Do Antibiotics Have a Role in the Pathogenesis of Juvenile Arthritis?

Horton DB, Scott FI, Haynes K, et al. Antibiotic exposure and juvenile idiopathic arthritis: a case-control study. Pediatrics. 2015;136(2):e333-e343.

It is apparent that disruption of the human microbiome can play a role in the development of chronic pediatric diseases such as inflammatory bowel disease and juvenile idiopathic arthritis (JIA). What has not been fully explored are the concept of antibiotic timing or further differentiating the effects of antibiotics on the microbiome from the effects of the infection.

To examine this relationship further, Daniel B. Horton, MD, MSCE, and colleagues created a nested case control study using an electronic medical records database from the United Kingdom. This database contains information about the demographic characteristics, diagnoses, specialist and hospital referrals, and outpatient prescriptions of patients of more than 550 practices of U.K. general practitioners. The study period for each patient spanned from registration to the date of the first JIA diagnostic code. Ten control subjects were age- and gender-matched to each case subject at the index date.

With each patient, antibiotic exposures were examined and characterized by type (antianaerobic vs non-antianaerobic, or individual class), date, and dose. Detailed studies of the route of metabolism of the medication and nonbacterial antimicrobial agents also were included. Antibiotic courses and hospitalizations within approximately a week of a documented infection were attributed to that infection. The effect of timing of the first and last antibiotic exposure during the study period was examined. The risk of treated and untreated upper respiratory infections also was studied to consider whether the infection itself rather than the antibiotics could be associated with the JIA diagnosis. The study used conditional logistic regression, accounting for matching. Sensitivity analyses were performed to rule out confounding factors.

Within this database of 454,457 children, 152 cases of JIA were diagnosed within 3.1 million person-years of follow up, reflecting an incidence of 4.9 occurrences per 100,000 person-years. Case subjects more commonly had a history of infection, hospitalization for infection, and more outpatient visits.

Even with adjustments for matching, autoimmune conditions, and previous infections, receiving one or more courses of antibiotics was associated with an increased risk of developing JIA. Adjusting for types or numbers of infection did not have a significant effect on the association. However, the magnitude of the association increased with additional antibiotic courses.

Antibiotics prescribed within 1 year of diagnosis of JIA showed the strongest association. In comparison, untreated infections were not associated with JIA during any time period. Interestingly, having multiple upper respiratory tract infections treated by antibiotics carried a strong association, no association was found between JIA and multiple untreated upper respiratory tract infections.

This thorough analysis suggests a possible role for antibiotic administration in the pathogenesis of JIA, possibly through microbiome dysregulation. It also gives further support to appropriate antibiotic stewardship, since some of these antibiotic prescriptions may have been unnecessary and their consequences avoidable.

Jessica Tomaszewski, MD, is an assistant clinical professor of pediatrics at the Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania, and a hospitalist pediatrician at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Delaware.

Charles A. Pohl, MD—Series Editor, is a professor of pediatrics, senior associate dean of student affairs and career counseling, and associate provost for student affairs at the Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania.