Mycophenolate and azathioprine in fibrotic ILD: no survival benefit, possible harm in two subtypes

Design

Multicentre retrospective target trial emulation (clone-censor-weighting)

Population

2,270 patients with non-IPF IIP, fibrotic HP or CTD-ILD

Primary outcome

3-year transplant-free survival

Effect

Non-IPF IIP HR 1.38 (95% CI 1.04 to 1.84); fibrotic HP HR 1.62 (1.09 to 2.40); no benefit in any subtype

Immunosuppression is often used for fibrotic interstitial lung disease other than idiopathic pulmonary fibrosis, although trial evidence is limited. This multicentre retrospective study used a clone-censor-weighting framework to emulate a randomised trial in 2,270 patients with non-IPF idiopathic interstitial pneumonia (1,022), fibrotic hypersensitivity pneumonitis (544) or connective tissue disease-associated ILD (704). Mycophenolate or azathioprine was started within 6 months in 18%, 30% and 31%, respectively.

The primary end point was 3-year transplant-free survival. Immunosuppression was not associated with better survival in any subtype. It was associated with worse survival in non-IPF idiopathic interstitial pneumonia (HR 1.38, 95% CI 1.04 to 1.84) and fibrotic hypersensitivity pneumonitis (HR 1.62, 1.09 to 2.40). Lung function trajectories did not differ in any subtype.

Emulated trials adjust for measured differences only. Patients who received immunosuppression were probably sicker or had more inflammatory features, so confounding by indication could explain apparent harm. The authors call for randomised trials.

• Do not assume immunosuppression helps survival in fibrotic ILD; this analysis found no benefit in any subtype.
• Be cautious in fibrotic hypersensitivity pneumonitis and non-IPF idiopathic pneumonia, where mortality was higher with treatment.
• Remove or limit exposure triggers in hypersensitivity pneumonitis before immunosuppression.
• Discuss ILD treatment in a multidisciplinary meeting and record the goal of therapy.
• Connective tissue disease-associated ILD was not shown to benefit or be harmed.

Why it matters

It challenges a long-standing default of treating inflammatory-looking fibrotic lung disease with immunosuppression.

Don't overread it

A retrospective emulation cannot prove harm; confounding by indication is likely, and current guidance has not changed on one study.

The statistics, in plain English

A hazard ratio of 1.62 for fibrotic hypersensitivity pneumonitis means a 62% higher rate of death or transplant over 3 years among those starting treatment, after weighting. It could reflect sicker patients rather than drug harm, because weighting cannot adjust for factors that were not measured.

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