Abstract Rationale Non-idiopathic pulmonary fibrosis (IPF) interstitial lung disease (ILD) is a heterogeneous process that demonstrates a variable response to immunosuppression. Corticosteroids are often considered first-line therapy, with non-steroidal immunosuppressants frequently added to enhance effectiveness and reduce corticosteroid exposure. However, evidence supporting upfront combination over initial corticosteroid monotherapy is limited. We, therefore, evaluated whether early addition of a non-steroidal immunosuppressant improves outcomes compared with initial corticosteroid monotherapy in patients with non-IPF ILD. Methods We emulated a target trial using ILD registries from the Mass General Brigham hospital network. Eligible participants were adults (≥18 years) with a diagnosis of non-IPF ILD who initiated corticosteroids for ILD management between January 2015 and August 2025. We excluded patients with any immunosuppressant use, including corticosteroids, during the prior 6 months. Time zero was the date of corticosteroid initiation. We compared the following two strategies through clone-censor-weight approach: early combination therapy starting a nonsteroidal immunosuppressant (mycophenolate mofetil, rituximab, azathioprine, tacrolimus, methotrexate, or cyclophosphamide) within 3 months after time zero, along with corticosteroids; and initiation of corticosteroid monotherapy without adding a nonsteroidal immunosuppressant during the first 3 months. The outcome was a composite of first ILD hospitalization, lung transplantation, or all-cause mortality. We estimated the 3-year risk difference and risk ratio with 95% confidence intervals (CIs) by weighted pooled logistic regression. Results A total of 302 patients were included in the emulated trial. Median (Q1, Q3) age was 65 (55, 72) years and 54% were female. Represented ILD subtypes included: interstitial pneumonia with autoimmune features (IPAF) 141 (47%), CTD-ILD 41 (14%), hypersensitivity pneumonitis 23 (8%), and other idiopathic ILD 97 (32%). Over a median follow-up of 25.5 months, component outcomes for combination vs monotherapy were: ILD hospitalization 25 (17%) vs 39 (20%); lung transplantation 10 (7%) vs 12 (6%); and death 51 (34%) vs 59 (30%). With monotherapy as the reference, the 3-year risk difference was −0.34 (95% CI, −13.9 to 11.9) percentage points and the risk ratio was 0.99 (0.78, 1.22). In subgroup analyses (combination vs. monotherapy), risk ratios were 0.88 (95% CI, 0.65 to 1.18) for CTD-ILD or IPAF and 1.41 (95% CI, 1.06 to 1.74) for non-CTD-ILD or non-IPAF. Conclusion In non-IPF ILD patients initiating systemic corticosteroids, we found no clear evidence that early corticosteroid-plus immunosuppressant therapy improved ILD event-free survival compared with corticosteroid monotherapy. In non-CTD-ILD and non-IPAF subgroups, early combination therapy was associated with worse prognosis, warranting cautious use and further confirmation. This abstract is funded by: Sidney and Deanna Wolk Family Foundation
Imai et al. (Fri,) studied this question.