COMMENTARY

Can Antibiotics Increase Risk for Juvenile Arthritis?

Laurie Scudder, DNP, NP; Daniel B. Horton, MD, MSCE

Disclosures

August 25, 2015

The Microbiome, Antibiotics, and Autoimmune Disease

Editor's Note:
The effect of antibiotic exposure on the infant gut microbiome is increasingly well recognized, and a growing body of evidence has linked this association with autoimmune conditions. A recently released retrospective study[1] conducted in children with newly diagnosed juvenile idiopathic arthritis (JIA) provided yet more evidence, finding that antibiotics were associated with newly diagnosed JIA in a dose- and time-dependent fashion.

Medscape spoke with Daniel B. Horton, MD, MSCE, a pediatric rheumatologist and postdoctoral research fellow working in the Department of Pediatrics at Rutgers Robert Wood Johnson Medical School. Dr Horton served as lead investigator of this study.

Medscape: What were the theoretical underpinnings of your study? How did you come to explore the relationship among antibiotics, autoimmune disease, and the disrupted microbiome?

Dr Horton: An increasing body of research has suggested a role of microbiome imbalance in the development of various chronic diseases, such as obesity; cardiovascular disease; and diseases of the immune system, including inflammatory bowel disease and different forms of arthritis in adults, including rheumatoid arthritis.[2]

Several papers showed a connection between antibiotic exposure in early childhood and the development of what we think are microbiome-related diseases, including pediatric obesity[3,4] and pediatric inflammatory bowel disease.[5,6] We also know clinically that arthritis is more common in people with inflammatory bowel disease and vice versa.[7] For these reasons, we decided to look at whether antibiotics were associated with arthritis in children.

Findings: Antibiotic Exposure and JIA

Medscape: You used a case/control design that relied on retrospective data in a medical database. Can you briefly describe your methodology and steps taken to ensure complete information?

Dr Horton: We were fortunate to have access to an electronic medical record database called The Health Improvement Network (THIN). This database has relatively comprehensive anonymous health data on demographics; diagnoses; and drug prescriptions, including antibiotics, for people who have received care from general practitioners across the United Kingdom. These data date back two decades or more, so there is a lot of rich clinical information to look at the relationship between drug exposure and various diseases of interest.

We first whittled all of these patients down to children who were registered in the database at or soon after the time of birth, so that we could study most of the antibiotic prescriptions that they received. In a group of about 450,000 children, we identified 152 who were diagnosed with JIA between 1 and 15 years of age, using a set of diagnosis codes that were previously shown to be valid in this setting.

For comparison, we randomly matched each child with JIA to 10 other children of the same gender who didn't have JIA and who were born around the same time. In this way, we could study a lifetime of infections and antibiotic exposures while controlling for age-related differences in the number of infections that children get.

Medscape: The main finding was an association between antibiotic use and later development of JIA. However, children with JIA have a higher incidence of infections. Could antibiotic use have merely been a marker for infection, and antibiotic use was higher in these children owing to unrecognized JIA? How were you able to control for confounding by infection?

Dr Horton: It's absolutely true that the association could just be a marker of infection in children at high risk of developing infections rather than evidence of a causal relationship. From the beginning, we sought to perform a variety of analyses with the aim of teasing apart this question.

Several analyses suggested that our findings were specific to antibiotics rather than the drugs being a simple marker of infection. I'll go through a few of them.

We adjusted for infection in the same models that we used to look at antibiotics. We know that children can have infections without receiving antibiotics, and occasionally children are given antibiotics for reasons other than infection. In these models, antibiotic exposure was a stronger risk factor for JIA than infections. We also tried to account for differences in types of infections and number of infections that children had in their lifetime. These models did not change the relationship that we found between antibiotics and arthritis.

When we looked at the timing of antibiotics and infections relative to diagnosis of JIA, children with arthritis were more likely to have received antibiotics recently but were not more likely to have had recent untreated infections. We classified cases by the time of the last antibiotic exposure: the past 6 months, 6-12 months earlier, 12-24 months earlier, and more than 24 months earlier.

When we looked at drugs that were used to treat nonbacterial infections (those caused by viruses or fungi), we saw no association between these drugs and JIA.

Finally, when we categorized infections as either treated with antibiotics or untreated, only the antibiotic-treated infections were associated with JIA. This was true even when we looked at upper respiratory tract infections that may not have warranted antibiotic treatment—a strong piece of evidence that antibiotic exposure, rather than infection, was the key factor.

Only one supplementary analysis supported the idea of antibiotics as a marker. Among children who never received antibiotics, those who developed JIA had an increased risk for recent infections. However, this analysis included just a small number of children—only 19 with JIA—and for technical reasons, it wasn't as rigorous as the main analyses.

So overall, many more analyses suggested that our findings were more specific to antibacterial antibiotics themselves rather than to infections in general or specific types of infections. But, having said that, it was still an observational study with all of its limitations, and we can't reach an absolute conclusion without more research.

Which Antibiotics Are Associated With JIA?

Medscape: Did you find any differences in rates of JIA according to antibiotic class?

Dr Horton: We did look at differences according to antibiotic class and spectrum of activity, because previous studies had shown that drugs targeting anaerobic bacteria were more strongly linked to inflammatory bowel disease in children, presumably because of their stronger effects on gut microbes. But we couldn't detect any differences among different drug classes or on the basis of antibacterial spectrum with respect to the risk for JIA.

However, the effect of antibiotic class wasn't one of our main research questions, and our study wasn't powered to address this issue specifically. A study conducted in Finland[8] had very similar findings to our own, with a positive association between early childhood antibiotic exposure and JIA. That study showed a particularly strong association among children who received clindamycin, which does have strong anti-anaerobic activity.

Questions about which drugs and which classes of drugs are associated with JIA are definitely important, and deserve future attention.

Medscape: What about age, race, sex, and other demographic variables? Was the association more prominent in any particular subgroup of children?

Dr Horton: It's definitely important to think about what subgroups might be more susceptible to any drug-related adverse event. We were somewhat limited in our ability to draw conclusions about demographic differences, in part because of the relatively small size of the study. We did look at age of diagnosis as a modifying factor but could not draw any firm conclusions because the majority of the children were around the same age (≤5 years).

The database that we used doesn't have a great record of race and ethnicity, so our study was limited with respect to those variables. We did not look specifically at differences based on sex, but it's an important consideration for future studies.

Mechanisms: The Issue of Timing

Medscape: One of your conclusions was that in addition to a dose-dependent relationship, there was a time-dependent relationship between antibiotic exposure and JIA. Antibiotics prescribed within 1 year of diagnosis showed the strongest association. How can that information be used in practice? Is it reasonable to monitor children differently after a course of antibiotics?

Dr Horton: In the big picture, I don't think we need to change our monitoring strategies. We need to reinforce the fact that antibiotics can have both short-term and long-term adverse effects. A majority of children receive antibiotics at some point in their lives, yet a very small proportion—about 0.1%—develop JIA. Children are at greater risk for other short-term side effects, such as diarrhea or rash, than of developing arthritis.

However, the issue of timing is important in thinking about the mechanism of this relationship. Other studies that looked at obesity and inflammatory bowel disease in children showed that very early exposures—in the first year or two of life—might increase the risk of developing these diseases more than later exposures. We think this could be related to disruption of microbial populations at a critical time when they are developing and interacting with the immune system and with metabolic pathways, which can lead to later health problems in some children.

To our surprise, we didn't find any relationship between JIA and the timing of first antibiotic exposure. On the other hand, the timing of the last antibiotic exposure seemed to be important in our study, given that children who developed arthritis were more likely to do so within 6-12 months of the last antibiotic course.

In thinking about this mechanistically, in most people, the communities of bacteria rebound within a relatively short amount of time—weeks, or perhaps a couple of months—after taking antibiotics. But we also know that antibiotics can cause longer-lasting changes in the bacterial communities of some people for 1 year or longer, particularly after repeated exposures.

If we assume that antibiotics disrupt bacterial populations and that bacterial disturbance adversely affects the immune system in susceptible people, we might expect to see the strongest effects of antibiotic-associated immune dysfunction within some limited period after taking antibiotics. And in fact, we saw this kind of pattern in our data. This is all speculation, of course, and these findings need to be replicated and studied further.

Medscape: In your paper, you and your colleagues caution that although your study documents an association between antibiotic use and later development of JIA, it does not prove causality. What should be the next step from a research perspective in exploring this issue further?

Dr Horton: It's impossible to do a randomized study to answer this question, so the next best thing is good observational epidemiologic and translational research. We now have two studies[1,8] suggesting a relationship between antibiotics and childhood arthritis, but it is still reasonable to look for other studies that can confirm this association in other large populations of children. Such studies might be better able to look at demographic risk factors, differences among drug classes, and perhaps even differences among types of arthritis, because ultimately JIA is a family of different diseases that share a common characteristic of chronic joint inflammation in young people.

We also need better translational research to look at the mechanisms behind this epidemiologic association.

Clinical Implications

Medscape: You found that children diagnosed with JIA were more likely to have mothers with autoimmune disease. Should a family history of autoimmune disease influence the clinician's decision to prescribe antibiotics in pediatric infection?

Dr Horton: I would say that antibiotic stewardship is as important for children with autoimmune problems in the family as with other children. We didn't show that the risk with antibiotic exposure was magnified in children with mothers who had autoimmune diseases, only that antibiotic exposure and family history of autoimmunity seemed to be independent risk factors.

Given how small the absolute risk for arthritis is after antibiotic exposure, even if the relationship is causal, at this point I don't think family history should strongly influence how we make the decision of whether to prescribe antibiotics, compared with all the other factors that go into this decision.

Medscape: Does your study provide any insight with respect to potential dietary or prebiotic/probiotic approaches that could be considered when treating children with antibiotics?

Dr Horton: It's an important question, and one that many parents wonder about when their child receives antibiotics. I thought about the same thing when my son was prescribed antibiotics a couple of weeks ago. The truth is, we need a lot more information about the mechanism of our findings and about the role of dietary and prebiotic/probiotic approaches before we can make any kind of recommendations about that.

Medscape: What is the next step, clinically? Should your study change practice, and if so, how?

Dr Horton: I don't think that our findings alone should change practice. We simply don't have enough information yet about what our findings mean or the mechanism connecting antibiotics and arthritis in children. But we need to acknowledge that antibiotics do have a long and growing list of potential downsides—both short-term side effects, such as fevers, allergic reactions, and Clostridium difficile infections, and long-term risks, such as drug resistance and possibly the development of various chronic diseases.

Although we aren't quite at the point where we can quantify all of these risks, in a general sense, we need to weigh them with the potential benefits of antibiotics whenever they are prescribed. Sometimes children definitely need antibiotics, other times they definitely don't, and sometimes it's just unclear. Parents need enough information to make informed decisions for their kids. And they need a good follow-up plan in case things don't go as expected.

On a systems level, antibiotic stewardship programs have been shown to be effective both in the inpatient and outpatient settings to limit unnecessary antibiotic prescribing and facilitate more appropriate drug choices. Even if antibiotics ultimately are just a marker for autoimmune disease rather than a cause, we already know enough about antibiotic overprescribing and the harms of antibiotics to say that there is a role for these kinds of programs.

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