Background/Purpose: Susceptibility to juvenile idiopathic arthritis (JIA) is presumed to be determined by the interplay of genes and environment. Our understanding of the genetic basis of JIA risk has increased markedly over the last few years, but the environmental factors remain largely unknown. The hygiene hypothesis suggests that exposure to microbes in early life may protect against the development of immune disorders. Measures of early life hygiene have been associated with asthma, allergy, multiple sclerosis (MS) and type 1 diabetes. Exposure to siblings may be a marker of exposure to childhood infection, and we have previously shown that higher infant sibling exposure prior to school age is associated with a decreased risk of MS. We therefore hypothesised that sibling exposure may also be associated with JIA.

Methods: Participants were drawn from the CLARITY JIA biobank in Victoria, Australia. Cases (n = 302; mean age 8.5y ± 4.7 SD; 67% female) were children born in Victoria who were diagnosed with JIA by a paediatric rheumatologist at the Royal Children’s Hospital (RCH), Melbourne. Systemic JIA cases were excluded. Controls (n = 676; mean age 7.1y ± 4.1 SD; 41% female) were healthy children born in Victoria and visiting the RCH day surgery unit for a minor surgical procedure. At recruitment, families completed a questionnaire that collected birthdates of the index child and siblings, along with data on other potential confounders including index child age and sex, maternal age at birth, gestational age at birth, child sleeping arrangements and socio-economic status. We compared birth order, only-child status, total number of siblings, and cumulative years of sibling exposure by age six, between cases and controls using logistic regression.

Results: We found that, compared to being an only child, having any siblings conferred a protective effect on JIA risk (adjusted OR = 0.46, 95% CI 0.28 – 0.74, p = 0.001). The protective effect appeared to increase with increasing number of siblings (Table 1). 

Table 1: Total number of siblings born within 18 years of the index child

A protective effect of siblings was also observed when we considered cumulative sibling years by age 6 (e.g. ≥ 3y exposure vs no exposure, adjusted OR = 0.49, 95% CI 0.30 – 0.79, p = 0.003). There was no association between birth order and JIA risk. We also compared cases to a second control sample (n = 341, mean age 8.1 years ± 3.6 SD; 45% female) collected from the community and weighted to represent the Victorian child population. JIA odds ratios were found to be similar by this approach, although confidence intervals were wider, reflecting the smaller size of the community control sample.

Conclusion: In the CLARITY JIA case-control sample, increased exposure to siblings is associated with a reduced risk of disease. This suggests that increased microbial exposure in childhood may confer protection against the development of JIA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sibling-exposure-and-risk-of-juvenile-idiopathic-arthritis/