Why antibiotic use in kids may lead to JIA

July 30, 2015

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As if antibiotic resistance wasn’t problem enough, researchers now believe antibiotic use may play a role in the development of juvenile idiopathic arthritis (JIA).

When penicillin was accidentally discovered almost 90 years ago, it made formerly life-threatening illnesses and infections treatable. Then decades of antibiotic overuse contributed to new problems, such as multidrug resistant organisms.

Now, some believe antibiotic overuse may also be causing disease development through the disturbance of the body’s microbiome. Specifically, researchers say there may be a link between the onset of JIA and antibiotic use.

A new study found that children who were prescribed antibiotics were twice as likely to develop JIA as children who did not receive antibiotics, and risks were highest in the first year after the antibiotic use and as the number of antibiotic courses increased, according to Daniel B. Horton, MD, MSCE, a research fellow with the Rutgers Biomedical and Health Sciences Child Health Institute of New Jersey and lead author of the new report.

“The overuse of antibiotics directly contributes to the development of resistant pathogens, and the emergence of bacterial resistance is a public health threat associated with significant morbidity and mortality,” add Jennifer L. Goldman, MD, MS, and Mary Anne Jackson, MD, of the Children’s Mercy Hospital and Clinics and the University of Missouri-Kansas City, in a commentary accompanying Horton’s paper in Pediatrics. “However, bacterial resistance is not the only unintended consequence of antibiotic overuse. Alterations in the intestinal flora can result in an immune misbalance leading to immune dysregulation and inflammation. Because antibiotic exposure results in significant intestinal dysbiosis, the relationship between antibiotic use and the development of chronic diseases has been investigated, with some convincing evidence directly associating antibiotic exposure with obesity and inflammatory bowel disease,” they write.

More than 2 million illnesses and 23,000 deaths are attributed to antibiotic resistance each year, according to the Centers for Disease Control and Prevention (CDC). As if that is not enough cause for concern, Horton’s research brings up new concerns, although he cautions that the connection between JIA and antibiotic use is not yet confirmed.

“Certain infections could trigger JIA in some children. In addition, children diagnosed with JIA could have abnormalities in their immune system well before their diagnosis,” Horton says. “Such abnormalities might make these children more susceptible to serious infections, which lead to more early antibiotic exposure. Under either alternative scenario, antibiotics would be a marker, rather than a direct cause, of arthritis. These issues need to be the subject of more research.”

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It may be difficult to pin down the cause of JIA, because the etiology of the disease-the most common rheumatic diagnosis in children-remains unclear. Genetics account for only 10% to 25% of cases, and environmental triggers such as viral infections have not been confirmed. Horton says he wanted to study the connection between JIA and antibiotics further after a previous study linked hospitalization in the first year of life to an increased risk of JIA.

“Disturbance of the human microbiome has been implicated in the development of chronic pediatric diseases, including inflammatory bowel disease (IBD). At least 1 category of JIA has been associated with distinct intestinal microbial populations,” Horton writes.

The study also notes that antibiotics have been shown to alter intestinal microbiota for up to 6 months.

For this study, 152 cases of JIA diagnosed in a cohort of 454,457 children were studied. Study subjects were aged 1 to 15 years and enrolled in an electronic medical records database in the United Kingdom shortly after birth that tracked their lifetime prescriptions. The researchers analyzed medications against the first JIA code in the database for each patient. They found that previous autoimmunity was prevalent among the JIA patients, who commonly had a history of infection and hospitalization for infection as well as outpatient visits. Horton says mothers of the study participants diagnosed with JIA also were nearly twice as likely to have autoimmune diseases.

After filtering JIA diagnoses against other autoimmune conditions and other factors, the research team found that just 1 antibiotic prescription was associated with an increased risk of developing JIA. Infection type related to the antibiotic usage did not impact the association, but additional antibiotic courses increased the magnitude of the association, according to the study. Additionally, antibiotics prescribed 6 months to 1 year prior to the first JIA symptom showed the strongest association, but infections left without treatment by antibiotics were not at all associated with JIA diagnosis throughout the study.

These associations suggest antibiotics play a role in the pathogenesis of JIA, Horton says.

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“This public health finding is potentially important, considering that approximately one-quarter of antibiotics prescribed for children, and an estimated one-half of antibiotics for acute respiratory infections, may be unnecessary and potentially avoidable,” he writes in the study. “The human microbiome plays important roles in immune regulation and self-tolerance. Disturbance of the intestinal microbiome has been linked to several autoimmune diseases, including IBD, rheumatoid arthritis, and at least one category of JIA. . . . Our finding that antibiotic exposure is most strongly associated with JIA within 1 year of diagnosis (and 6 months of first symptom/referral) supports the hypothesis that antibiotic-induced microbiome dysregulation could precipitate JIA in children predisposed to this disease.”

The study also found that children with JIA are also at higher risk for infection, and Horton says it’s not clear whether more infections led to more antibiotics and triggered autoimmunity, or whether children with JIA have more illness because of immunity dysfunction and the antibiotics are merely a marker.

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As far as a theory for how antibiotic use could lead to JIA, Horton says researchers are still unsure.

“At this point in time, the mechanism by which antibiotics might contribute to the development of arthritis is unclear. Antibiotic use has been linked to other childhood diseases, such as [IBD]. People with [IBD] can have abnormal populations of microbes (bacteria, viruses, etc) in the gut that seem to relate to abnormalities in the intestinal immune system,” he says. “Early evidence suggests that some children with certain forms of arthritis may also have different populations of gut bacteria compared to other children. It is too early to say whether these bacterial differences, and our findings on antibiotics, reflect underlying pathophysiology or chance associations.”

Although the pathophysiology remains uncertain, Horton says 1 thing is clear-pediatricians should prescribe antibiotics with care.

“A majority of children receive antibiotics, but only about 1 in 1000 children have arthritis. So even if antibiotics do contribute to the development of arthritis, it’s clearly not the only factor,” Horton says. “That said, we need to acknowledge that antibiotics have a long-and growing-list of potential downsides, both short-term side effects (including fever and allergic reactions) and long-term risks (such as drug resistance and possibly the development of various chronic diseases). These collective risks need to be weighed against the potential benefits whenever antibiotics are prescribed.”

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Goldman agrees, noting that about 150,000 emergency department visits each year are attributed to antibiotic-associated adverse events in the United States alone. “The burden on the healthcare system, patients, and families should not be underestimated when a child prescribed an unnecessary antibiotic develops an unanticipated adverse drug event requiring immediate medical attention,” Goldman and Jackson write in their commentary. “Similarly, development of a Clostridium difficile infection after an unneeded course of antibiotic can result in significant morbidity and even mortality. Although some may argue that these unintended consequences are relatively infrequent, the risk of developing a complication from an untreated upper respiratory infection is even rarer.”

Goldman says Horton’s study and her commentary highlight the importance of the unintended consequences of antibiotic use. She says antibiotics are prescribed at 1 in 5 pediatric ambulatory visits, and more than 10 million of those prescriptions are for maladies for which antibiotic therapy is not necessary, such as viral infections.

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“Antibiotics are life saving and enable clinicians to effectively treat infections in our patients. However, inappropriate antibiotic prescribing occurs frequently,” Goldman says. “In cases where antibiotics are unneeded, we are placing our children at unnecessary risk of well-recognized undesired complications of antibiotics: gastrointestinal distress, Clostridium difficile infection, idiosyncratic drug reactions such as rash, and the development of resistant bacteria that will be more difficult to treat in the future. More recent data suggest that we are likely unaware of other unintended consequences of antibiotics, and an association between antibiotic use and chronic diseases such as obesity and arthritis have been described.”

Goldman, like Horton, calls for additional research on the JIA connection to antibiotic use, and Goldman says pediatricians should work to adhere to CDC guidelines on prescribing antibiotics for children in the outpatient setting.