Funding

NIH - R01AR074436

Antibiotics, Juvenile Idiopathic Arthritis, and Antirheumatic Treatment Response

Funder: National Institutes of Health , National Institute of Arthritis and Musculoskeletal and Skin Diseases

PI: Daniel Horton, Rutgers University

Period of Performance: August 15, 2019 - June 30, 2023

Objectives

Antibiotics are overprescribed in pediatric populations, and antibiotic-exposed children can have signs of gut microbiota imbalance (dysbiosis) for months to years afterwards. Gut microbiota play key roles in immune development and function. Correspondingly, dysbiosis and early childhood antibiotic exposure have been implicated as potential causes of juvenile idiopathic arthritis (JIA). Studies on antibiotics and JIA have been restricted to two European populations of mostly young children, and their findings need replication and deeper examination in broader, more diverse populations. The use of conventional and biologic disease-modifying antirheumatic drugs (DMARDs) has vastly improved outcomes for children with JIA, but response to specific drugs is variable and difficult to predict. Methotrexate (MTX), the most common DMARD used to treat JIA, is toxic to certain commensal bacteria found in higher abundance in children with JIA. Moreover, early evidence suggests that certain gut microbiota can metabolize MTX, and adults with rheumatoid arthritis who respond poorly to MTX may have different gut microbiota from responders. There is a critical need to understand better how a potentially modifiable factor—antibiotic exposure—affects variability in JIA incidence, phenotype, and therapeutic response to DMARDs such as MTX so that children receive appropriate, effective medicines. This project’s long-term goal is to ensure that all children with JIA receive effective and safe treatment and to identify new modalities for JIA treatment and prevention. 

 

The overall objective of this proposal is to understand how antibiotics affect the risk of developing JIA and the response to standard JIA treatments. This project will (1) test how patterns of antibiotic exposure relate to incident JIA and JIA phenotype and (2) determine whether recent antibiotic exposure in children with JIA starting DMARDs is associated with early changes in therapy. The central hypothesis is that antibiotic exposure increases the risk of JIA and impairs the therapeutic response to MTX more than to other DMARDs, such as tumor necrosis factor inhibitors. 

 

The project team will use administrative claims data to conduct retrospective cohort studies on the effects of antibiotic exposure in large, diverse general pediatric populations (AIM 1) and in patients with JIA starting MTX and other DMARDs (AIM 2). The proposed research will yield novel and important information about the potential risks of antibiotics in relation to the most common pediatric rheumatic disease and standard antirheumatic drugs. This research will produce critical clues about underlying mechanism for potentially differential responses to specific DMARDs. Furthermore, this project will lay important foundations for future interventions to limit infections and inappropriate antibiotic use in children and potentially to manipulate microbiota in order to treat or prevent JIA and promote DMARD effectiveness and safety.
 

Supported Publications that Include Dr. Parlett

• Rege S , Parlett LE , Neikirk AL et al . New diagnoses of juvenile idiopathic arthritis early in the COVID-19 pandemic analysis of a large United States commercial insurance database .J Clin Rheumatol. 2025; 31 (1) : 40-4 . doi: 10.1097/RHU.0000000000002154 .
• Horton DB , Parlett LE , Huang C et al . Jia diagnoses and trends from 2006-2019: has the U.S. ICD-9-to-ICD-10 transition created coding artifacts? . Poster presented at: 2021 American College of Rheumatology ACR Convergence; November 05 - November 09, 2021; Virtual . https://acrabstracts.org/abstract/jia-diagnoses-and-trends-from-2006-2019-has-the-u-s-icd-9-to-icd-10-transition-created-coding-artifacts/ .
• Horton DB , Yang Y , Neikirk AL et al . Impact of the COVID-19 pandemic on the management of juvenile idiopathic arthritis: analysis of United States commercial insurance data .J Clin Rheumatol. 2023; 29 (8) : 388-95 . doi: 10.1097/RHU.0000000000002035 .
• Horton DB , Neikirk AL , Yang Y et al . Childhood asthma diagnoses declined during the COVID-19 pandemic in the United States .Respir Res. 2023; 24 (1) : 72 . doi: 10.1186/s12931-023-02377-7 .