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


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

In This Article


Our study included 101 019 women from the NHS II among whom we documented 132 cases of CD (crude incidence rate 6.5/100 000 person-years) and 186 cases of UC (crude incidence rate 9.2/100 000 person-years) over 2 016 163 person-years of follow-up. The median age of IBD diagnosis was 50 years (range 33–69 years); 89% of the diagnoses were before the age of 60 years. A total of 20 710 women (20.5%) had one IMD, 4,613 (4.6%) had two and 940 (0.9%) had more than two IMDs (Figure S1). Among those with one IMD, the most common IMDs were asthma (31.7%), rosacea (18.9%) and AD (16.1%). A total of 39.4% of CD patients and 26.6% of UC patients had at least one IMD prior to IBD diagnosis. The most commonly diagnosed IMD in these patients was asthma, followed by AD and rosacea (Figure 1). The age-standardised characteristics according to number of IMDs are summarised in Table 1. Participants with greater number of IMDs were more likely to have family history of IBD as well as other IMDs. Higher BMI and regular NSAIDs use were more prevalent among those with higher burden of IMDs.

Figure 1.

Immune-mediated diseases among participants with Crohn's disease and ulcerative colitis in the Nurses' Health Study II (1995–2017). This figure shows the number and proportion of participants who were diagnosed with immune-mediated diseases at the time of diagnosis of Crohn's disease (n = 132) and ulcerative colitis (n = 186)

In the age-adjusted model, compared to participants with no history of IMD (crude incidence rate 5.1/100 000 person-years), those with one (crude incidence rate 12.0/100 000 person-years) and two or more IMDs (crude incidence rate 12.0/100 000 person-years) had an elevated risk of CD (HR 2.57; 95% CI 1.77–3.74 and HR 2.74; 95% CI 1.36–5.49, respectively; P trend < 0.0001) (Table 2). Adjusting for key environmental risk factors for IBD only modestly attenuated the increase in the risk of CD associated with one (HR 2.35; 95% CI 1.60–3.45) and two or more IMDs (HR 2.46; 95% CI 1.21–5.01). More granular characterisation of women with two or more IMDs demonstrated that the highest numerical risk of CD was among those with three or more IMDs (crude incidence rate 17.8/100 000 person-years; HR 3.40; 95% CI 0.81–14.21), while the HRs for those with one and two IMDs were numerically similar (2.35 and 2.29) (Table S2).

Dichotomous classification of IMDs showed that compared to women with no IMDs, those with one or more IMDs had a 2.6-fold increase in CD risk in the age-adjusted model (HR 2.60; 95% CI 1.82–3.70), which remained largely unchanged upon adjusting for environmental factors (HR 2.36; 95% CI 1.64–3.41) (Table 3). Among the individual IMDs, a statistically significant elevated risk was individually noted with asthma (HR 2.49, 95% CI 1.26–4.90), AD (HR 3.58, 95% CI 1.84–6.94), psoriasis (HR 3.67; 95% CI 1.59–8.47) and rosacea (HR 2.53; 95% CI 1.21–5.30). Adjusting for environmental factors resulted in only a modest attenuation compared to the age-adjusted associations for each of these diseases. A history of less common IMDs, including RA, SLE, T1D, MS and GBS, as a joint exposure was also associated with a trend towards an increased risk of CD (HR 1.96; 95% CI 0.89–4.34).

In contrast to the association with CD, we found a weaker association between a history of IMD and risk of UC. Compared to women with no IMDs (crude incidence rate 8.7/100 000 person-years), those with one (crude incidence rate 11.1/100 000 person-years) and two or more IMDs (crude incidence rate 11.6/100 000 person-years) had no increase in risk of UC in the age-adjusted model (HR 1.36; 95% CI 0.95–1.94 and HR 1.55; 95% CI 0.79–3.07, respectively), although a weak trend across strata was noted (P trend 0.03; Table 2). Similar to CD, adjustment for relevant environmental factors did not modify this association. The difference in the observed association between CD and UC was statistically significant (P heterogeneity 0.037), suggesting the stronger clustering of IMDs with CD than UC. Multivariable model demonstrated that a history of any IMD was not associated with a higher risk of UC (HR 1.24, 95% CI 0.88–1.74) (Table 4). None of the individual IMDs demonstrated a statistically significant association with UC, with HRs of individual IMD ranging from 0.67 to 1.61 (all P > 0.05).

We then performed various sensitivity and subgroup analyses. Allowing participants diagnosed with other IMDs to continue contributing person-years to the reference group after diagnosis demonstrated a moderate attenuation in all the tested associations, with the exception of AD and psoriasis and CD risk, which remained strongly associated (Table S3 and Table S4). The results remained unchanged upon additional adjustment for Mediterranean diet (HR1 IMD 2.34; 95% CI 1.60–3.44; HR≥ 2 IMDs 2.46; 95% CI 1.21–5.01) or vitamin D intake (HR1 IMD 2.32; 95% CI 1.58–3.40; HR≥ 2 IMDs 2.41; 95% CI 1.19–4.91). The increase in risk of CD associated with a history of IMD was similar among those who had a family history of IMD and those without (P interaction 0.63) (Table S5). An increase in risk of CD with one and two or more IMDs was also noted in those who had no family history of IBD (Table S6).