Groundbreaking AAD Guidelines Assess Links Between AD, Comorbidities

Dermatology Times, Dermatology Times, April 2022 (Vol. 43. No. 4), Volume 43, Issue 4
Pages: 26

The American Academy of Dermatology’s newest guideline focuses on awareness of other health conditions associated with atopic dermatitis in adult patients.

The American Academy of Dermatology (AAD) has released new guidelines on atopic dermatitis (AD) and its comorbidities.1 The AAD dives into the evidence supporting these comorbidities—which include subjects like bone health and cardiovascular diseases—as the first part of a 4-part series and has discovered possible stronger evidence to support some associations. A multidisciplinary work group was created to evaluate evidence and determine the association between AD and these other conditions.

In its systematic review, the work group used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) to weigh the certainty of evidence for AD and a range of comorbid conditions.2-5 Based on the strength and quality of evidence, the work group released statements on the various associations.

Atopic and Allergic Conditions

The meta-analysis found that 24.8% of adult patients with AD have asthma (95% CI, 223, 22.2%-27.5%) but with substantial heterogeneity across studies. Also, those with AD are 3 times as likely to have asthma compared with the general population. There appears to be a stronger association between severe AD and asthma than mild or moderate cases.

Results of a cross-sectional population-based survey that defined AD by Patient Oriented Eczema Measure scores found that patients with severe AD had a relative risk (RR) of 2.38 (95% CI, 1.91-2.85) for asthma compared with the participants without AD, with small risk seen with moderate AD (RR, 1.94; 95% CI, 1.66-2.21) and mild AD (RR, 1.34; 95% CI, 1.12-1.56).6

The work group determined that the concept of atopic march as an explanation for these associations is unproven. However, an immune response at other epithelial surfaces like the gastrointestinal tract (food allergy), upper respiratory tract (allergic rhinitis), and lower respiratory tract (asthma) was unproven.7 Longitudinal studies have shown that patients with multiple atopic morbidities usually do not have AD before developing other atopic conditions, which may suggest that other factors need to be investigated beyond barrier disruption.8,9

Turning to pediatric cases, the work group found that evidence showed that patients with asthma between ages 7 and 13 were also associated with a more persistent AD phenotype.10 The work group suggested that this knowledge may help when counseling pediatric patients about managing AD into their adulthood. Also, targeted therapies, like dupilumab (Dupixent; Sanofi and Regeneron), were found to improve outcomes of both severe AD and asthma.11,12

Findings regarding atopic dermatitis (AD) in adults included the following:

  • AD is associated with asthma (moderate-quality evidence).
  • Greater AD severity is associated with increasing asthma prevalence (moderate-quality evidence).

Next, the work group looked at food allergies, which already had a highly suggested association with AD, and got a better picture of the relationship. They found “clear evidence” of a link in adult patients, but the prevalence of food allergies among the AD patient population (11%; 95% CI, 6%-16%) is limited by heterogeneity across studies.1 The heterogeneity was related to the definition of the food allergy, the type of food, and the use of self-report, physician diagnosis, or administrative codes.

There may be a relationship between the severity of AD and IgE-mediated food allergy, with the odds of having a food allergy compared with the general population increasing from mild (RR, 1.48; 95% CI, 0.89-2.07) to moderate (RR, 2.40; 95% CI, 1.54-3.27) to severe (RR, 8.49; 95% CI, 5.44-11.54) AD.6 The clinical implications of the association between AD and food allergies are unclear, the work group continued.

The statements are:

  • AD in adults is associated with food allergies (high-quality evidence).
  • Greater AD severity is associated with increasing food allergy prevalence (moderate-quality evidence).

Addressing allergic rhinitis, conjunctivitis, and eosinophilic esophagitis, the work group acknowledged that although AD is not studied as much as asthma regarding its association with allergic rhinitis, it is still recognized as a common comorbidity of AD and is a component of some diagnostic criteria for AD.13,14

“In studies comparing the prevalence or incidence of allergic rhinitis between AD and the general population or general clinic population controls, AD was consistently associated with allergic rhinitis, but the magnitude of the association varied widely across different study designs and populations,” the work group wrote.

Little evidence supports the associations between AD and allergic conjunctivitis and eosinophilic esophagitis, according to the work group.

The statements are:

  • AD in adults is associated with allergic rhinitis (moderate-quality evidence).
  • The association between AD in adults and allergic conjunctivitis is uncertain (low-quality evidence).
  • AD in adults may be associated with eosinophilic esophagitis (low-quality evidence).

Immune-Mediated Conditions

Investigators of many epidemiologic studies identified an association between AD and alopecia areata (AA).15 Findings from a Danish study showed that the adjusted odds ratio (OR) for the association between AD and AA was 26.31 (95% CI, 14.48-47.70).16 Some of the strength may be because of diagnostic bias, but the work group still found it to be valid. They also addressed the contention that AD is related to a worse prognosis of AA severity and response to treatment, but related studies are limited. Results of an AA registry study did show that AD is associated with a higher likelihood of having alopecia totalis or universalis, but the finding was not statistically significant (OR, 1.24; 95% CI, 0.95-1.61).17

There are no targeted systemic treatments approved for AA. Dupilumab may be a potentialoption but was also reported to cause new-onset alopecia areata.18 Additionally, Janus kinase inhibitors show promise for both AD and AA but are not yet approved in the United States for either indication.19

The statement is:

  • AD in adults is associated with alopecia areata (moderate-quality evidence).

Urticaria was also reviewed. In a study on autoimmune conditions, investigators from Denmark demonstrated a strong association between chronic urticaria and AD (OR, 9.92; 95% CI, 6.43-15.32).16 Findings from another study showed that patients with chronic urticaria were more likely to receive a diagnosis of AD (HR, 3.1; 95% CI, 2.0-4.8).20

In a clinical setting, itch is a common complaint among patients with either condition, and scratching can worsen the dermatitis. In study findings, omalizumab (Xolair; Genentech), an anti-IgE monoclonal antibody, has been shown to treat chronic idiopathic urticaria effectively in adults. However, it had mixed results when studied in randomized controlled trials in pediatric AD.21,22

The statement is:

  • AD in adults is associated with urticaria (moderate-quality evidence).

Cardiovascular Diseases

There is an established risk between systemic inflammation and cardiovascular disease, and targeting inflammation reduces the risk of cardiovascular events.23 That connection prompted research into a potential link between AD and cardiovascular disease. Vascular inflammation and markers of atherosclerosis were shown to correlate with markers of helper T-cell 2 inflammation in the skin and blood of patients with AD, and patients with AD have increased levels of proteins associated with cardiovascular risk, the work group explained.24, 25

There may be a slight association between AD and hypertension, peripheral and coronary artery disease, congestive heart failure, and acute events such as myocardial infarction and cardiovascular death. The work group stated that, in general, these associations as strong as those for AD and psoriasis, so they added qualifying remarks to those statements. In the meta-analysis of the occurrence of hypertension in adults with AD compared with controls, the OR was 1.06 (95% CI, 1.00-1.13).1 When pooling cohort studies for the association between AD and congestive heart failure, the HR was 1.25 (95% CI, 1.03-1.53).1

In an epidemiologic cohort study from the UK, AD severity gradients were seen for:26

  • Myocardial infarction (mild AD: HR, 1.00; 95% CI, 0.91-1.10; moderate: HR, 1.07; 95% CI, 0.97-1.18; severe: HR, 1.37; 95% CI, 1.12-1.68);
  • stroke (mild AD: HR, 1.06; 95% CI, 0.97-1.15; moderate: HR, 1.09; 95% CI, 1.00-1.20; severe: HR, 1.20; 95% CI, 0.99-1.46);
  • congestive heart failure (mild AD: HR,1.12; 95% CI, 1.02-1.24; moderate: HR, 1.20; 95% CI, 1.09-1.33; severe: HR, 1.67; 95% CI, 1.36-2.05); and
  • cardiovascular death (mild AD: HR, 0.90; 95% CI, 0.89-0.98; moderate: HR, 1.01; 95% CI, 0.93-1.10; severe: HR, 1.30; 95% CI, 1.10-1.53).

It should be noted treatment is frequently used as a proxy to define AD severity in epidemiologic studies, like the one above.

The work group wrote that the clinical implications of these associations are unclear, and current trials in AD did not demonstrate an increased risk of venous thromboembolism.27-33

The statements are:

  • AD in adults is probably associated with hypertension (moderate-quality evidence).*Remark: The evidence suggests a small magnitude of association between AD and hypertension in adults.
  • AD in adults is probably associated with coronary artery disease (moderate-quality evidence). *Remark: The evidence suggests a small magnitude of association between AD and coronary artery disease in adults.
  • AD in adults is probably associated with peripheral artery disease (moderate quality evidence). * Remark: The evidence suggests a small to moderate magnitude of association between AD and peripheral artery disease in adults, with greater AD severity associated with a greater magnitude of association.
  • The association between AD in adults and myocardial infarction is uncertain (low-quality evidence).
  • Severe AD in adults may be associated with myocardial infarction (low-quality evidence).
  • The association between AD in adults and stroke is uncertain (very-low-quality evidence).
  • AD in adults is probably associated with congestive heart failure (moderate-quality evidence). * Remark: The evidence suggests a small to moderate magnitude of association between AD and congestive heart failure in adults, with greater AD severity associated with a greater magnitude of association.
  • AD in adults is probably associated with thromboembolic diseases (moderate-quality evidence). * Remark: The evidence suggests a small magnitude of association between AD and thromboembolic diseases in adults.
  • AD in adults may be associated with cardiovascular death (low-quality evidence). *Remark: The evidence suggests a small magnitude of association between AD and cardiovascular death in adults.

Metabolic Disorders

Current evidence suggests a small association between adult AD and obesity and dyslipidemia. Data from 8 cross-sectional studies that the work group pooled showed that AD was or is associated with 36% increased odds of obesity (OR, 1.36; 95% CI, 1.01-1.83) and 13% increased odds of hypercholesterolemia (OR, 1.13; 95% CI, 1.09-1.18) compared with the general population.1 As this point, it is unclear if the AD severity affects the association of obesity.34,35 The association may vary geography.36

AD may have an inverse association with diabetes. The work group found that AD was associated with a lower risk of diabetes overall (OR, 0.89; 95% CI, 0.80-0.99) and type 2 diabetes specifically (OR, 0.83; 95% CI, 0.76-0.90).1 Only 2 studies compared metabolic syndrome as a whole in individuals with and without AD.37,38

The statements are:

  • AD in adults is probably associated with obesity (moderate-quality evidence).
  • AD in adults is probably associated with dyslipidemia (moderate-quality evidence).
  • AD in adults may not be associated with diabetes (low-quality evidence).
  • The association between AD in adults and metabolic syndrome is uncertain (very-low-quality evidence)

Bone Health

Taiwanese investigators reported that AD was associated with an increased risk of developing osteoporosis (HR, 4.72; 95% CI, 3.68-6.05).39 Also, findings of a UK cohort study showed that the risk of fracture associated with AD was modestly increased overall (HR, 1.07; 99% CI, 1.05-1.09) and slightly higher for those with severe AD (HR, 1.22; 99% CI, 1.14-1.30).40 Additionally, the risk was much higher for fractures related to osteoporosis, with severe AD associated with 200%, 66%, and 50% increased rates of spinal, pelvic, and hip fractures, respectively.40

Although investigators have offered various potential explanations for the association between AD, osteoporosis, and fractures, further research is needed to determine the true mechanism, according to the work group. Some explanations suggest that chronic systemic inflammation leads to aberrant bone metabolism and increased bone loss.41-43 Also, on average, patients with AD are more likely to be deficient in vitamin D, and sleep disruptions caused by AD may lead to increased risk of injury in general.44,45 Oral corticosteroids can heighten the risk of fractures, possibly affecting patients with AD who are being treated with those agents.46-48 The evidence of topical corticosteroid use and its relation to risk of fractures is being studied but remains unclear.49

The statments are:

  • AD in adults is associated with osteoporosis (high-quality evidence).
  • AD in adults is associated with bone fractures (moderate-quality evidence).

Skin Infection

The association between AD and staphylococcal skin infection is well established.50 Herpes superinfection (herpes simplex virus [HSV] or eczema herpeticum) is a more severe complication of AD,51 and results of a UK cohort study showed HSV infections to be more than twice as common among people with AD compared with the general population, the work group explained.52

AD is also associated with serious cutaneous infections (defined as those that lead to hospitalization, are life-threatening, or require treatment in an inpatient setting), according to data from hospitals across the United States (OR, 4.62; 95% CI, 4.51-4.74).1 It was also found that bacterial skin infections and HSV are more likely to occur with poorly controlled dermatitis; successful treatment may reduce the incidence of these infections.53

The statement is:

  • AD in adults is associated with skin infection (moderate-quality evidence).

Mental Health

Various studies have investigated the likelihood of patients with AD to experience depression and anxiety. After analyzing 4 studies that included 11,244 adults with AD and 149,713 controls, the work group found that AD was associated with double the odds of self-reported or clinician-diagnosed depression (odds ratio [OR], 1.99; 95% CI, 1.53-2.59).1 Pooling 4 studies with 157,222 adults with AD and 300,719,113 controls showed similar data for anxiety (OR, 1.40; 95% CI, 1.12-1.75).1

The work group found that adult patients with AD were more likely to have suicidal thoughts than adults without AD (OR, 1.71; 95% CI, 1.43-2.03). However, there is less evidence on an association with death from suicide, and study results were conflicting. 54-57

Although the reasons for the association between AD, depression, and anxiety remain undetermined, a possible explanation is the psychological burden of itch, poor sleep, and decreased quality of life caused by the skin condition. This is supported by data from clinical trials that found that an improvement in AD reduced symptoms of depression and anxiety in patients with moderate to severe AD.58,59

In adults, atopic dermatitis (AD):

  • is associated with clinician-diagnosed depression (moderate-quality evidence),
  • is associated with clinician-diagnosed anxiety (moderate-quality evidence), and
  • may be associated with suicide (low-quality evidence).

Substance Abuse

The work group considered both national and international research on AD and substance abuse. Findings of a Danish population study showed that alcohol abuse was more common in adult patients with AD (OR, 1.38; 95% CI, 1.24-1.53), whereas results of a US population-based survey found that the alcohol intake of adults with AD was more likely to be moderate (OR, 1.33; 95% CI, 1.09-1.62) and heavier (OR, 1.58; 95% CI, 1.23-2.03) compared with controls.60,61

Regarding smoking, results of a US-based population survey revealed that AD was associated with smoking more than 100 cigarettes (OR, 1.32; 95% CI, 1.18-1.47) in one’s lifetime and being a current smoker (OR, 1.28; 95% CI, 1.12-1.45).61

The work group commented that most studies on the link between alcohol use and smoking are cross-sectional, making causality difficult to determine. “As with depression and anxiety, an association [with alcohol and cigarette smoking] could be explained by the burden of AD increasing patients’ likelihood of engaging in those harmful behaviors,” the work group stated. Results of a cohort study on US nurses found no association between cigarette smoking and developing AD.62

In adults, atopic dermatitis (AD):

  1. may be associated with alcohol abuse disorders (low-quality evidence) and
  2. may be associated with cigarette smoking (low-quality evidence).

ADHD AND AUTISM

Currently, more research is available on associations between AD and attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders in the pediatric vs adult patient population. The associations for pediatric patients with AD and these comorbidities will be covered in a future practice guideline.

Just 2 studies were available on possible links, and only 1—a US population-based trial—examined the association of ADHD in adults and included controls from the general population.63,64 Those results did reveal an association (OR, 1.61; 95% CI, 1.25-2.06). The single study that compared the prevalence of autism spectrum disorders among adults with AD to adults with non-AD dermatologic conditions showed a positive association; however, CIs were very wide, preventing definitive conclusions.64

In adults, atopic dermatitis (AD):

  1. may be associated with attention-deficit/hyperactivity disorder (ADHD; low-quality evidence) and
  2. has an uncertain association autism spectrum disorders (very-low-certainty evidence).

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