Original Article

Atopic Eczema in Adulthood and Risk of

Depression and Anxiety: A Population-Based
Cohort Study
Yochai Schonmann, MD, MSca,b,c,*, Kathryn E. Mansfield, MBBS, BSc, MRes, PhDa,*,
Joseph F. Hayes, MBChB, MSc, PhDd,e, Katrina Abuabara, MD, MsCE, MAf, Amanda Roberts, BScg,
Liam Smeeth, MBChB, FRCGP, FFPH, FRCP, MSc, PhD, FMedScia, and Sinéad M. Langan, FRCP, MSc, PhDa,h,i London
and Nottingham, United Kingdom; Petah Tikva and Tel-Aviv, Israel; and San Francisco, Calif

What is already known about this topic? Atopic eczema is a common debilitating skin condition. An association be-
tween atopic eczema and common mental disorders is well documented, but its nature and temporal direction remain
unclear.

What does this article add to our knowledge? Individuals affected with atopic eczema are more likely to develop new
depression (14% increased incidence) and anxiety (17% increased incidence). The observed dose-response relationship
between atopic eczema severity and depression supports a causal mechanism for the association.

How does this study impact current management guidelines? Recent atopic eczema guidelines comment briefly on
the influence of psychological and emotional factors on the clinical course of atopic eczema. Our findings suggest that
depression and anxiety should be addressed explicitly in updated guidelines.

BACKGROUND: Atopic eczema is a common and debilitating Deprivation, glucocorticoid treatment, obesity, smoking, and
condition associated with depression and anxiety, but the nature harmful alcohol use.
of this association remains unclear. RESULTS: We identified 526,808 adults with atopic eczema who
OBJECTIVE: To explore the temporal relationship between were matched to 2,569,030 without. Atopic eczema was associated
atopic eczema and new depression/anxiety. with increased incidence of new depression (HR, 1.14; 99% CI,
METHODS: This matched cohort study used routinely collected 1.12-1.16) and anxiety (HR, 1.17; 99% CI, 1.14-1.19). We
data from the UK Clinical Practice Research Datalink, linked to observed a stronger effect of atopic eczema on depression with
hospital admissions data. We identified adults with atopic increasing atopic eczema severity (HR [99% CI] compared with
eczema (1998-2016) using a validated algorithm, and up to 5 no atopic eczema: mild, 1.10 [1.08-1.13]; moderate, 1.19 [1.15-
individuals without atopic eczema matched on date of diagnosis, 1.23]; and severe, 1.26 [1.17-1.37]). A dose-response association,
age, sex, and general practice. We estimated the hazard ratio however, was less apparent for new anxiety diagnosis (HR [99%
(HR) for new depression/anxiety using stratified Cox regression CI] compared with no atopic eczema: mild, 1.14 [1.11-1.18];
to account for age, sex, calendar period, Index of Multiple moderate, 1.21 [1.17-1.26]; and severe, 1.15; [1.05-1.25]).

a
Department of Non-Communicable Disease Epidemiology, Faculty of Epidemi- LOND1). The findings and conclusions in this report are those of the authors and
ology and Population Health, London School of Hygiene and Tropical Medicine, do not necessarily represent the views of the funders.
London, United Kingdom Conflicts of interest: K. Abuabara reports personal fees from TARGETDerm for
b
Clalit Health Services, Department of Family Medicine, Rabin Medical Center, guidance on the development of an atopic dermatitis registry outside the submitted
Petah Tikva, Israel work. The rest of the authors declare no support from any organization for the
c
Department of Family Medicine, Sackler Faculty of Medicine, Tel-Aviv University, submitted work; no financial relationships with any organizations that might have
Tel-Aviv, Israel an interest in the submitted work in the previous 3 years; and no other relation-
d
Division of Psychiatry, University College London, London, United Kingdom ships or activities that could appear to have influenced the submitted work.
e
Camden and Islington National Health Service (NHS) Foundation Trust, London, Received for publication February 28, 2019; revised manuscript received and
United Kingdom accepted for publication August 16, 2019.
f
Department of Dermatology, University of California San Francisco, San Francisco, Available online August 31, 2019.
Calif Corresponding author: Kathryn E. Mansfield, MBBS, BSc, MRes, PhD, London
g
Nottingham Support Group for Carers of Children with Eczema, Nottingham, School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. E-mail:
United Kingdom kathryn.mansfield@lshtm.ac.uk.
h
St John’s Institute of Dermatology, Guy’s & St Thomas’ Hospital National Health * These authors contributed equally to this work.
Service (NHS) Foundation Trust and King’s College London, London, United 2213-2198
Kingdom Ó 2019 The Authors. Published by Elsevier Inc. on behalf of the American Academy
i
Health Data Research UK, London, United Kingdom of Allergy, Asthma & Immunology. This is an open access article under the CC
This work was supported by a Wellcome Senior Research Fellowship in Clinical BY license (http://creativecommons.org/licenses/by/4.0/).
Science (grant no. 205039/Z/16/Z), and Health Data Research UK (grant no. https://doi.org/10.1016/j.jaip.2019.08.030

248
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VOLUME 8, NUMBER 1

anxiety, then this would suggest: (1) a major population impact;

Abbreviations used (2) a potential role for targeted mental health screening for in-
BMI- Body mass index dividuals with atopic eczema; and (3) the possibility of mental
CPRD- Clinical Practice Research Datalink health modification through improved atopic eczema control (eg,
HES- Hospital Episode Statistics
using new biologic agents). Therefore, we aimed to investigate
HR- Hazard ratio
the association between atopic eczema and newly diagnosed
depression and anxiety, and whether any association increased
with increasing atopic eczema severity, through a longitudinal
CONCLUSIONS: Adults with atopic eczema are more likely to analysis of UK primary care electronic health record data.
develop new depression and anxiety. For depression, we
observed a dose-response relationship with atopic eczema METHODS
severity. Ó 2019 The Authors. Published by Elsevier Inc. on
Study design and setting
behalf of the American Academy of Allergy, Asthma & Immu-
We conducted a cohort study, using routinely collected primary
nology. This is an open access article under the CC BY license
care electronic health record data from practices contributing to the
(http://creativecommons.org/licenses/by/4.0/). (J Allergy Clin
UK Clinical Practice Research Datalink (CPRD) and linked hospital
Immunol Pract 2020;8:248-57)
admissions data from the Hospital Episode Statistics (HES) database.
Key words: Atopic eczema; Atopic dermatitis; Anxiety; Depres- The CPRD covers approximately 7% of the UK population, is broadly
sion; Population-based; Severity representative of the general population, and includes demographic
information, diagnoses, prescriptions, and secondary care referrals.35
Diagnoses are recorded in the CPRD using Read codes,36 and have
been demonstrated to be valid.37,38 The CPRD ensures high-quality
INTRODUCTION data through algorithmic analysis of gaps in data entry and deaths
Atopic eczema (eczema, atopic dermatitis) is a chronic re- recorded by each practice.35 HES includes data on all the National
lapsing inflammatory skin disease. It can cause intense itching Health Serviceefunded inpatient hospital stays in England since
and discomfort. Itch and disfiguring lesions result in sleeplessness 1997, including diagnoses recorded using the International
and social embarrassment, impairing the quality of life of both Classification of Diseases, Tenth Revision coding system.39 Linkage to
sufferers and their families.1,2 Atopic eczema is common (20% of HES data is available in approximately 80% of English CPRD prac-
children and up to 10% of adults in developed countries) and is a tices. The study period was from January 2,1998, to March 31, 2016.
major cause of years lost because of disability.2-4 Emerging evi-
dence suggests that biologic agents, an effective treatment mo- Ethical approval
dality for severe atopic eczema,2,5,6 may also reduce symptoms of The study protocol was approved by the Independent Scientific
depression and anxiety among people with atopic eczema.7 Advisory Committee (ISAC) for the CPRD (ISAC protocol no.
Mental health disorders are one of the leading causes of 16_100RA) and the London School of Hygiene and Tropical
disability worldwide,8 with depression and anxiety together ac- Medicine (Reference: 15460). Informed consent was not required,
counting for more than half of that burden.9 Depression, man- because the study used anonymized data.
ifesting as loss of interest and enjoyment in ordinary things and
experiences, affects approximately 4.4% of the global population; Study population
anxiety disorders, characterized by excessive fear, anxiousness, or Individuals with atopic eczema and disease sever-
avoidance of perceived threats, affect approximately 3.6%.10 ity. Atopic eczema diagnosis was based on a validated algorithm
Both depression and anxiety are associated with increased (positive predictive value of 82%) requiring a record of at least 1
morbidity and mortality.11-15 Atopic eczema has been shown to diagnostic code for atopic eczema and at least 2 records for atopic
be associated with common mental disorders (depression and eczema therapy.40 Systemic glucocorticoids were not included in the
anxiety) and suicidality in cross-sectional studies that have validated algorithm to identify atopic eczema, and their use is
frequently relied on self-reported exposures and outcomes.16-25 generally discouraged41 (see this article’s “Codes and treatments used
Individuals with atopic eczema may be more likely to experi- in algorithm definition of atopic eczema” section in the Online
ence depression and anxiety through the effects of itch and Repository at www.jaci-inpractice.org). Other inclusion criteria
discomfort, disfigurement, and perceived social-stigmatization26- were: adults 18 years and older; eligible for HES linkage; registered
28
; in addition, poor sleep related to atopic eczema may increase with a CPRD practice meeting CPRD patient- and practice-level
the risk of mental illness.29,30 Inflammatory mediators in atopic quality control standards; and contribution of valid follow-up time
eczema could also contribute to the development of depres- during the study period (January 2, 1998, to March 31, 2016).
sion.22,31 However, those with depression and anxiety could also To capture the progressive nature of atopic eczema and to avoid
be more likely to consult for a physical condition such as atopic immortal-time bias, atopic eczema severity was modeled as a time-
eczema. Because longitudinal evidence is scarce and conflicting, updated variable.42 We categorized severity into 3, mutually exclu-
the temporality of any association between atopic eczema and sive, progressive categories (mild, moderate, and severe) according to
depression and anxiety, and whether the relationship changes recorded atopic eczema therapy.5,43,44 By default, all individuals
with increasing atopic eczema severity, remains unclear.32-34 with atopic eczema were classified as having mild disease. They could
Insight into the temporal relationship between atopic eczema be recategorized as having (1) moderate atopic eczema if potent
and depression/anxiety could guide the clinical approach to this topical steroids or calcineurin inhibitors were prescribed or (2) severe
vulnerable group with visible and potentially stigmatizing skin atopic eczema, if there was a record for a referral to a dermatologist,
disease. Atopic eczema is common, so if people with atopic or a record for systemic treatment. Individuals with moderate/severe
eczema are indeed at increased risk of new-onset depression or disease kept their severity category until the end of follow-up and
250 SCHONMANN ET AL J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2020

could not be recategorized as having milder disease (see this article’s deemed plausibly associated with both exposure and outcome, and
“Codes and treatments used in algorithm definition of atopic not on the causal pathway (ie, potential confounders). We consid-
eczema” section). ered BMI, smoking status, harmful alcohol use, and high-dose oral
glucocorticoid as possible mediators of the association between
Comparison group of individuals without atopic atopic eczema and depression/anxiety. The data sources and defi-
eczema. Each atopic eczemaeexposed individual was matched nitions used to identify all covariates are detailed in this article’s
(without replacement) with up to 5 individuals without atopic “Algorithms to identify BMI and steroid use data” and “Algorithms
eczema on sex, age, general practice, and calendar time. Unexposed to identify BMI and steroid use data” sections in the Online Re-
individuals had no record of a diagnostic code for atopic eczema (in pository at www.jaci-inpractice.org and morbidity code lists are
CPRD or HES) but were required to have at least 1 year of follow- available to download.49
up in CPRD as well as meet all other inclusion criteria. To minimize
selection bias due to the exclusion of unmatched individuals and
closely adjust for its effects, age was matched in 15-year strata and Statistical analysis
used as the underlying time scale for all analysis. To avoid mis- We assessed the effect of the atopic eczema exposure on each
classifying unexposed person-time, individuals could contribute outcome (depression or anxiety) using Cox regression stratified by
unexposed person-time until the date of their first record of a matched set. We included the covariates used for matching in an
diagnostic code for atopic eczema, regardless of later therapies pre- initial crude model (implicitly adjusted for sex and general practice
scribed (see Figure E1 in this article’s Online Repository at www. by stratification on matched set, and for age through the underlying
jaci-inpractice.org). timescale). We then adjusted for the remaining prespecified po-
tential confounders (calendar period and Index of Multiple
Outcomes Deprivation) in an adjusted model. Finally, we also further adjusted
We considered depression and anxiety as separate outcomes, with for potential mediators of the relationship between atopic eczema
onset defined as the date of the first recorded diagnosis in either and depression/anxiety (BMI; smoking; harmful alcohol and high-
CPRD or HES (any inpatient hospital diagnosis). Codes for the dose oral glucocorticoid use) in a third model. To preserve
depression outcome were those compatible with unipolar depres- matching, analyses only included valid matched sets; that is, entire
sion,45 and for the anxiety outcome, included those consistent with matched sets were excluded if the atopic eczemaeexposed indi-
generalized anxiety and panic disorders. We considered broader vidual was excluded (because of preexisting outcome diagnosis at
definitions of depression and anxiety in prespecified sensitivity an- cohort entry, or because of missing BMI or smoking data in the
alyses (see this article’s “Code lists for the outcomes (depression and models including possible mediators of the relationship between
anxiety)” section in the Online Repository at www.jaci-inpractice. atopic eczema and depression/anxiety), or if no individuals without
org). atopic eczema remained in the set.
The absolute incidence rates of new depression and anxiety could
Defining follow-up
be directly calculated among those with atopic eczema, but matching
Individuals entered the cohort at the latest of: practice registration
precluded a similar approach in those without atopic eczema
date plus 12 months; the date their practice met CPRD quality
(because this was not a representative sample of the general popu-
control standards; the date an individual met our atopic eczema
lation). We, therefore, estimated incidence rates in those without
diagnosis definition; or the start of the study (January 2, 1998).
atopic eczema by multiplying rates in those with atopic eczema by
Individuals without atopic eczema entered the cohort on the same
the corresponding estimated hazard ratio (HR) (after inverting it to
day as their matched atopic eczemaeexposed case. We included a
compare unexposed with exposed).50 We calculated attributable risks
mandatory “wash-in” period of 12 months before cohort entry to
as the difference between the incidence rates in those with and
ensure adequate time to capture true incident outcome diagnoses, as
without atopic eczema, and the population-attributable risks by
well as other baseline variables (eg, body mass index [BMI] and
using the estimated HR and assuming the prevalence of atopic
smoking).46
eczema to be 10%.51
Cohort members were followed until the first of the
We conducted a series of sensitivity analyses to explore possible
following events: anxiety or depression diagnosis (depending on
sources of bias introduced by: strict definitions of the psychiatric
analysis); a diagnosis suggesting an alternative cause for each
outcome (ie, organic depression or dementia for depression diagnoses; use of a “mixed” incident and prevalent cohort; differ-
ential practice attendance; or restrictive algorithm-based definitions
analyses; obsessive-compulsive disorder or post-traumatic stress
of atopic eczema (see Table E3 in this article’s Online Repository at
disorder for anxiety analyses; and schizophrenia or bipolar
disease for both depression and anxiety analyses); record of a www.jaci-inpractice.org).
In prespecified secondary analyses, we (1) redefined atopic eczema
morbidity code for an atopic eczema diagnosis (for the unex-
exposure using atopic eczema severity as a time-updated variable and
posed group); death date recorded in CPRD; end of registra-
compared incidence rates of depression and anxiety in those with
tion with practice; last data collection from practice; or the end
mild, moderate, or severe atopic eczema to those with no atopic
of the study (March 31, 2016).
eczema and (2) explored possible effect modification of the rela-
Covariates tionship between atopic eczema and depression/anxiety by age, sex,
Covariate selection was guided by a literature review and con- and calendar period.
struction of a directed acyclic graph to avoid collider bias47,48 (see We checked the proportional hazards assumption for the main
this article’s “Directed acyclic graph” section, Figure E2, and analysis models through visual inspection of Schöenfeld residual
Tables E1 and E2 in the Online Repository at www.jaci-inpractice. plots. All P values reported are based on likelihood-ratio tests, with
org). Age, calendar period, sex, and level of deprivation (as quintiles 99% CI.52 Statistical analysis was performed using Stata, version
of the Index of Multiple Deprivation score) and ethnic group were 15.1 (StataCorp LP, College Station, Texas).
J ALLERGY CLIN IMMUNOL PRACT SCHONMANN ET AL 251
VOLUME 8, NUMBER 1

FIGURE 1. Flow diagram showing the creation of the cohort and reasons for exclusion (1998-2016). ONS, Office for National Statistics;
UTS, up-to-standard.
252 SCHONMANN ET AL J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2020

TABLE I. Characteristics of people with and without atopic eczema at cohort entry for both depression and anxiety cohorts
Depression cohort Anxiety cohort
Without atopic eczema With atopic eczema Without atopic eczema With atopic eczema
Characteristic* (n [ 1,588,277) (n [ 392,433) (n [ 1,827,908) (n [ 426,430)
Follow-up (y), median (IQR) 4.21 (1.63-8.62) 4.72 (1.86-9.12) 4.18 (1.62-8.6) 4.71 (1.85-9.13)
Sex: female, n (%) 802,909 (50.6) 211,118 (53.8) 981,824 (53.1) 237,527 (55.7)
Age (y), n (%)
18-39 828,072 (52.1) 195,455 (49.8) 941,183 (51.5) 210,764 (49.4)
40-59 355,209 (22.4) 89,126 (22.7) 431,329 (23.6) 100,592 (23.6)
60 404,996 (25.5) 107,852 (27.5) 455,396 (24.9) 115,074 (27.0)
Index of Multiple Deprivation
(quintiles), n (%)
1 (least deprived) 395,025 (24.9) 99,161 (25.3) 443,389 (24.3) 104,672 (24.6)
2 368,687 (23.2) 91,856 (23.4) 419,555 (23.0) 98,500 (23.1)
3 311,975 (19.6) 76,756 (19.6) 360,901 (19.7) 84,121 (19.7)
4 295,103 (18.6) 72,538 (18.5) 346,152 (18.9) 80,198 (18.8)
5 (most deprived) 217,487 (13.7) 52,122 (13.3) 257,911 (14.1) 58,939 (13.8)
BMI (kg/m2), mean
SD 25.74
5.1 26.01
5.3 25.87
5.2 26.18
5.4
Normal (18.5-24.9 kg/m2), n (%) 574,056 (36.1) 147,216 (37.5) 663,955 (36.3) 158,315 (37.1)
Underweight (<18.5 kg/m2), n (%) 40,118 (2.5) 9,830 (2.5) 46,346 (2.5) 10,536 (2.5)
Overweight (25.0-29.9 kg/m2), n (%) 397,525 (25.0) 105,468 (26.9) 460,537 (25.2) 114,921 (27.0)
Obese (30.0 kg/m2), n (%) 209,823 (13.2) 60,643 (15.5) 258,799 (14.2) 70,714 (15.6)
Missing, n (%) 366,755 (23.1) 69,276 (17.7) 398,271 (21.8) 71,944 (16.9)
Smoking status, n (%)
Nonsmoker 833,152 (52.5) 211,240 (53.8) 939,278 (51.4) 222,529 (52.2)
Current/ex-smoker 638,023 (40.2) 168,778 (43.0) 763,295 (41.8) 191,066 (44.8)
Missing 117,102 (7.4) 12,415 (3.2) 125,335 (6.9) 12,835 (3.0)
Harmful alcohol use, n (%) 23,244 (1.5) 7,114 (1.8) 31,639 (1.7) 9,119 (2.1)
High-dose glucocorticoids (20 mg/d 65,155 (4.1) 42,738 (10.9) 78,579 (4.3) 47,840 (11.2)
prednisolone equivalent dose), n (%)
IQR, Interquartile range; SD, standard deviation.
*See this article’s “Definitions for included covariates” section in the Online Repository at www.jaci-inpractice.org for details of variable definitions.

RESULTS outcomes. There was a 1.14-fold (99% CI, 1.12-1.16) increase

Baseline characteristics in the HR for depression in those with atopic eczema compared
We identified 3,095,838 adults aged 18 years or older, with those without, after adjusting for age, sex, general practice,
including 526,808 with atopic eczema, and matched them to current calendar period, and Index of Multiple Deprivation at
2,569,030 without eczema (Figure 1). Further exclusions of in- cohort entry (Table II. For full model, see Table E6 in this
dividuals with relevant preexisting psychiatric diagnoses on or article’s Online Repository at www.jaci-inpractice.org). Atopic
before the start of follow-up yielded 2,467,791 participants in eczema was also associated with a 1.17-fold (99% CI, 1.14-1.19)
the cohort for analyses with depression as the outcome, and increase in the risk of anxiety. Both estimates were attenuated
2,650,629 with anxiety as the outcome (all belonging to “valid after additionally adjusting for BMI, smoking status, harmful
sets,” that is, matched sets with at least 1 exposed and 1 unex- alcohol use, and high-dose glucocorticoid use (variables that may
posed individual). Median follow-up was similar in both cohorts: mediate the relationship between atopic eczema and depression/
4.7 (interquartile range, 1.6-8.6) years for individuals with atopic anxiety) (depression: HR, 1.10; 99% CI, 1.10-1.12; anxiety:
eczema and 4.2 (interquartile range, 1.9-9.1) years for those HR, 1.12; 99% CI, 1.10-1.15). The absolute excess risk of
without atopic eczema (Table I). The mean age of the atopic depression/anxiety among those with atopic eczema that could
eczemaeexposed individuals was 43.9
21.7 years in the be considered due to atopic eczema (attributable risk) was 160
depression cohort and 44.1
21.43 years in the anxiety cohort. per 100,000 person-years with atopic eczema (99% CI,
Participants with atopic eczema were less likely to have 146-186) for depression and 144 per 100,000 for anxiety (99%
missing BMI values or smoking status, compared with those CI, 115-153) although the excess risk of depression/anxiety in
without atopic eczema, and those with missing information were the population that could be considered due to atopic eczema
more likely to be young and male (see Tables E4 and E5 in this (population-attributable risk) was 1.4% (95% CI, 1.2-1.6) for
article’s Online Repository at www.jaci-inpractice.org). depression and 1.7% (1.4-1.9) for anxiety (see Table E7 in this
article’s Online Repository at www.jaci-inpractice.org) (these
Main analysis estimates were calculated assuming a 10% prevalence of atopic
We explored diagnoses compatible with unipolar depression, eczema and would increase if atopic eczema were more
generalized anxiety disorder, and panic disorders as the primary common).
J ALLERGY CLIN IMMUNOL PRACT SCHONMANN ET AL 253
VOLUME 8, NUMBER 1

TABLE II. HRs (99% CI) from Cox regression for the association between atopic eczema and anxiety and depression
Additionally adjusted for potential mediatorsz
Minimally adjusted, Adjusted,
Cohort No. Events/PYAR HR (99% CI)* HR (99% CI)† No. Events/PYAR HR (99% CI)
Depression
No atopic eczema 1,588,277 102,882/8,935,934 1.00 (reference) 1.00 (reference) 1,054,673 76,638/6,531,745 1.00 (reference)
Atopic eczema 392,433 31,322/2,354,118 1.14 (1.12-1.16) 1.14 (1.12-1.16) 316,332 27,405/2,042,715 1.10 (1.07-1.12)
Anxiety
No atopic eczema 1,818,796 82,137/10,187,499 1.00 (reference) 1.00 (reference) 1,237,423 63,592/7,566,056 1.00 (reference)
Atopic eczema 424,109 24,283/2,543,384 1.17 (1.14-1.19) 1.17 (1.14-1.19) 345,967 21,666/2,223,508 1.12 (1.09-1.15)
IMD, Index of Multiple Deprivation; PYAR, person-years at-risk.
All models were fitted to people with complete data for all included variables. Matched sets without at least 1 individual with atopic eczema and 1 without were excluded. HRs
were estimated from a Cox regression model with current age as the underlying time scale, stratified by matched set (sex, age, and general practice).
*Minimally adjusted model accounted for the matching variables (1,980,710 participants in the depression cohort [1,920,172 unique people] and 2,242,905 in the anxiety cohort
[2,171,784 unique people]).
†The adjusted model additionally included current calendar period (years: 1998-2001, 2002-2006, 2007-2011, and 2012-2016) and quintiles of IMD at cohort entry (same
participants as in the minimally adjusted).
zAdditionally adjusted for potential mediators: BMI (categorized as normal, 18.5-24.9 kg/m2; underweight, <18.5 kg/m2; overweight 25.0-29.9 kg/m2; and obese 30.0 kg/
m2), smoking status, and alcohol and high-dose glucocorticoid use (20 mg/d prednisolone equivalent dose), both as time-updated variables (1,371,005 participants in the
depression cohort [1,322,284 unique people] and 1,583,390 participants in the anxiety cohort [1,583,390 unique people]).

Our sensitivity analyses showed broadly similar effect esti- DISCUSSION

mates—those from the main analysis (Table E3). Main findings
We found that (treated) atopic eczema was associated with a
14% increase in the risk of newly diagnosed depression (adjusted
Secondary analyses HR; 99% CI, 1.12-1.16) and a 17% increase in the risk of a
Atopic eczema severity. Regardless of atopic eczema subsequent anxiety diagnosis (adjusted HR; 99% CI, 1.14-1.19).
severity level, we saw evidence for an association between These associations were only slightly attenuated after further
atopic eczema and both depression and anxiety (Figure 2). adjusting for potential mediators of the association between
Compared with those without atopic eczema, the risk of atopic eczema and anxiety/depression (BMI, smoking status, and
depression increased with increasing atopic eczema severity (P alcohol and high-dose glucocorticoid use) and were present at all
< .0001 for linearity; P ¼ .3832 for departure from linearity levels of atopic eczema disease severity. Risk of a new depression
in the adjusted model; and P ¼ .6983 for departure from diagnosis increased linearly with increasing atopic eczema
linearity in the model additionally adjusted for potential me- severity, providing strong evidence for a dose-response associa-
diators). However, the results of analyses exploring the rela- tion. The outcomes were diagnoses compatible with unipolar
tionship between atopic eczema severity and anxiety did not depression, generalized anxiety disorder, and panic disorders, but
demonstrate a similarly clear dose-response relationship; for we considered broader definitions of depression/anxiety in sub-
mild and moderate atopic eczema, there was some evidence of sequent sensitivity analyses.
a similar dose-response increase, but there was strong statis-
tical evidence for departure from linearity (P < .0001) (see Strengths and limitations
Table E8 in this article’s Online Repository at www.jaci- We identified a large, nationally representative sample of
inpractice.org). people, the largest reported to date,20,21 ensuring precise effect
estimations and increased generalizability. We used a validated
diagnostic algorithm to identify atopic eczema in primary care,53
Effect modification by sex, age, and calendar peri- and relied on highly specific physician diagnoses rather than self-
od. We saw some evidence (P < .0001) for sex modifying the reported outcomes.54-56 We chose the covariates included in the
effect of atopic eczema on depression, with a slightly higher risk analysis on the basis of a priori reasoning (see this article’s
of depression in those with atopic eczema compared with those “Directed acyclic graph” section; Figure E2).48 Although some
without in men (1.19; 99% CI, 1.16-1.23) than in women chronic conditions may be associated with atopic eczema,57 as
(1.11; 99% CI, 1.08-1.13). We saw a similar pattern for risk of well as with depression/anxiety,58 in the context of this study, we
anxiety in those with and without atopic eczema after strati- did not consider these conditions fit the definition for con-
fying on sex (HR [99% CI]: men, 1.22 [99% CI, 1.17-1.27]; founding because the potential confounder (chronic comorbid-
women, 1.14 [99% CI, 1.11-1.17]; P ¼ .0003 for interaction). ity) could be considered to be either a consequence of the
We also saw evidence for effect modification by current age, outcome (anxiety/depression), or to mediate the relationship
with the HR comparing those with atopic eczema to those between exposure and outcome (see this article’s “Directed
without for both depression (P < .0001) and anxiety (P ¼ acyclic graph” section).
.0052) being higher in those aged 40 to 59 years, compared We deemed other factors (ie, BMI, smoking, systemic glu-
with younger and older age groups. There was no evidence of a cocorticoids, harmful alcohol use) as likely mediators of the effect
change in the effect of atopic eczema on both depression (P ¼ of atopic eczema on depression and anxiety, rather than con-
.3229) and anxiety (P ¼ .287) in different calendar periods (see founders; we consequently adjusted for these variables separately.
Table E9 in this article’s Online Repository at www.jaci- Atopic eczema may be associated with the later development of
inpractice.org). conditions such as cardiovascular disease and various
254 SCHONMANN ET AL J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2020

FIGURE 2. HRs (99% CI) for the association between eczema severity (time-updated) and depression and anxiety. IMD, Index of Multiple
Deprivation. All models were fitted to people with complete data for all included variables. Sets without at least 1 exposed and 1 un-
exposed were excluded. HRs were estimated from a Cox regression model with current age as the underlying time scale, stratified by
matched set (sex, age, and general practice). A minimally adjusted model accounted for the matching variables (1,980,710 participants in
the depression cohort [1,920,172 unique people] and 2,242,905 in the anxiety cohort [2,171,784 unique people]). The adjusted model
additionally included current calendar period (years: 1998-2001, 2002-2006, 2007-1201, and 2012-2016,) and quintiles of IMD at
cohort entry (same participants as in the minimally adjusted). A final model, additionally adjusted for potential mediators, also included
BMI (categorized as normal, 18.5-24.9 kg/m2; underweight, <18.5 kg/m2; overweight 25.0-29.9 kg/m2; obese 30.0 kg/m2), smoking
status, and alcohol and high-dose corticosteroid use (20 mg/d prednisolone equivalent dose), both as time-updated variables
(1,371,005 participants in the depression cohort [1,322,284 unique people] and 1,583,390 in the anxiety cohort [1,583,390 unique
people]). *Compared with no atopic eczema. †Depression: P values were less than .0001 for linearity in all models, and for departure
from linearity were as follows: minimally adjusted P ¼ .3810; adjusted P ¼ .3832; and additionally adjusted for potential mediators P ¼
.6983. zAnxiety: P values were less than .0001 for linearity in all models, and less than .0001 for departure from linearity in all models.

malignancies,50,57 but exploring the potential mediating role of absence in symptoms). Consequently, we considered individuals
chronic comorbidity was beyond the scope of our analysis. as having moderate or severe disease from the date they met the
The study also has several limitations. The algorithm we used respective definition, and may therefore have wrongly classified
to define atopic eczema excluded untreated individuals, reducing people as having moderate/severe eczema when their symptoms
its sensitivity to detect milder cases.59 This limitation was miti- had reduced or resolved. The result of wrongly classifying in-
gated by the availability of primary care data, because 97% of dividuals as having more severe disease when their symptoms had
those with atopic eczema in the United Kingdom are managed in actually remitted would only be to dilute the effect of eczema
primary care,60,61 and by including emollients, which are severity on depression/anxiety and bias our effect estimate to
routinely prescribed for atopic eczema in the United Kingdom.62 null.
The results also remained robust in sensitivity analyses using less- Follow-up began in adulthood, resulting in a mixed cohort of
restrictive atopic eczema definitions. Analyses stratified by atopic prevalent and incident (newly diagnosed) atopic eczema cases,
eczema severity provided further reassuring evidence of an asso- introducing possible bias due to left truncation (ie, the possibility
ciation between atopic eczema and anxiety/depression even of an outcome event occurring before cohort entry), with
among mild cases. However, our definition of atopic eczema consequent underestimation or overestimation of the effect of
severity might have misclassified individuals with severe atopic atopic eczema on depression and anxiety. However, following
eczema as having less severe disease if they refused medical only incident cases when exploring predominantly adult-onset
therapy.63 Misclassification of disease status or severity may have outcomes would have shortened follow-up and limited the
overestimated or underestimated the real association between study’s power. In addition, the exact onset date of a relapsing
severity of eczema and anxiety/depression because early symp- condition such as atopic eczema cannot be captured accurately in
toms of depression/anxiety could influence diagnostic and routinely collected data. In such circumstances, a dynamic cohort
treatment preferences. However, general practitioners recorded including prevalent cases is preferred.64 A sensitivity analysis
their depression/anxiety diagnoses independently and prospec- offered evidence against bias introduced by including both
tively, so reverse causality likely affected all study participants “incident” and prevalent atopic eczema cases in our cohort
equally regardless of atopic eczema status (ie, nondifferential because it showed broadly similar results in those with prevalent
misclassification, suggesting bias toward the null rather than a atopic eczema and those more likely to have new-onset atopic
spurious association). eczema.
A further limitation of our eczema severity definition was that Smoking status and/or BMI were not recorded for some study
we were unable to capture symptom reduction or resolution participants, and it is likely that whether smoking status/BMI
(absence of a record for eczema does not necessarily mean was recorded or not was dependent on having atopic eczema or
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VOLUME 8, NUMBER 1

anxiety/depression (ie, missing not-at-random). BMI and Although our results apply directly to UK primary care, they
smoking status are often captured opportunistically and are are likely to be relevant in other settings, especially where there is
therefore more likely to be recorded in those who consult their primary careeoriented universal access to health care. Mental
general practitioner more frequently (due to health-seeking illness is underdiagnosed in people with skin or other chronic
behavior or chronic conditions).65 Although previous studies diseases,69-71 but their detection and treatment might improve
suggested no clear-cut association between physical illness and atopic eczema control by facilitating better adherence to skin
detection of psychiatric diagnoses in primary care,66,67 the pos- disease treatment,72 or through direct anti-inflammatory actions
sibility of selection bias when applying complete case analysis (ie, of antidepressants.73 Current UK guidelines address only the
including only those with complete data) remains. In our study, management of atopic eczema in children, emphasizing the
this did not affect the main analysis, because the variables con- importance of assessing the psychosocial well-being and quality
taining missing data were not included in the main adjusted of life.74 Recent guidelines from the European Academy of
analysis (they were considered as potential mediators). Compa- Dermatology and Venereology comment briefly on the influence
rable results from the model including smoking and BMI also of psychological and emotional factors on the clinical course of
provide evidence against substantial bias introduced by missing atopic eczema.5 Neither of these guidelines mentions the long-
data. Finally, general practitioners do not routinely record pa- term mental health implications of atopic eczema. Our find-
tients’ quality of sleep, and we were not able to assess the extent ings suggest that depression and anxiety should be addressed
to which itch-related sleep disturbances mediate the development explicitly in future guideline updates. Further research is needed
of depression and anxiety among people with atopic eczema.30 to explore and define possible mediators; to characterize sub-
populations at increased risk (eg, those with adult-onset atopic
Comparisons to existing literature eczema, or those with more active variants of the disease); and to
An association between atopic eczema, depression, and anxiety elucidate the feasibility and effectiveness of screening, early
has been described in cross-sectional and case-control studies, in detection, and prevention of depression and anxiety among those
which the temporal sequence (ie, whether atopic eczema precedes with atopic eczema.
depression or anxiety, or vice versa) could not be determined.16-
22
The few longitudinal studies that addressed this question had CONCLUSIONS
inconsistent results.32-34 These studies were limited by short Individuals affected with atopic eczema were more likely to
follow-up windows34; inclusion of selected, nonrepresentative develop depression and anxiety, regardless of atopic eczema
populations (eg, male military conscripts34 or secondary care severity. Strong evidence for a dose-response relationship be-
diagnoses32,33); no account of atopic eczema disease severity32,34; tween atopic eczema severity and depression supports a causal
low-quality or no individual-level information on lifestyle vari- association. These results highlight the importance of a
ables32,34; and reliance on disease-specific medication usage as a comprehensive bio-psycho-social approach to limit common
nonspecific proxy measure to ascertain depression and anxi- mental disorders in those with atopic eczema and could guide
ety.33,34 Notably, a recent Danish cohort study demonstrated recommendations for the management of atopic eczema.
point estimates that were in line with the estimates reported in
our study, but the association was not evident in the adjusted
models that included health care consumption.33 Acknowledgments
This work uses data provided by patients and collected by the
Interpretation and clinical implications UK National Health Service as part of their care and support.
Atopic eczema, like several other chronic conditions,58 is The research questions, design, conduct, and initial results and
associated with depression/anxiety. The link to chronic mental interpretation of the findings of this study have been overseen by
illness further supports the view of atopic eczema as a systemic SL's Wellcome Senior Clinical Fellowship steering committee,
disorder.68 Our results suggest that the association between which includes lay representation. A patient-representative, A.R.,
atopic eczema and depression/anxiety is not substantially medi- was involved in this study as a coauthor. We are not able to
ated through glucocorticoid treatment, obesity, smoking, or disseminate the results of the research directly to study partici-
harmful alcohol intake. Evidence against a dose-response asso- pants because the data used were anonymized.
ciation between atopic eczema severity and anxiety could not
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ONLINE REPOSITORY collection in our study, it seems unlikely that any misclassifica-
tion of eczema severity would be differentially associated with the
METHODS future outcome, nor does it seem to be of a magnitude large
Codes and treatments used in algorithm definition of enough to substantially bias the effect estimate. In such cir-
atopic eczema cumstances, an estimate of trend would be biased downwards,E15
Using a validated algorithm,E1 atopic eczema diagnosis was which would only strengthen the validity of a demonstrated
determined by a combination of any recorded atopic eczema biological gradient.
diagnostic code in primary care (CPRD, using Read codes) or Our choice of treatments used to define moderate and severe
inpatient hospital admission data (HES, using International atopic eczema is broadly consistent with previous similar
Classification of Diseases, Tenth Revision codes recorded in any attempts,E4-E9 but also reflects some international variability in
diagnostic position of any episode of care), and 2 atopic eczema prescription practices. For example, although topical calcineurin
therapies (recorded on separate days in primary care or hospital inhibitors are indeed recommended for use in mild disease by
records). recent European guidelines,E16 they are not used for this indi-
To avoid immortal-time bias, the date of diagnosis was set as cation in the United Kingdom (where our study is set). The
the date of the latest recorded component (ie, atopic eczema European Medicines Agency has issued a recommendation for
diagnostic code or second record for atopic eczema therapy) in cautious use of topical tacrolimus and pimecrolimus due to po-
the algorithm. tential risks of skin cancer and lymphoma.E17 In the United
By default, all individuals with atopic eczema were classified as Kingdom, these preparations are not considered as first-line
having mild disease. They could be recategorized as having options for mild atopic eczema, and they can be initiated only
moderate atopic eczema from the earliest of (1) second potent by specialistsE10,E18; consequently, we used a prescription for a
topical steroid treatment within a year or (2) first calcineurin calcineurin inhibitor as a marker of moderate eczema.
inhibitor treatment. Mild or moderate cases could be recatego- Read codes and International Classification of Diseases codes
rized as severe, from the earliest of (1) first systemic treatment for defining atopic eczema and atopic eczema treatments can be
atopic eczema excluding oral glucocorticoids (ie, a record of a downloaded.E19
prescription for cyclosporine, azathioprine, mycophenolate, or Drugs used for treating eczema.
methotrexate), or (2) first phototherapy code, or (3) first referral
to secondary care for atopic eczema.  emollients
Using electronic health records allowed us to conduct a  topical glucocorticoids
population-based analysis powered to explore the association  topical tacrolimus and pimecrolimus
between atopic eczema, and depression and anxiety. However,  oral glucocorticoids
the analysis was limited to data routinely captured in primary  azathioprine
care, which does not include objective assessment of patients’  ciclosporin
eczema disease severity using validated scoring systems (eg,  methotrexate
Eczema Area and Severity Index and SCORing Atopic Derma-  mycophenolate mofetil
titis).E2 To date, there are no validated measures for ascertaining
the severity of atopic eczema using routinely collected data.E3 Code lists for the outcomes (depression and anxiety)
However, the approach we used to overcome this limitation Development of code lists. The monitoring and man-
(ie, use of prescribed therapies) is commonly used in the agement of depression is financially incentivized in UK primary
dermato-epidemiology literature.E4-E9 care through the Quality and Outcomes Framework,E20 which
In the United Kingdom, for example, systemic treatments uses a list of Read codes to define new occurrences of depres-
may be initiated only by dermatologists,E10 making this proxy sion.E21 This resulted in some standardization of codes used in
measure a highly specific one, because it implies assessment by a general practice, but was also highlighted as a contributing reason
trained specialist. Although this method may misclassify in- for a growing trend among general practitioners to use symptom
dividuals with severe eczema who declined therapy,E11 findings codes for depression (eg, “depressive symptoms” and “Low
from secondary care registries suggest that 60% to 80% of mood”) rather than definitive diagnostic codes (eg, “major
specialist-diagnosed severe eczema cases did have a history of depression”).E22,E23 Symptom codes are also increasingly used by
systemic treatment.E12,E13 Findings from recent publications also general practitioners in the United Kingdom for patients with
support the validity of this approach: A positive predictive value anxiety, despite the fact that anxiety diagnosis and treatment are
of 93.6% was demonstrated for the diagnosis of severe atopic not included in the Quality and Outcomes Framework. This
eczema using Israeli health records,E4 and a Danish validation trend possibly reflects diagnostic uncertainty and a reluctance to
study assessing a similar approach among patients with psoriasis stigmatize patients.E24,E25
suggested 91% sensitivity and 83% specificity for detection of We compiled preliminary lists of potential codes using key-
severe disease.E14 words from the Medical Subjects Headings list and clinical
Relying on prescribed therapies as a proxy measure for disease knowledge, as previously suggested.E26,E27 This initial list of
severity may not be fully calibrated with other established scores, codes was compared with and augmented by a code list from the
making severity-stratumespecific estimates harder to interpret. Clinical research using Linked Bespoke studies and Electronic
However, a prescribed treatment criterion is likely to perform health Records website (a platform that aims to offer researchers
well in separating those with a more severe manifestation (ie, predefined code lists and algorithms to identify clinical pheno-
good discrimination). Because of the prospective nature of data types using electronic health record data)E28 and previously
J ALLERGY CLIN IMMUNOL PRACT SCHONMANN ET AL 257.e2
VOLUME 8, NUMBER 1

published lists used to define depressionE21,E29-E32 and anx- attention deficit/hyperactivity disorder, rheumatoid arthritis,
iety.E29,E31-E33 Subsequently, we categorized the relevant codes renal diseases, and inflammatory bowel disorder-
into several subcategories, on the basis of clinical knowledge, s).E7,E8,E36,E46,E47 To guide covariate selection a priori, and to
literature review, and the expert opinion of several coauthors avoid collider bias, we constructed a directed acyclic graph
experienced in general practice (Y.S.), UK clinical practice and (Figure E2).E48
EHR research (S.M.L., J.F.H., and K.E.M.), and psychiatry and Chronic diseases could play a mediating role in the association
psychiatric epidemiology using electronic health record data between atopic eczema and depression/anxiety, but could also be
(J.F.H.). The list was finalized through a discussion and more likely to be diagnosed among those with depression/anxi-
consensus process. ety, and therefore introduce collider bias. Chronic comorbidities
Codes for depression were categorized as follows: were, therefore, not included in our analyses.
A potential confounder (1) must be a risk factor for the
1. “Core” codes: Compatible with “classic unipolar” depression outcome (ie, a cause, or surrogate for a cause, of depression/
diagnoses, of various severities.E34 Broadly following the anxiety); (2) must be associated with the exposure (ie, atopic
Quality and Outcomes Frameworkeeligible diagnoses,E21 eczema); and (3) cannot be an intermediate step on the causal
and in line with previous publications.E29-E32 path between exposure and outcome (ie, it must not mediate the
2. Symptom codes. association between atopic eczema and depression/anxiety) nor
3. Nondefinitive codes: Including broader definitions of be a consequence of the outcome (depression/anxiety).E49
depression, depression due to transient causes, and Although some chronic conditions may be associated with
depression-related administrative codes. atopic eczema,E50 as well as with depression/anxiety,E51 in the
4. History codes: Asserting a history of depression context of this study, we did not consider that these chronic
We used a similar framework to define incident anxiety cases. conditions fit the definition for confounding because the po-
Codes compatible with generalized anxiety disorder and panic tential confounder (chronic comorbidity) could be considered to
disorder were considered as “core” diagnoses. Codes for specific either be a consequence of the outcome (anxiety/depression) or
phobias were included in the nondefinite category.E24,E29,E32,E33 to mediate the relationship between exposure and outcome. Even
We used codes classified as core codes to define the primary though our study specifically excluded preexisting psychiatric
outcomes in the main analyses and explored the possible intro- diagnoses, there is a possibility of undiagnosed mental illness, so
duction of bias through sensitivity analyses (Table E2). chronic conditions could still be potential consequences of
Individuals were excluded from the depression or anxiety anxiety or depression because (1) most primary care patients with
cohort after matching if they had a relevant “core,” “symptom,” depression initially present with somatic symptoms,E52 and
or “nondefinitive” code recorded at any time before cohort entry increased general practitioner attendance is associated with earlier
(ie, those with previous depression were excluded from the diagnosis of chronic conditions,E53,E54 and (2) depression/anxi-
depression cohort, and those with previous anxiety were excluded ety (ie, the outcomes) are well-established independent risk fac-
from the anxiety cohort). Individuals with a code for a clinical tors for chronic medical conditions.E55-E58 Therefore, we did not
term including a “history of” anxiety or depression recorded at adjust for chronic comorbidities as confounders, because
any time were also excluded from the relevant cohort, because adjusting for factors that may be influenced by both the exposure
the timing of their diagnosis could not be ascertained. and the outcome would introduce collider bias.E49,E59
The recording of our depression/anxiety outcomes is likely to Alternatively, we could regard chronic comorbidities as medi-
be biased among those with codes compatible with alternative ators of the relationship between atopic eczema (exposure) and
etiologies for the outcome (ie, organic depression or dementia for anxiety/depression (outcomes). By adjusting for lifestyle factors (ie,
the depression cohort, obsessive-compulsive disorder or post- BMI, smoking, and harmful alcohol use) as potential mediators,
traumatic stress disorder for the anxiety cohort, and schizo- we were able to capture, at least some of, the effect of atopic eczema
phrenia or bipolar disease for both cohorts). We, therefore, on chronic comorbidities (ie, considering lifestyle factors as being
excluded people with these conditions if diagnosed before the on the causal pathway between atopic eczema and chronic
index date, and censored participants upon a subsequent diag- comorbidities such as cardiovascular disease). Of note here, addi-
nosis (such alternative diagnoses were, by an order of magnitude, tional adjustment for potential mediators (Table II) only slightly
less frequent than depression/anxiety). If excluded individuals attenuated the effect of atopic eczema on anxiety/depression,
were in the atopic eczemaeexposed group at baseline, their suggesting that further adjustment for chronic comorbidities may
respective matched unexposed individuals were also excluded. have limited impact. So, although atopic eczema may predict
Read codes and International Classification of Diseases codes conditions such as cardiovascular disease and various malig-
can be downloaded.E19 nancies,E7,E50 exploring the potential mediating role of chronic
Read codes used to define bipolar disease and schizophrenia comorbidity was beyond the scope of our analysis.
were taken from the Clinical research using Linked Bespoke
studies and Electronic health Records website.E28 Definitions for included covariates
The date of birth was set as July 1 for all participants, because
Directed acyclic graph CPRD supplies year of birth only (to ensure patient anonymity).
A review of the literature revealed several conditions associated Calendar period was categorized as 1998 to 2001, 2002 to 2006,
with atopic eczema: age,E35-E39 female sex,E36-E41 socioeconomic 2007 to 2011, and 2012 to 2016, to account for changes in
status,E35,E36 ethnicity, health care interactions/health anx- clinical, diagnostic, and administrative practices over the study
iety,E35,E41-E43 obesity,E44 smoking status,E36 alcohol period that may have influenced the measurement of exposure,
use,E36,E38,E45 diabetes,E8,E36,E46 malignancies,E36,E46 and outcomes, and other covariates. Socioeconomic deprivation was
chronic conditions (including asthma, cardiovascular diseases, assigned through categorizing each participant’s 2007 Index of
257.e3 SCHONMANN ET AL J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2020

Multiple Deprivation (IMD) score categorized in quintiles. The Algorithms to identify BMI and steroid use data
IMD is an index of deprivation updated by the Department for Body mass index. Read codes for BMI category were not
Communities and Local Government every few years, combining used (because they are rarely recorded). Instead BMI was
information from 7 domains: income, employment, health and calculated using height and weight measures recorded closest to
disability, education, barriers to housing and services, living the cohort entry date (1 year before to 1 month after the cohort
environment, and crime.E60 IMD data are available for the years entry date; if not available, then the nearest in the year following
2004, 2007, 2010, and 2015. We chose 2007 as the midpoint of cohort entry was taken; if not available, then the nearest value in
the study (January 1998 to March 2016). IMD was assigned on the year before cohort entry was taken; if not available, then
the basis of individual postcode of residence, or on 2010 nearest weight value recorded after the first year was used). We
practice-location if other data were unavailable. regarded improbable values of BMI (BMI < 10 kg/m2 or BMI >
BMI was categorized as underweight (<18.5 kg/m2), normal 60 kg/m2) as errors, and therefore considered these data as
(20-24 kg/m2), overweight (25-29 kg/m2), and obese (>30 kg/ missing. Smoking status was categorized as current/ex or none on
m2), in line with the World Health Organization catego- the basis of record closest to cohort entry date.
rization.E61 Harmful alcohol use was based on relevant morbidity
coding or prescriptions for drugs used to maintain alcohol absti-
nence, with status changing at first primary care record suggesting Glucocorticoid dose. The daily dose of oral glucocorticoid
harmful alcohol use. High-dose oral glucocorticoid use was defined was calculated as the number of pills prescribed numeric daily
as greater than or equal to 20 mg/d prednisolone equivalent dose, dose (NDD)  dose per tablet. Where NDD was missing, a
for the duration of the patients’ prescription and 3 months after the “hot-deck” style imputation method was adopted, which
end of the prescription (glucocorticoids included deflazacort, replaced missing data with comparable data from the same set.
dexamethasone, prednisone, prednisolone). Smoking status and An extra binary variable for quantity of tablets per prescription
BMI were defined on the basis of status recorded closest to the date was created, categorizing quantity about the median number into
an individual entered the cohort. Missing doses of glucocorticoids low and high. If a patient had any other record with the same
were completed by using data from the entire data set. (See quantity and dose per tablet, the median NDD among those
"Algorithms to identify BMI and steroid use data" for a full records was used where NDD was missing. If a patient had no
description of the data completion algorithms.) recorded NDD but had any other record of the same dose per
For a sensitivity analysis, ethnicity was included as covariate, tablet and quantity as a binary variable, the median NDD among
based on a previously validated algorithm.E62 Ethnicity was those records was used. If a patient did not have a recorded
assigned to 5 categories: white, South Asian, black, other, or NDD or quantity, but had records for the same dose per tablet,
mixed. First, the most common ethnicity in CPRD was used, then the median NDD among those records was used. If there
then the latest ethnicity in CPRD was used where several eth- was no record of NDD, dose per tablet or quantity, but there
nicities were recorded equally, and finally HES ethnicity was were other patients in the data set in the same 5-year age band, of
used where CPRD ethnicity was missing. Because the quality of the same sex, with the same dose per tablet and quantity, the
the recording for ethnicity was acceptable only from 2006 median NDD for those records was used. Finally, if none of the
onwards,E62 we restricted this analysis to those registering with above were possible, patients in the data set in the same 5-year
the CPRD general practice after January 1, 2006. age band, of the same sex, with the same dose per tablet and
Read codes and International Classification of Diseases codes quantity as a binary variable, the median NDD among these
used to identify covariates can be downloaded.E19 records was used.
J ALLERGY CLIN IMMUNOL PRACT SCHONMANN ET AL 257.e4
VOLUME 8, NUMBER 1

FIGURE E1. Visual representation of the cohort entry criteria and follow-up process.

FIGURE E2. Directed acyclic graph illustrating implicitly assumed causal structure underlying our adjusted models.
257.e5 SCHONMANN ET AL J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2020

TABLE E1. Univariable associations between covariates and depression

Variable Events/PYAR Rate/100,000 PYAR HR (99% CI)
Atopic eczema exposure
Without atopic eczema 102,882/8,935,934 1,151 (1,142-1,161) 1.00 (reference)
With atopic eczema 31,322/2,354,118 1,331 (1,311-1,350) 1.14 (1.11-1.16)
Atopic eczema severity
Unexposed 102,882/8,935,934 1,151 (1,142-1,161) 1.00 (reference)
Mild 19,116/1,436,377 1,331 (1,306-1,356) 1.10 (1.07-1.12)
Moderate 10,301/786,352 1,310 (1,277-1,344) 1.19 (1.15-1.23)
Severe 1,905/131,389 1,450 (1,367-1,538) 1.25 (1.16-1.35)
Sex
Male 49,110/5,599,286 877 (867-887) NA
Female 85,094/5,690,766 1495 (1482-1509) NA
Age at cohort entry (y)
18-19 24,147/1,511,015 1,598 (1,572-1,625) 1.00 (reference)
20-29 26,094/1,698,066 1,537 (1,512-1,561) 1.00 (0.88-1.14)
30-39 23,230/1,817,250 1,278 (1,257-1,300) 1.10 (0.84-1.44)
40-49 17,298/1,599,240 1,082 (1,061-1,103) 1.01 (0.65-1.57)
50-59 12,621/1,569,384 804 (786-823) 1.29 (0.71-2.36)
60-69 11,943/1,542,594 774 (756-793) 2.30 (1.16-4.56)
70-79 12,633/1,133,250 1,115 (1,090-1,141) 3.50 (1.69-7.25)
80 6,238/419,254 1,488 (1,440-1,537) 3.95 (1.82-8.59)
Calendar period (y)
1998-2001 22,063/1,422,827 1,551 (1,524-1,578) 1.00 (reference)
2002-2006 37,260/2,937,645 1,268 (1,252-1,285) 0.75 (0.64-0.87)
2007-2011 42,449/3,973,737 1,068 (1,055-1,082) 0.59 (0.49-0.71)
2012-2016 32,432/2,955,843 1,097 (1,082-1,113) 0.56 (0.46-0.69)
IMD (quintiles)
1 (least deprived) 28,280/2,942,268 961 (947-976) 1.00 (reference)
2 28,468/2,687,862 1,059 (1,043-1,075) 1.11 (1.08-1.14)
3 26,471/2,229,329 1,187 (1,169-1,206) 1.22 (1.19-1.26)
4 27,669/1,995,052 1,387 (1,366-1,409) 1.46 (1.41-1.51)
5 (most deprived) 23,316/1,435,541 1,624 (1,597-1,652) 1.72 (1.66-1.79)
BMI (kg/m2), mean
SD
Normal (18.5-24.9 kg/m2) 3,613
206,460 1,750 (1,677-1,827) 1.00 (reference)
Underweight (<18.5 kg/m2) 47,272
3,898,062 1,213 (1,198-1,227) 0.85 (0.80-0.90)
Overweight (25.0-29.9 kg/m2) 32,541
2,989,894 1,088 (1,073-1,104) 0.89 (0.84-0.94)
Obese (30.0 kg/m2) 21,096
1,521,982 1,386 (1,362-1,411) 1.08 (1.01-1.14)
Smoking status
Nonsmoker 61,985/6,112,858 1,014 (1,004-1,025) 1.00 (reference)
Current/ex-smoker 66,260/4,456,536 1,487 (1,472-1,502) 1.60 (1.57-1.63)
Harmful alcohol use*
No 129,457/11,080,950 1,168 (1,160-1,177) 1.00 (reference)
Yes 4,747/209,102 2,270 (2,187-2,357) 2.57 (2.43-2.71)
High-dose glucocorticoids* (20 mg/d prednisolone equivalent dose)
No 132,592/11,219,476 1,182 (1,173-1,190) 1.00 (reference)
Yes 1,612/70,576 2,284 (2,142-2,435) 2.10 (1.92-2.29)

NA, Not applicable/available; PYAR, person-years at-risk.

Univariable HRs are derived from Cox regression models with current age as the underlying timescale, stratified by matched set (sex, age, and general practice). Models were
fitted to patients with complete data who are included in valid sets (ie, with at least 1 exposed and 1 unexposed individual).
*Measured as a time-updated variable.
J ALLERGY CLIN IMMUNOL PRACT SCHONMANN ET AL 257.e6
VOLUME 8, NUMBER 1

TABLE E2. Univariable associations between covariates and anxiety

Variable Events/PYAR Rate/100,000 PYAR HR (99% CI)
Atopic eczema exposure
Without atopic eczema 82,137/10,187,499 806 (799-814) 1.00 (reference)
With atopic eczema 24,283/2,543,384 955 (939-971) 1.17 (1.14-1.19)
Atopic eczema severity
Unexposed 82,137/10,187,499 806 (799-814) 1.00 (reference)
Mild 15,093/1,543,672 978 (957-998) 1.14 (1.11-1.17)
Moderate 7,822/853,452 917 (890-944) 1.21 (1.17-1.26)
Severe 1,368/146,259 935 (872-1003) 1.14 (1.04-1.25)
Sex
Male 32,586/5,928,234 550 (542-558) NA
Female 73,834/6,802,649 1,085 (1,075-1,096) NA
Age at cohort entry (y)
18-19 18,218/1,582,297 1,151 (1,130-1,174) 1.00 (reference)
20-29 22,028/1,950,021 1,130 (1,110-1,149) 0.80 (0.69-0.92)
30-39 20,658/217,9519 948 (931-965) 0.66 (0.51-0.86)
40-49 14,555/1,892,615 769 (753-786) 0.66 (0.44-0.99)
50-59 10,918/1,779,862 613 (598-629) 0.51 (0.29-0.90)
60-69 9,436/1,668,280 566 (551-581) 0.62 (0.32-1.19)
70-79 7,603/1,210,115 628 (610-647) 0.72 (0.35-1.48)
80 3,004/468,173 642 (612-673) 0.86 (0.39-1.93)
Calendar period (y)
1998-2001 16,323/1,572,503 1,038 (1,017-1,059) 1.00 (reference)
2002-2006 28,605/3,294,860 868 (855-881) 0.96 (0.80-1.15)
2007-2011 32,291/4,494,729 718 (708-729) 0.83 (0.67-1.03)
2012-2016 29,201/3,368,791 867 (854-880) 0.87 (0.69-1.10)
IMD (quintiles)
1 (least deprived) 23,246/3,239,958 717 (705-730) 1.00 (reference)
2 23,013/2,989,450 770 (757-783) 1.09 (1.05-1.22)
3 20,698/2,535,226 816 (802-831) 1.15 (1.11-1.19)
4 21,398/2,296,647 932 (915-948) 1.30 (1.25-1.35)
5 (most deprived) 18,065/1,669,602 1,082 (1,061-1,103) 1.42 (1.36-1.48)
BMI (kg/m2), mean
SD
Normal (18.5-24.9 kg/m2) 3,109
236,632 1,314 (1,255-1,376) 1.00 (reference)
Underweight (<18.5 kg/m2) 40,808
4,412,253 925 (913-937) 0.86 (0.81-0.91)
Overweight (25.0-29.9 kg/m2) 25,695
3,365,057 764 (751-776) 0.85 (0.80-0.90)
Obese (30.0 kg/m2) 16,016
1,823,430 878 (861-896) 0.90 (0.84-0.96)
Smoking status
Nonsmoker 51,195/6,778,933 755 (747-764) 1.00 (reference)
Current/ex-smoker 51,622/5,186,043 995 (984-1007) 1.44 (1.42-1.47)
Harmful alcohol use*
No 102,616/12,465,556 823 (817-830) 1.00 (reference)
Yes 3,804/265,326 1,434 (1,375-1,495) 2.32 (2.18-2.46)
High-dose glucocorticoids* (20 mg/d prednisolone equivalent dose)
No 105,057/12,646,811 831 (824-837) 1.00 (reference)
Yes 1,363/84,071 1,621 (1,512-1,738) 2.12 (1.92-2.34)

NA, Not applicable/available; PYAR, person-years at-risk.

Univariable HRs are derived from Cox regression models with current age as the underlying timescale, stratified by matched set (sex, age, and general practice). Models were
fitted to patients with complete data who are included in valid sets (ie, with at least 1 exposed and 1 unexposed individual).
*Measured as a time-updated variable.
 257.e7
TABLE E3. Description, justification, and summary results of sensitivity analyses
Depression Anxiety
Analysis Description Justification No. Events/PYAR Adjusted HR* (99% CI) No. Events/PYAR Adjusted HR* (99% CI)

SCHONMANN ET AL
Main analysis 1,980,710 134,204/11,290,052 1.14 (1.12-1.16) 2,242,905 106,420/12,730,883 1.17 (1.14-1.19)
Sensitivity Repeating the primary analysis To explore potential bias
analysis 1 using progressively less-strict introduced by low sensitivity to
definitions of psychiatric detect psychiatric diagnoses in
diagnoses electronic health records, as
well as by general
practitioner’s use of symptom
codes, instead of diagnostic
codes
(1a) Initially including symptom 1,980,710 211,534/10,970,276 1.16 (1.14-1.17) 2,242,905 175,874/12,420,852 1.18 (1.16-1.20)
codes in the definitions of
outcomes
(1b) Subsequently also adding 1,980,710 227,393/10,908,249 1.15 (1.14-1.17) 2,242,905 202,679/12,353,235 1.18 (1.16-1.20)
“nondefinitive” diagnostic
codes
Sensitivity Repeating the primary analysis To separate “true prevalent” cases
analysis 2 separately for prevalent and from likely incident atopic
incident atopic eczema cases. eczema cases to explore
Stratifying the analysis on the possible bias due to the choice
time since the initial diagnosis of a “prevalent” cohort design
(0-4 or 5 y)
(2a) “Incident” cohort 1,431,318 97,372/8,445,494 1.17 (1.15-1.20) 1,646,703 77,545/9,614,471 1.19 (1.16-1.22)
(2b) “Prevalent” cohort 549,392 36,832/2,844,558 1.05 (1.01-1.09) 596,202 28,875/3,116,412 1.10 (1.06-1.15)
Sensitivity Repeating the primary analysis To explore potential bias due to 1,825,694 125,472/10,460,654 1.16 (1.14-1.18) 2,086,308 100,225/11,882,522 1.19 (1.16-1.21)
analysis 3 including only those who differential recording of
consulted their general exposure, covariates, and
practitioner in the year before outcomes among practice
cohort entry attenders and nonattenders.
Robust effect implies
insensitivity to bias introduced
by varying degrees of health
care contact
Sensitivity Repeating the primary analysis To explore the sensitivity of the 2,514,107 173,793/14,708,229 1.07 (1.05-1.09) 2,838,141 135,719/16,515,260 1.10 (1.08-1.12)
analysis 4 on redefined cohorts with a results to the definition of
less-restrictive atopic eczema atopic eczema (eg, those with

J ALLERGY CLIN IMMUNOL PRACT

definition: atopic eczema childhood atopic eczema may
diagnosis was ascertained have been erroneously
using only atopic eczema excluded from the primary
diagnostic codes, with no analysis if they switched
requirement for a therapeutic practice in adulthood, and did

JANUARY 2020
code not require further treatments)
 VOLUME 8, NUMBER 1
J ALLERGY CLIN IMMUNOL PRACT
Sensitivity Repeating the primary analysis on To explore the sensitivity of the 2,002,613 135,552/11,329,039 1.14 (1.12-1.16) 2,267,537 107,660/12,771,273 1.16 (1.14-1.19)
analysis 5 redefined cohorts with a less- results to the definition of
restrictive definition for those atopic eczema
without atopic eczema
(unexposed): individuals with
an atopic eczema diagnosis but
without 2 further eczema
treatments were considered not
to have atopic eczema, and
could therefore be included in
the pool of unexposed
participants. The cohort of
patients with atopic eczema
remained the same (ie, eczema
was defined as having at least 1
diagnostic code and 2
treatment codes)
Sensitivity Additionally adjusting for To examine whether the omission 276,853 8,251/649,041 1.16 (1.06-1.26) 340,161 8,481/80,4170 1.29 (1.18-1.40)
analysis 6 ethnicity (white, South Asian, of ethnicity from the primary
black, other, or mixed, analysis may have introduced
identified from CPRD and HES bias, because reliable ethnicity
data). Analysis was restricted data exists only for that period
to those registered in 2006 or
later, because ethnicity
recording before 2006 is
selective, and of low qualityE62
PYAR, Person-years at-risk.
All models were fitted to patients with complete data for all included variables. Sets without at least 1 exposed and 1 unexposed were excluded. HRs were estimated from a Cox regression model with current age as the underlying timescale,
stratified by matched set (sex, age, and general practice), and adjusted for current calendar period (years: 1998-2001, 2002-2006, 2007-2011, and 2012-2016,) and quintiles of IMD at cohort entry.
*All HRs are for the outcome (ie, depression/anxiety) among those with atopic eczema, compared with those without atopic eczema.

SCHONMANN ET AL
257.e8
 257.e9
TABLE E4. Exploring missing data—distribution of baseline characteristics in depression study population (overall, those with complete data, those with missing BMI, and those with
missing smoking status)
Overall depression Mediation model Individuals with Individuals with missing
sample sample* missing BMI smoking status

SCHONMANN ET AL
(n [ 1,980,710 (n [ 1,371,005 (n [ 436,031 (n [ 129,517
[100%]) [69.2%]) [22.0%]) [6.5%])
Without atopic With atopic Without atopic With atopic Without atopic With atopic Without atopic With atopic
eczema eczema eczema eczema eczema eczema eczema eczema
(n [ 1,588,277 (n [ 392,433 (n [ 1,054,673 (n [ 316,332 (n [ 366,755 (n [ 69,276 (n [ 117,102 (n [ 12,415
Atopic eczema status, n (%) [100%]) [100%]) [66.4%]) [80.6%]) [23.1%]) [17.65%]) [7.4%]) [3.2%])
Follow-up (y), median (IQR) 4.21 (1.63-8.62) 4.72 (1.86-9.12) 4.91 (1.95-9.49) 5.26 (2.18-9.88) 2.80 (1.13-6.18) 2.75 (1.14-5.86) 2.30 (0.86-5.23) 1.75 (0.75-3.96)
Sex: female, n (%) 802,909 (50.55) 211,118 (53.80) 593,302 (56.25) 182,005 (57.54) 136,354 (37.18) 25,982 (37.51) 40,402 (34.50) 4,446 (35.81)
Age (y), n (%)
18-19 268,216 (16.89) 74,303 (18.93) 71,409 (6.77) 33,343 (10.54) 151,841 (41.40) 38,048 (54.92) 42,890 (36.63) 6,906 (55.63)
20-29 314,643 (19.81) 64,699 (16.49) 183,603 (17.41) 51,753 (16.36) 78,605 (21.43) 11,823 (17.07) 25,088 (21.42) 1,869 (15.05)
30-39 245,213 (15.44) 56,453 (14.39) 182,352 (17.29) 50,871 (16.08) 39,497 (10.77) 5,087 (7.34) 13,467 (11.50) 802 (6.46)
40-49 181,584 (11.43) 46,172 (11.77) 146,905 (13.93) 42,742 (13.51) 23,994 (6.54) 3,108 (4.49) 8,836 (7.55) 417 (3.36)
50-59 173,625 (10.93) 42,954 (10.95) 147,029 (13.94) 40,500 (12.80) 18,447 (5.03) 2,179 (3.15) 7,006 (5.98) 300 (2.42)
60-69 177,634 (11.18) 44,460 (11.33) 154,768 (14.67) 42,306 (13.37) 15,287 (4.17) 1,903 (2.75) 5,518 (4.71) 286 (2.30)
70-79 143,603 (9.04) 39,351 (10.03) 117,080 (11.10) 36,146 (11.43) 16,782 (4.58) 2,692 (3.89) 6,094 (5.20) 575 (4.63)
80 83,759 (5.27) 24,041 (6.13) 51,527 (4.89) 18,671 (5.90) 22,302 (6.08) 4,436 (6.40) 8,203 (7.01) 1,260 (10.15)
IMD (quintiles), n (%)
1 (least deprived) 395,025 (24.87) 99,161 (25.27) 266,815 (25.30) 80,001 (25.29) 88,989 (24.26) 17,547 (25.33) 28,477 (24.32) 3,164 (25.49)
2 368,687 (23.21) 91,856 (23.41) 247,499 (23.47) 74,522 (23.56) 83,470 (22.76) 15,846 (22.87) 25,338 (21.64) 2,706 (21.80)
3 311,975 (19.64) 76,756 (19.56) 206,425 (19.57) 61,540 (19.45) 71,649 (19.54) 13,673 (19.74) 22,828 (19.49) 2,656 (21.39)
4 295,103 (18.58) 72,538 (18.48) 194,459 (18.44) 58,471 (18.48) 68,535 (18.69) 12,819 (18.50) 22,398 (19.13) 2,270 (18.28)
5 (most deprived) 217,487 (13.69) 52,122 (13.28) 139,475 (13.22) 41,798 (13.21) 54,112 (14.75) 9,391 (13.56) 18,061 (15.42) 1,619 (13.04)
BMI (kg/m2), mean
SD 25.74
5.08 26.01
5.25 25.87
5.06 26.03
5.24 NA NA 24.78
5.60 25.63
5.89
Normal (18.5-24.9 kg/m2), n (%) 574,056 (36.14) 147,216 (37.51) 30,884 (2.93) 9,320 (2.95) NA NA 610 (0.52) 91 (0.73)
Underweight (<18.5 kg/m2) 40,118 (2.53) 9,830 (2.50) 486,260 (46.11) 143,793 (45.46) NA NA 3,829 (3.27) 513 (4.13)
Overweight (25.0-29.9 kg/m2) 397,525 (25.03) 105,468 (26.88) 351,348 (33.31) 103,722 (32.79) NA NA 1,932 (1.65) 332 (2.67)
Obese (30.0 kg/m2) 209,823 (13.21) 60,643 (15.45) 186,181 (17.65) 59,497 (18.81) NA NA 1,106 (0.94) 239 (1.93)
Missing 366,755 (23.09) 69,276 (17.65) NA NA NA NA 109,625 (93.61) 11,240 (90.54)
Smoking status, n (%)
Nonsmoker 833,152 (52.46) 211,240 (53.83) 576,625 (54.67) 169,241 (53.50) 163,523 (44.59) 38,553 (55.65) NA NA

J ALLERGY CLIN IMMUNOL PRACT

Current/ex-smoker 638,023 (40.17) 168,778 (43.01) 478,048 (45.33) 147,091 (46.50) 93,607 (25.52) 19,483 (28.12) NA NA
Missing 117,102 (7.37) 12,415 (3.16) NA NA 109,625 (29.89) 11,240 (16.22) NA NA
Harmful alcohol use, n (%)† 23,244 (1.46) 7,114 (1.81) 18,235 (1.73) 6,437 (2.03) 2,729 (0.74) 583 (0.84) 546 (0.47) 68 (0.55)
High-dose glucocorticoids, n (%)†,z 65,155 (4.10) 42,738 (10.89) 48,539 (4.60) 35,368 (11.18) 9,732 (2.65) 6,323 (9.13) 1,712 (1.46) 776 (6.25)

IQR, Interquartile range; NA, not applicable/available.

JANUARY 2020
*Individuals with complete data on BMI and smoking status, belonging to a valid set (ie, a set with at least 1 exposed and 1 unexposed individual).
†Status recorded at or before cohort entry.
z20 mg/d prednisolone equivalent dose.
 VOLUME 8, NUMBER 1
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TABLE E5. Exploring missing data—distribution of baseline characteristics in anxiety study population (overall, those with complete data, those with missing BMI, and those with missing
smoking status)
Included in the model Individuals with
additionally adjusted missing smoking
Overall anxiety sample for potential mediators* Individuals with missing BMI status (n [ 138,170
(n [ 2,254,338 [100%]) (n [ 1,592,373 [70.1%]) (n [ 470,215 [20.9%]) [6.1%])
Without atopic With atopic Without atopic With atopic Without atopic With atopic
Without atopic With atopic eczema eczema eczema eczema eczema eczema
eczema eczema (n [ 1,244,303 (n [ 348,070 (n [ 398,271 (n [ 71,944 (n [ 125,335 (n [ 12,835
Atopic eczema status, n (%) (n [ 1,827,908) (n [ 426,430) [68.1%]) [81.6%]) [21.8%]) [16.9%]) [6.9%]) [3.0%])
Follow-up (y), median (IQR) 4.18 (1.62-8.57) 4.71 (1.85-9.13) 4.80 (1.91-9.38) 5.21 (2.15-9.85) 2.78 (1.11-6.15) 2.75 (1.14-5.87) 2.28 (0.85-5.16) 1.75 (0.75-3.95)
Sex: female, n (%) 981,824 (53.71) 237,527 (55.70) 737,936 (59.31) 206,628 (59.36) 157,984 (39.67) 28,048 (38.99) 45,792 (36.54) 4,729 (36.84)
Age (y), n (%)
18-19 278,370 (15.23) 75,587 (17.73) 77,429 (6.22) 34,665 (9.96) 154,202 (38.72) 38,118 (52.98) 43,453 (34.67) 6,893 (53.70)
20-29 363,408 (19.88) 71,126 (16.68) 219,418 (17.63) 57,707 (16.58) 86,304 (21.67) 12,401 (17.24) 26,926 (21.48) 1,945 (15.15)
30-39 299,405 (16.38) 64,051 (15.02) 226,984 (18.24) 58,096 (16.69) 45,625 (11.46) 5,534 (7.69) 15,000 (11.97) 864 (6.73)
40-49 224,547 (12.28) 52,644 (12.35) 183,675 (14.76) 48,993 (14.08) 28,124 (7.06) 3,408 (4.74) 9,839 (7.85) 449 (3.50)
50-59 206,782 (11.31) 47,948 (11.24) 176,065 (14.15) 45,339 (13.03) 21,176 (5.32) 2,384 (3.31) 7,738 (6.17) 327 (2.55)
60-69 199,628 (10.92) 47,523 (11.14) 174,165 (14.00) 45,245 (13.00) 16,891 (4.24) 2,042 (2.84) 6,024 (4.81) 303 (2.36)
70-79 157,992 (8.64) 41,379 (9.70) 127,811 (10.27) 37,861 (10.88) 18,891 (4.74) 3,002 (4.17) 6,792 (5.42) 652 (5.08)
80 97,776 (5.35) 26,172 (6.14) 58,756 (4.72) 20,164 (5.79) 27,058 (6.79) 5,055 (7.03) 9,563 (7.63) 1,402 (10.92)
IMD (quintiles), n (%)
1 (least deprived) 443,389 (24.26) 104,672 (24.55) 305,648 (24.56) 85,271 (24.50) 95,192 (23.90) 17,897 (24.88) 29,969 (23.91) 3,203 (24.96)
2 419,555 (22.95) 98,500 (23.10) 287,847 (23.13) 80,701 (23.19) 90,126 (22.63) 16,398 (22.79) 26,988 (21.53) 2,797 (21.79)
3 360,901 (19.74) 84,121 (19.73) 244,871 (19.68) 68,311 (19.63) 78,086 (19.61) 14,301 (19.88) 24,583 (19.61) 2,776 (21.63)
4 346,152 (18.94) 80,198 (18.81) 234,775 (18.87) 65,633 (18.86) 75,275 (18.90) 13,414 (18.65) 24,299 (19.39) 2,347 (18.29)
5 (most deprived) 257,911 (14.11) 58,939 (13.82) 171,162 (13.76) 48,154 (13.83) 59,592 (14.96) 9,934 (13.81) 19,496 (15.56) 1,712 (13.34)
BMI (kg/m2), mean
SD 25.87
5.22 26.18
5.41 25.99
5.21 26.20
5.40 NA NA 24.90
5.65 25.70
5.97
Normal (18.5-24.9 kg/m2), n (%) 663,955 (36.32) 158,315 (37.13) 36,355 (2.92) 10,070 (2.89) NA NA 671 (0.54) 103 (0.80)
Underweight (<18.5 kg/m2), n (%) 46,346 (2.54) 10,536 (2.47) 567,834 (45.63) 155,158 (44.58) NA NA 4,277 (3.41) 541 (4.22)
Overweight (25.0-29.9 kg/m2), n (%) 460,537 (25.19) 114,921 (26.95) 408,820 (32.86) 113,265 (32.54) NA NA 2,230 (1.78) 355 (2.77)
Obese (30.0 kg/m2), n (%) 258,799 (14.16) 70,714 (15.58) 231,294 (18.59) 69,577 (19.99) NA NA 1,300 (1.04) 268 (2.09)
Missing, n (%) 398,271 (21.79) 71,944 (16.87) NA NA NA NA 116,857 (93.24) 11,568 (90.13)
Smoking status, n (%)

SCHONMANN ET AL
Nonsmoker 939,278 (51.39) 222,529 (52.18) 663,686 (53.34) 180,172 (51.76) 175,018 (43.94) 39,251 (54.56) NA NA
Current/ex-smoker 763,295 (41.76) 191,066 (44.81) 580,617 (46.66) 167,898 (48.24) 106,396 (26.71) 21,125 (29.36) NA NA
Missing 125,335 (6.86) 12,835 (3.01) NA NA 116,857 (29.34) 11,568 (16.08) NA NA
Harmful alcohol use† 31,639 (1.73) 9,119 (2.14) 24,994 (2.01) 8,222 (2.36) 3,740 (0.94) 791 (1.10) 697 (0.56) 107 (0.83)
High-dose glucocorticoids†,z 78,579 (4.30) 47,840 (11.22) 59,842 (4.81) 40,269 (11.57) 10,773 (2.70) 6,598 (9.17) 1,908 (1.52) 820 (6.39)

IQR, Interquartile range; NA, not applicable/available.

*Individuals with complete data on BMI and smoking status, belonging to a valid set (ie, a set with at least 1 exposed and 1 unexposed individual).

257.e10
†Status recorded at or before cohort entry.
z20 mg/d prednisolone equivalent dose.
257.e11 SCHONMANN ET AL J ALLERGY CLIN IMMUNOL PRACT
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TABLE E6. Main analyses—full models for the association between all included variables and anxiety/depression
Depression Anxiety
Additionally adjusted Additionally adjusted for
Minimally adjusted Adjusted for potential mediators Minimally adjusted Adjusted potential mediators
Included variable HR (99% CI) HR (99% CI) HR (99% CI) HR (99% CI) HR (99% CI) HR (99% CI)
Atopic eczema
Without atopic eczema 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
With atopic eczema 1.14 (1.12-1.16) 1.14 (1.12-1.16) 1.10 (1.07-1.12) 1.17 (1.14-1.19) 1.17 (1.14-1.19) 1.12 (1.09-1.15)
Calendar period (y)
1998-2001 NA 1.00 (reference) 1.00 (reference) NA 1.00 (reference) 1.00 (reference)
2002-2006 NA 0.74 (0.64-0.86) 0.76 (0.64-0.91) NA 0.95 (0.79-1.14) 0.95 (0.7-1.16)
2007-2011 NA 0.59 (0.49-0.71) 0.63 (0.51-0.77) NA 0.82 (0.67-1.02) 0.81 (0.64-1.02)
2012-2016 NA 0.55 (0.45-0.68) 0.58 (0.46-0.73) NA 0.86 (0.68-1.08) 0.84 (0.65-1.08)
IMD (quintiles)
1 (least deprived) NA 1.00 (reference) 1.00 (reference) NA 1.00 (reference) 1.00 (reference)
2 NA 1.11 (1.08-1.14) 1.08 (1.04-1.12) NA 1.09 (0.05-1.12) 1.06 (1.02-1.10)
3 NA 1.22 (1.19-1.26) 1.16 (1.12-1.21) NA 1.15 (0.11-1.19) 1.11 (1.07-1.16)
4 NA 1.46 (1.41-1.51) 1.34 (1.29-1.40) NA 1.30 (1.25-1.35) 1.23 (1.18-1.28)
5 (most deprived) NA 1.72 (1.66-1.79) 1.53 (1.46-1.60) NA 1.42 (1.36-1.48) 1.31 (1.25-1.37)
BMI (kg/m2)
Normal NA NA 1.00 (reference) NA NA 1.00 (reference)
Underweight NA NA 0.87 (0.81-0.92) NA NA 0.88 (0.82-0.93)
Overweight NA NA 0.91 (0.86-0.97) NA NA 0.87 (0.81-0.93)
Obese NA NA 1.08 (1.02-1.15) NA NA 0.91 (0.85-0.97)
Smoking status
Nonsmoker NA NA 1.00 (reference) NA NA 1.00 (reference)
Current/ex-smoker NA NA 1.47 (1.44-1.51) NA NA 1.36 (1.33-1.39)
Harmful alcohol use
No NA NA 1.00 (reference) NA NA 1.00 (reference)
Yes NA NA 2.09 (1.96-2.22) NA NA 1.99 (1.86-2.13)
High-dose glucocorticoids
No NA NA 1.00 (reference) NA NA 1.00 (reference)
Yes NA NA 1.84 (1.69-2.07) NA NA 1.94 (1.75-2.16)
NA, Not applicable/available.
All models were fitted to patients with complete data for all included variables. Sets without at least 1 exposed and 1 unexposed individual were excluded. HRs were estimated
from a Cox regression model with current age as the underlying timescale, stratified by matched set (sex, age, and general practice).
Minimally adjusted: N ¼ 1,980,710 (1,920,172 unique people) in the depression cohort and N ¼ 2,242,905 (2,171,784 unique people) in the anxiety cohort.
Adjusted for current calendar period and IMD at cohort entry (same participants as in minimally adjusted model).
Additionally adjusted for potential mediators: BMI (categorized as normal, 18.5-24.9 kg/m2; underweight, <18.5 kg/m2; overweight 25.0-29.9 kg/m2; and obese 30.0 kg/m2),
smoking status, and alcohol and high-dose corticosteroid use (20 mg/d prednisolone equivalent dose), as time-updated variables. N ¼ 1,371,005 individuals (1,322,284 unique
people) in the depression cohort and N ¼ 1,583,390 (1,583,390 unique people) in the anxiety cohort.
 VOLUME 8, NUMBER 1
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TABLE E7. Absolute incidence rates, incidence rate differences (attributable risks), and population-attributable risks of depression and anxiety
Estimated incidence rate
Estimated incidence rate HR comparing rate of depression/anxiety in (per 100,000 PYAR) Estimated population-
(per 100,00 PYAR) those with to those without Inverse HR (99% CI) of depression/anxiety Estimated incidence rate difference attributable risk (%)
Cohort in people with atopic eczema atopic eczema (99% CI)* (99% CI)† in people without atopic eczema (per 100,000 PYAR) (99% CI) (99% CI)z
Depression 1331 1.14 (1.12-1.16) 0.88 (0.86-0.89) 1171 (1145-1185) 160 (146-186) 1.4 (1.2-1.6)
Anxiety 955 1.17 (1.14 to 1.19) 0.85 (0.84-0.88) 811 (802-840) 144 (115-153) 1.7 (1.4-1.9)
PYAR, Person-years at-risk.
*Adjusted for current calendar period (years: 1998-2001, 2002-06, 2007-11, and 2012-16) and quintiles of IMD at cohort entry.
†Comparing people without atopic eczema to people with atopic eczema.
zEstimated as P(HR  1)/(1 þ P(HR  1)) where P, the prevalence of atopic eczema, is assumed to be 10% and HR is the estimated HR.

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257.e12
257.e13 SCHONMANN ET AL J ALLERGY CLIN IMMUNOL PRACT
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TABLE E8. Association between atopic eczema and anxiety/depression, by severity of atopic eczema vs no atopic eczema
Minimally adjusted Adjusted Additionally adjusted for
Cohort/exposure No. Events/PYAR HR (99% CI) HR (99% CI) potential mediators HR (99% CI)
Depression*
Without atopic eczema 1,588,277 102,882/8,935,934 1.00 (reference) 1.00 (reference) 1.00 (reference)
With atopic eczema
Mild 287,944 19,116/1,436,377 1.10 (1.07-1.13) 1.10 (1.08-1.13) 1.07 (1.04-1.10)
Moderate 135,485 10,301/786,352 1.19 (1.15-1.23) 1.19 (1.15-1.23) 1.14 (1.10-1.18)
Severe 24,777 1,905/131,389 1.25 (1.16-1.35) 1.26 (1.17-1.37) 1.17 (1.08-1.28)
Anxiety†
Without atopic eczema 1,818,796 82,137/10,187,499 1.00 (reference) 1.00 (reference) 1.00 (reference)
With atopic eczema
Mild 310,205 15,093/1,543,672 1.14 (1.11-1.18) 1.14 (1.11-1.18) 1.11 (1.07-1.14)
Moderate 147,261 7,822/853,452 1.22 (1.17-1.26) 1.21 (1.17-1.26) 1.15 (1.11-1.20)
Severe 27,538 1,368/146,259 1.14 (1.05-1.25) 1.15 (1.05-1.25) 1.07 (0.97-1.18)
PYAR, Person-years at-risk.
All models were fitted to patients with complete data for all included variables. Sets without at least 1 exposed and 1 unexposed individual were excluded. HRs were estimated
from a Cox regression model with current age as the underlying timescale, stratified by matched set (sex, age, and general practice).
Minimally adjusted: N ¼ 1,980,710 (1,920,172 unique people) in the depression cohort and N ¼ 2,242,905 (2,171,784 unique people) in the anxiety cohort.
Adjusted for current calendar period and IMD at cohort entry (same participants as in minimally adjusted model).
Additionally adjusted for potential mediators: BMI (categorized as normal, 18.5-24.9 kg/m2; underweight, <18.5 kg/m2; overweight, 25.0-29.9 kg/m2; and obese, 30.0 kg/
m2), smoking status, and alcohol and high-dose corticosteroid use (20 mg/d prednisolone equivalent dose), as time-updated variables. N ¼ 1,371,005 individuals (1,322,284
unique people) in the depression cohort and N ¼ 1,583,390 (1,583,390 unique people) in the anxiety cohort.
*P values were <.0001 for linearity in all models, and 0.3810, 0.3832, and 0.6983 for departure from linearity in minimally adjusted, confounder-adjusted-, and additionally
adjusted for potential mediators models, respectively.
†P values were <.0001 for linearity in all models and <.0001 for departure from linearity in all models.
J ALLERGY CLIN IMMUNOL PRACT SCHONMANN ET AL 257.e14
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TABLE E9. Secondary analysis, adjusted models: association between atopic eczema and depression/anxiety, stratified on sex, current
age (18-39, 40-59, 60þ y), and calendar period (1998-2001, 2002-2006, 2007-2011, 2012-2016)
Depression Anxiety
Stratum/exposure No. Events/PYAR Adjusted HR* (99% CI) No. Events/PYAR Adjusted HR* (99% CI)
Sex† P < .0001 P ¼ .0003
Males
No atopic eczema 785,368 3,8219/4,512,990 1.00 (reference) 841,681 25,390/4,806,123 1.00 (reference)
Atopic eczema 181,315 10,891/1,086,295 1.19 (1.16-1.23) 187,784 7,196/1,122,110 1.22 (1.17-1.27)
Females
No atopic eczema 802,909 64,663/4,422,944 1.00 (reference) 977,115 56,747/5,381,375 1.000 (reference)
Atopic eczema 211,118 20,431/1,267,822 1.11 (1.08-1.13) 236,325 17,087/1,421,273 1.14 (1.11-1.17)
Current age† P < .0001 P ¼ .0052
18-39
No atopic eczema 828,072 48,992/3,265,435 1.00 (reference) 938,376 39,939/3,696,223 1.00 (reference)
Atopic eczema 195,455 14,175/834,206 1.10 (1.06-1.13) 210,072 11,476/901,165 1.14 (1.10-1.18)
40-59
No atopic eczema 485,291 26,208/2,553,247 1.00 (reference) 588,395 23,023/3,064,427 1.00 (reference)
Atopic eczema 123,489 8,624/675,274 1.22 (1.18-1.27) 138,864 7,031/756,141 1.21 (1.17-1.26)
60
No atopic eczema 530,344 27,682/3,117,252 1.00 (reference) 595,827 19,175/3,426,849 1.00 (reference)
Atopic eczema 139,919 8,523/844,638 1.12 (1.08-1.16) 149,256 5,776/886,077 1.15 (1.10-1.21)
Calendar period† P ¼ .3229 P ¼ .2871
1998-2001
No atopic eczema 476,794 17,175/1,143,231 1.00 (reference) 533,384 12,824/1,274,519 1.00 (reference)
Atopic eczema 113,944 4,888/279,596 1.14 (1.09-1.19) 121,449 3,499/297,984 1.15 (1.09-1.21)
2002-2006
No atopic eczema 762,671 28,735/2,341,702 1.00 (reference) 863,959 22,307/2,652,645 1.00 (reference)
Atopic eczema 187,774 8,525/595,943 1.15 (1.11-1.19) 201,836 6,298/642,215 1.15 (1.10-1.19)
2007-2011
No atopic eczema 1,000,682 32,533/3,137,512 1.00 (reference) 1,148,842 24,850/3,589,229 1.00 (reference)
Atopic eczema 256,158 9,916/836,225 1.12 (1.08-1.16) 277,719 7,441/905,501 1.18 (1.13-1.22)
2012-2016
No atopic eczema 923,647 24,439/2,313,488 1.00 (reference) 1,068,458 22,156/2,671,107 1.00 (reference)
Atopic eczema 248,593 7,993/642,355 1.15 (1.12-1.20) 270,531 7,045/697,684 1.19 (1.14-1.24)
PYAR, Person-years at-risk.
*All models were fitted to individuals with complete data for all included variables. Sets without at least 1 exposed and 1 unexposed individual were excluded. HRs were
estimated from a Cox regression model with current age as the underlying timescale, stratified by matched set (sex, age, and general practice), and adjusted for current calendar
period (years: 1998-2001, 2002-06, 2007-11, and 2012 16) and quintiles of IMD at cohort entry.
†P values for interaction and for stratum-specific effect were derived through likelihood-ratio tests.
257.e15 SCHONMANN ET AL J ALLERGY CLIN IMMUNOL PRACT
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