Addressing the Immunopathogenesis of Atopic Dermatitis: Advances in Topical and Systemic Treatment
Several immunologic mediators—phosphodiesterase (PDE), interleukin (IL), small molecules, and Janus kinase—have been implicated in the pathogenesis of atopic dermatitis, and evidence has shown that blocking these mediators can help modify the disease process. Several new topical medications have been developed that target the enzyme PDE; crisaborole was recently approved by the US Food and Drug Administration (FDA) for the treatment of atopic dermatitis, and phase II studies have been completed on OPA-15406. The phase III clinical trial results of the systemic medication dupilumab, an inhibitor of the IL-4 receptor α subunit (which inhibits both IL-4 and IL-13 signaling), are currently being reviewed by the FDA. Semin Cutan Med Surg 36(supp2):S45-S48 © 2017 published by Frontline Medical Communications
Atopic dermatitis; crisaborole; eczema; dupilumab; interleukin inhibition; OPA-15406; phosphodiesterase-4 inhibition
The basic nature of atopic dermatitis (AD)—that it is the manifestation of an immune-mediated inflammatory process—has been recognized for several decades. Research has revealed that type 2 T helper cells (TH2) play an important role in this process, as does dysfunction of the skin barrier. More recently, improved understanding of the pathogenesis of AD has prompted changes in our treatment strategies and spurred the development of new therapies. This article discusses two new topical medications that target the enzyme phosphodiesterase (PDE) (crisaborole and OPA-15406), current thinking on the role of systemic agents in AD, as well as new and emerging systemic agents. In recent years, several immunologic mediators—PDE, small molecules, and Janus kinase—have been shown to be important in the course of AD, both because they have been implicated in the pathogenesis of AD and because of evidence that blocking these mediators can help change the disease process.
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The diagnosis of atopic dermatitis can be challenging because the type and appearance of skin lesions can vary and some common cutaneous conditions—such as seborrheic dermatitis (“cradle cap”) in infants—may coexist. In most cases, attention to characteristic features of AD leads to the correct diagnosis. Awareness of clinical circumstances that should lead to consideration of some rare conditions in the differential diagnosis also is important.
Recently published studies that have furthered the understanding of the role of filaggrin, filaggrin gene mutations, and transepidermal water loss have demonstrated that daily, full-body emollient applications, beginning at birth, may prevent the expression of AD in susceptible children. For all patients with AD, the use of adequate skin hydration combined with the prompt application of ointment or cream moisturizers (“soak and seal”) remains the cornerstone of AD therapy.
Recent advances in understanding the complex pathophysiology of AD have led to the development of new and emerging topical and systemic medications that may effectively manage the signs and symptoms of AD in patients who do not respond adequately to standard treatment regimens. These include the topical phosphodiesterase-4 inhibitor crisaborole, recently approved for use in AD by the US Food and Drug Administration (FDA), and the subcutaneously administered interleukin-4 receptor α subunit inhibitor dupilumab, for which phase III pivotal study data are now available.
Clinicians must remain up-to-date on the findings from clinical studies on the diagnosis and management of AD, as well as the benefits and risks of all treatment options available, to make the appropriate choices for management of their individual patients.
By reading and studying this supplement, participants should be better able to:
- Discuss the features of AD that should allow a clinical diagnosis of the condition in most patients, and list the factors in children and adults that should lead to the consideration of alternative diagnoses or identification of comorbid conditions.
- Explain how the current understanding of the role of the epidermal skin barrier and transepidermal water loss should affect—and continue to improve— the day-to-day care of patients with AD.
- More effectively individualize patient treatment strategies by considering the full range of current and emerging therapeutic options.
- Consider the evidence-based recommendations in the current guidelines for the diagnosis and treatment of AD published by the American Academy of Dermatology.
- Describe the rationales and mechanisms of action of the new and emerging therapies for AD, particularly the recently approved topical agent crisaborole and the systemic medication dupilumab (phase III study results under FDA review at the time of publication of this supplement).
Individuals in a position to control the content of this educational activity are required to disclose: 1) the existence of any relevant financial relationship with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients with the exemption of non-profit or government organizations and non-health care related companies, within the past 12 months; and 2) the identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.
Lawrence F. Eichenfield, MD, Advisory Board/Speaker: Valeant Pharmaceuticals North America LLC. Consultant: Anacor Pharmaceuticals, Inc./Pfizer Inc., Eli Lilly and Company, Genentech, Inc., Otsuka America Pharmaceutical, Inc./Medimetriks Pharmaceuticals, Inc., Sanofi Genzyme/Regeneron Pharmaceuticals, TopMD, Valeant. Investigator: Sanofi Genzyme/Regeneron.
Linda F. Stein Gold, MD, Consultant: Anacor. Grant/Research: Anacor, GlaxoSmithKline. Data Monitoring Committee: Otsuka.
Staff and Advisory Board Disclosures: The CME & PD staff pediatricians, family practitioners, and Advisory Board have nothing to disclose.
CME/CE Reviewers: Cindy England Owen, MD, Assistant Professor, Division of Dermatology, University of Louisville School of Medicine, has no relevant financial relationships to disclose. The PIM planners and managers, Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CHCP; Judi Smelker- Mitchek, MBA, MSN, RN; and Jan Schultz, MSN, RN, CHCP, have nothing to disclose.
Global Academy for Medical Education Staff: Sylvia H. Reitman, MBA, DipEd; Jenny Campano; Tristan Nelsen, MNM, CMP, HMCC; and Joanne Still have no relevant financial relationships to disclose.
Off-Label/Investigational Use Disclosure
This CME/CE activity discusses the off-label use of certain approved medications as well as data from clinical trials on investigational agents. Any such material is identified within the text of the articles.
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1. Hanifin JM, Chan SC, Cheng JB, et al. Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol. 1996;107:51-56.Hanifin JM, Chan SC, Cheng JB, et al. Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol. 1996;107:51-56.
2. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75:494-503.e4.
3. Zane LT, Eichenfield LF, Call RS, et al. Long-term safety of crisaborole topical ointment, 2%, in children and adults with mild-to-moderate atopic dermatitis. J Immunol. 2016;196(1 suppl):191.28. Abstract. http://www.jimmunol.org/ content/196/1_Supplement/191.28.abstract?sid=7d17786c-6ccc-4878-b44f- 252f6405158f. Accessed January 3, 2017.
4. Hanifin JM, Ellis CN, Frieden IJ, et al. OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): A phase-II randomized, double-blind, placebo-controlled study. J Am Acad Dermatol. 2016; 75:297-305.
5. Proudfoot LE, Powell AM, Ayis S, et al; European Dermato-Epidemiology Network (EDEN). The European TREatment of severe Atopic eczema in children Taskforce (TREAT) survey. Br J Dermatol. 2013;169:901-909.
6. Totri CR, Eichenfield LF, Logan K, et al. Prescribing practices for systemic agents in the treatment of severe pediatric atopic dermatitis in the US and Canada: The PeDRA TREAT survey. J Am Acad Dermatol. 2017;76:281-285.
7. Simpson EL, Bieber T, Guttman-Yassky E, et al; SOLO 1 and SOLO 2 Investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335-2348.
This continuing medical education (CME/CE) supplement was developed from a satellite symposium held at the Skin Disease Education Foundation’s 17th Annual Las Vegas Dermatology Seminar, November 11, 2016, in Las Vegas, Nevada. The Guest Editors acknowledge the editorial assistance of Global Academy for Medical Education and Joanne Still, medical writer, in the development of this supplement. The manuscript was reviewed and approved by the Guest Editors as well as the Editors of Seminars in Cutaneous Medicine and Surgery. The ideas and opinions expressed in this supplement are those of the Guest Editors and do not necessarily reflect the views of the supporter, Global Academy for Medical Education, the University of Louisville, Postgraduate Institute for Medicine, or the Publisher.
* Chief, Pediatric and Adolescent Dermatology, Professor of Dermatology and Pediatrics, Rady Children’s Hospital, University of California, San Diego School of Medicine, San Diego, California
† Director of Dermatology Research, Henry Ford Health System, Detroit, Michigan
Publication of this CME/CE article was jointly provided by University of Louisville, Postgraduate Institute for Medicine, and Global Academy for Medical Education, LLC, and is supported by an educational grant from Anacor Pharmaceuticals, Inc. The authors have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.
Lawrence F. Eichenfield, MD, Advisory Board/Speaker: Valeant Pharmaceuticals North America LLC. Consultant: Anacor/Pfizer Inc., Eli Lilly and Company, Genentech, Inc., Otsuka America Pharmaceutical, Inc./Medimetriks Pharmaceuticals, Inc., Sanofi Genzyme/Regeneron Pharmaceuticals, TopMD, Valeant. Investigator: Sanofi Genzyme/Regeneron. Linda F. Stein Gold, MD, Consultant: Anacor. Grant/Research: Anacor, GlaxoSmithKline. Data Monitoring Committee: Otsuka.
Address reprint requests to: Lawrence F. Eichenfield, MD, Rady Children’s Hospital, 8010 Frost Street, Suite 602, San Diego, CA 92123; firstname.lastname@example.org
1085-5629/13/$-see front matter © 2017 Frontline Medical Communications doi:10.12788/j.sder.2017.012