EXPERT ANALYSIS FROM THE EADV CONGRESS
VIENNA (FRONTLINE MEDICAL NEWS) – Newly enhanced appreciation of the profound burden of comorbidities associated with adult atopic dermatitis (AD) is provided by the Liberty AD-AWARE study, investigators said at a joint program of the International Eczema Council and the International Psoriasis Council held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.
“I think the only reason we thought psoriasis is a systemic disease and atopic dermatitis is not is because people were researching it much more in psoriasis. I think atopic dermatitis will emerge as potentially more systemic than psoriasis, including the comorbidities. It’s just a matter of time before the evidence is put forth for atopic dermatitis,” predicted Emma Guttman-Yassky, MD, PhD, professor and vice chair of the department of dermatology at Mount Sinai School of Medicine in New York.
In fact, it’s already starting. She noted that, just in a space of months, Danish investigators reported finding coronary artery plaques using cardiac CT angiography in 48% of a group of patients with severe AD, compared with 38% with severe psoriasis, and 21% of matched controls ( Am J Med. 2015 Dec;128[12]:1325-34.e2 ). Then the investigators followed up with a national population-based study showing that Danish adults with severe AD were at an adjusted 2.4-fold increased risk of acute MI, compared with matched controls ( BMJ Open 2016;6:e011870 doi:10.1136/bmjopen-2016-011870 ).
Dr. Guttman-Yassky noted that 85% of cases of AD begin before 5 years of age. Many cases resolve later in childhood, but for others it becomes a chronic lifelong condition. And while the burden of AD has been well characterized in the pediatric population, that’s not so in affected adults. This was the impetus for the Liberty AD-AWARE (Adults With Atopic Dermatitis Reporting on their Experience) study, an Internet-based cross-sectional survey of more than 1,500 adults with AD receiving their care from dermatologists at eight major U.S. academic medical centers.
Eric L. Simpson, MD , a coinvestigator with Dr. Guttman-Yassky in Liberty AD-AWARE, observed that the study documented self-reported high rates of a range of psychiatric, cardiovascular, allergic, respiratory, and infectious diseases in participants. And while a cross-sectional study can’t establish causality, it’s important to appreciate that rates of these comorbidities were across the board significantly higher in the 1,028 patients with moderate to severe AD over the prior 12 months than in the 491 classified as having mild AD.
He drew special attention to the neuropsychiatric issues, including clinically significant levels of anxiety and depression, adult ADHD, and sleep disorders. Indeed, 50% of patients with moderate to severe AD had a Hospital Anxiety and Depression Scale score of 8 or more on the HADS-A, HADS-D, or both.
These associations between AD and mental health problems have been confirmed in other studies. For example, a recent analysis of data on more than 354,000 children and nearly 35,000 adults in the United States demonstrated that AD was independently associated with a 14% increased likelihood of attention-deficit/hyperactivity disorder in children and a 61% increased risk in adults. Those risks of ADHD rose far higher in individuals with severe AD and sleep disruption ( Br J Dermatol. 2016 Nov;175[5]:920-9 ).
A number of theories have been put forth to explain these associations, including altered brain development stemming from early exposure to inflammatory cytokines or perhaps shared genetic predisposition, but Dr. Simpson proposed a simpler explanation which carries more optimistic implications.
“I suspect the mental health problems associated with adult atopic dermatitis are probably nonspecific sequelae of any chronic skin disorder involving severe itch and sleep disturbances,” said Dr. Simpson, professor of dermatology at Oregon Health & Science University, Portland.
Moreover, there is good reason to believe that novel therapies targeting inflammation more effectively than what’s been available to date may help improve mental health outcomes, as well as asthma in affected adults with AD, he added. He cited a phase IIb, randomized, double-blind, placebo-controlled study for which he was lead investigator. In this trial, 16 weeks of treatment with dupilumab, a first-in-class investigational blocker of the interleukin-4/interleukin-13 signaling pathway, not only resulted in significant reductions in itch and sleep problems, it also decreased anxiety and depression symptoms and improved multiple validated measures of health-related quality of life ( J Am Acad Dermatol. 2016 Sep;75[3]:506-15 ).
Liberty AD-AWARE provides hints of the profound cumulative negative impact moderate to severe AD can have on a patient’s life course. Among the group with moderate to severe disease, 7.5% said AD had a large negative effect on their pursuit of an education, 10.7% said their disease had influenced their career choice “a lot/very much,” 13.3% were unemployed for reasons other than being retired or a student, and 17.1% reported an annual family income of less than $25,000. All these rates were multifold higher than in patients with mild AD in the study, which didn’t include a non-AD control group.
Dr. Guttman-Yassky observed that 42% of the moderate to severe AD group in Liberty AD-AWARE reported their current treatments were ineffective at controlling their disease, even though study participants were presumably receiving high-quality care at academic medical centers. Twenty-eight percent of patients with inadequately controlled AD had used phototherapy or an immunomodulatory drug within the past 7 days, underscoring the limitations of those forms of therapy in patients with more severe AD as well as the need for new and better treatments.
Dr. Guttman-Yassky has played a key role in the paradigm shift regarding understanding of the pathogenesis of AD as involving not just disordered skin barrier function but also immunologic impairment. She was senior author of a study that showed the nonlesional skin of patients with AD is characterized by high-level expression of inflammatory cytokines, whereas the nonlesional skin of psoriasis patients is not, an observation that serves to highlight the need for proactive treatments for AD ( J Allergy Clin Immunol. 2011 Apr;127[4]:954-64.e1-4 ). Later, she and her coworkers demonstrated that AD is characterized by greater levels of T-cell activation among central and effector CD4+ and CD8+CLA+ and CD8+CLA– memory cell subsets ( J Allergy Clin Immunol. 2015 Jul;136[1]:208-11 ).
More recently, she was also senior author of a landmark study that provides a mechanism to account for the reason AD patients would potentially have more comorbid illnesses than psoriasis patients. The investigators demonstrated that AD is accompanied by systemic expansion of transitional and chronically activated memory B cells, plasmablasts, and IgE-expressing memory B cells in both skin and blood. In other words, AD is characterized by a greater level of systemic immune activation, compared with psoriasis, where activated T cells are largely confined to the skin, and activated central memory B cells don’t figure prominently (J Allergy Clin Immunol. 2016 Jan;137[1]:118-29.e5).
The Liberty AD-AWARE study was sponsored by Sanofi and Regeneron. Dr. Simpson and Dr. Guttman-Yassky reported receiving research grants from and serving as consultants to those and other pharmaceutical companies.
