## **Supplementary Online Content**

Chiesa Fuxench ZC, Wan J, Wang S, et al. Risk of inflammatory bowel disease in patients with atopic dermatitis. *JAMA Dermatol.* Published online August 30, 2023. doi:10.1001/jamadermatol.2023.2875

**eTable 1.** Risk of Inflammatory Bowel Disease in Patients With Atopic Dermatitis Stratified by Disease Severity: Primary and Sensitivity Analyses

**eTable 2.** E-Value Computations for Both Relative Risk and Confidence Interval Closest to the Null

This supplementary material has been provided by the authors to give readers additional information about their work.

| | Adjusted Hazards Ratio (95% Confidence Interval) | | | | | | | | | |
|-----------------------------------------------------------------------|--------------------------------------------------|----------------------|----------------------|----------------------|--------------------------|------------------------------------|----------------------|----------------------|--|--|
| Outcome | Pediatric Cohort (<18 y/o) | | | | Adult Cohort (>= 18 y/o) | | | | | |
| | Atopic Dermatitis Disease Severity | | | | | Atopic Dermatitis Disease Severity | | | | |
| | Overall AD | Mild | Moderate | Severe | Overall AD | Mild | Moderate | Severe | | |
| All inflammatory bowel disease | | | | | | | | | | |
| Primary analysis | 1.44 (1.31, 1.58) | 1.36 (1.22, 1.51) | 1.48 (1.24, 1.77) | 2.59 (1.94, 3.45) | 1.34 (1.27, 1.40) | 1.18 (1.10, 1.26) | 1.44 (1.34, 1.55) | 2.27 (1.96, 2.64) | | |
| Excluding patients with asthma | 1.44 (1.29, 1.61) | 1.40 (1.24, 1.59) | 1.40 (1.11, 1.76) | 2.55 (1.75, 3.72) | 1.33 (1.25, 1.40) | 1.14 (1.06, 1.23) | 1.47 (1.36, 1.59) | 2.37 (2.00, 2.82) | | |
| Excluding patients with asthma or allergic rhinitis | 1.44 (1.28, 1.62) | 1.42 (1.24, 1.61) | 1.29 (1.00, 1.66) | 2.70 (1.84, 3.97) | 1.32 (1.25, 1.41) | 1.13 (1.05. 1.23) | 1.47 (1.35, 1.60) | 2.38 (1.99, 2.85) | | |
| Restricted to patients seen at least yearly during follow-up | 1.37 (1.25, 1.51) | 1.30 (1.17, 1.45) | 1.39 (1.16, 1.67) | 2.45 (1.84, 3.26) | 1.31 (1.24, 1.37) | 1.16 (1.08, 1.23) | 1.41 (1.31, 1.51) | 2.22 (1.91, 2.58) | | |
| Restricted to patients seen for >= 1 year prior to cohort entry | 1.44 (1.31, 1.58) | 1.36 (1.22, 1.51) | 1.48 (1.24, 1.77) | 2.59 (1.94, 3.45) | 1.34 (1.27, 1.40) | 1.18 (1.10, 1.26) | 1.44 (1.34, 1.55) | 2.27 (1.96, 2.64) | | |
| Restricted to patients with at least 5 years of follow-up | 1.41 (1.28, 1.56) | 1.33 (1.19, 1.49) | 1.49 (1.23, 1.79) | 2.41 (1.77, 3.27) | 1.31 (1.24, 1.39) | 1.15 (1.07, 1.24) | 1.42 (1.31, 1.54) | 2.18 (1.85, 2.57) | | |
| Excluding patients with IBD-related medications | 1.47 (1.33,1.61) | 1.39 (1.25, 1.55) | 1.52 (1.27, 1.82) | 2.51 (1.86, 3.40) | 1.35 (1.28, 1.42) | 1.20 (1.13, 1.29) | 1.47 (1.37, 1.58) | 2.17 (1.81, 2.59) | | |
| Crohn's disease only | | | | | | | | | | |
| Primary analysis | 1.74 (1.54, 1.97) | 1.59 (1.38, 1.83) | 1.66 (1.30, 2.11) | 4.80 (3.55, 6.49) | 1.36 (1.26, 1.47) | 1.14 (1.03, 1.27) | 1.38 (1.23, 1.55) | 3.50 (2.91, 4.20) | | |
| Excluding patients with asthma | 1.79 (1.54, 2.07) | 1.67 (1.41, 1.97) | 1.72 (1.27, 2.32) | 4.58 (3.06, 6.85) | 1.38 (1.26, 1.50) | 1.13 (1.00, 1.28) | 1.42 (1.24, 1.61) | 3.72 (3.03, 4.58) | | |
| Excluding patients with asthma or allergic rhinitis | 1.78 (1.53, 2.08) | 1.68 (1.41, 2.00) | 1.60 (1.16, 2.23) | 4.83 (3.20, 7.28) | 1.35 (1.23, 1.49) | 1.13 (0.99, 1.28) | 1.37 (1.19, 1.58) | 3.55 (2.84, 4.44) | | |
| Restricted to patients seen at least yearly during follow-up | 1.67 (1.47, 1.88) | 1.53 (1.33, 1.76) | 1.56 (1.22, 1.98) | 4.54 (3.36, 6.13) | 1.33 (1.23, 1.44) | 1.12 (1.01, 1.24) | 1.35 (1.21, 1.52) | 3.41 (2.84, 4.09) | | |
| Restricted to patients seen for >= 1 year prior to cohort entry | 1.74 (1.54, 1.97) | 1.59 (1.38, 1.83) | 1.66 (1.30, 2.11) | 4.80 (3.55, 6.49) | 1.36 (1.26, 1.47) | 1.14 (1.03, 1.27) | 1.38 (1.23, 1.55) | 3.50 (2.91, 4.20) | | |

**eTable 1. Risk of Inflammatory Bowel Disease in Patients With Atopic Dermatitis Stratified by Disease Severity: Primary and Sensitivity Analyses** 

| Restricted to patients with at least 5 years of follow-up | 1.70 (1.49, 1.94) | 1.56 (1.34, 1.81) | 1.63 (1.27, 2.10) | 4.38 (3.17, 6.04) | 1.33 (1.22, 1.45) | 1.12 (0.99, 1.26) | 1.33 (1.17, 1.51) | 3.31 (2.70,4.05) |
|-----------------------------------------------------------------------|----------------------|----------------------|----------------------|-----------------------|----------------------|----------------------|----------------------|----------------------|
| Excluding patients with | 1.86 | 1.72 | 1.83 | 4.69 | 1.41 | 1.22 | 1.49 | 3.24 |
| IBD-related medications | (1.64, 2.11) | (1.49, 1.99) | (1.43, 2.33) | (3.37, 6.52) | (1.30, 1.53) | (1.10, 1.36) | (1.33, 1.67) | (2.56, 4.10) |
| Ulcerative colitis only | | | | | | | | |
| Primary analysis | 1.09 | 1.07 | 1.03 | 1.65 | 1.32 | 1.14 | 1.43 | 2.40 |
| | (0.94, 1.27) | (0.90, 1.27) | (0.77, 1.40) | (1.02, 2.67) | (1.24, 1.41) | (1.05, 1.24) | (1.31, 1.57) | (2.00, 2.88) |
| Excluding patients with | 1.06 | 1.11 | 0.78 | 1.43 | 1.29 | 1.08 | 1.45 | 2.29 |
| asthma | (0.89, 1.27) | (0.91, 1.35) | (0.51, 1.19) | (0.74, 2.77) | (1.20, 1.38) | (0.98, 1.20) | (1.31, 1.61) | (1.85, 2.83) |
| Excluding patients with | 1.04 | 1.12 | 0.59 | 1.55 | 1.30 | 1.08 | 1.47 | 2.45 |
| asthma or allergic rhinitis | (0.86, 1.25) | (0.92, 1.38) | (0.35, 0.99) | (0.80, 3.00) | (1.21, 1.41) | (0.97, 1.20) | (1.32, 1.64) | (1.97, 3.04) |
| Restricted to patients seen at least yearly during follow-up | 1.05 (0.90, 1.22) | 1.03 (0.87, 1.22) | 0.98 (0.73, 1.32) | 1.57 (0.97, 12.55) | 1.29 (1.21, 1.38) | 1.12 (1.02, 1.22) | 1.40 (1.28, 1.53) | 2.34 (1.96, 2.81) |
| Restricted to patients seen for >= 1 year prior to cohort entry | 1.09 (0.94, 1.27) | 1.07 (0.90, 1.27) | 1.03 (0.77, 1.40) | 1.65 (1.02, 2.67) | 1.32 (1.24, 1.41) | 1.14 (1.05, 1.24) | 1.43 (1.31, 1.57) | 2.40 (1.00, 2.88) |
| Restricted to patients with at least 5 years of follow-up | 1.07 (0.91, 1.26) | 1.05 (0.87, 1.26) | 1.02 (0.75, 1.40) | 1.55 (0.93, 2.59) | 1.32 (1.23, 1.42) | 1.13 (1.02, 1.24) | 1.45 (1.31, 1.60) | 2.31 (1.89, 2.82) |
| Excluding patients with | 1.11 | 1.10 | 1.07 | 1.50 | 1.33 | 1.18 | 1.48 | 2.13 |
| IBD-related medications | (0.95, 1.29) | (0.92, 1.31) | (0.79, 1.44) | (0.88, 2.56) | (1.25, 1.42) | (1.08, 1.28) | (1.35, 1.62) | (1.69, 2.68) |

| Inflammatory Bowel Disease | | | | | |
|----------------------------|-----------------|---------------|-----------------|-----------------|----------------------------|
| Age Cohort | AD1 severity | Relative Risk | Lower limit CI2 | E-value for RR3 | E-value for lower limit CI |
| Pediatric cohort | Overall | 1.44 | 1.31 | 2.24 | 1.95 |
| Pediatric cohort | Mild | 1.36 | 1.22 | 2.06 | 1.74 |
| Pediatric cohort | Moderate | 1.48 | 1.24 | 2.32 | 1.79 |
| Pediatric cohort | Severe | 2.59 | 1.94 | 4.62 | 3.29 |
| Adult cohort | Overall | 1.34 | 1.27 | 2.01 | 1.86 |
| Adult cohort | Mild | 1.18 | 1.10 | 1.64 | 1.43 |
| Adult cohort | Moderate | 1.44 | 1.34 | 2.24 | 2.01 |
| Adult cohort | Severe | 2.27 | 1.96 | 3.97 | 3.33 |
| Crohn's Disease | | | | | |
| Age Cohort | AD severity | Relative Risk | Lower limit CI | E-value for RR | E-value for lower limit CI |
| Pediatric cohort | Overall | 1.74 | 1.54 | 2.87 | 2.45 |
| Pediatric cohort | Mild | 1.59 | 1.38 | 2.56 | 2.10 |
| Pediatric cohort | Moderate | 1.66 | 1.30 | 2.71 | 1.92 |
| Pediatric cohort | Severe | 4.80 | 3.55 | 9.23 | 6.56 |
| Adult cohort | Overall | 1.36 | 1.26 | 2.06 | 1.83 |
| Adult cohort | Mild | 1.14 | 1.03 | 1.54 | 1.21 |
| Adult cohort | Moderate | 1.38 | 1.23 | 2.10 | 1.76 |
| Adult cohort | Severe | 3.50 | 2.91 | 6.46 | 5.27 |
| Ulcerative Colitis | | | | | |
| Age Cohort | AD severity | Relative Risk | Lower limit CI | E-value for RR | E-value for lower limit CI |
| Pediatric cohort | Overall | 1.09 | 0.94 | 1.40 | 1 |
| Pediatric cohort | Mild | 1.07 | 0.90 | 1.34 | 1 |
| Pediatric cohort | Moderate | 1.03 | 0.77 | 1.21 | 1 |
| Pediatric cohort | Severe | 1.65 | 1.02 | 2.69 | 1.16 |
| Adult cohort | Overall | 1.32 | 1.24 | 1.97 | 1.79 |
| Adult cohort | Mild | 1.14 | 1.05 | 1.54 | 1.28 |
| Adult cohort | Moderate | 1.43 | 1.31 | 2.21 | 1.95 |
| Adult cohort | Severe | 2.40 | 2.00 | 4.23 | 3.41 |

## **eTable 2. E-Value Computations for Both Relative Risk and Confidence Interval Closest to the Null**

JAMA Dermatology

<jats:sec id="ab-doi230037-4"><jats:title>Importance</jats:title><jats:p>Data on the association between atopic dermatitis (AD) and inflammatory bowel disease (IBD) are inconsistent. Few studies have examined the association of AD or AD severity with risk of ulcerative colitis (UC) and Crohn disease (CD) separately.</jats:p></jats:sec><jats:sec id="ab-doi230037-5"><jats:title>Objectives</jats:title><jats:p>To examine the risk of new-onset IBD, UC, and CD in children and adults with AD.</jats:p></jats:sec><jats:sec id="ab-doi230037-6"><jats:title>Design, Setting, and Participants</jats:title><jats:p>This population-based cohort study assessed patients with AD matched with up to 5 controls on age, practice, and index date. Treatment exposure was used as a proxy for AD severity. Data were retrieved from The Health Improvement Network, a UK electronic medical record database, for January 1, 1994, to February 28, 2015. Data analysis was performed from January 8, 2020, to June 30, 2023.</jats:p></jats:sec><jats:sec id="ab-doi230037-7"><jats:title>Main Outcomes and Measures</jats:title><jats:p>Outcomes of interest were incident IBD, UC, and CD. Logistic regression was used to examine the risk for each outcome in children and adults with AD compared with controls.</jats:p></jats:sec><jats:sec id="ab-doi230037-8"><jats:title>Results</jats:title><jats:p>A total of 1 809 029 pediatric controls were matched to 409 431 children with AD (93.2% mild, 5.5% moderate, and 1.3% severe). The pediatric cohort ranged in median age from 4 to 5 years (overall range, 1-10 years), was predominantly male (936 750 [51.8%] controls, 196 996 [51.6%] with mild AD, 11 379 [50.7%] with moderate AD, and 2985 [56.1%] with severe AD), and with similar socioeconomic status. A total of 2 678 888 adult controls were matched to 625 083 adults with AD (65.7% mild, 31.4% moderate, and 2.9% severe). The adult cohort ranged in median age from 45 to 50 years (overall range, 30-68 years) and was predominantly female (1 445 589 [54.0%] controls, 256 071 [62.3%] with mild AD, 109 404 [55.8%] with moderate AD, and 10 736 [59.3%] with severe AD). In fully adjusted models, children with AD had a 44% increased risk of IBD (hazard ratio [HR], 1.44; 95% CI, 1.31-1.58) and a 74% increased risk of CD (HR, 1.74; 95% CI, 1.54-1.97), which increased with worsening AD; however, they did not have increased risk of UC (HR, 1.09; 95% CI, 0.94-1.27) except for those with severe AD (HR, 1.65; 95% CI, 1.02-2.67). Adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk of IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk of CB, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk of UC, with risk increasing with worsening AD.</jats:p></jats:sec><jats:sec id="ab-doi230037-9"><jats:title>Conclusion and Relevance</jats:title><jats:p>In this cohort study, children and adults with AD had an increased risk of IBD, with risk varying by age, AD severity, and IBD subtype. These findings provide new insights into the association between AD and IBD. Clinicians should be aware of these risks, particularly when selecting systemic treatments for AD in patients who may have coincident gastrointestinal symptoms.</jats:p></jats:sec>

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Data on the association between atopic dermatitis (AD) and inflammatory bowel disease (IBD) are inconsistent. Few studies have examined the association of AD or AD severity with risk of ulcerative colitis (UC) and Crohn disease (CD) separately.
To examine the risk of new-onset IBD, UC, and CD in children and adults with AD.
This population-based cohort study assessed patients with AD matched with up to 5 controls on age, practice, and index date. Treatment exposure was used as a proxy for AD severity. Data were retrieved from The Health Improvement Network, a UK electronic medical record database, for January 1, 1994, to February 28, 2015. Data analysis was performed from January 8, 2020, to June 30, 2023.
Outcomes of interest were incident IBD, UC, and CD. Logistic regression was used to examine the risk for each outcome in children and adults with AD compared with controls.
A total of 1 809 029 pediatric controls were matched to 409 431 children with AD (93.2% mild, 5.5% moderate, and 1.3% severe). The pediatric cohort ranged in median age from 4 to 5 years (overall range, 1-10 years), was predominantly male (936 750 [51.8%] controls, 196 996 [51.6%] with mild AD, 11 379 [50.7%] with moderate AD, and 2985 [56.1%] with severe AD), and with similar socioeconomic status. A total of 2 678 888 adult controls were matched to 625 083 adults with AD (65.7% mild, 31.4% moderate, and 2.9% severe). The adult cohort ranged in median age from 45 to 50 years (overall range, 30-68 years) and was predominantly female (1 445 589 [54.0%] controls, 256 071 [62.3%] with mild AD, 109 404 [55.8%] with moderate AD, and 10 736 [59.3%] with severe AD). In fully adjusted models, children with AD had a 44% increased risk of IBD (hazard ratio [HR], 1.44; 95% CI, 1.31-1.58) and a 74% increased risk of CD (HR, 1.74; 95% CI, 1.54-1.97), which increased with worsening AD; however, they did not have increased risk of UC (HR, 1.09; 95% CI, 0.94-1.27) except for those with severe AD (HR, 1.65; 95% CI, 1.02-2.67). Adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk of IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk of CB, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk of UC, with risk increasing with worsening AD.
In this cohort study, children and adults with AD had an increased risk of IBD, with risk varying by age, AD severity, and IBD subtype. These findings provide new insights into the association between AD and IBD. Clinicians should be aware of these risks, particularly when selecting systemic treatments for AD in patients who may have coincident gastrointestinal symptoms.

Risk of Inflammatory Bowel Disease in Patients With Atopic Dermatitis.

Risk of Inflammatory Bowel Disease in Patients With Atopic Dermatitis

Risk of Inflammatory Bowel Disease in Patients With Atopic Dermatitis

Clinical Summary

What was studied

Key findings

Study limitations

Clinical implications

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