In this study from a large multicenter pediatric IBD registry, EIMs were reported in 6% before diagnosis of IBD, accounting for 25% of the total first EIMs reported by the end of the study follow-up period. EIMs before diagnosis of IBD were found more frequently in children who were older than 5 years at diagnosis. Subsequent EIM incidence after diagnosis of IBD differed by type of EIM, but not by age at IBD diagnosis, race/ethnicity or IBD type. Cumulative incidence was similar to the range reported in prior adult studies 2-5, 10
. However our data show a much lower incidence among children compared with prior (and smaller) pediatric reports. Grossman et al, reported that 68% of 41 children and adolescents with IBD had EIMs. In a study of 184 children with IBD, Stawarski et al found that 50% of those with CD and 80% of those with UC had at least one EIM 6, 7
. However while both investigators included osteopenia, they also added growth delay as an EIM.
A prevalence study of 873 adults revealed that age at presentation did not affect the likelihood of EIM occurrence, similar to our finding in the 1552 patients without EIMs at IBD diagnosis3
. However, comparisons with prior studies are problematic because of differences in patient population size, demographics and methods. A report by Monsen et al. excluded stomatitis and episcleritis from the EIMs, while Bernstein et al excluded arthropathies from their study 11, 12
. No large cohort cumulative incidence study has been reported to date.
Our data reveal a non-significant but clinically relevant trend for higher risk of EIMs among girls. This finding could possibly be explained by the hypothesis that autoimmune diseases are more common in girls and is consistent with our earlier report of gender differences among children with Crohn’s disease 13
. A report by Lakatos et al on 873 adult patients also found EIMs more prevalent in females than males 14
. Bernstein et al, found gender variation related to types of EIMs 11
Our finding of no difference in risk by race/ethnicity is consistent with Eidelwein et al, who found no differences in symptom presentation and EIMs between Caucasians and African American pediatric patients 15
While our analysis did not reveal strong evidence of variation in the overall incidence of EIMs by type of IBD, specific EIMs were more prevalent in patients with CD 3, 6, 9, 11, 16
. Previous reports of prevalence of EIMs have also documented increased risk in patients with CD compared with UC, with the exceptions of PSC and ocular manifestations 2, 4, 9, 14 17
. The cumulative incidence of PSC was 2.1% in this study, within the range reported in prior prevalence adult studies 3, 11, 18, 19
. The cumulative incidence of PSC was higher in UC than CD, similar to other studies 9, 11, 14, 20
. The incidence in children may be higher than described in this study because clinical presentation of PSC in childhood is frequently different from that of PSC in adults and a high index of suspicion is required to make diagnosis of PSC in children. Though, our study did not show any gender difference in the incidence of PSC, other studies have shown that males have increased risk compared to females 11, 20-24
Arthritis and aphthous stomatitis were the most frequent EIMs before diagnosis of IBD, while osteopenia/osteoporosis was the most common EIM after diagnosis of IBD. Peripheral arthritis was more common than axial arthritis. The cumulative incidence of peripheral arthritis at 10 years was 4.2%, lower than in three previous studies 9, 25, 26
. The difference in results may be explained by differences in methods, study population and the type of referral centers. The high incidence of osteopenia/osteoporosis may be due to malabsorption of calcium and/or vitamin D, low body mass index, corticosteroid exposure, disease activity and elevation of inflammatory cytokines 27, 28
. The pathogenesis of osteopenia/osteoporosis is poorly understood, and patients with CD may develop bone-mineralization disorders even without exposure to corticosteroids. 29
As a multicenter registry, our study had several innate limitations. Although our study population was drawn primarily from tertiary care referral centers, most pediatric IBD patients are followed in such centers, so our findings should be representative for pediatric patients with IBD. Information on EIMs at diagnosis of IBD was retrospective. No a priori standard criteria were developed for the definition of each EIM. Risk of EIMs in relation to disease severity could not be assessed with this dataset. The effects of therapy of the underlying IBD on EIMs were not evaluated in this study. Some clinical presentations related directly to therapy of IBD may have been included as EIMs. Impaired growth, unique to the pediatric age group, was also not evaluated in this study, as the influence of the primary disease including disease activity could not be clarified from our data.
In our large cohort of pediatric IBD patients, EIMs were relatively uncommon before diagnosis of IBD, but substantially increase after diagnosis. Race and type of IBD provided no information about risk, but risk may be slightly higher among girls. Because many EIMs may be treatment-related and can significantly complicate treatment, effects of IBD therapy on EIMs deserve further prospective investigation.