What is the role of Azathioprine (Immunosuppressive medication) in Interstitial Lung Disease (ILD)?

From the Guidelines

Azathioprine is conditionally recommended as a first-line option for the treatment of interstitial lung disease (ILD) in people with systemic autoimmune rheumatic diseases, particularly in connective tissue disease-associated ILD and chronic hypersensitivity pneumonitis, as supported by the 2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) guideline 1.

Key Considerations

• The typical dosing regimen for azathioprine starts at 50 mg daily, with gradual titration up to 2-3 mg/kg/day based on patient tolerance and response.
• Before initiating azathioprine, patients should undergo TPMT (thiopurine methyltransferase) enzyme testing to assess the risk of bone marrow toxicity, as recommended by the consensus guidelines for evaluation and management of pulmonary disease in Sjögren's 1.
• Regular monitoring is essential, including complete blood counts, liver function tests, and renal function every 1-2 weeks initially, then monthly once on a stable dose.
• The medication typically takes 3-6 months to show full efficacy, and treatment duration is often long-term in responding patients.
• Azathioprine works by inhibiting purine synthesis and DNA replication, thereby suppressing T and B lymphocyte proliferation and reducing inflammation in the lungs.
• Common side effects include nausea, vomiting, bone marrow suppression, and elevated liver enzymes, as noted in the state-of-the-art evidence in the treatment of systemic sclerosis 1.

Patient Advice

• Patients should be advised to avoid live vaccines while on therapy and to report any signs of infection promptly, as azathioprine increases infection risk.
• Patients should also be aware of the potential risks of drug-induced pneumonitis, GI upset, hepatotoxicity, bone marrow suppression, rash, and hypersensitivity syndrome associated with azathioprine use, as highlighted in the consensus guidelines for evaluation and management of pulmonary disease in Sjögren's 1.

Treatment Approach

• The treatment approach for ILD in systemic sclerosis should include a combination of immunosuppressive therapy, anti-fibrotic therapy, and supportive interventions, as outlined in the state-of-the-art evidence in the treatment of systemic sclerosis 1.
• Azathioprine may be considered as a maintenance therapy after induction with cyclophosphamide or if ILD is mild, as noted in the state-of-the-art evidence in the treatment of systemic sclerosis 1.

From the Research

Azathioprine in Interstitial Lung Disease (ILD)

• Azathioprine (AZA) is used as an immunosuppressive therapy for ILD, particularly in connective tissue disease-associated ILD (CTD-ILD) 2, 3, 4.
• Studies have shown that AZA can improve or stabilize lung function in patients with ILD, including those with myositis-related ILD (M-ILD) and CTD-ILD 2, 4.
• A retrospective study found that AZA treatment was associated with improved forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) in patients with M-ILD 2.
• Another study found that AZA was effective in stabilizing or improving lung function in patients with CTD-ILD, with 66% of patients showing stabilization or improvement in pulmonary function during treatment 4.

Comparison with Other Therapies

• AZA has been compared to other immunosuppressive therapies, such as mycophenolate mofetil (MMF) and cyclophosphamide (CYC), in the treatment of ILD 2, 3, 5.
• A study found that AZA and MMF had similar efficacy in improving lung function in patients with M-ILD, but AZA was associated with a lower prednisone dose at 36 months 2.
• Another study found that AZA was more effective than CYC in improving lung function in patients with systemic sclerosis (SSc)-associated ILD 5.

Safety and Tolerability

• AZA has been shown to be generally well-tolerated in patients with ILD, but can cause adverse events such as elevated liver enzymes and non-respiratory side effects 3, 4.
• A study found that 27% of patients with CTD-ILD discontinued AZA treatment due to side effects, mostly within the first 3 months 4.
• Another study found that AZA was associated with a higher frequency of adverse events compared to MMF in patients with M-ILD 2.