Vivian Y. Shi, MD
University of Arkansas for Medical Sciences
Little Rock, Arkansas

From April 23 to April 25, dermatologists from across the globe came together to participate in the American Academy of Dermatology Virtual Meeting Experience 2021 (AAD VMX 2021). This year’s meeting included a wide-ranging library of 75 digital sessions and more than 800 ePosters, covering topics from acne to vitiligo and everything in between.
 
Vivian Y. Shi, MD, is associate professor of dermatology at the University of Arkansas for Medical Sciences, Little Rock, and an accomplished researcher and educator.  Her focus includes skin-barrier repair, complex inflammatory skin conditions, trans-epidermal drug delivery, and integrative dermatology. Dr Shi spoke with Dermatology Advisor to share insights into, and key takeaways from, the most recent research on atopic dermatitis (AD) presented at AAD VMX 2021.

AAD VMX 2021 included interesting posters and video presentations on AD. Which of these abstracts did you find the most interesting?

There were many great presentations at the meeting on the topic of AD. I found the trial reports on emerging topical and systemic immunomodulator1-4 [baricitinib, delgocitinib, and upadacitinib], as well as some of the comparative trials involving dupilumab nonresponders,5,6 interesting and impactful.

Your presentation on the integrative management of AD7 clarified for viewers the scope of options available for AD treatment, including cannabinoids. In addition, a poster8 showed high patient interest in medical cannabis products, including for the treatment of AD. Could you discuss the role of cannabinoids in AD therapy and highlight where these therapies might be headed?

Cannabinoids are considered complementary and alternative medicine. They are lipid compounds that bind to cannabinoid receptors in the body. The skin has myriad cannabinoid receptors on nearly all cell types, including keratinocytes, immune cells, sebaceous cells, and neurons. So cannabinoids can modulate a range of skin functions.
 
There are 3 major types of cannabinoids. Phytocannabinoids are derived from plants; the most well-known type is the marijuana, or Cannabis, plant. Animals and humans make our cannabinoid fatty acids, called endocannabinoids. And there are synthetic cannabinoids that are used in laboratory studies. The ideal cannabinoid for AD, whether through topical or oral administration, would be one with little or no psychoactivity — that is, containing minimal or no tetrahydrocannabinol (THC) — and with potent anti-inflammatory and anti-itch properties.
 
The US Food and Drug Administration (FDA) does not provide a clear definition for cannabinoid products. Topical cannabinoid formulations can be considered cosmeceuticals, and oral cannabinoids can be considered a dietary supplement. Because these products are not biotherapeutics, strict guidelines on formulation and testing are lacking. Therefore, products can contain cannabinoids with highly varied properties.
 
A number of small randomized controlled trials and larger uncontrolled trials9-12 have shown that topical cannabinoid formulations can be helpful for AD and have anti-inflammatory effects comparable to those of mild- and mid-potency topical corticosteroids. However, more mechanistic studies and larger randomized controlled clinical studies are needed.

Given how cultural views on cannabis are shifting, do you think the FDA is interested in allowing investigators to research cannabis further, or are they still not interested because of its status as a classified substance?

It’s hard to say, but I’m optimistic. Cannabis that contains THC is still categorized as a Schedule I substance, according to the Controlled Substances Act,13 because of its high addictive potential. This places restrictions on cannabinoid research, to an extent. The lack of standardization in formulations is also a challenge in widely recommending cannabinoid products. For example: Manufacturer A might have a highly pure cannabinoid product that doesn’t have any psychogenic properties, whereas Manufacturer B could claim to have the same product but the amount of THC varies.
 
Despite early, small studies showing benefits and a favorable adverse effect profile, the current sentiment on cannabinoid use in dermatology is still cautious optimism. Many unknowns remain: Where are patients getting these products? Who is making them? How often should they be used, at what concentration, and for how long? These are practical challenges that need to be solved first.
 
It is noteworthy that patients with AD have a defective skin barrier; they are more likely to absorb whatever is applied on the skin. That’s one more reason why these products need to be safe, especially when used on children in whom the skin barrier is immature and the body surface-to-volume ratio is greater.

AAD VMX 2021 included several posters discussing the results of the BREEZE-AD514-18 trial (ClinicalTrials.gov Identifier: NCT03435081), all of which demonstrated either generally positive or significant results for the treatment of AD with baricitinib. If baricitinib is ultimately approved by the FDA to treat AD, how might these results alter the future AD treatment paradigm?

It’s an exciting time to be in the AD space. Baricitinib is just one of several systemic immunomodulators for AD in the pipeline.

Historically, people with AD who have an inadequate response to topical medication and phototherapy would be put on an immunosuppressant, which can have serious adverse effects when used long-term. Dupilumab became available in 2017, and it was paradigm-changing for my patients and my practice. It transformed our lives for the better.

Fast forward a few years, and we have many patients who are doing great on dupilumab, but some are looking for more options. These might be patients who are partial or nondurable responders to dupilumab, who prefer oral therapy, who have developed adverse effects from dupilumab, such as treatment-emergent conjunctivitis, or any combination of these reasons for wanting other options.

It seems like flexibility is key for these patients, especially because AD is a chronic condition. Baricitinib could be a competitive option, if approved.

Baricitinib is an exciting alternative to oral immunosuppressants and dupilumab. Many people with AD are in remission or have significantly improved while on dupilumab, but some still have a less-than-ideal response or have developed adverse effects. Baricitinib is a Janus kinase (JAK) inhibitor; as a class, these agents appear to be highly efficacious for AD and have a relatively favorable adverse effect profile. However, we need longer-term and real-life data to be more certain.
 
JAK inhibitors appear to work faster than dupilumab in terms of itch reduction and might have flexible dosing, given their oral formulation. Flexibility is important for patients because some might have intermittently flaring AD and might not want, or need, continuous systemic treatment. Unlike biologics, JAK inhibitors theoretically do not carry tolerance potential — eg, through development of antidrug-antibodies — and therefore can potentially be tapered up or down according to disease severity. It remains to be seen whether JAK inhibitors can be safely and efficaciously added to dupilumab for patients who require additional systemic therapy for better skin clearance.

Two AAD VMX 2021 ePosters discussed outcomes associated with dupilumab in patients with AD. The first19 was a case series on dupilumab treatment in 2 young patients following organ transplantation, and the second was a record review of patients with HIV infection who were treated with dupilumab.20 In both studies, dupilumab seemed effective and well tolerated, and it caused no negative outcomes related to either HIV control or transplantation success. Are there other comorbidities for which traditional AD therapies raise concerns for clinicians? If so, how should clinicians proceed when treating these patients?

Before dupilumab, people with HIV infection had very limited options for treating AD if they did not adequately respond to topical medications or phototherapy. All we had to offer beyond those treatments were systemic immunosuppressants, which were bad news for someone who was already immunosuppressed.
 
Dupilumab is a highly targeted immunomodulator that specifically blocks interleukin-4 and interleukin-13 signaling — the main drivers of AD and many other atopic diseases, such as asthma — while leaving other components of the immune system intact. So, one’s ability to fight infection and malignancy remains largely intact. I’m glad to see real-world reports demonstrating the safety of dupilumab in immunosuppressed patients. This further confirms that dupilumab is not immunosuppressive.

Researchers shared the results of a 2020 study focused on closing gaps in AD care through the use of patient-provider web apps designed to support shared decision-making.21 More than 50% of providers in the study rated their confidence in facilitating shared decision-making “high,” but data show discordance between patient and provider perceptions about matters such as treatment satisfaction and understanding of medication choices. How can providers use digital resources to facilitate mutual understanding, communication, and shared decision-making, with a goal of improving AD care?

We are entering an exciting era of AD management, in which technology allows patients to more accurately track their disease course, triggers, and treatments, and to communicate with their physician. Technology has provided a bridge for shared decision-making between us and our patients. AD is a dynamic disease, and we are only seeing a snapshot of the patient’s disease course in the office. Eczema-tracking apps allow us to gain more insight into a patient’s disease course, triggers, medication adherence, and treatment response between visits. In a way, technology allows us to “be there” without being able to be there.
 
The rapidly growing selection of disease trackers is super-exciting, although several potential barriers still exist before there can be widespread adoption by patients and physicians. First, physicians need to be incentivized to encourage patients to use the apps and be willing to use the information provided by the patients through the app; this can be in the form of making AD office visits easier or establishing a better avenue for compensation.
 
The second barrier is strategic avoidance of information overload. How can the huge amount of data collected about a patient’s disease be boiled down to a convenient summary? And how can less-pertinent information be filtered out?
 
These apps might also solve a centuries-long problem in medicine: the discrepancy between perceived quality of communication between physicians and patients. The information gathered by apps can potentially close this gap and work alongside patients to track treatment progress and response. That way, both parties can see whether outcomes match their expectations.
 
EczemaWise is a useful app developed by the National Eczema Association. It’s a comprehensive tool with which patients can track their disease severity, symptoms, triggers, medications, and responses, and can share that information with their physician.
 
In terms of moving to a digital model, I think it is really patient-dependent. Some patients are tech-savvy and have rapidly adopted this technology in their health care. Those with lower health literacy and technology literacy, however, might face barriers in adapting to the use of technology. Some of my patients do not even have a smartphone or access to the internet!
 
In addition, the language used in apps and educational material should have the proper readability level for the general public. The American Medical Association recommends that health-education material be written at a sixth-grade reading level; however, research by my team shows that much online patient-education content is written at a high-school or even college readability level. Widespread adoption of health apps therefore requires that they are user-friendly and accessible.

Key Takeaways

  • Dermatologists are expressing “cautious optimism” about the future use of cannabinoid-containing products to treat conditions such as AD. Although small studies have shown benefit, many questions must still be answered through large randomized controlled trials before topical cannabinoid products become a treatment norm.
  • Approval of baricitinib — among other systemic immunomodulators in the pipeline — could be paradigm-changing for both physicians and patients, offering the potential of flexible dosing in tandem with a favorable adverse-effect profile.
  • Technology is poised to provide patients and physicians with a new way to accurately track their disease and manage their triggers, all while sharing data with their physician. However, mobile health apps have a long way to go and require a thoughtful approach to maximize usability by both patients and providers.

The Q&A was edited for clarity and length.

Disclosure

Vivian Y. Shi, MD, reported affiliations with Sanofi Genzyme; Regeneron Pharmaceuticals, Inc.; AbbVie; Eli Lilly and Company; Novartis International AG; Sun Pharmaceutical Industries Ltd.; LEO Pharma A/S; Pfizer, Inc.; Menlo Therapeutics Inc.; Dermira, Inc.; Burt’s Bees, Inc.; Galderma, S.A.; Kiniksa Pharmaceuticals; UCB, S.A.; Altus Medical Laboratories; MyOR; Gpskin; and Skin Actives Scientific.

References

1. King B, Maari C, Lain E, et al. Extended safety analysis of baricitinib 2-mg in adult patients with atopic dermatitis: an integrated analysis from 8 randomized clinical trials. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 27030.

2. Simpson EL, Warren RB, Eichenfield LF, et al. Rapid skin improvement with upadacitinib with or without topical corticosteroids (TCS) in moderate-to-severe atopic dermatitis (AD): results from 3 phase 3 studies (Measure Up 1, Measure Up 2, and AD Up). Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 27915.

3. Nakagawa H, Oda M. Delgocitinib ointment in pediatric patients with atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and an open label, long-term extension study. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 25094.

4. Eichenfield LF, Simpson EL, Siegfried EC, et al. Efficacy and safety of ruxolitinib cream among adolescents with atopic dermatitis: pooled results from two phase 3 studies. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 27633.

5. Shi V, Bhutani T, Deleuran M, et al. Abrocitinib in the treatment of moderate-to-severe atopic dermatitis refractory to dupilumab treatment: an analysis of JADE-EXTEND, a phase 3 long-term extension study. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 27590.

6. Yosipovitch G, Thyssen JP, Paul C, et al. Effect of abrocitinib versus dupilumab and placebo on patient-reported outcomes (PROs) in moderate-to-severe atopic dermatitis (AD) in JADE COMPARE. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 27237.

7. Shi V. Integrative management for atopic dermatitis. Presented at: AAD VMX 2021, April 23-25, 2021; Presentation F026.

8. Yeroushalmi S, Nemirovsky DR, Feldman DA, Nelson K, Sparks A, Friedman A. Consumer attitudes and behaviors on medical cannabis in dermatology. Abstract. Presented at: AAD VMX) 2021, April 23-25, 2021; ePoster 27653.

9. Del Rosso JQ. Use of a palmitoylethanolamide-containing nonsteroidal cream for treating atopic dermatitis: impact on the duration of response and time between flares. Cosmetic Dermatology. 2007;20(4):208-211.

10. Pulvirenti N, Nasca MR, Micali G. Topical adelmidrol 2% emulsion, a novel aliamide, in the treatment of mild atopic dermatitis in pediatric subjects: A pilot study. Acta Dermatovenerol Croat. 2007;15(2):80-83.

11. Eberlein B, Eicke C, Reinhardt H-W, Ring J. Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). J Eur Acad Dermatol Venereol. 2008;22(1):73-82. doi: 10.1111/j.1468-3083.2007.02351.x

12. Kemeny L. Comparative study of S236 cream and hydrocortisone 1% in patients with atopic dermatitis. J Am Acad Dermatol. 2005;52(3 Suppl):P86.

13. United States Food and Drug Administration. FDA Regulation of cannabis and cannabis-derived products, including cannabidiol (CBD). Updated January 22, 2021. Accessed May 10, 2021. www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd

14. Yosipovitch G, Papp K, Forman S, et al. The contribution of itch and skin severity improvements to the Dermatology Life Quality Index in patients with atopic dermatitis in a baricitinib phase 3 study, BREEZE-AD5. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 26670.

15. Lio P, Soung J, Cather J, et al. Rapid and concurrent improvements in the signs and symptoms of atopic dermatitis with baricitinib in the phase 3 study, BREEZE-AD5. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 26691.

16. Bissonnette R, Korman N, Lockshin B, et al. Baricitinib, an oral, reversible Janus kinase-1 and -2 inhibitor, for atopic dermatitis: head and neck response from BREEZE-AD5. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 26237.

17. Kwatra S, Forman S, Cruz A, et al. Baricitinib treatment result in clinically meaningful itch reduction and enhanced quality of life in patients with moderate-to-severe atopic dermatitis: results from BREEZE-AD5. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 25447.

18. Eichenfield LF, Maverakis E, Tan J, et al. Improvements in work productivity following baricitinib treatment in patients with moderate-to-severe atopic dermatitis: results from BREEZE-AD5. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 25423.

19. Gupta R, Maguiness S, Boull C. Use of dupilumab for atopic dermatitis in young post-transplant patients – a case series of 2 patients. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 26229.

20. Nusbam K, Kaffenberger B, Paradiso M, et al. Dupilumab for treatment of atopic dermatitis in patients living with HIV. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 27011.

21. Lio PA, Fantus PP, Eichenbrenner PJ, et al. Atopic dermatitis web apps: tethered tools to support patients and providers in shared decision-making, self-management, and therapy access. Abstract. Presented at: AAD VMX 2021, April 23-25, 2021; ePoster 25407.

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Reviewed May 2021