 1,25 dihydroxyvitamin D3 (calcitriol) in seven children. Pediatr Dermatol. 1999;16:53-58.
- Hulshof MM, Pavel S, Breedveld FC, et al. Oral calcitriol as a new therapeutic modality for generalized morphea. Arch Dermatol. 1994;130:1290-1293.
- Seyger MM, Van den Hoogen FH, de Boo T, et al. Low-dose methotrexate in the treatment of widespread morphea. J Am Acad Dermatol. 1998;39:220-225.
- Uziel Y, Feldman BM, Krafchik BR, et al. Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr. 2000;136:91-95.
- Van den Hoogen FH, Boerbooms AM, Aswaak AJ, et al. 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. 1996;35:364-372.
- Manno R, Boin F. Immunotherapy of systemic sclerosis. Immunotherapy. 2010;2:863-878.
- Liossis SN, Bounas A, Andonopoulos AP. Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology (Oxford). 2006;45:1005-1008.
- Swigris JJ, Olson AL, Fischer A, et al. Mycophenolate mofetil is safe, well tolerated, and preserves lung function in patients with connective tissue disease-related interstitial lung disease. Chest. 2006;130:30-36.
- Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest. 2008;133:455-460.
- Henness S, Wigley FM. Current drug therapy for scleroderma and secondary Raynaud's phenomenon: evidence-based review. Curr Opin Rheumatol. 2007;19:611-618.
- Yüksek J, Sezer E, KöseoÄŸlu D, Markoç F, YÄ±ldÄ±z H. Scleredema treated with broad-band ultraviolet A phototherapy plus colchicine. Photodermatol Photoimmunol Photomed. 2010;26:257-260.
- Daoussis D, Antonopoulos I, Liossis SN, Yiannopoulos G, Andonopoulos AP. Treatment of systemic sclerosis-associated calcinosis: a case report of rituximab-induced regression of CREST-related calcinosis and review of the literature. Semin Arthritis Rheum. 2012;41:822-829.
- Ikeda T, Uede K, Hashizume H, Furukawa F. The Vitamin A derivative etretinate improves skin sclerosis in patients with systemic sclerosis. J Dermatol Sci. 2004;34:62-66.
- Yatsyshyn N, Yatsyshyn R, Neyko YE. Telmisartan improves endothelial function in scleroderma patients with pulmonary hypertension. J Hypertens. 2010;28:e550.
- Abou-Raya A, Abou-Raya S, Helmii M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud’s phenomenon and digital ulcers. J Rheumatol. 2008;35:1801-1808.
- Dziadzio M, Denton CP, Smith R, et al. Losartan therapy for Raynaud’s phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum. 1999;42:2646-2655.