Combination Advanced Therapy Exposures in Immune-Mediated Inflammatory Diseases Are Associated with Increased Infection Risk, Even with Short Median Duration

Objectives In immune-mediated inflammatory diseases (IMIDs), multiple advanced therapy (targeted synthetic/biologic disease-modifying antirheumatic drugs ts/bDMARDs) concurrent exposures may occur. We assessed the duration, and infectious risks of combination advanced therapy (CAT) exposure in IMID in the United States. Methods We created a cohort of initiators of any advanced IMID therapy using MarketScan administrative health data (2016-2023). Treatment episodes began at initiation and ended after a dispensation/infusion gap of ≥5 half-lives. Episodes were classified as CAT with any 30+ day overlap between advanced therapy classes. Patients were followed from start of the first advanced therapy (time zero) until disenrollment, death, or study end (December 31, 2024). We described baseline characteristics of those exposed to CAT and estimated multivariate hazard ratios (HR) for persistence of the first CAT episode, defined as time until discontinuation of at least one of the combined advanced therapies. We adjusted for baseline age, sex, IMID, comorbidities, conventional synthetic DMARDs (csDMARDs), and glucocorticoids. We also assessed HRs for first serious infection (defined as requiring hospitalization or intravenous antibiotics) comparing person-time on combined vs single advanced therapy, adjusting for the same covariates. Results There were 270,198 individuals initiating 693,375 episodes of advanced therapy. Of these, 38,456 individuals (14.2%) initiated 52,212 episodes of CAT. Mean age at CAT initiation was 49 (standard deviation 13.5) years; 62.5% were female. Among 38,456 CAT users, the most common IMIDs were psoriasis, PsO (36.6%), inflammatory bowel disease, IBD (30.0%), rheumatoid arthritis, RA (28.0%) and psoriatic arthritis, PsA (18.9%). Baseline glucocorticoid use was common (44.0%). Among CAT episodes, 51.2% involved TNFα inhibitor exposure (overlapping most commonly with IL17 inhibitors, IL12/23 inhibitors, anti-adhesion molecules, JAK inhibitors or CTLA-4 agonists). Median duration of first CAT exposure was 42 days. Factors associated with lower duration of CAT exposure included RA (HR 1.27, 95% CI 1.24–1.31) and concomitant csDMARDs. Lower HRs were seen with PsO (HR 0.82, 95% CI 0.79–0.84), IBD (HR 0.85, 95% CI 0.83–0.88), and baseline Charlson Comorbidity Index ≥3 (HR 0.77, HR 0.67–0.89). During CAT exposure there were 4.8 serious infections per 100 person-years (95% CI 4.3–5.3). In multivariate analysis, CAT exposure was associated with an increased HR for serious infection (HR 1.20, 95% CI 1.08–1.33) (Table) vs single advanced therapy. Table. Risk of serious infection associated with combination advanced therapy exposures Conclusion In individuals starting advanced IMID therapy, 14.2% had CAT exposures, lasting a median of 42 days. CAT exposure was associated with serious infection risk.