US Pharm. 2012;37(4):54-58.
Scleroderma, also referred to as systemic sclerosis (SSc), is a multisystem autoimmune disorder of the connective tissue. It consists mainly of immunologic and vascular changes, and is characterized by fibrosis and degenerative changes in the skin and other organs (e.g., heart, lungs, kidneys, gastrointestinal [GI] tract). Severe esophageal dysfunction is the most common visceral complication, while lung involvement (e.g., pulmonary fibrosis, interstitial lung disease) is the leading cause of death.1-4
SSc has three main features: excessive collagen production and deposition, vascular damage, and inflammation or autoimmunity. It is classified into two subsets based on skin involvement: limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc).1-3 Raynaud’s phenomenon is usually the first clinical manifestation of lcSSc and is typically seen in the majority of SSc patients. It is defined as a bilateral, episodic reaction of the fingers, toes, and/or nose caused by arterial vasospams.5,6 In certain cases, Raynaud’s phenomenon may be present for years before fibrosis is apparent.4,7 Therefore, early identification and close monitoring of patients with Raynaud’s phenomenon may provide valuable prognostic information to clinicians.8
The incidence of SSc is estimated to be 2.3 to 22.8 cases per 1 million persons per year. It affects approximately 75,000 to 100,000 people in the United States.9,10 SSc is reported to occur more commonly in women than in men (3:1 to 14:1, respectively), is usually diagnosed between 30 and 50 years of age, and has been linked to genetic predisposition as well as environmental exposure (e.g., industrial solvents).4,9 Although its etiology in unknown, immunologic abnormalities, fibroblast activation, chronic inflammation, and vascular damage are believed to be the main pathogenic elements of SSc. Early microvascular damage, mononuclear cell infiltrates, and fibrosis are generally followed by very densely packed collagen in the dermis, loss of cells, and atrophy in later stages of the disease.4 In the majority of patients, anticentromere and antitopoisomerase-I autoantibodies are detected, reflective of immunologic changes.6,11 In addition to genetic predisposition, it has also been hypothesized that psychological or mechanical stress (e.g., surgery, trauma, or injury) can also activate or exacerbate the pathogenic process of SSc.12
The criteria for SSc are the oldest of the rheumatic diseases.13 In 1980, the American Rheumatism Association presented the Preliminary Clinical Criteria for Systemic Sclerosis, which consisted of proximal scleroderma as the major criterion and sclerodactyly on the fingers and/or toes, digital pitting scars or loss of substance of the digital finger pads, and bibasilar pulmonary fibrosis as the minor criteria for diagnosis. Diagnosis of SSc is fulfilled if a patient meets the major criterion or two of the minor criteria. Over the years, these criteria were found to lack specificity for the diagnosis of early SSc because emphasis was placed on cutaneous manifestations, but not other vascular or immunologic changes that may occur prior to the onset of Raynaud’s phenomenon or other skin changes.10,13
In 2001, additional criteria were proposed for the classification of early SSc, known as limited SSc (lSSc). In addition to immunologic testing, confirmed Raynaud’s phenomenon, abnormal nailfold capillary patterns, and/or SSc-specific autoantibodies were recommended for early diagnosis of lSSc. For lcSSc, the presence of digital cutaneous changes is required in addition to the criteria for lSSc. Skin sclerosis is generally confined to the hands, forearms, face, and neck. The diagnosis of dcSSc requires the criteria for lSSc plus the presence of proximal cutaneous changes. Patients with dcSSc commonly have chest, abdomen, upper arm, and/or shoulder involvement, and are also at greater risk for developing various disease complications (e.g., organ damage) than those with lcSSC.6
Rheumatologists are key in the management of SSc. Their expertise and experience will help in developing appropriate and individualized treatment plans, which may be complex and challenging. Patients with dcSSc and visceral organ involvement may be particularly difficult to manage due to the numerous complications that can arise. Currently, there are no FDA-approved therapies for SSc; however, the goals of therapy are to prevent complications and reduce morbidity associated with SSc. Select agents, which have shown benefit and/or promise in the treatment of SSc patients, are reviewed below.
Glucocorticoids: Corticosteroids are used in numerous autoimmune disorders for their immunosuppressant and anti-inflammatory properties. Despite limited data, oral prednisone may be prescribed for its systemic effects, while topical corticosteroids (e.g., triamcinolone) may be used to help prevent progression and improve scleroderma affecting the scalp and forehead. In most cases, glucocorticoids are used for controlling pain caused by arthralgias or myalgias (similar to nonsteroidal anti-inflammatory drugs [NSAIDs]). However, these agents should be used for the shortest duration possible to avoid long-term consequences such as osteoporosis, glucose abnormalities, ocular disorders, and weight gain. In addition, prednisone is associated with an increased risk of scleroderma renal crisis, especially at higher doses (>40 mg/day). Therefore, alternative analgesics, such as NSAIDs and acetaminophen, can be administered as initial agents for arthralgias.14,15
Vitamin D Analogues: These compounds have also shown promise in the treatment of SSc by affecting keratinocyte differentiation and proliferation. Topical calcipotriene ointment has been reported to be well tolerated and to yield improvement in a small group of patients with localized SSc after 3 months of treatment.16 Calcitriol also inhibits fibroblast proliferation, collagen synthesis, and, potentially, T-lymphocyte activation. Oral dosages of 0.5 to 0.75 mcg daily have been well tolerated and seen to increase joint mobility and extensibility of the skin after 3 to 7 months of treatment.17,18
Immunosuppressants: These drugs have also been used in SSc with debatable benefits. Methotrexate, an antirheumatic agent, may suppress the immune system in addition to inhibiting DNA synthesis and cell reproduction in abnormal cells. Although it has been studied and found effective in a number of autoimmune disorders, data are limited regarding methotrexate use in SSc patients. In a few case studies investigating the use of methotrexate with or without concomitant corticosteroid therapy in a small sample of patients, methotrexate was found to yield a significant benefit in resistant and active localized SSc with no serious adverse reactions reported after 3 to 6 months of therapy.19,20 In one randomized, placebo-controlled, double-blind study of 29 SSc patients in the treatment group (who received weekly injections of methotrexate), methotrexate demonstrated significant improvements in skin induration and handgrip strength after a 6-month follow-up period.21 CBCs, platelet counts, liver function, blood urea nitrogen (BUN), creatinine, and estimated glomerular filtration rate should be monitored at baseline and throughout the duration of therapy.
Cyclosporine, another immunosuppressant agent, selectively inhibits the release of interleukin (IL)-2 from activated T lymphocytes; IL-2 is believed to be elevated in patients with early SSc. In one open-label trial of 10 SSc patients, a decrease in skin induration was noted; however, no improvement was seen in pulmonary or cardiac involvement after a 48-week follow-up. Nephrotoxicity occurred frequently, but was transient and seen primarily with the use of higher doses of cyclosporine (>3 to 4 mg/kg/day).22 In addition to carefully monitoring renal function, hypertension, and bone marrow suppression, it is important to remember that cyclosporine can interact with a number of other medications as well.
Antifibrotic Agents: Antifibrotics are also used in SSc due to the extensive fibrosis and related complications that may occur. D-penicillamine is a chelating agent involved in the cross-linkages of collagen. In one retrospective study with a mean follow-up period of 38 months, results showed various benefits in early SSc patients including a considerable decrease in degree and extent of skin thickness, significant reduction in the rate of new visceral organ involvement, and significant increase in 5-year cumulative survival rate.23 In a multicenter, double-blind, randomized clinical trial conducted years later, investigators noted that there were no statistical differences in skin induration, incidence of renal crises, or survival rate between the high-dose (750-1,000 mg/day) and low-dose (125 mg every other day) D-penicillamine groups after a 24-month follow-up period. In addition, the majority of adverse events (including proteinuria) occurred in patients receiving the higher doses of D-penicillamine. Therefore, it was concluded that there is no therapeutic benefit for using more than 125 mg every other day for SSc.24
Colchicine may also have a role in SSc as a result of its interference with collagen synthesis, fibroblast proliferation reduction, enhancement of collagenase activity, and anti-inflammatory properties. It is generally well tolerated and was found to improve skin elasticity, mouth opening, and finger motility, and to reduce dysphagia in a small, uncontrolled study.25 CBCs, liver function, and renal function should be monitored at baseline and periodically during treatment.
Potential Treatments: Other agents and interventions that have limited data available but show promise in the treatment of SSc and its manifestations include interferon gamma, minocycline, psoralen UVA, losartan, telmisartan, prazosin, mycophenolate mofetil, oral etretinate, etanercept, thalidomide, imatinib mesylate, statins, and allogeneic bone marrow or stem cell transplantation.15,26-37 All of these potential treatments, as well as the aforementioned therapeutic agents, require additional controlled clinical trials with larger sample sizes in order to better evaluate the potential benefits and risks for each and utilize them appropriately in the individualized care of patients with SSc.
A number of recommendations for SSc (based on clinical data and expert opinion) have been published by the European League Against Rheumatism (EULAR)/Scleroderma Trials and Research (EUSTAR) group (TABLE 1). In regard to skin involvement, dihydropyridine calcium channel blockers (usually oral nifedipine) are recommended as first-line therapy for the reduction of severity and frequency of SSc-related digital vasculopathy. These agents are vasodilators that help to improve peripheral circulation and reduce vasospasms (i.e., Raynaud’s phenomenon). For severe Raynaud’s phenomenon or active digital ulcers, patients with SSc should be given IV prostanoids (usually iloprost) due to their prolongation of vasodilation, reduction of platelet aggregation, and promotion of endothelial cell lining. Bosentan, a dual endothelin receptor antagonist found to reduce the frequency of new digital ulcers, is recommended in cases that fail therapy with calcium channel blockers and/or prostanoids.13,15,34
In patients with lung involvement, specifically pulmonary arterial hypertension (PAH), bosentan is strongly recommended as a result of data that demonstrated the prevention of deterioration in exercise capacity and improved survival in patients with SSc-associated PAH. Sildenafil, a selective type 5 phosphodiesterase inhibitor, may also be considered for SSc-associated PAH since data have demonstrated significant improvement in hemodynamics, exercise capacity, and functional class. In severe cases, IV epoprostenol may be used. This agent is also a vasodilatory prostaglandin, which inhibits platelet aggregation and has been reported to improve exercise capacity, hemodynamics, severity of Raynaud’s phenomenon, and healing of digital ulcers.13,15,34
Methotrexate is recommended for SSc-associated skin involvement owing to improvements in skin scores noted with its use. Cyclophosphamide has also been reported to improve skin changes; however, it should be considered for the treatment of SSc-associated interstitial lung disease because of its effects on improving lung function tests, dyspnea, and quality of life.13,15,34
For SSc-associated renal crisis, angiotensin-converting enzyme (ACE) inhibitors are recommended for treatment. In addition to their renoprotective effects, ACE inhibitors have demonstrated effective blood pressure control in patients with SSc. However, prophylactic use is not supported due to the potential for poorer outcomes in patients who develop SSc renal crisis.13,15,34,35
In cases of SSc-associated GI issues, proton pump inhibitors are recommended for the prevention of gastroesophageal reflux, esophageal ulcers, and strictures. Prokinetic agents (e.g., octreotide, cisapride) may be considered for SSc patients with symptomatic motility disturbances such as dysphagia. Experts also suggest that the rotation of antibiotics may be useful in SSc patients with malabsorption, which is secondary to bacterial overgrowth.36-38
In conjunction with appropriate rheumatologic interventions, certain lifestyle modifications may help to alleviate various signs and symptoms associated with SSc. Patients should be cautioned about consuming large doses of vitamin C (>1,000 mg/day) due to its potential to stimulate collagen formation and enhance its deposition. Exercise and physical and/or occupational therapy are also encouraged to maintain good mobility and minimize or delay contractures. GI involvement may necessitate changes in diet such as incorporating smaller frequent meals throughout the day rather than larger meals. In addition, patients with SSc should be instructed to keep digital ulcers dry and clean and to avoid dermal contact with any potentially corrosive or abrasive substances. In addition, protecting fingers and toes from trauma or cold temperatures, as well as maintaining a core body temperature, may help prevent episodes of Raynaud’s phenomenon and subsequent damage.9,39
Role of the Pharmacist
The treatment of SSc and its complications is complex and requires careful evaluation of the available literature. In collaboration with physicians and other health care providers, pharmacists must assess the risks and benefits of each therapeutic option prior to formulating a treatment plan. All interventions should be individualized and carefully monitored for adverse events. In addition, potential drug interactions should always be reviewed and taken into consideration when finalizing a treatment regimen. Pharmacists are a valuable source of information and should provide comprehensive counseling for patients with SSc.
1. Rocco VK, Hurd ER. Scleroderma and scleroderma-like disorders. Semin Arthritis Rheum. 1996;16:22-69.
2. White B, Bauer EA, Goldsmith LA, et al. Guidelines for clinical trials in systemic sclerosis (scleroderma). I. 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.
3. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15:202-205.
4. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360:1989-2003.
5. Hummers LK, Wigley FM. Management of Raynaud’s phenomenon and digital ischemic lesions in scleroderma. Rheum Dis Clin North Am. 2003;29:293-313.
6. LeRoy EC, Medsger TA. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28:1573-1576.
7. Charles C, Clements P, Furst DA. Systemic sclerosis: hypothesis-driven treatment strategies. Lancet. 2006;367:1683-1691.
8. Belch JF. Raynaud’s phenomenon: its relevance to scleroderma. Ann Rheum Dis. 1991;50:839-845.
9. Chifflot H, Fautzi, Sordet C, et al. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008;37:223-235.
10. Scleroderma (systemic sclerosis). American College of Rheumatology. www.rheumatology.org/practice/clinical/patients/diseases_and_conditions/scleroderma.asp. Accessed January 25, 2012.
11. Barnett AJ, Miller M, Littlejohn GO. The diagnosis and classification of scleroderma (systemic sclerosis). Postgrad Med J. 1988;64:121-125.
12. Hui KK, Johnston MF, Brodsky M, et al. Scleroderma, stress and CAM utilization. Evid Based Complement Alternat Med. 2009;6:503-506.
13. 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.
14. 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.
15. Walker KM, Pope J. Expert agreement on EULAR/EUSTAR recommendations for the management of systemic sclerosis. J Rheumatol. 2011;38:1326-1328.
16. Cunningham BB, Landells ID, Langman C, et al. Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol. 1998;39:211-215.
17. 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.
18. Hulshof MM, Pavel S, Breedveld FC, et al. Oral calcitriol as a new therapeutic modality for generalized morphea. Arch Dermatol. 1994;130:1290-1293.
19. 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.
20. Uziel Y, Feldman BM, Krafchik BR, et al. Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr. 2000;136:91-95.
21. 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.
22. Clements PJ, Lachenbruch PA, Sterz M, et al. Cyclosporine in systemic sclerosis. Results of a forty-eight-week open safety study in ten patients. Arthritis Rheum. 1993;36:75-83.
23. Steen VD, Medsger TA Jr, Rodnan GP. D-Penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis. Ann Intern Med. 1982;97:652-669.
24. Clements PJ, Furst DE, Wong WK, et al. High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis. Arthritis Rheum. 1999;42:1194-1203.
25. Alarcon-Segovia D, Ramos-Niembro F, Ibanez de Kasep G, et al. Long-term evaluation of colchicines in the treatment of scleroderma. J Rheumatol. 1979;6:705-712.
26. Yatsyshyn N, Yatsyshyn R, Neyko YE. Telmisartan improves endothelial function in scleroderma patients with pulmonary hypertension. J Hypertens. 2010;28:e550.
27. 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.
28. Gordon JK, Mersten J, Lyman S, et al. Imatinib mesylate (Gleevec) in the treatment of systemic sclerosis: interim results of a phase IIa, one year, open label clinical trial. Presented at: American College of Rheumatology Scientific Meeting; Philadelphia, PA; 2009.
29. 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.
30. 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.
31. 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.
32. 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.
33. Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest. 2008;133:455-460.
34. 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.
35. Penn H, Denton CP. Diagnosis, management and prevention of scleroderma renal disease. Curr Opin Rheumatol. 2008;20:692-696.
36. 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.
37. 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.
38. Sjogren RW. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum. 1994;37:1265-1282.
39. Sapadin AN, Fleischmajer R. Treatment of scleroderma. Arch Dermatol. 2002;138:99-105.
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