What is the role of Methotrexate (MTX) in treating Sjögren's syndrome?

Methotrexate in Sjögren's Syndrome

Methotrexate has limited evidence for efficacy in primary Sjögren's syndrome and is not recommended as a standard treatment for sicca symptoms or systemic disease, though it may be considered for specific extraglandular manifestations such as cutaneous vasculitis or as a steroid-sparing agent in select cases of systemic involvement. 1

Evidence Base and Limitations

The evidence supporting methotrexate use in Sjögren's syndrome is notably weak compared to other rheumatologic conditions:

• No high-quality randomized controlled trials demonstrate efficacy for the primary manifestations of Sjögren's syndrome (sicca symptoms or systemic disease activity) 1
• The 2020 EULAR guidelines explicitly state there is insufficient evidence to recommend one immunosuppressive agent over another in Sjögren's syndrome, including methotrexate, due to lack of head-to-head studies and unacceptable adverse event rates (41-100%) in available trials 1
• A 1996 pilot study showed improvement in subjective symptoms (dry mouth, dry eyes) but no improvement in objective parameters of glandular function, with 41% of patients requiring dose reduction due to asymptomatic transaminase elevation 2
• A 2010 review concluded there is "still no convincing evidence that methotrexate is of benefit in primary Sjögren's syndrome" 3

When Methotrexate May Be Considered

Cutaneous Vasculitis

• Methotrexate can be effective for cutaneous vasculitis associated with Sjögren's syndrome, where it may produce complete response when other treatments (including rituximab and azathioprine) fail 4
• Consider methotrexate as an early therapeutic strategy before rituximab for cutaneous vasculitis manifestations 4

Steroid-Sparing Agent for Systemic Disease

• In patients with active systemic disease (ESSDAI score >5) requiring long-term corticosteroids, methotrexate may be used as a glucocorticoid-sparing agent, though this is based on extrapolation rather than direct evidence 1
• The decision must weigh potential benefits against risks on a case-by-case basis 1

CNS/Myelopathy Involvement

• For myelopathy associated with Sjögren's syndrome, methotrexate is listed among nonsteroidal immunosuppressants that may be considered in conjunction with corticosteroids when first-line corticosteroid therapy fails 5
• However, cyclophosphamide appears to be the preferred agent based on adverse effect profile and efficacy for this manifestation 5

Critical Safety Concern: Drug-Induced Interstitial Lung Disease

Methotrexate is specifically listed as a medication that can cause drug-induced ILD in Sjögren's patients (approximately 1% risk), which is a critical consideration given that Sjögren's patients may already have underlying pulmonary involvement 1

• Clinicians must maintain high vigilance for pulmonary complications when using methotrexate in Sjögren's syndrome 1
• Progressive or refractory respiratory symptoms may require bronchoscopy, biopsy, and/or immediate medication withdrawal 1
• Corticosteroids may be needed if significant symptoms and respiratory impairment develop from drug-induced ILD 1

Preferred Alternatives for Systemic Sjögren's Disease

For patients with moderate-to-severe systemic disease requiring immunosuppression:

• Mycophenolate mofetil (MMF) or azathioprine are recommended as first-line steroid-sparing or adjunct agents for Sjögren's-related interstitial lung disease 1
• Rituximab should be considered for severe, refractory systemic disease, as it has the highest level of evidence among biologics tested in Sjögren's syndrome (>400 patients studied) 1
• Cyclophosphamide or rituximab are preferred for rapidly progressive or life-threatening manifestations 1

Common Pitfalls to Avoid

• Do not use methotrexate expecting improvement in sicca symptoms or objective glandular function—the evidence does not support this 2, 3
• Do not overlook baseline and serial pulmonary assessment before and during methotrexate therapy, given the risk of drug-induced ILD in a population already at risk for pulmonary complications 1
• Do not continue methotrexate if hepatic transaminases remain elevated, as this occurred in 41% of patients in the pilot study 2
• Avoid using methotrexate as monotherapy for systemic Sjögren's disease—if immunosuppression is needed, it should typically be combined with corticosteroids 1