Immune-mediated Diseases and Risk of Crohn's Disease or Ulcerative Colitis

A Prospective Cohort Study

Chun-Han Lo; Hamed Khalili; Paul Lochhead; Mingyang Song; Emily W. Lopes; Kristin E. Burke; James M. Richter; Andrew T. Chan; Ashwin N. Ananthakrishnan

Disclosures

Aliment Pharmacol Ther. 2021;53(5):598-607. 

In This Article

Discussion

Epidemiologic studies have demonstrated a clustering of IMDs within individuals with IBD and their families. In this large prospective cohort of US women, we demonstrate a twofold increase in risk of CD (but not UC) among women with other IMDs. This risk was dose-dependent with a greater number of IMDs being associated with a higher incidence of CD. Specifically, asthma, AD, psoriasis and rosacea were all individually associated with increased risk of CD. Importantly, we also demonstrate that these findings were only modestly attenuated after adjustment for environmental factors, suggesting that common diet and lifestyle risk factors do not fully explain the increased co-occurrence of these diseases.

Several observational studies have suggested that individuals with a pre-existing IMD may be more likely to go on to develop IBD. In a population-based cohort in Alberta, Canada, Kuenzig et al[28] reported a 50% increase in risk of CD among those with asthma. Summarised in a meta-analysis from the same group that included 18 observational studies, asthma was associated with an increase in risk of CD but not UC.[29] Using health insurance data, another study similarly showed that there is a modest increase in risk of both CD and UC among those with AD.[30] We, and others, have previously demonstrated an increase in risk of CD among those with psoriasis[31,32] and rosacea.[33,34] In a meta-analysis of cohort studies, the association between psoriasis and CD was stronger than noted for UC,[31] similar to our observations.

Our study overcomes some important weaknesses of prior studies. First, a critical limitation of prior literature is the inability to adjust for environmental determinants of disease. The clustering of IMDs may be explained through contributions from shared genetics, environmental influences and gut microbiome. For example, smoking is a common risk factor among various IMDs and has been associated with CD,[12] asthma,[14] psoriasis,[16] RA[18] and SLE.[35] Socioeconomic status, as part of the 'hygiene hypothesis', may also underpin the occurrence of several of these IMDs.[36] There have been reports of a positive correlation between gross national product and incidence of asthma, T1D and MS in Europe[37] and CD in Manitoba, Canada.[38] Being able to adjust for key confounders is critical to our understanding of the biologic basis of the clustering of IMDs. The persistence of our findings after detailed adjustment for environmental determinants suggest that perhaps shared genetics and immunologic pathways play a stronger role in the clustering of these IMDs.[39,40] Second, many prior studies have relied on administrative codes rather than confirmed cases to identify occurrence of IBD or other IMDs. Reliance on administrative data introduces bias when patients with an IMD come into contact with the healthcare system more frequently than those without. This may result in more frequent IBD diagnoses due to greater rates of diagnostic testing or more frequent administrative coding from heightened suspicion even in the absence of a confirmed diagnosis. In addition, cross-sectional studies cannot determine sequence of diagnosis of IMDs. Case-control studies are also limited by their inability to provide absolute incidence rates and a lifetime risk. This absolute incidence is an important parameter to estimate the utility of either at-risk screening or interventions for primary prevention. In addition, most prior studies focused on a single IMD and much less is known about the impact of multiple IMDs on the risk of CD and UC. Here we demonstrate that the highest numerical increase in risk and absolute incidence of CD was noted in individuals with three or more IMDs.

Meta-analyses of GWASs[41,42] identified over 200 confirmed IBD risk loci, many of which are shared between CD and UC. A number of these risk loci have been implicated in other IMDs. In AD, two established susceptibility loci (IL18R1/IL18RAP, TNFRSF6B) reported in GWAS[43] conferred risk of CD with an effect in the same direction.[44,45] Similarly, psoriasis and IBD share several genetic susceptibility loci such as 1p31.1 (IL23R) and 5q33.1 (IL12B), both of which have been identified in the pathogenesis of psoriasis and IBD.[46,47] Another common compartment likely influenced by both genetics and the environment is the gut microbiome. One study[48] demonstrated that the gut microbiome of psoriatic arthritis patients was characterised by a reduction in Akkermansia and Ruminococcus, a profile similar to that previously described in patients with CD.[49–51] An increase in secretory IgA levels in these patients suggested an increased immune activation in the intestine that accompanied the dysbiosis. Another study reported an increase in the abundance of Collinsella in RA patients,[52] as noted similarly in stool samples of patients with fistulising phenotype of CD.[53]Collinsella may increase gut permeability by lowering the expression of tight junction protein in epithelial cells and inducing the expression of interleukin IL-17 network cytokines,[52] both of which have been implicated in the development of IBD.[54,55]

There are several strengths to our study. The prospective design, long-term follow-up, large sample size and high rates of completed follow-up allow for robust estimation of the magnitude of association as well as a clearer delineation of the temporal relationship between the development of IMDs and the diagnosis of CD or UC. The availability of detailed and validated information on covariates allowed us to control for various shared environmental risk factors between IMDs that may have confounded the associations. In addition, our IBD cases were confirmed through detailed medial record review by board-certified gastroenterologists blinded to exposure information. The elevated risk of CD associated with other IMDs suggests that there should be a heightened suspicion for CD in such individuals and early referral for evaluation. Given the low absolute risk, it is likely that most individuals with an IMD who have co-existing gastrointestinal symptoms may have an alternate aetiology. However, in the right clinical circumstance, one may need to consider a lower threshold for non-invasive blood tests and assessment of faecal inflammatory markers such as calprotectin in individuals with unexplained gastrointestinal symptoms in the setting of other IMDs.

We readily acknowledge several limitations. First, the ascertainment of IMDs was based on self-report. While some misclassification bias is possible, the effect of this should be modest as our study participants were healthcare professionals and high validity of self-report has been established previously (Table S1). Similarly, while we identified the occurrence of various IMDs, this may not have been comprehensive, particularly for the rarer IMDs. As above, such misclassification would introduce a bias towards the null, thereby strengthening our findings. Second, we were able to adjust for various environmental risk factors. However, as with all observational studies, the possibility of unmeasured or residual confounding could not be excluded. Third, the median age of IBD diagnosis is higher than other population-based cohorts due to the age structure of our cohorts. Fourth, we did not have information on medications use to treat the underlying IMDs including use of biologics that may also have treated subclinical IBD. However, we do not expect this to significantly alter our findings for several reasons. Our associations were significant even for various IMDs that do not share common long-term maintenance treatments with IBD. Also, the effect of such treatments, if there is a biologic impact, would be to decrease risk of overt IBD in that population, biasing towards the null. This would only strengthen the magnitude of our findings. Finally, our study population consists of female registered nurses who were mostly white. Therefore, extrapolating our findings to men or individuals of other ethnicities should be performed with caution. However, prior studies have not identified gender to significantly alter genetic risk or the impact of environmental determinants of disease.

In conclusion, we demonstrate that individuals with one or more IMDs are at a higher lifetime risk of CD or UC due to shared genetics or early-life exposures rather than diet or lifestyle. While there may not be a role for routine screening, those with suspicious symptoms may benefit from a lower threshold for early evaluation of suspected IBD.

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