What is the role of Azathioprine in Interstitial Lung Disease (ILD), specifically in Usual Interstitial Pneumonia (UIP)?

From the Guidelines

Azathioprine is not recommended as a treatment for rapidly progressive interstitial lung disease (RP-ILD) in people with systemic autoimmune rheumatic diseases (SARD). According to the 2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) guideline for the treatment of interstitial lung disease in people with SARD, there is no evidence to support the use of azathioprine as a first-line treatment option for RP-ILD 1. The guideline conditionally recommends against the use of azathioprine, as well as other medications such as methotrexate, leflunomide, TNFi, abatacept, tocilizumab, nintedanib, pirfenidone, and plasma exchange, as first-line treatment options for RP-ILD. Instead, the guideline recommends upfront combination therapy, which may include glucocorticoids, rituximab, cyclophosphamide, IVIG, tacrolimus, mycophenolate, or JAKi, as first-line treatment for RP-ILD 1.

Some key points to consider when treating RP-ILD include:

• The use of azathioprine is not typically recommended for RP-ILD, and its use may be harmful in certain cases 1.
• The treatment of RP-ILD should be individualized based on the specific disease diagnosis, disease severity, and patient factors, with careful monitoring for potential side effects 1.
• Upfront combination therapy is recommended as first-line treatment for RP-ILD, and may include a variety of medications such as glucocorticoids, rituximab, cyclophosphamide, IVIG, tacrolimus, mycophenolate, or JAKi 1.
• Early referral for lung transplantation is recommended for patients with SARD and RP-ILD, as it may improve survival and quality of life 1.

It's worth noting that while azathioprine may not be recommended for RP-ILD, it may still have a role in treating other forms of interstitial lung disease (ILD) with inflammatory components, such as connective tissue disease-associated ILD or hypersensitivity pneumonitis, typically at doses of 1-2 mg/kg/day 1. However, treatment decisions should be made on a case-by-case basis, taking into account the specific ILD diagnosis, disease severity, and patient factors, with careful monitoring for potential side effects.

From the Research

Azathioprine in ILD UIP

• Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD) 2.
• The use of azathioprine in patients with CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), has been studied, and the results show that azathioprine can stabilize or improve lung function in these patients 2, 3.
• A retrospective cohort analysis found that the combined incidence rate of adverse outcomes, including death, transplant, and respiratory hospitalization, was similar between patients treated with azathioprine and those treated with mycophenolate mofetil 2.
• Another study found that azathioprine can stabilize or improve CTD-ILD, with most patients who tolerated the drug achieving long-term stabilization or improvement of lung function 3.
• However, a systematic review and meta-analysis found that the evidence for the efficacy of azathioprine in interstitial lung disease (ILD) was of very low certainty, and more research is needed to support its use 4.

Treatment Outcomes

• Azathioprine has been shown to improve pulmonary function in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) 5.
• A study found that immunosuppression with azathioprine, mycophenolate mofetil, or rituximab was associated with an improved trajectory in forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) compared to the pretreatment pulmonary function trajectory 5.
• However, another study found that the use of azathioprine in patients with ILD was limited by early drug intolerance, with 27% of patients discontinuing treatment due to side effects 3.

Comparison with Other Treatments

• Azathioprine has been compared to mycophenolate mofetil in the treatment of CTD-ILD, and the results show that both treatments can stabilize or improve lung function 2, 3.
• A systematic review and meta-analysis found that mycophenolate mofetil may support preservation of pulmonary function, but the evidence was of very low certainty 4.
• More research is needed to compare the efficacy of azathioprine with other treatments for ILD, including mycophenolate mofetil and rituximab 5, 4.