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CME ARTICLE
Year : 2019  |  Volume : 20  |  Issue : 1  |  Page : 1-4

Atopic dermatitis: Update on comorbidities and therapeutic advances


1 Pacific Northwest University of Health Sciences, Yakima, WA, USA
2 University of Washington School of Medicine, Seattle, WA, USA
3 University of Washington School of Medicine; Department of Pediatrics, Division of Dermatology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USA

Date of Web Publication14-Dec-2018

Correspondence Address:
Prof. Robert Sidbury
Department of Pediatrics, Division of Dermatology, Seattle Childrenfs Hospital, University of Washington School of Medicine, Seattle, WA 98105
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_92_18

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  Abstract 


Atopic dermatitis (AD) is a chronic inflammatory disorder that primarily affects the skin. Recent literature has expanded our knowledge of associated comorbidities. In this review, we will discuss sleep loss, attention deficit hyperactivity disorder, obesity, and anemia as they relate to AD. We will also review two recently approved medications and how they fit into the therapeutic ladder.

Keywords: Atopic dermatitis, co-morbidity, therapy, obesity, peanut allergy


How to cite this article:
Kim K, Crimp C, Sidbury R. Atopic dermatitis: Update on comorbidities and therapeutic advances. Indian J Paediatr Dermatol 2019;20:1-4

How to cite this URL:
Kim K, Crimp C, Sidbury R. Atopic dermatitis: Update on comorbidities and therapeutic advances. Indian J Paediatr Dermatol [serial online] 2019 [cited 2019 Jan 19];20:1-4. Available from: http://www.ijpd.in/text.asp?2019/20/1/1/247563




  Introduction Top


Atopic dermatitis (AD) is a common, chronic inflammatory skin condition that manifests with recurring pruritic rashes. With a worldwide prevalence of up to 20%, AD typically presents in childhood and affects approximately 3.2 million children in the United States.[1] In 2015, the cost of AD was reported to be $5.297 billion in the US alone. The National Eczema Association recently characterized the physical, psychosocial, and financial impact in a “Burden of Disease” review by Drucker et al.[2] In addition to well-described comorbidities such as food allergy and asthma, new associations such as sleep loss, attention deficit hyperactivity disorder (ADHD), obesity, and anemia have been described.[3] In this review, we will discuss these newer putative comorbidities, as well as fascinating data on peanut allergy prevention as it relates to eczema patients. Finally, we will briefly review two recently approved medications: crisaborole and dupilumab, and how they fit into our therapeutic armamentarium.


  Sleep Disruption Top


Sleep disturbance negatively impacts quality of life in many AD patients.[4] Patients with moderate-to-severe AD lose up to 2.1 h of sleep a night, while parents lose on average 1.9 h. Chang et al. demonstrated a significant reduction in sleep efficacy, longer sleep onset latency, an increase in wakefulness after sleep onset, more sleep fragmentation, and less nonrapid eye movement sleep in children with AD.[5] Fishbein et al. corroborated most of these findings in a separate cohort.[6] Both studies revealed an inverse relationship between the severity of AD and sleep disturbances.

Why and how AD affects sleep is incompletely understood. Itch and scratching movements are certainly disruptive but may not tell the entire story. The role of melatonin and neuroendocrine dysregulation has been investigated.[5],[6],[7],[8],[9],[10],[11],[12] Muñoz-Hoyos et al. found low levels of circulating melatonin in pediatric patients with AD exacerbations.[9] Chang et al. have shown that melatonin supplementation benefits sleep in AD patients, although this has not been replicated to date and our personal experience has been less impressive.[13] Larger controlled studies will be necessary to better understand the role of melatonin in AD care.

Attention deficit hyperactivity disorder

An association between ADHD and AD was first postulated in 2009, since that time multiple studies from diverse populations have demonstrated a link. Schmitt et al. performed a systemic review included 20 studies that concluded patients with atopic disease were more likely to have ADHD.[14] Yaghmaie et al., utilizing the 2007 National Survey of Children's Health, found that children with AD have an increased incidence of ADHD compared to those without AD.[15] This association is stronger in earlier onset and more severe AD.[16]

There are several hypotheses to explain this association. Initial investigation explored the role of inflammatory cytokines. During an allergic reaction, inflammatory cytokines activate neuroimmunologic pathways and alter central neurotransmitter metabolism, potentially resulting in symptoms of ADHD.[17],[18] Sleep loss has also been considered a common denominator. Multiple investigators have shown a stronger association between AD and ADHD when sleep disruption is present.[19],[20] Children with AD and sleep disruptions are 2.5 times more likely to be diagnosed with ADHD.[20] There is also a positive correlation between the severity of AD and ADHD.[15],[20] Finally, the use of first-generation antihistamines, as well as the presence of multiple comorbidities positively, correlates with the likelihood of AD patients developing ADHD, but further investigation is necessary.[21],[22]


  Obesity Top


A more traditional concern of providers caring for infants with severe AD is often concerned with the failure to thrive. Recent data have linked the opposite end of that spectrum: Obesity. Several theories have been proposed to explain this link. At an early age, developing immune systems are more vulnerable to hypersensitivity reactions.[23] Obesity can lead to a proinflammatory state which could predispose toward atopic diseases.[24] Prolonged obesity >2.5 years or onset before 5 years of age is associated with the development of AD.[25] This strength of association is greater in a patient with more severe AD.[26],[27] Adult studies have shown similar findings.[28] An alternative explanation is that obesity is a consequence of AD, but not due to a shared pathomechanism; AD and its resultant impact on activities can increase the risk of obesity as well as cardiovascular disease due to a more sedentary lifestyle.[29] It should be noted that there is a mixed literature with some studies showing no association between obesity and AD.[30],[31],[32]


  Anemia Top


A recent cross-sectional study has also suggested that children with AD are almost two times more likely to be diagnosed with anemia.[33] The mechanism is unknown but may be due to iron deficiency or anemia of chronic disease. Although further studies will be needed to confirm this link, it is prudent that providers consider this possibility in patients with AD who complain of fatigue. Sleep disruption is a ready explanation and can potentially obscure an alternative diagnosis like anemia unless proactively considered.


  Food Allergies, Eczema, and Primary Peanut Allergy Prevention Top


Children with AD are likelier to develop IgE-mediated food sensitization with reported rates from 15% to 40%.[34],[35] A much smaller percentage, however, clearly benefit from selected food avoidance pointing out two things as follows: (a) AD is multifactorial and rarely due solely to food allergy and (b) false-positive IgE tests in the setting of AD are common. In 2010, a multidisciplinary expert panel at the US National Institute of Allergy and Infectious Diseases (NIAIDs) discouraged routine allergy testing not guided by history. They specifically recommended testing in children <5-year-old with persistent AD despite optimal topical therapy or with a history of an immediate reaction after ingestion of a specific food.[36] Testing for food allergy in atopic infants is complicated by the low positive predictive value of food-specific serum IgE and skin-prick tests in this population.[34],[37] These NIAID guidelines do not recommend arbitrary elimination diets, as allergen avoidance has not been shown to conclusively reduce the severity of AD or prevent allergy development.[36] These recommendations were amended in 2017, to accommodate fascinating data about the development of peanut allergy.[38]

The NIAID addendum guidelines are based on the results of the Learning Early About Peanut (LEAP) study that found a significant reduction in peanut allergy when peanut products were introduced early in at-risk infants (defined as those with prior egg allergy, severe eczema, or both).[39] The LEAP study definition of high-risk infants was based on a prior study that found egg allergy and severe eczema to be risk factors for peanut sensitization (odds ratio [OR] 2.31 [95% confidence interval [CI] 1.39–3.86] and OR 2.47 [95% CI 1.14–5.34], respectively).[40] The LEAP trial randomized 640 children between 4 and 11 months of age at high risk of developing peanut allergy to consume or avoid peanut products until 5 years of age, at which time a peanut oral food challenge was conducted to assess for allergy. Of those infants with negative initial skin-prick peanut testing, there was an 86.1% relative reduction in the prevalence of peanut allergy in the consumption group (1.9% allergic) compared to the avoidance group (13.7% allergic).[39]

These impressive results led to the addendum NIAID guidelines that recommend the introduction of peanut products at 4–6 months of age in infants with prior egg allergy, severe eczema, or both with preemptive peanut-SIgE or skin-prick testing to risk-stratify infants for the safety of peanut introduction. The guidelines further recommend peanut introduction at about 6 months of age for infants with mild-to-moderate eczema; ad hoc peanut introduction according to family and cultural norms for infants without eczema; and no recommendation for prior allergy testing in these groups.[38] Dermatologists will be on the frontlines as the population at greatest risk of peanut allergy are those with severe AD; early evaluation by SIgE level or referral for skin-prick testing will be necessary for patients to benefit from early peanut consumption.

Although these guidelines represent an exciting change in practice and opportunity for providers caring for AD patients to reduce the increasing rates of peanut allergy, there will no doubt be implementation challenges. The practical implications and long-term consequences of early peanut protein introduction in patients with AD will define themselves over time. In the short term, dermatologists who care for infants with eczema will need to tailor their approach to peanut protein testing and introduction.


  Therapeutic Advances Top


Crisaborole

Crisaborole ointment, a topical phosphodiesterase inhibitor, was approved in 2017, by the US food and drug administration (FDA) for the treatment of mild-to-moderate AD in patients 2 years and older. In phase 3 trials, nearly one-third of patients in the treatment group achieved the primary outcome of clear or almost clear by Investigator Global Assessment (IGA) (33% vs. 25% P < 0.001).[41] There were no serious adverse events, although application site stinging was seen more commonly in the treatment group (4.4% vs. 1.2% P < 0.001%). Early experience with this novel product has suggested that stinging was underrepresented in the pivotal trials. As with the topical calcineurin inhibitors 17 years earlier, clinicians will develop strategies to mitigate this complaint and incorporate this new, nonsteroidal option into the therapeutic armamentarium.

Dupilumab

Before March 29, 2017, the only US FDA approved the systemic medication for moderate-to-severe AD was prednisone. The advent of dupilumab, now approved for patients older than 18 years of age, has providing a considerably more appealing option. Dupilumab is a biologic agent that inhibits interleukin (IL)-4/IL-13 signaling, a critical pathway in the AD inflammatory cascade. Pivotal phase 3 trials showed that dupilumab 300 mg subcutaneous (SC) administered every other week was as effective in achieving clear or almost clear on an IGA as a weekly injection (39% vs. 38%); both doses were significantly superior to placebo (10% P < 0.001).[42] The most noteworthy adverse event was conjunctivitis, seen in roughly 1 out of 10 dupilumab-treated patients. Although no patients dropped out, subsequent cases of scarring ectropion have been reported.[43] The etiology is unknown, but speculation has queried the role of demodex and eosinophils.[44] Interestingly, a similar conjunctivitis signal was neither seen in phase 2 pediatric data in Europe nor has it been seen in dupilumab trials in other atopic diseases (e.g., asthma and polyposis). Dermatologists using dupilumab should refamiliarize themselves with the diagnosis and management of conjunctivitis.[45]


  Conclusion Top


Emerging research reveals that AD may be a systemic disease much as we think of psoriasis.[46] Comorbidities associated with AD span from mental health disorders to obesity, anemia, and even cardiovascular disease.[3] Further research will be required to clarify causation versus mere association, but providers taking care of AD patients would do well to consider the whole patient, not just the skin. Broader thinking of this sort, coupled with rapid development of new, targeted therapies, will mean better outcomes for AD patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Sleep Disruption
Obesity
Anemia
Food Allergies, ...
Therapeutic Advances
Conclusion
References

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