Rising Cases of Drug-Induced Pulmonary Fibrosis: Analysis of the Food and Drug Administration Adverse Event Reporting System (Faers) Database, 2000-2022

Purpose: Pulmonary fibrosis (PF) is a severe, progressive disease which has been increasing in prevalence. We conducted a systematic search in the FDA Adverse Event Reporting System (FAERS) to determine the drugs most commonly suspected with PF.Methods: In a retrospective review of the FAERS database from 2000-2022, we used the search terms “pulmonary fibrosis” and “idiopathic pulmonary fibrosis” and excluded reports with patients under the age of 18 years, and patients with unknown sex or age. Reports were sorted by generic drug names, and counted and trended over time using regression analysis.Results: From 2000-2022, there were 24,095,935 adverse drug events reported in FAERS, of which 17,520 (0.07%) were reported as PF. Excluding reports containing patients with unknown age (5,255), sex (122), and age below 18 years old (155), our final study cohort consisted of 11,988 reports. The mean age of the study cohort was 66.5 + 13.1 years and 6,248 patients (52.1%) were male. The lowest and highest number of reports per year were 252 and 1,049 reports in 2001 and 2020, respectively, which reflected an increase of 316%. Linear and exponential regression on the entire cohort of 11,988 reports revealed positive slopes over time with an R2 of 0.81 and 0.88, respectively. The top five drug classes associated with PF were disease modifying antirheumatic drugs (DMARDs, 39.4%), antineoplastic agents (26.4%), cardiovascular agents (12.6%), corticosteroids (4.6%), and immunosuppressive agents (4.0%). The top 10 drugs reported to be associated with PF from 2000 to 2022 were methotrexate (1,350, 11.3%), etanercept (977, 8.1%), adalimumab (819, 6.8%), amiodarone (792, 6.6%), infliximab (565, 4.7%), rituximab (561, 4.6%), hydroxychloroquine (515, 4.3%), leflunomide (406, 3.3%), tocilizumab (389, 3.2%), and abatacept (430, 3.5%). Linear regression on the number of reports for each of the top 10 drugs revealed a significant positive slope from 2000 to 2022 for methotrexate, etanercept, adalimumab, rituximab, hydroxychloroquine, leflunomide, tocilizumab, and abatacept (all, p<0.01). Amiodarone and infliximab did not have a slope that differed significantly from a null hypothesis of stable reports over time.Conclusion: A 23-year analysis of the FAERS database revealed exponentially increasing adverse event reports of PF. Significant annual increases in reporting of PF suspected with DMARDs and antineoplastic agents were identified. While our study has limitations, it highlights important trends which should be used to guide PF research related to drugs of potential importance.