Methotrexate Pneumonitis

Methotrexate pneumonitis is a hypersensitivity type lung reaction to methotrexate that can happen at any dose, route or duration. It occurs in about 1 to 7% of patients treated for rheumatoid arthritis, psoriasis, inflammatory bowel disease and cancer, usually in the first year.

Risk factors are age over 60 years, pre-existing lung disease, diabetes, low albumin, renal impairment, previous disease modifying drugs and rheumatoid pleuropulmonary involvement. It is not related to the cumulative dose.

Pathophysiology. A delayed hypersensitivity reaction with lymphocytic and granulomatous inflammation of the alveolar walls, with direct toxicity to alveolar cells and disturbed folate metabolism contributing. Infection with Pneumocystis can mimic it, and may coexist.

Subacute onset over days to weeks of dry cough, dyspnoea, fever and malaise, sometimes with rash and mucositis. Examination shows tachypnoea, fine crackles and hypoxaemia. Eosinophilia is found in about half.

Severe hypoxaemia, high fever or rapid worsening needs urgent assessment since infection is the main alternative.

• Clinical diagnosis after exclusion of infection, with a temporal link to methotrexate and improvement on stopping.
• High resolution CT: patchy or diffuse ground glass opacity, centrilobular nodules, consolidation, and sometimes mosaic attenuation or septal thickening.
• Lung function: restriction with reduced DLCO, and hypoxaemia on arterial blood gas.
• Full blood count (eosinophilia, cytopenias), inflammatory markers, liver and renal function (renal impairment raises drug levels).
• Bronchoalveolar lavage with lymphocytosis and microbiology including Pneumocystis testing, and cultures for bacteria, mycobacteria and viruses. Biopsy only when the diagnosis is unclear.
• Exclude heart failure and pulmonary embolism.

Differential diagnosis.

• Pneumocystis pneumonia and other opportunistic infection
• Rheumatoid arthritis associated interstitial lung disease
• Other drug induced pneumonitis (leflunomide, biologics)
• Heart failure
• Pulmonary embolism
• Organising pneumonia of another cause

• Stop methotrexate immediately and do not restart.
• Corticosteroid: prednisolone 0.5 to 1 mg/kg daily (30 to 60 mg) until clinical and radiological improvement, then taper over 4 to 8 weeks. For severe respiratory failure, methylprednisolone 500 to 1000 mg intravenously daily for 3 days.
• Empirical cover for infection until it is excluded: for example ceftriaxone 2 g intravenously daily with azithromycin 500 mg daily, plus co-trimoxazole for Pneumocystis in those at risk, since the two conditions are hard to separate early.
• Supportive care: oxygen, with ventilatory support when needed. Folinic acid does not treat the pneumonitis, and has no proven benefit.
• Alternative disease treatment: the underlying arthritis or psoriasis is managed with other agents (for example a different conventional or biologic drug, avoiding leflunomide because of pulmonary risk), chosen with the specialist.
• Prophylaxis against Pneumocystis when prednisolone is 20 mg or more daily for over 4 weeks: co-trimoxazole 960 mg three times weekly (avoid in those continuing methotrexate for other reasons because of marrow toxicity).
• Prevention: check baseline chest radiograph, full blood count, liver and renal function, and avoid methotrexate in significant lung or renal disease. Folic acid 5 mg weekly reduces other toxicities.

Complications and prognosis. Most recover in weeks after stopping, but mortality is about 10 to 20% in severe cases. Fibrosis can persist in a minority.

Monitoring. Review at 1 week, 4 weeks and 3 months with oxygen saturation, spirometry and DLCO, and CT if symptoms or lung function do not recover.

Referral and escalation. Refer to a respiratory physician for hypoxaemia, uncertain cause or poor response, and to the prescribing specialist for alternative therapy.