What is the role of Methotrexate (MTX) in the treatment of neurosarcoidosis?

Role of Methotrexate in the Treatment of Neurosarcoidosis

Methotrexate is the recommended second-line agent for neurosarcoidosis patients who have been treated with glucocorticoids and have continued disease, based on its demonstrated ability to significantly reduce relapse rates compared to other immunomodulators. 1

Treatment Algorithm for Neurosarcoidosis

First-Line Therapy

• Glucocorticoids are the established first-line treatment for clinically significant neurosarcoidosis
  • Indicated by strong recommendation in the 2021 ERS clinical practice guidelines 1
  • Used in 81% of neurosarcoidosis patients as initial therapy with favorable outcomes in 71% of patients treated with glucocorticoids alone 1

Second-Line Therapy: Methotrexate

• Methotrexate should be added when:
  • Glucocorticoid therapy alone fails to control disease
  • Disease relapses during glucocorticoid tapering
  • Glucocorticoid-related adverse effects become problematic

Methotrexate has demonstrated superior efficacy compared to other second-line agents:

• Significantly reduces neurosarcoidosis relapse rate (hazard ratio 0.47,95% CI 0.25–0.87; p=0.02) 1
• Provides longer time to relapse compared to mycophenolate mofetil (28 versus 11 months; p=0.049) 1
• Results in lower yearly relapse rate than mycophenolate mofetil (0.2 versus 0.6 relapses per year) 1

Third-Line Therapy

• For patients who fail or cannot tolerate methotrexate and glucocorticoids, infliximab should be added 1
• Infliximab has shown good neuroimaging and functional outcomes in neurosarcoidosis patients 1

Mechanism and Evidence for Methotrexate in Neurosarcoidosis

Methotrexate works through multiple mechanisms:

• Reduces percentage of lymphocytes in bronchoalveolar lavage fluid 2
• Decreases spontaneous release of hydrogen peroxide and tumor necrosis factor from alveolar macrophages 2
• Acts as an effective steroid-sparing agent 3, 4

Clinical evidence supporting methotrexate use:

• In a retrospective analysis of 40 neurosarcoidosis patients, methotrexate demonstrated superior outcomes compared to mycophenolate mofetil 1
• Long-term studies show methotrexate is well-tolerated with significant steroid-sparing effects and efficacy for chronic symptomatic sarcoidosis 3
• A recent study (2022) confirmed methotrexate as the most frequently used second-line therapy for neurosarcoidosis, with favorable outcomes in approximately 50% of patients 5

Practical Considerations and Monitoring

When using methotrexate:

• Typically administered orally once weekly
• Dosage adjusted based on white blood cell count 3
• Requires monitoring for potential hepatic toxicity, which is the most common serious adverse effect 3
• Consider liver biopsy for patients on long-term therapy if liver function tests become abnormal 3

Important Caveats

• Clinical evidence for neurosarcoidosis treatment is limited by absence of randomized controlled trials 1
• Treatment decisions are based on retrospective studies with varied outcome measures 1
• While methotrexate is the preferred second-line agent, TNF-α antagonists (particularly infliximab) may be more effective for refractory cases 5
• Early consideration of TNF-α antagonists may be warranted in aggressive or refractory neurosarcoidosis 5
• The stepwise approach to neurosarcoidosis treatment considers not only efficacy but also drug cost, side-effect profile, and ease of use 1

Methotrexate remains the cornerstone second-line therapy for neurosarcoidosis based on its demonstrated efficacy in reducing relapse rates and its favorable side effect profile compared to other immunomodulatory agents.