- 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
- No benefit in any subtype; HR 1.38 (non-IPF IIP) and 1.62 (fibrotic HP) for worse survival
Immunosuppression is widely used in fibrotic interstitial lung disease other than IPF, with limited trial evidence. This multicentre retrospective study of 2,270 patients — non-IPF idiopathic interstitial pneumonia, fibrotic hypersensitivity pneumonitis and connective tissue disease-associated ILD — used a clone-censor-weighting framework to emulate a trial of starting mycophenolate or azathioprine within six months against not starting.
Immunosuppression was not associated with better three-year transplant-free survival or lung function trajectory 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). In CTD-ILD, there was neither benefit nor harm.
Target-trial emulation reduces but cannot remove confounding by indication: sicker or faster-progressing patients are more likely to be started on treatment. Current guidelines, particularly for CTD-ILD where trial data exist, have not changed, and this study should not lead to stopping effective therapy. It does strengthen the case for randomised trials and for reviewing whether an individual patient is actually benefiting.
- Continue guideline-based immunosuppression in CTD-ILD; this study does not overturn it.
- Review each patient on immunosuppression for objective benefit in lung function and symptoms.
- Consider antifibrotic therapy in progressive pulmonary fibrosis regardless of immunosuppression.
- Prioritise antigen avoidance in fibrotic hypersensitivity pneumonitis.
- Discuss the uncertain benefit with patients when starting immunosuppression in non-CTD fibrotic ILD.
Why it matters
It challenges a routine prescribing habit that has rested more on reasoning than on trials.
Don't overread it
This is an observational emulation; confounding by indication may explain the apparent harm, and guidelines are unchanged.
The statistics, in plain English
A hazard ratio of 1.62 means a higher rate of death or transplant among those started on treatment. Because treatment was not randomised, sicker patients may have been more likely to receive it, which would produce this pattern.
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