To investigate the potential environmental associations for polyarticular JRA and rheumatoid arthritis, we examined risk factors for the intermediate phenotype of rheumatoid factor positivity in healthy children with increased genetic risk for rheumatoid arthritis, polyarticular JRA and T1DM. We observed several significant interaction terms that suggested that the risk factors of rheumatoid factor differed by HLA‐DR4 status, leading to separate investigations of environmental risk factors in DR4‐positive and DR4‐negative children.
In HLA‐DR4‐negative children, breast feeding for >3 months was associated with a decreased risk of rheumatoid factor positivity, which is consistent with a previous study that found that children with JRA were less likely to have been breast fed than controls,10
and with a study in adults that suggested that rheumatoid arthritis was less likely to develop in those who had been breast fed.20
Interestingly, we did not find an association with duration of exclusive breast feeding, nor timing of introduction of cereals in the infant diet, two factors that have been shown to influence the risk of other forms of autoimmunity in children, such as diabetes16,21,22
and coeliac disease.17,23
This suggests that the protective effect of breast feeding on rheumatoid factor positivity may be due to the immune‐modulating effects of breast milk, including large amounts of immunoglobulin (Ig)A and antigen tolerance capabilities, rather than to a delay in the introduction of foreign dietary antigens. We also found that having regular exposure to a person other than a parent who smokes increases the risk of rheumatoid factor positivity in children who are HLA‐DR4 negative, which is consistent with the observation that current parental smoking was more prevalent in a group of children diagnosed with JRA.14
The reason for the observed increased risk with being around a care giver who smokes, but not with being around a parent who smokes is not clear, but it may be due to the way the question is phrased and to the relative amount of exposure. Conceivably, a child may spend more time with the person who is taking care of it during the day, while the parents are at work. Thus, they may have a greater chance of exposure to tobacco smoke than if the parents smoke. Also, it is possible that parents may make an effort to avoid smoking around their child. The questions regarding the parents smoking are worded in a slightly different way, which may have accentuated this difference. For example, when we ask whether the parents “currently smoke”, we never specifically ask if the parents smoke in front of the children, whereas the other question is phrased to pick up whether “the child is exposed to cigarette smoke on a regular basis … from anyone other than the parents”, which may represent a more intense exposure. As to what factor in cigarette smoke may lead to rheumatoid factor production, in adult rheumatoid arthritis models it is postulated that tobacco smoke may initiate the autoimmune response by stimulating B cells directly,24
resulting in increased levels of rheumatoid factor.
Breast feeding duration and exposure to tobacco smoke were not associated with rheumatoid factor positivity in the DR4‐positive children. The lack of environmental risk factors in the group with HLA‐DR4 may possibly be related to a multi‐hit aetiology, where those without the genetic susceptibility marker need environmental exposures to convert to autoantibody positivity whereas those who already have a genetic susceptibility marker do not need these exposures to become positive.
Another interesting finding in this cohort is that HLA‐DR4 was not associated with rheumatoid factor positivity in healthy children. This finding is similar to that reported by others who have recently found that HLA seems to be associated with anti‐cyclic citrullinated‐peptide positive rheumatoid arthritis rather than with rheumatoid factor.25
Although tobacco smoke exposure has been associated with the development of rheumatoid arthritis and rheumatoid factor positivity and, more recently, strongly associated with the presence of anti‐cyclic citrullinated peptide in HLA DR4‐positive patients with rheumatoid arthritis,26
on the basis of our finding of passive tobacco smoke exposure and rheumatoid factor in HLA‐DR4‐negative children, there may be another genetic association besides HLA‐DR4 that may be responsible for the link between smoking and rheumatoid factor production. In support of this, a recent study suggests that exposure to tobacco smoke increased the risk of rheumatoid arthritis among older Caucasian women who were not positive for the HLA‐DRB1 shared epitope, which includes HLA‐DR4, and is the best known genetic risk factor for rheumatoid arthritis; however, tobacco exposure did not increase the risk of disease in those positive for the shared epitope.27
A limitation of this study is that no physical examination was performed on these children to determine whether they had clinically relevant disease in addition to rheumatoid factor autoantibodies. Figure 1 shows the range of rheumatoid factor levels in the children. Although some of the positive levels were near the cut‐off of 15 IU/ml, half were >20 IU/ml and one third at
40 IU/ml. A positive rheumatoid factor level in this study was used as an intermediate phenotype for JRA and rheumatoid arthritis based on levels in adults. It is unclear what a rheumatoid factor positive level truly is in children, as there are no population data, to our knowledge. Thus, using the adult level as a cut off may not be a true representation of a positive level in children. There was also no follow‐up for disease or worsening of autoimmunity, although this is something we would like to pursue. Small numbers within some of the groups resulted in marginal associations, so an association of a small effect could have been missed. Our study population was at increased risk of rheumatoid arthritis and polyarticular JRA based on HLA‐DR4 prevalence, which limits the generalisability of our results to the general population. A major strength of this study is the prospective data collection, which increased accuracy and eliminated recall bias because all exposures were assessed before the measurement of the outcome. In addition, the use of an autoantibody‐negative comparison group from within the DAISY cohort reduced the possibility of selection bias.
These findings indicate that environmental influences may affect children's immune responses as evidenced by rheumatoid factor positivity. An additional follow‐up of this and other cohorts of children and adults is necessary to elucidate whether these influences result in clinical diseases such as polyarticular JRA and seropositive rheumatoid arthritis.