Utilization and Risk of Serious Infection Associated with TNF-α Inhibitors in Children and Young Adults

This dissertation examined use of tumor necrosis factor-alpha inhibitors (TNFI) and risk of TNFI-associated serious infection compared to oral immunosuppressants in children and young adults with juvenile idiopathic arthritis (JIA)/rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Four retrospective cohort studies were conducted using the Truven Health MarketScan Research Database (2009-2013). TNFI treatment patterns, early TNFI therapy rates, and time to TNFI initiation were examined in incident JIA/RA and IBD cohorts. Serious infections were defined as those requiring hospitalization. Cox proportional hazard models were used to estimate the risk of serious infection associated with TNFIs in JIA and IBD cohorts. High-dimensional propensity score models were used to control for potential confounding. In two studies examining treatment patterns, 18.6% of the incident JIA/RA cohort initiated TNFIs, and etanercept was most commonly used, while in the incident IBD cohort, 27.6% initiated TNFIs, and infliximab was most commonly used. In both cohorts, time from new diagnosis to first TNFI prescription was shorter in more recent years. Specifically, early TNFI therapy increased over time in the IBD cohort. In a third study, 2,495 JIA patients were followed for 1,810 person-years. Serious infection rates were 2.7/100 person-years for TNFIs and 1.28/100 person-years for disease-modifying antirheumatic drugs (DMARD). TNFI monotherapy posed a 2.7-fold increase in risk of serious infection compared to DMARDs alone. In the fourth study, 10,838 IBD patients were followed for 9,849 person-years. Serious infection rates were 5.25/100 person-years for TNFIs and 3.59/100 person-years for immunomodulators (methotrexate and thiopurines). New use of TNFI monotherapy was associated with a 1.36-fold higher risk of serious infection compared to immunomodulator initiation. The risk of serious infection differed by individual TNFIs and route of administration. This dissertation characterized the utilization of TNFIs and indicated that a more aggressive treatment approach has emerged for children and young adults with JIA/RA and IBD despite an FDA warning about TNFI-associated serious infections. However, study findings support the warning for children with JIA and IBD. This dissertation provides insights into how TNFIs are being used and informs decision-making about use of these drugs–particularly regarding balancing the benefits and risks of TNFIs.