Scleroderma: Preventing Complications and Reducing Morbidity

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

Diagnosis

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

Minor criteria:

· 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.

Nonpharmacologic Management

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

Pharmacologic Management

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.

Symptomatic Treatment

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

Antifibrotic Agents

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 2^{14,25,29,30-35}). Additional studies are needed to ensure that the agents are effective and the benefits outweigh the risks.²⁵

End Note

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.

References:

• Chifflot H, Fautzi, Sordet C, et al. Incidence and prevalence of systemic sclerosis: a systematic literature review.
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• 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.
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• 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.
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