What are the considerations for using methotrexate (Disease-Modifying Antirheumatic Drug) in patients with rheumatoid arthritis (RA) and interstitial lung disease (ILD)?

Methotrexate in Rheumatoid Arthritis with Interstitial Lung Disease

Methotrexate can be safely used in patients with rheumatoid arthritis (RA) who have mild and stable interstitial lung disease (ILD), as it is not associated with progression of existing ILD and may actually improve survival outcomes.

General Considerations for Methotrexate in RA-ILD

• Methotrexate is conditionally recommended over alternative DMARDs for patients with RA who have clinically diagnosed mild and stable airway or parenchymal lung disease, or incidental ILD detected on imaging, who have moderate-to-high disease activity 1
• Although methotrexate can rarely be associated with idiosyncratic pneumonitis, observational data suggest that methotrexate is not associated with progression of existing ILD 1
• Recent evidence indicates that methotrexate treatment during follow-up was actually associated with improved survival in RA-ILD patients (HR 0.13,95% CI 0.02-0.64) 2
• A 2021 case-control study with international validation samples found that methotrexate use was associated with a reduced risk of developing RA-ILD (adjusted OR 0.43,95% CI 0.26-0.69) 3

Risk Assessment and Patient Selection

• Patients with preexisting lung disease should be informed of their potentially increased risk of methotrexate pneumonitis prior to initiating treatment 1
• The recommendation for methotrexate use in RA-ILD is conditional because some clinicians and patients may prefer an alternative option rather than accept any additional risk of lung toxicity 1
• The severity of lung disease, rather than the tomographic pattern, is associated with mortality in RA-ILD patients 2
• Older patients with RA-ILD tend to have worse prognosis, which should be considered in treatment decisions 2

Monitoring Recommendations

• When starting methotrexate or increasing the dose, ALT (with or without AST), creatinine, and CBC should be performed every 1-1.5 months until a stable dose is reached and every 1-3 months thereafter 1
• Clinical assessment for side effects and risk factors should be performed at each visit 1
• Methotrexate should be stopped if there is concern for methotrexate pneumonitis, and some experts would stop it if ILD developed while on methotrexate 1
• Baseline work-up for patients starting methotrexate should include a chest x-ray obtained within the previous year 1

Dosing and Administration

• Oral methotrexate should be started at 10-15 mg/week, with escalation of 5 mg every 2-4 weeks up to 20-30 mg/week, depending on clinical response and tolerability 1, 4
• Parenteral administration should be considered in case of inadequate clinical response or intolerance to oral methotrexate 1
• Prescription of at least 5 mg folic acid per week with methotrexate therapy is strongly recommended to reduce side effects 1, 4

Alternatives and Special Considerations

• For patients with RA-ILD, the 2023 ACR/CHEST guideline conditionally recommends against leflunomide, methotrexate, TNF inhibitors, and abatacept as first-line ILD treatment options 1
• However, methotrexate may be continued in patients with ILD who are receiving it for extrapulmonary manifestations of RA 1
• For patients with progressive ILD, particularly those with a UIP pattern, some experts would consider nintedanib as a treatment option 1
• If methotrexate must be discontinued due to concerns about ILD, alternative DMARDs such as hydroxychloroquine, sulfasalazine, or leflunomide may be considered 5

Risk-Benefit Analysis

• Methotrexate has an important role as an anchor treatment in RA and there is a lack of alternatives with similar efficacy and/or superior long-term safety profiles 1
• A meta-analysis showed a small but significant increase in the risk of lung disease in patients with RA treated with methotrexate compared with other DMARDs (RR 1.10,95% CI 1.02-1.19) 6
• However, a nationwide population-based study found no increased risk of ILD with methotrexate treatment (HR 1.00,95% CI 0.78,1.27) at 5-year follow-up 7
• The benefits of methotrexate in controlling RA disease activity may outweigh the potential risks in patients with mild and stable ILD 1, 2

Common Pitfalls to Avoid

• Do not automatically exclude methotrexate as a treatment option for all RA patients with ILD, as evidence suggests it may be safely used in those with mild and stable disease 1, 3
• Distinguish between methotrexate pneumonitis (an acute hypersensitivity reaction) and progression of underlying ILD, as they require different management approaches 1
• Do not continue methotrexate if there are signs of worsening respiratory symptoms that could indicate methotrexate pneumonitis 1
• Avoid abrupt discontinuation of methotrexate if it needs to be stopped; gradual discontinuation is conditionally recommended 1