A review of comorbidities in atopic dermatitis

Atopic comorbidities

AD has been considered the earliest clinical presentation of the “allergic march,” which also includes asthma, allergic rhinitis, and food hypersensitivity. Specific immunoglobulin E (s-IgE) levels and skin prick tests are used to define the allergic and non-allergic types of asthma and rhinitis that are linked to AD.^[13,14] There is a well-established correlation between atopic diseases, which can be attributed to skin barrier failure caused by Th2/Th22 skewing.^[15] Skin barrier dysfunction in AD patients lets allergens penetrate transcutaneously.^[16] Rhinitis and asthma, at 27.5% and 40.5%, respectively, are the most common atopic comorbidities in adults with AD. These rates are higher in severe disease and childhood AD. In addition, filaggrin mutations were linked to increased asthma risk in the general population as well as an even greater risk in children who had AD and were sensitized to dust mites, grass, and cat dander.^[17]

Food sensitivity and allergy rates are 28.6% and 24.1%, respectively, in people with AD.^[11] Inquiring about gastrointestinal and respiratory atopic symptoms from patients is crucial as it influences the choice of medication. In addition, the prevalence of eosinophilic esophagitis is increased in patients with AD, which is associated with peripheral eosinophilia and higher IgE levels. Eosinophilic esophagitis is also closely associated with personal and family atopic predisposition (such as rhinitis and food allergies).^[18]

Ocular comorbidities

Ocular disorders have been related to AD due to many variables, including allergic comorbidity, disease activity, infection, and dupilumab therapy.^[19] The most common ocular findings in AD are anterior subcapsular cataracts, recurrent conjunctivitis, and keratoconus. AD patients may also experience keratitis, glaucoma, and posterior subcapsular cataracts, although these conditions are less prevalent.^[20] In a recent SR, the overall prevalence of conjunctivitis in AD patients was found to be 31.7%, and no significant difference was observed between genders. In addition, the prevalence is higher in Europe. Conjunctivitis is more frequent in AD with active illness. The most prevalent subtypes of conjunctivitis among AD patients were rhinoconjunctivitis and allergic conjunctivitis (32.9% and 31.8%, respectively).^[19]

The interaction of inflammation, mechanical stress, barrier disruption, and micro-organisms may predispose to ocular comorbidities.^[21] Conjunctivitis, blepharitis, and keratitis are not just disease-related symptoms; the pooled proportion of side effects associated with the IL-4RA biologic dupilumab were 29.8%, 22.0%, and 1.4%, respectively.^[19] In AD, ocular comorbidities may be interrelated and increases the disease burden. Detailed questioning and examination of the presence of ocular symptoms are crucial.

Psychiatric and neurological comorbidities

High prevalence of sleep disruption, social isolation, stigmatization, and severe pruritus have all been implicated with an increased risk of anxiety, depression, and suicidality in AD patients.^[16] Psychiatric comorbidities (such as depression and anxiety) increase the disease burden in both adults and children. Nearly one in six AD patients experienced clinical depression, one in four experienced depressive symptoms, and one in eight experienced suicidal thoughts, according to an SR and meta-analysis.^[22] In another meta-analysis where AD and psychiatric comorbidities were evaluated, the risk of depression and anxiety increased twofold, and the risk of suicidal thoughts was increased fourfold in AD.^[23] Increased depression in AD may contribute to increased suicidality. On the other hand, many suicidal people do not fulfill the diagnostic criteria for depression.^[24] Further, compared to children (4 of 6 studies (pooled odds ratio [OR], 1.31; 95% confidence interval [CI], 0.99–1.75), AD was linked to greater risks of depression in adults (16 of 20 studies [pooled OR, 2.08; 95% CI, 1.70–2.55]). Many studies show that depressive symptoms decrease with different topical, oral, systemic, and biological AD treatments. ^[25-27]

Adults and children with AD use antidepressants at a higher rate than those without; however, they were noticeably higher in AD adults. The difficulty of treating AD increases familial stress. While parental depression is more prevalent in children with AD than without (29.3% vs. 20.3%), it is not associated with AD in their offspring. Interestingly, according to a prospective single-center study, mothers had a higher risk of depression (OR 2.0 [95% CI, 1.1–3.6]) than fathers.^[22] AD also negatively affects sleep quality. Sleep disorders can be seen in 47–80% of children and 33–90% of adults with AD. Moreover, as disease severity increases in AD, the prevalence and severity of sleep disorders is also increased. The “itching-scratching cycle,” which increases at night, is the main factor that disrupts sleep quality.^[28] Especially in children, sleep disturbances can lead to neurodevelopmental delays and attention deficit hyperactivity disorder.^[29] In a cohort study in which 145 children with AD were evaluated, a significant increase in the frequency of neurological diseases such as migraine and epilepsy was detected.^[10]

Autoimmune comorbidities

There have been suggestions that AD is actually an “umbrella” term with an autoimmune profile at its core. Autoimmune diseases, such as dermatologic, gastrointestinal, and rheumatologic, are more prevalent in adult patients with AD, particularly smokers.^[30] Patients with AD have 1.5–2 times higher rates of chronic urticaria, celiac disease, inflammatory bowel disease (IBD), systemic lupus erythematosus, and RA as compared to controls. ^[30-33]

Patients with vitiligo, particularly those with early onset or AA, seem to be more susceptible to AD. The OR of AA in patients with AD is raised tenfold.^[11] In addition, patients with alopecia totalis and alopecia universalis were more susceptible than patients with patchy alopecia.^[34] Although it is uncertain, the correlations may be explained by shared pathways, such as thymic stromal lymphopoietin^[35] and Th17.^[36] There may be common genetics behind the association; for example, filaggrin gene mutations in patients with AA were discovered to be related to more severe AA.^[37] A large study showed an increased RR of RA, Crohn’s disease, and ulcerative colitis in patients with AD (RR: 1.72, 1.34 and 1.25, respectively).^[38]

Cardiovascular comorbidities and association with metabolic syndrome

Although there are contradictory data about whether AD is connected with being overweight or obese, a meta-analysis revealed that patients with AD had a higher prevalence of being overweight and obese, and weight loss improved their eczema symptoms.^[39] According to SRs, both active and passive smoking is connected with an increase in AD prevalence in children and adults. However, the impact of smoking on the severity of AD was not studied, and AD was not linked to maternal smoking during pregnancy.^[40]

A recent SR that included 51 reviews found that approximately 1 in 6 patients with AD had hypertension, and the prevalence was higher in studies conducted in the USA. Moderate-to-severe AD, but not a mild disease, was associated with a higher odds of hypertension.^[41] In AD, systemic inflammation, chronic sleep disturbance, higher rates of obesity, and the use of systemic corticosteroids and cyclosporine A increase the risk of hypertension. In a current study evaluating vascular inflammation and skin and blood immune biomarkers in AD through fludeoxyglucose F18 positron emission tomography-computed tomography, increased vascular inflammation and increased Th2 response in AD have been found to be associated with cardiovascular comorbidities.^[42] There are conflicting data regarding the association of AD and metabolic syndrome. While a cross-sectional study showed an increased prevalence of metabolic syndrome components in AD patients, there are SRs in which AD was found to be associated only with central obesity.^[43,44]

Malignancies

There are controversial studies on the risk of lymphoma in patients with AD. In an SR confirming a marginally elevated risk of lymphoma in severe AD, the importance of differential diagnosis with cutaneous T-cell lymphoma (CTCL) in adult-onset and severe AD is emphasized.^[45] A multicenter study from Europe has reported a fourfold increase in the incidence rate (IR) of lymphoma in children treated with tacrolimus and a less than twofold increase in the IR of CTCL in adults who received topical calcineurin inhibitor (TCI) treatment compared with users of topical corticosteroids.^[46] In addition, a 10-year follow-up cohort study in AD children using topical pimecrolimus for a minimum of 6 weeks reported a 2.6-fold increase in the standardized incidence ratio for lymphoma.^[47] However, moderate-certainty evidence from current studies suggests that TCIs do not increase the risk of cancer in patients with AD and that TCIs are safe to use in their optimal treatment.^[48] In a recent retrospective observational case series of adult AD patients treated with dupilumab, a reversible and benign lymphoid reaction mimicking CTCL was observed.^[49] In an SR and meta-analysis based on population-based cohort studies, it has been suggested that AD increases the risk of keratinocyte and renal cancer but plays a preventive role in lung and respiratory system cancers.^[50]

Others (infection, osteoporosis, and contact dermatitis)

Disturbances in the skin barrier, defects in cutaneous innate immunity due to increased type 2 inflammation, lower levels of antimicrobial peptides, colonization with Staphylococcus aureus, and changes in cutaneous microbiome all contribute to an increased rate of infections in AD.^[51] Impaired cellular immunity leads to herpes simplex, varicella zoster, verrucae, and molluscum contagiosum infections in AD patients.^[52] Moreover, the increased frequency of bacterial infections is also known; in an SR and meta-analysis, a 20-fold increased S. aureus colonization has been reported.^[53]

AD was linked to increased odds of infections involving the ear, throat, and urinary tract, and extracutaneous infections in an SR that included seven studies.^[54] Two studies found a correlation between AD and increased risks of meningitis and infected endocarditis.^[54]

AD and hand eczema are both chronic and recurrent inflammatory pruritic skin diseases. Experimental investigations have demonstrated that AD skin loses more transepidermal water and absorbs more irritants and allergens than healthy skin.^[55] In a meta-analysis including 26 studies, the prevalence of hand eczema was found to be three- and four-fold higher in AD patients compared to controls.^[56] Furthermore, an SR on the correlation with allergic contact dermatitis (ACD) revealed a 1.5-fold increase in the risk of ACD in patients with milder types of AD. Contact sensitivity to compositae mix and chromium was more common in AD patients, but there was no significant difference between AD and non-AD people in terms of the overall prevalence of contact sensitization to common allergens.^[57] Even if AD is associated with a higher risk of ACD than the general population, the magnitude of this association is rather minor. That is, only a small percentage of AD patients appear to develop ACD.^[16] Therefore, patch testing is not recommended for all AD patients. According to expert consensus opinions, patch testing should be considered in AD patients “with dermatitis that does not improve with topical therapy, atypical/changing distribution of eczema, or a pattern suggestive of ACD, therapy-resistant hand eczema in the working population, late-onset AD, and/or before starting systemic immunosuppressants for dermatitis treatment.”^[58]

Systemic inflammation, smoking, physical inactivity, Vitamin D deficiency, and corticosteroid or psycholeptic use have been reported to increase the risk of osteoporosis.^[5,40,59]

According to recent AD guidelines from the American Academy of Dermatology, adult AD is linked to both bone fractures (moderate-quality evidence) and osteoporosis (high-quality evidence).^[60]

Biomarkers of comorbidities

Over the past few decades, numerous potential AD biomarkers have been put out. Thymus and activation-regulated chemokine, for example, has been found to be a biomarker of the severity of AD. It was proposed that C-C motif chemokine 22 (CCL22) might serve as a biomarker of therapy response.^[61,62] However, there is a shortage of high-quality studies examining biomarkers linked to the development of comorbidities, and no biomarkers are approved for clinical use in monitoring patients of AD. In a recent SR, where 56 articles were included, and 146 candidate biomarkers were evaluated, the most frequently reported biomarkers were filaggrin mutations and allergen-s-IgE. Some of the findings are intriguing, particularly in the case of asthma, where s-IgE and/or skin prick tests may help identify whether patients are at risk of acquiring asthma or wheezing.^[63] However, the methodology and results are highly heterogeneous, and the risk of bias is medium/high. Further independent validation studies should use standardized evaluation procedures to account for confounding variables.

Importance of comorbidities in AD management

One factor that determines disease follow-up in AD is the impact of comorbidities on the burden of disease. Comprehensive examinations may also detect comorbidities accompanying AD and be predictive of AD treatment selection (e.g., cyclosporin may improve conjunctivitis, and sarilumab may improve asthma).

In the case of comorbid autoimmune diseases such as IBD, RA, AA, or severe asthma, specific preference for JAKi or biologics provides significant benefit in AD patients with comorbidities.^[11] Nevertheless, the use of JAKi generally has been linked to an increased risk of cancer and cardiovascular disease.^[64] However, in a study conducted with JAKi (abrocitinib, baricitinib, and upadacitinib) at different doses, no increase in the risk of serious infection, non-melanoma skin cancer, other cancers, major adverse cardiovascular events, venous thromboembolism, and nasopharyngitis were detected.^[65] Although there are conflicting data on this subject, this should be taken into consideration when choosing treatment for this group of patients.