In this nested case-control study in a population-representative medical records database from the United Kingdom, children with newly diagnosed juvenile idiopathic arthritis (JIA) were compared with age- and gender-matched control subjects randomly selected from general practices containing at least one case, excluding those with inflammatory bowel disease, immuno-deficiency, or other systemic rheumatic diseases. Conditional logistic regression was used to examine the association between antibacterial antibiotics (including number of antibiotic courses and timing) and JIA after adjusting for significant confounders. Any antibiotic exposure was associated with an increased rate of developing JIA [adjusted OR 2.1 (95% CI 1.2, 3.5)]. This relationship was dose dependent [adjusted OR over 5 antibiotic courses 3.0 (95% CI 1.6,5.6)], strongest for exposures within 1 year of diagnosis, and did not substantively change when adjusting for number or type of infections. In addition, antibiotic-treated upper respiratory tract infections were more strongly associated with JIA than untreated upper respiratory tract infections. The authors concluded that antibiotics were associated with newly diagnosed JIA in a dose- and time-dependent fashion. Antibiotic exposure may play a role in JIA pathogenesis, perhaps mediated through alterations in the microbiome.

Relevance: Juvenile idiopathic arthritis (JIA) is globally recognized as the commonest chronic musculoskeletal disease affecting children [1]. The individual and societal impacts of this chronic condition on quality of life, productivity and health-care costs have been well documented [1,2]. Although it is well recognized as an autoimmune condition, its precise etiology and the complex interplay of factors causing and/or worsening the clinical condition are unclear. A certain degree of similarity is anticipated in the causal pathway of diverse conditions that broadly fit under the umbrella of autoimmune diseases. It is therefore not surprising that perturbations though to be involved in inflammatory bowel disease, type I diabetes mellitus, celiac disease would be explored in rheumatic conditions as well. This recent publication [3] reported a case-control study exploring the relationship between usage of antibiotics in early childhood and the subsequent diagnosis of JIA.

Critical appraisal: The case-control study design is used to study association between exposure to ‘risk factors’ and the occurrence of disease. Briefly, it involves recruitment of people with the outcome of interest (disease) designated as cases, and those without the outcome (disease) designated as controls; and working backwards in time to identify their exposure status. This design is especially useful to study relatively rare outcomes (diseases) particularly if the time period between exposures to outcome is long. Although it is placed relatively low on the evidence hierarchy [4] on account of high susceptibility to bias, it is an excellent design to study the effect of risk factors to which research participants cannot be ethically exposed. There are several tools available for critical appraisal of case-control studies, but in general they revolve around step-wise evaluation of three issues viz appraisal of validity, assessment of results and exploration of local applicability. Appraisal using such tools is summarized in Tables I and II [5,6].

The investigators used several methodological refinements to minimize bias and provide robust results. They also tried to distinguish the effect of antibiotics from the effect of infections, which was missing in the previous study [7]. They considered several sources of bias and confounding; and attempted to address them effectively. For these reasons, the data from this study are considered reliable. However, inexplicably Table I shows a total of 1672 participants (152 cases + 1520 controls) at one place but only 1662 (1280 exposed + 382 unexposed) at another place. The investigators did not consider subgroup analyses base on different types of JIA.

Overall this well-conducted study suggests that antibiotic usage in childhood is associated with a greater risk of developing JIA in later childhood. In contrast, there are three well-known pieces of information that complicate the puzzle. First, if antibiotics are responsible for causation of JIA, it follows that health-care systems where childhood antibiotic use is rampant (India is a classic example) should witness the highest incidence/prevalence of JIA. Unfortunately, there is no robust population-based prevalence data in India to support or refute this. However, there is a single study [8] evaluating prevalence of musculoskeletal symptoms in school children (6-17 y) where one case of JIA was identified among 2059 children studied. From this, the authors calculated a population prevalence of 48.5/100,000 school children. A similar study in Oman reported a prevalence of 20 per 100,000 [9]. In contrast, the prevalence in developed countries is variably reported to range from 100-400 per 100,000 (A), although more recent estimates suggest 50-60/ 100,000 in one region of the USA [10], 90/100,000 in Sweden (L), and 33.5/100,000 in this study [3]. Of course, the limited Indian data cannot be reliably compared with other studies on account of methodological differences; however clinical experience also does not suggest an unusually high burden of JIA.

If early [7] and more recent [3] antibiotic exposure increase the risk of developing JIA, it would be expected that countries with high burden of neonatal sepsis (such as India) would have very high burden of JIA, and that too presenting at a relatively younger age.

Further, there is no data from developed or developing countries to suggest that population subgroups exposed to greater frequency and/or duration of antibiotics (such as children with primary or secondary immune deficiencies) have higher prevalence of JIA. Of course, the reverse has been noted i.e children with JIA (or other autoimmune conditions) have greater frequency of infections requiring antibiotics [11]. Some authors have reported co-existing JIA and primary immune deficiencies [12-15] , but it is unclear which came first, although there is a report of a small cohort of 25 primary immune-deficiency patients in Turkey who were observed to later develop (rather be diagnosed with) diverse auto-immune conditions [16].

One other issue is that most auto-immune diseases (including JIA) have a female preponderance, whereas antibiotic exposure is generally gender independent. All these points suggest that while antibiotic usage could contribute, it is unlikely to be the absolute cause of development of JIA.

Extendibility: The study setting, population characteristics (ethnicity, genetic background, environmental exposures, etc) and health-care system are very different from our country. However, the conclusion that antibiotic usage could be linked to JIA appears extendible to India also. Unfortunately, the contrary pieces of evidence complicate the picture, making it difficult to draw a firm conclusion. Nevertheless, it goes without saying that unnecessary antibiotic use must be restricted to the maximum extent possible. Further, all antibiotic therapy must be well documented in terms of indication, drugs used, dosage and duration.

Conclusions: This well-designed case-control study suggests that antibiotic use in early childhood could have a dose-dependent impact on subsequent development of JIA.

1. Kumar S. Need for determining the incidence and prevalence of JIA in developing countries: the Indian predicament. Rheumatology. 2010;49:1598-9.

2. Minden K, Niewerth M, Listing J, Möbius D, Thon A, Ganser G, et al. The economic burden of juvenile idiopathic arthritis-results from the German paediatric rheumatologic database. Clin Exp Rheumatol. 2009;27:863-9.

3. Horton DB, Scott FI, Haynes K, Putt ME, Rose CD, Lewis JD, et al. Antibiotic Exposure and Juvenile Idiopathic Arthritis: A Case-Control Study. Pediatrics. 2015;136:e333-43.

4. No authors listed. Oxford Centre for Evidence-based Medicine – Levels of Evidence (March 2009). Available from: http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed September 14, 2015.

5. Critical Appraisal Skills Programme (CASP): 11 questions to help you make sense of a case control study. Available from: http://media.wix.com/ugd/dded87_63fb65dd4e0548 e2bfd0a982295f839e.pdf. Accessed September 14, 2015.

6. No authors listed. The Bradford Hill Criteria. Available from: http://www.southalabama.edu/coe/bset/johnson/bonus/Ch11/Causality%20criteria.pdf. Accessed September 14, 2015.

7. Arvonen M, Virta LJ, Pokka T, Kröger L, Vähäsalo P. Repeated exposure to antibiotics in infancy: a predisposing factor for juvenile idiopathic arthritis or a sign of this group’s greater susceptibility to infections? J Rheumatol. 2015;42:521-6.

8. Abujam B, Mishra R, Aggarwal A. Prevalence of musculoskeletal complaints and juvenile idiopathic arthritis in children from a developing country: A school-based study. Int J Rheum Dis. 2014;17:256-60.

9. Abdwani R, Abdalla E, Al Abrawi S, Al-Zakwani I. Epidemiology of juvenile idiopathic arthritis in Oman. Pediatr Rheumatol Online J. 2015;13:33.

10. Krause ML, Crowson CS, Michet CJ, Mason T, Muskardin TW, Matteson EL. Juvenile idiopathic arthritis in Olmsted County 1960-2013. Arthritis Rheumatol. 2015;Aug 28:doi: 10.1002/art.39323. (Epub ahead of print)

11. Salonen PH, Säilä H, Salonen JH, Vuorela M, Kautiainen H, Lyytikäinen O, et al. Bloodstream infections among children with juvenile idiopathic arthritis: a prospective study from the onset of disease. Clin Exp Rheumatol. 2014;32:979-83.

12. Patiroglu T, Akar HH, Gunduz Z, Sisko S, Ng YY. X-linked agammaglobulinemia in two siblings with a novel mutation in the BTK gene who presented with polyarticular juvenile idiopathic arthritis. Scand J Rheumatol. 2015;44:168-70.

13. Váncsa A, Tóth B, Szekanecz Z. BTK gene mutation in two non-identical twins with X-linked agammaglobulinemia associated with polyarticular juvenile idiopathic arthritis. Isr Med Assoc J. 2011;13:579-80.

14. Abolhassani H, Amirkashani D, Parvaneh N, Mohammadinejad P, Gharib B, Shahinpour S, et al. Autoimmune phenotype in patients with common variable immunodeficiency. J Investig Allergol Clin Immunol. 2013;23:323-9.

15. Ludvigsson JF, Neovius M, Hammarström L. Association between IgA deficiency & other autoimmune conditions: A population-based matched cohort study. J Clin Immunol. 2014;34:444-51.

16. Patiroglu T, Gungor HE, Unal E. Autoimmune diseases detected in children with primary immunodeficiency diseases: Results from a reference centre at middle anatolia. Acta Microbiol Immunol Hung. 2012;59:343-53.

Joseph L Mathew

In this paper, Horton, et al. make a compelling case for implicating antimicrobials with evolution of juvenile idiopathic arthritis (JIA). A recent study from another center also showed an association, albeit indirect, with JIA [1]. JIA remains the commonest rheumatic disease of childhood and is associated with significant morbidity.

There is no gainsaying the fact that antimicrobials are frequently misused in children. It is also known that use of antimicrobials in early childhood significantly alters the human microbiome and may predispose to long-term and, seemingly unrelated, consequences. These include, amongst others, inflammatory bowel disease and obesity [2-4].

In this study, authors suggest that use of antimicrobials in children may have some role to play in the pathogenesis of JIA. Their conclusion is based on a nested case-control study from the United Kingdom conducted on an apparently ‘population-representative medical records database’. The data, however, need to be interpreted with some caution. JIA is a complex clinical entity [5,6]. Its etiology remains unknown and the pathogenesis poorly understood. It must also be understood that JIA is by no means a single disease entity but a conglomerate of disparate clinical conditions having chronic arthritis as the common denominator. Further, each of these conditions may have a different etiology [5,6]. At least two types of JIA are considered to be rather distinctive in their clinical presentation and pathogenesis. For instance, it is now well known that systemic JIA (sJIA) is more of an autoinflammatory rather than an autoimmune disorder [7]. Similarly the clinical phenotype of enthesitis related arthritis (ERA) is very different from, say, polyarticular or oligoarticular JIA. ERA has a distinct association with preceding gastrointestinal or genito-urinary infections while the other types of JIA do not [8,9]. Horton, et al. do not specify how many of their patients had sJIA or ERA. It is difficult to interpret the data in absence of this information. It may perhaps have been more prudent to exclude these two categories of JIA from final analysis.

Nevertheless paediatricians, and especially paediatric rheumatologists, would do well to keep the results of this study in mind the next time they see a child with JIA, and the next time they consider prescribing an antimicrobial to a child!

1. Arvonen M, Virta LJ, Pokka T, Kröger L, Vähäsalo P. Repeated exposure to antibiotics in infancy: a predisposing factor for juvenile idiopathic arthritis or a sign of this group’s greater susceptibility to infections? J Rheumatol. 2015; 42:521-6.

2. Conte MP, Schippa S, Zamboni I, 　Penta M,　Chiarini F,　Seganti L, et al. Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease. Gut. 2006;55:1760-7.

3. Bailey LC,　Forrest CB,　Zhang P,　Richards TM,　Livshits A,　DeRusso PA. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr.　2014;168:1063-9.

4. Jernberg C, Löfmark S,　Edlund C,　Jansson JK. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology. 2010; 156:3216-23.

5. Consolaro A, Varnier GC, Martini A, Ravelli A. Advances in biomarkers for paediatric rheumatic diseases. Nat Rev Rheumatol. 2015;11:265-75.

6. Hersh AO, Prahalad S. Immunogenetics of　juvenile idiopathic arthritis: A comprehensive review. J Autoimmun. 2015; Aug 21:doi: 10.1016/j.jaut.2015.08.002. [Epub ahead of print]

7. Martini A. Systemic juvenile idiopathic arthritis. Autoimmun Rev. 2012; 12:56-9.

8. Ramanathan A,　Srinivasalu H,　Colbert RA. Update on juvenile spondyloarthritis. Rheum Dis Clin North Am　2013; 39:767-88.

9. Stoll ML, Kumar R, Morrow CD, 　Lefkowitz EJ,　Cui X,　Genin A, et al. Altered microbiota associated with abnormal humoral immune responses to commensal organisms in enthesitis related arthritis. Arthritis Res Therap. 2014;16:486.

Surjit Singh

Investigators have used the Health Improvement Network, a population-based medical records database in the United Kingdom that contains comprehensive diagnostic and outpatient prescription data, to identify people younger than 16 years of age who were newly diagnosed with arthritis. The 152 children with juvenile arthritis were matched, for age and sex, with 1520 control subjects from general practices in the United Kingdom. They looked for antibiotic prescriptions in these 152 children in the last one year. The risk of developing arthritis was found to increase as exposure to antibiotics increased. However, there was no association between the development of arthritis and exposure to nonbacterial antimicrobial agents, including antifungal and antiviral drugs. After adjustment for the number and type of infections children had, the associations did not change significantly. The age at which children were exposed to antibiotics also had no significant effect on the associations.

Authors suggest that alterations in the human microbiome might be implicated in the development of autoimmune diseaases; and that includes inflammatory bowel disease and rheumatoid arthritis and perhaps psoriatic arthritis; all of which have some common features with juvenile arthritis. If the association between antibiotics and juvenile arthritis is true, judicious use of antibiotics might be one of the few ways we have to prevent JIA and other autoimmune diseases.