What is the role of methotrexate (MTX) in treating scleroderma?

Methotrexate Use in Scleroderma

Methotrexate is recommended for the treatment of skin manifestations in early diffuse systemic sclerosis, showing modest but beneficial effects on skin thickening, though its effects on other organ manifestations have not been established. 1

Evidence for Methotrexate in Systemic Sclerosis

Efficacy for Skin Manifestations

• Methotrexate may be considered for treatment of skin manifestations in early diffuse systemic sclerosis (SSc) based on randomized controlled trials (RCTs) showing improvement in skin scores 1
• Two RCTs have evaluated methotrexate in systemic sclerosis:
  • First RCT (29 patients): Intramuscular methotrexate 15 mg/week for 24 weeks showed a trend toward improvement in total skin score (p=0.06 vs placebo) 1
  • Second RCT (73 patients): Oral methotrexate 10 mg/week for 12 months decreased the University of California Los Angeles skin score (ES 0.5) and modified Rodnan skin score (ES 0.5) compared to placebo 1

Dosing Considerations

• Most clinical trials used relatively low doses of methotrexate (10-15 mg/week) 1
• Higher doses (up to 25 mg/week), similar to those used in other rheumatic diseases, are often prescribed in clinical practice but have not been formally studied in SSc 1
• For optimal efficacy, treatment should be continued for at least 12 months, as longer treatment duration has shown more significant improvement in skin scores 2

Safety Profile

• Safety concerns with methotrexate include liver toxicity, pancytopenia, potential teratogenicity, and possible induction of lung injury/interstitial lung disease 1
• In clinical trials, there were few premature discontinuations due to adverse events (number needed to harm 16 and 34.5 in both RCTs) 1
• There was a non-significant trend toward lower mortality in methotrexate-treated patients compared to placebo (three vs seven deaths; p<0.18) 1

Methotrexate in Localized Scleroderma (Morphea)

Efficacy in Juvenile Localized Scleroderma

• Methotrexate has stronger evidence for efficacy in juvenile localized scleroderma than in systemic sclerosis 1
• A high-quality randomized, double-blind, placebo-controlled trial showed that methotrexate (15 mg/m², maximum 20 mg weekly) with initial corticosteroids significantly reduced disease relapse compared to placebo with corticosteroids (32.6% vs 70.8%, p<0.005) 3
• Only 6.5% of methotrexate-treated patients developed new lesions compared to 16.7% in the placebo group 3
• Methotrexate resistance is rare in juvenile localized scleroderma, with only 4 out of 57 patients (7%) showing resistance in one study 4

Treatment Protocol for Localized Scleroderma

• For active localized scleroderma, methotrexate (15 mg/m²/week oral or subcutaneous) is recommended in combination with systemic corticosteroids during the initial inflammatory phase 1
• Methotrexate should be maintained for at least 12 months after achieving clinical improvement before tapering 1
• For methotrexate-refractory or methotrexate-intolerant patients, mycophenolate mofetil (500-1000 mg/m²) may be used as a second-line treatment 1

Comparative Efficacy with Other Agents

• Cyclophosphamide has also been shown in RCTs to improve skin changes in SSc patients and is the preferred agent for SSc-related interstitial lung disease 1
• Other agents such as mycophenolate mofetil, azathioprine, or cyclosporine A are used to treat skin involvement in SSc, although their efficacy has not been studied as extensively as methotrexate 1
• In the 2023 state-of-the-art evidence review, methotrexate showed a between-group difference of approximately 5 points in modified Rodnan skin score compared to placebo, though this did not reach statistical significance (p<0.17) 1

Clinical Approach to Using Methotrexate in Scleroderma

When to Consider Methotrexate

• Early diffuse cutaneous systemic sclerosis with predominant skin involvement 1
• Patients without significant interstitial lung disease (where cyclophosphamide or mycophenolate mofetil may be preferred) 1
• For localized scleroderma, especially linear, deep, generalized, or pansclerotic forms 1

Monitoring and Management

• Regular assessment of skin thickness using validated measures (modified Rodnan skin score) 1
• Monitor for common side effects including nausea, headache, and transient hepatotoxicity 1
• Liver function tests should be performed regularly to detect hepatotoxicity 1
• Complete blood counts to monitor for pancytopenia 1

Common Pitfalls and Limitations

• Inadequate treatment duration is a common pitfall; methotrexate should be continued for at least 12 months to achieve optimal benefit 1
• Using doses that are too low (less than 15 mg/week) may limit efficacy based on clinical experience, though higher doses have not been formally studied in RCTs 1
• Methotrexate has limited evidence for efficacy in organ manifestations beyond skin involvement 1
• Potential for lung toxicity requires careful consideration, especially in patients with pre-existing interstitial lung disease 1