Juvenile idiopathic arthritis (JIA) includes several types of childhood arthritis involving chronic joint inflammation. This inflammation begins before patients reach the age of 16, with symptoms lasting at least 6 weeks to be considered chronic. JIA may involve one or many joints and can cause other symptoms such as fevers, rash and/or eye inflammation. JIA is an autoimmune rheumatic disease, meaning that it involves a malfunctioning immune system that causes inflammation.
The microbiome consists of trillions of microorganisms that reside in the mouth, intestines, skin and various other body surfaces, regulating metabolic and immune function. Dysregulation of the human microbiome may be involved in the development of autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease (IBD). In addition, early antibiotic use has been associated with IBD development in children. A study by researchers at the University of Pennsylvania in Philadelphia, Nemours A.I. duPont Hospital for Children in Wilmington, Delaware, and Rutgers Biomedical and Health Sciences in Newark, New Jersey, aimed to determine whether or not early antibiotic use might increase the risk of newly diagnosed JIA as well.
“The reasons why certain children develop JIA remain poorly understood. Previous studies have shown that genetics explains less than half of cases of JIA. Other studies have not consistently identified any one particular environmental trigger,” said Daniel Horton, MD, of Nemours and a lead author of the study. “Given the potential role of the microbiome and antibiotic use in the development of other pediatric autoimmune diseases, we aimed to determine whether antibiotics were associated with newly diagnosed JIA. This connection has not been reported in the scientific literature before and would provide additional evidence of the adverse effects of antibiotics in children. At the same time, such a study could reveal a new risk factor for a poorly understood chronic childhood disease.”
The research team conducted a case-control study using data from The Health Improvement Network, a United Kingdom population-based medical records database with comprehensive diagnostic and outpatient prescription data. They identified children with a new diagnosis of JIA before age 16 using validated diagnostic codes (positive predictive value 86 percent). Age- and sex-matched control subjects were randomly selected in a 10:1 ratio from general practices. Eligible subjects needed to be registered within three months of their birthdate. Individuals with prior IBD, immunodeficiency, autoimmune connective tissue disease or vasculitis were excluded. The association between antibiotic prescriptions and JIA diagnosis was determined by conditional logistic regression.
Using these methods, the research team identified 153 children diagnosed with JIA. Antibiotic exposure was associated with an increased risk of developing JIA after adjusting for confounders (adjusted odds ratio 2.6, 95 percent CI 1.5, 4.6). This risk increased with each additional prescription. These results did not significantly change when adjusting for the number or type of infections. Age of exposure did not significantly modify this association.
The researchers found a relationship between antibiotics and newly diagnosed JIA that was similar across different antibiotic classes, although notably use of non-bacterial antimicrobial agents (such as antifungal or antiviral drugs) was not associated with JIA. In order to ensure that the main finding was not just due to early symptoms of JIA, sensitivity analyses excluding data up to 12 months before the index date, the association between antibiotics and new diagnosis of JIA did not substantively change.
The study’s authors concluded that antibiotic exposure was associated with the development of JIA in a large population of children. This association was stronger for children exposed to multiple courses of antibiotics and appeared specific to antibacterial drugs alone. This study suggests that there is a role for antibiotic exposure in JIA disease pathogenesis, perhaps mediated through alteration in the microbiome.
"This study adds to a growing literature on the potential harms of antibiotic use in children. While antibiotics are certainly essential to treating some infections, these drugs are also overprescribed for other infections (frequently respiratory) that will usually resolve without treatment,” said Dr. Horton. “If the link between antibiotics and juvenile arthritis can be confirmed, antibiotic avoidance (in the right clinical situation) might be one of the few ways we have to prevent this life-changing disease. We still need to understand more about the biology that connects antibiotics, infections, the microbiome, genetics and chronic arthritis in children. Additional research in this area may also lead to novel ways of preventing and treating juvenile arthritis, similar to what is emerging now for inflammatory bowel disease.”
Funding sources for this study included the Rheumatology Research Foundation, National Institutes of Health: the National Institute of General Medical Sciences, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute of Diabetes and Digestive and Kidney Diseases.
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Paper Number: 929
Antibiotic Exposure and the Development of Juvenile Idiopathic Arthritis: A Population-Based Case-Control Study
Daniel B. Horton1, Frank I. Scott IV2, Kevin Haynes1, Mary E. Putt1, Carlos D. Rose3, James D. Lewis1 and Brian L. Strom4, 1Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 2Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA, 3Division of Rheumatology, Nemours A.I. duPont Hospital for Children, Thomas Jefferson University, Wilmington, DE, 4Rutgers Biomedical and Health Sciences, Newark, NJ
Background/Purpose: Dysregulation of the human microbiome has been implicated in the development of several autoimmune diseases, including rheumatoid arthritis and inflammatory bowel disease (IBD). Moreover, antibiotic exposure has been linked with the development of IBD in children. This study aimed to determine whether early antibiotic exposure increases the risk of incident juvenile idiopathic arthritis (JIA) in a general pediatric population.
Methods: A nested case-control study was conducted using The Health Improvement Network, a United Kingdom population-based medical records database with comprehensive diagnostic and outpatient prescription data. Children with incident JIA diagnosed before age 16 were identified by validated diagnostic codes (positive predictive value 86%). Age- and sex-matched control subjects were randomly selected with incidence density sampling in a 10:1 ratio from general practices taking care of at least 1 child diagnosed with JIA. Eligible subjects needed to be registered within 3 months of their birthdate. Individuals with prior IBD, immunodeficiency, autoimmune connective tissue disease, or vasculitis were excluded. The association between antibiotic prescriptions and JIA diagnosis was determined by conditional logistic regression.
Results: There were 153 children diagnosed with JIA in the study population (table 1). Any antibiotic exposure was associated with an increased risk of developing JIA after adjusting for confounders (adjusted OR 2.6, 95% CI 1.5,4.6) (table 2). This risk increased with the number of prescriptions in a dose-dependent manner. These results did not significantly change when adjusting for the number or type of infections. Age of exposure did not significantly modify this association. The relationship between antibiotics and incident JIA was similar across different antibiotic classes, although use of non-bacterial antimicrobial agents (e.g., antifungal, antiviral) was not associated with JIA. In sensitivity analyses excluding data up to 12 months before the index date, the association between antibiotics and incident JIA did not substantively change.
Conclusion: Antibiotic exposure was associated with an increased incidence of JIA in a dose-dependent fashion in a large pediatric population. This study implicates a role for antibiotic exposure in disease pathogenesis, perhaps mediated through alteration in the microbiome.
Disclosure: D. B. Horton, NoneF. I. Scott IV, NoneK. Haynes, NoneM. E. Putt, NoneC. D. Rose, NoneJ. D. Lewis, NoneB. L. Strom, None
Meeting Link: American College of Rheumatology Annual Meeting
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