Atopic dermatitis: Comorbidities and associated diseases

Authors:: Jonathan I Silverberg, MD, PhD, MPH; William Howe, MD
Section Editors:: Robert P Dellavalle, MD, PhD, MSPH; Moise L Levy, MD; Joseph Fowler, MD
Deputy Editor:: Rosamaria Corona, MD, DSc

Literature review current through: May 2024.

This topic last updated: May 06, 2024.

INTRODUCTION — Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease that commonly affects both children and adults. It is widely recognized that AD carries an increased risk of progression to other atopic diseases, including asthma, allergic rhinitis, allergic rhinoconjunctivitis, and food allergy (the so-called "atopic march") [1]. However, AD has also been associated with a number of nonallergic disorders, including autoimmune, metabolic, and psychiatric disorders [2-6].

This topic will discuss the allergic and nonallergic comorbidities of AD. The pathogenesis, clinical manifestations, diagnosis, and treatment of AD are discussed separately.

●(See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Treatment of atopic dermatitis (eczema)".)

●(See "Management of severe, refractory atopic dermatitis (eczema) in children".)

●(See "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults".)

ALLERGIC RHINITIS, ASTHMA, AND FOOD ALLERGY — Patients with AD and a genetic predisposition to produce immunoglobulin E (IgE) following exposure to allergens may develop a typical sequence of AD, allergic rhinitis/conjunctivitis, asthma, and food allergy at certain ages (the so-called "atopic march") [7-9]. Multiple studies indicated that the risk of developing respiratory allergies is inversely associated with the age of onset of AD. In a Canadian cohort of 2311 children with AD, allergic sensitization detected by skin prick testing at age one year was associated with a sevenfold increased risk of asthma at age three compared with absence of allergic sensitization (relative risk [RR] 7.04, 95% CI 4.13-11.99) [10].

●Asthma – The association between AD and asthma is well established. The prevalence of asthma in adults with AD is estimated to be approximately 25 percent [2]. The risk of asthma is higher in patients with severe AD compared with patients with mild or moderate disease [2] and in patients with AD persisting into adolescence [11].

●Food allergy – In a meta-analysis of 320 observational studies including over 225,000 individuals with AD and over 1.1 million individuals without AD, the pooled prevalences of food sensitivity, food allergy, and challenge-proven food allergy were 48.4 percent (95% CI 43.7-53.2), 32.7 percent (95% CI 28.8-36.6), and 40.7 percent (95% CI 34.1-47.5), respectively, among patients with AD compared with 17.9 percent (95% CI 12.7-23.7), 9.4 percent (95% CI 7.8-11.4), and 15.5 percent (95% CI 7.9-25.2), respectively, among patients without AD [12]. The prevalence of food sensitivity and food allergy was higher in children ≤2 years of age and in individuals with severe AD.

Patients with AD also have an increased risk of food-induced urticaria/anaphylaxis [13,14], eosinophilic esophagitis, and chronic rhinosinusitis/nasal polyps [15]. (See "Role of allergy in atopic dermatitis (eczema)".)

Whether there is a cause-effect relationship between AD and subsequent development of atopic and allergic comorbidities is still debated. The observation that the prevalence of asthma and food allergies increases with increasing AD severity supports the hypothesis that epicutaneous sensitization to allergens, including food allergens (eg, peanut antigen in household dust), can occur in early life in children with AD due to the defective skin barrier [16-21]. However, food sensitization is clinically irrelevant for the course of AD in most cases, and serum IgE should not be used for the diagnosis of food allergy in the absence of clinical reactions to the ingestion of a certain food. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

ICHTHYOSIS VULGARIS — Loss-of-function variants in the filaggrin gene (FLG), which causes ichthyosis vulgaris, confer an increased risk of developing AD and are associated with early-onset, moderate to severe, and persistent eczema [22-24]. (See "Ichthyosis vulgaris".)

It is estimated that approximately 10 to 30 percent of patients with AD also have ichthyosis vulgaris [25,26]. These patients usually show palmar hyperlinearity (picture 1 and picture 2) and keratosis pilaris (picture 3 and picture 4). (See "Keratosis pilaris".)

EYE DISEASES — Ocular comorbidities occurring in patients with AD include atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). AKC is a chronic, allergic, ocular disease that most often occurs in adults with a history of AD [27]. VKC most commonly occurs in children living in warm, dry, subtropical climates [28]. Ocular itching, burning, tearing, and mucus discharge are common symptoms. Complications include keratoconus, infectious keratitis, and blepharitis. (See "Atopic keratoconjunctivitis" and "Vernal keratoconjunctivitis".)

AUTOIMMUNE DISORDERS — A large body of evidence supports the association of AD with cutaneous and noncutaneous autoimmune disorders.

●A Danish study using data on over 8000 patients with AD and over 40,000 age- and sex-matched controls from nationwide health registers found a statistically significant association between AD and alopecia areata, vitiligo, rheumatoid arthritis, and Sjögren's disease [29].

●Similar results were provided by a Swedish population-based case-control study that included over 104,000 cases of AD matched with over 1 million controls from the general population [30]. AD was associated with a twofold increased risk of any autoimmune disorder (odds ratio [OR] 1.97, 95% CI 1.93-2.01).

●A meta-analysis of nine observational studies found an approximately 30 percent increased risk of rheumatoid arthritis in patients with AD (OR 1.28, 95% CI 1.07-1.53) [31]. Of note, this association appeared to be unidirectional as no increased risk of AD was found in studies assessing comorbidities in patients with rheumatoid arthritis.

PSYCHIATRIC DISORDERS — There is a growing body of evidence that a number of psychiatric disorders and symptoms, including impaired psychosocial functioning, attention deficit hyperactivity disorder, learning disability, depression, and anxiety disorders, are more common among adults and children with AD than in the general population [32-35]. The association of AD with psychosocial distress and other psychiatric disorders may be influenced by the perceived disease severity and other factors that negatively affect quality of life, such as the loss of sleep, disabling pruritus, social embarrassment, and impaired social functioning [33,36].

Attention deficit hyperactivity disorder — The results of a 2010 systematic review of 20 studies including over 170,000 individuals and several subsequent observational studies suggest an association between AD and attention deficit hyperactivity disorder in children as well as in adults [32,37-42]. The mechanisms underlying attention deficit hyperactivity disorder and AD are unknown. Sleep disturbance secondary to nocturnal pruritus, elevated levels of psychologic stress, and the effects of proinflammatory cytokines on brain development are the leading hypotheses to explain this association [40,43,44]. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis" and "Attention deficit hyperactivity disorder in adults: Epidemiology, clinical features, assessment, and diagnosis".)

Depression and anxiety disorder — Several cohort studies and meta-analyses have found an association between AD and anxiety disorder, depression, suicidal ideation, and attempted suicide in adults and children [32,45-50].

●An analysis of data on over 90,000 children from the 2007 National Survey of Children's Health in the United States found that the prevalence of depression and anxiety disorders among children with AD was significantly higher than among their peers without AD (6.5 versus 3.4 percent, and 7.3 versus 4.1 percent, respectively) and showed an increasing trend with increasing parent- and caregiver-reported severity of dermatitis [32].

●A large longitudinal cohort study using data from the Taiwan National Health Insurance Research Database from 1998 to 2008 assessed the risk of developing major depression or anxiety disorders later in life among more than 8000 adolescents and adults with AD and age- and sex-matched controls [45]. This study found that patients with AD had an increased risk of developing major depression (hazard ratio [HR] 6.56, 95% CI 3.64-11.84), any depressive disorder (HR 5.44, 95% CI 3.99-7.44), and anxiety disorders (HR 3.57, 95% CI 2.55-4.98).

●A 2019 meta-analysis of 37 observational studies found a nearly twofold increased risk of depression in patients with AD compared with individuals without AD (odds ratio [OR] 1.71, 95% CI 1.48-1.98). Based on data from 14 studies, patients with AD were also more likely to have suicidal ideation (OR 1.97, 95% CI 1.19-3.25) [49].

●The association between AD and suicidality was examined in another meta-analysis of 15 observational studies including over 310,000 patients with AD and nearly 4.5 million controls [48]. Compared with persons without AD, patients with AD were found to have an increased risk of suicidal ideation (pooled OR 1.44, 95% CI 1.25-1.65) and suicide attempts (pooled OR 1.36, 95% CI 1.09-1.70). Two of the included studies reporting on the risk of completed suicide among patients with AD provided conflicting results [51,52].

The results of these studies emphasize the need for a multidisciplinary approach to the management of AD that includes patient and parent/caregiver education and psychologic and behavioral support (see "Treatment of atopic dermatitis (eczema)"). Clinicians treating AD should be vigilant for depressive symptoms, especially in patients with severe disease who may need psychiatric referral.

OBESITY AND METABOLIC SYNDROME — The association between AD and obesity in children and adults is controversial [53-57].

●A 2022 pooled analysis of eight cross-sectional studies found a modest association between AD and obesity (odds ratio [OR] 1.36, 95% CI 1.01-1.83) and a weak association with hypercholesterolemia (OR 1.13, 95% CI 1.09-1.18) [2]. The study also found that AD was associated with a slightly lower risk of type 2 diabetes (OR 0.83, 95% CI 0.76-0.90).

●A 2015 systematic review and meta-analysis of 30 observational studies found that being overweight and obese were associated with increased prevalence of AD in Asia and North America (OR 1.23, 95% CI 1.11-1.41, and OR 1.47, 95% CI 1.21-1.79, respectively) [58].

However, the mechanisms underlying this association are largely unknown.

CARDIOVASCULAR DISEASE — Previous studies evaluating the association between AD and cardiovascular disease provided conflicting evidence.

●A 2018 large population-based study using 1998 to 2015 data from the United Kingdom Clinical Practice Research Datalink compared the data from nearly 400,000 adult patients with AD and 1.5 million controls matched by age, sex, calendar time, and age and date at cohort entry [59]. This study found that patients with AD and, in particular, those with severe disease (as defined by the type of treatment or specialist referral) had a modest increase in the risk of cardiovascular disease, including myocardial infarction (hazard ratio [HR] 1.37, 95% CI 1.12-1.68), unstable angina (HR 1.41, 95% CI 1.02-1.95), heart failure (HR 1.67, 95% CI 1.36-2.05), atrial fibrillation (HR 1.35, 95% CI 1.14-1.59), and cardiovascular death (HR 1.30, 95% CI 1.10-1.53). Although known confounding factors (eg, body mass index, smoking, hypertension, hyperlipidemia, diabetes) had been adjusted for, the possibility that the results were driven by residual confounding cannot be excluded. In addition, this study could not determine whether AD per se or treatments for AD confer an increased risk of cardiovascular disease. Despite these caveats, this study indicates that in adults presenting with severe AD, screening for cardiovascular disease and known risk factors for cardiovascular disease may be appropriate.

●A 2017 cross-sectional analysis of data from the Canadian Partnership for Tomorrow Project including nearly 260,000 Canadian residents aged 30 to 74 years, of whom approximately 21,000 had a history of AD, found that AD was associated with a mild reduction in the risk of hypertension (odds ratio [OR] 0.87, 95% CI 0.83-0.90), type 2 diabetes (OR 0.78, 95% CI 0.71-0.84), myocardial infarction (OR 0.87, 95% CI 0.75-1.00), and stroke (OR 0.79, 95% CI 0.66-0.95) after adjusting for age, sex, ethnic background, body mass index, smoking 100 cigarettes, weekly alcohol intake, average daily sleep, and weekly physical activity [60].

●A 2017 meta-analysis using adjusted data from 13 studies did not find an association between AD and myocardial infarction (pooled OR 1.03, 95% CI 0.88-1.21), stroke (OR 1.12, 95% CI 0.95-1.32), or hypertension (OR 1.10, 95% CI 0.97-1.24) but found a nearly 50 percent increased risk of angina pectoris (OR 1.48, 95% CI 1.23-1.79) [61].

VENOUS THROMBOEMBOLISM — AD appears to be associated with a small risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism [62-65].

●In a United States study using administrative claims data from 2010 through 2019 from Optum Clinformatics Data Mart that included over 1 million adult patients with AD and matched controls, the VTE incidence was slightly higher among patients with AD compared with patients without AD (0.73 versus 0.59 per 100 person-years) [62].

●A United Kingdom study using data from The Health Improvement Network evaluated the VTE risk in children and adults with AD [63]. In the pediatric cohort that included over 400,000 children with AD and over 1.8 million children without AD, multivariable analysis showed that AD was associated with a 23 percent increased risk for DVT (hazard ratio [HR] 1.23, 95% CI 1.02-1.48) after adjusting for known risk factors for VTE. A similar modest increase in the risk of DVT was found in the adult cohort with over 625,000 patients with AD and nearly 2.7 million controls without AD (HR 1.14, 95% CI 1.11-1.18).

OSTEOPENIA/OSTEOPOROSIS — The association between AD and bone health impairment is controversial. Observational studies evaluating the association of AD with low bone mass density, osteopenia or osteoporosis, and risk of fractures have reported conflicting results [66].

●A Korean population-based case-control study that included patients <50 years with and without AD did not find a difference in the prevalence of low bone mass density between individuals with AD and those without AD [67].

●A large population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink that included over 520,000 individuals with AD and over 2.5 million individuals without AD found a modest, but statistically significant, association between AD and increased hip, pelvic, spinal, and wrist fractures after adjusting for age, sex, general practice, and date of cohort entry (hazard ratio [HR] 1.10, 99% CI 1.08-1.12) [68].

ANEMIA — An analysis of caregiver-reported and self-reported data on over 200,000 children and adolescents from the 1997 to 2013 United States National Health Interview Survey found that children with a history of atopic disorders, including eczema, asthma, hay fever, or food allergy, have an increased risk of anemia (for eczema, odds ratio [OR] 1.83, 95% CI 1.58-2.13) [69]. The risk was much higher in children with all four disorders (adjusted OR 7.87, 95% CI 5.17-12). Using laboratory data from the 2014 to 2015 National Health and Nutrition Examination Survey on over 30,000 children, the authors found that children with a current history of atopic eczema had a twofold increased risk of anemia, particularly microcytic anemia (OR 2.03, 95% CI 1.20-3.46).

Another study using data from the Korean universal health insurance system found an increased risk of iron deficiency anemia among children with AD (OR 1.42, 95% CI 1.37-1.47) [70].

Whether anemia in children with AD is related to chronic inflammation or malnutrition secondary to dietary restrictions in patients suspected to have food allergies is unknown. Further ad hoc-designed studies are needed to confirm this association and clarify the underlying mechanisms.

INFLAMMATORY BOWEL DISEASE

●A population-based study using 1994 to 2015 data from the United Kingdom Health Improvement Network examined the association between AD and inflammatory bowel disease (IBD) in over 400,000 children with AD and 1.8 million matched controls and in over 625,000 adults with AD and nearly 2.7 million matched controls [71]. The study found a 44 percent increased risk of IBD (hazard ratio [HR] 1.44, 95% CI 1.31-1.58) in children with AD and a 34 percent increased risk of IBD (HR 1.34, 95% CI 1.27-1.40) in adults with AD. In both the pediatric and adult cohort, the risk was highest for patients with severe AD (HR 2.59, 95% CI 1.94-3.45, and HR 2.27, 95% CI 1.96-2.64, respectively). (See "Definitions, epidemiology, and risk factors for inflammatory bowel disease".)

●In a retrospective study comparing a cohort of 364 adult patients with AD followed up in a specialized adult AD clinic between 2013 and 2021 with 725 age- and sex-matched patients seen over the same period at the general dermatology clinic at the same institution, the prevalence of IBD in patients with AD was higher than in patients without AD (2.5 versus 1 percent), although the difference was not statistically significant [72]. After adjusting for age, sex, and smoking status by multivariable analysis, patients with AD had an increased risk of IBD (odds ratio [OR] 3.89, 95% CI 1.28-11.85). However, this result should be interpreted with caution due to the small number of IBD cases in the study population and the wide CI of the estimated OR.

●A cohort study using nationwide longitudinal commercial insurance claims data from the Unites States between 2004 and 2020 that included over 123,000 patients with AD did not find an increased risk of IBD among patients with AD compared with patients without chronic inflammatory skin diseases (HR1.02, 95% CI 0.92-1.12 for ulcerative colitis, and HR 1.08, 95% CI 0.94-1.23 for Crohn disease) [73].

●Another nationwide cohort study that included 36,400 patients with AD and 364,000 matched controls without AD from the National Health Insurance Research Database of Taiwan did not find an increased risk of IBD among patients with AD compared with those without AD (16-year cumulative incidence rate 0.047, 95% CI 0.040-0.054, and 16-year cumulative incidence rate 0.047, 95% CI 0.025-0.096, respectively) [74].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atopic dermatitis".)

SUMMARY

●Atopic dermatitis and risk of comorbid diseases – The association of atopic dermatitis (AD) with other atopic disease, including asthma, allergic rhinitis, allergic rhinoconjunctivitis, and food allergy, is widely recognized. However, there is increasing evidence that AD is associated with a number of nonallergic disorders. (See 'Introduction' above.)

●Other atopic diseases – Patients with AD and a genetic predisposition to produce IgE following exposure to allergens may develop comorbid atopic conditions, including asthma, rhinoconjunctivitis, and food sensitivity or allergy. Although the rate of food sensitization is high in patients with AD and especially in infants and young children, food sensitization is clinically irrelevant for the course of AD in most cases. (See 'Allergic rhinitis, asthma, and food allergy' above.)

●Ichthyosis vulgaris – There is a well-known association between AD and ichthyosis vulgaris, the most common inherited disorder of keratinization caused by loss-of-function variants in the FLG gene, encoding profilaggrin, a protein involved in the formation of the epidermal barrier. (See "Ichthyosis vulgaris".)

●Autoimmune disorders – Multiple lines of evidence support the association of AD with cutaneous and noncutaneous autoimmune disorders, including alopecia areata, vitiligo, and rheumatoid arthritis. (See 'Autoimmune disorders' above.)

●Psychiatric disorders – Impaired psychosocial functioning, attention deficit hyperactivity disorder, learning disability, depression, and anxiety disorders are more common among adults and children with AD than in the general population. They may be influenced by the perceived disease severity, loss of sleep, disabling pruritus, and social embarrassment. (See 'Psychiatric disorders' above.)

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Topic 143875 Version 2.0

خرید پکیج

Atopic dermatitis: Comorbidities and associated diseases

References