Clinical Update

Atopic Dermatitis

Renee Akers, PharmD, RPh, CPh

Introduction

Atopic dermatitis (AD) is a chronic skin condition most common among children and less common among adults. AD begins in childhood, with 1 in 5 infants estimated to be affected compared with 1 in 50 adults.1 By adolescence, 60% of cases resolve independently.2 Persons with AD often have comorbidities such as food allergy, asthma, allergic rhinitis, urticaria, depression, anxiety, osteoporosis, bone fracture, cardiovascular disease, and skin infection.3

AD can present in acute or chronic forms and is characterized as a highly pruritic and inflammatory condition. An acute flare will ooze, bleed, and become red and swollen from scratching or rubbing. Chronic flares over time become thick, dry, and discolored, often from breakouts occurring in the same spot. Areas on persons with light skin may look bruised or pink after flares heal, whereas persons with darker skin may have hyper- or hypopigmentation and papules in resolved regions.2

Infants develop flares on the scalp, cheeks, neck, elbows, front of the knees, and knuckles. In contrast, children present with areas in the elbow crease, the back of the knee, and the hands and feet. In adolescence and adulthood, flares appear as dry skin and red, inflamed patches on the head, neck, and body creases.2

If left untreated, AD reduces the patient’s quality of life because of severe itching, interrupted sleep, and the increased long-term risk of developing asthma and allergies. A recent survey of patients with AD revealed that patients think treatments do not work and are not available or affordable.4 Therefore, understanding genetic and environmental factors and implementing appropriate stepwise treatment, structured follow-up, and patient counseling can reduce flares, advance therapy, and improve quality of life.5

Etiology

Genetics may increase the risk of developing this disorder for those with family members who have AD. Approximately 50% of individuals with AD have a filaggrin gene mutation associated with AD development.5 Filaggrin gene mutations cause a weak skin barrier and skin dryness by allowing moisture loss and allergen exposure through loose protein junctions. Skin ceramide deficiency exacerbates skin dryness, and overactive epidermal proteases degrade the skin barrier.5 Lastly, an exaggerated cell-mediated immune response involving the Janus-kinase (JAK) cytokine pathway and IgE-induced hypersensitivity add to the cascade of dysfunction in AD.5,6

Genetics is not a singular factor in the development of AD. Studies have shown that environmental pollution, low temperature, urban setting, fast-food consumption, tobacco smoke, and obesity increase the risk for AD.5

Screening and Diagnosis

Because of a lack of cost-effective, objective screening tests, AD diagnosis is based on clinical signs and symptoms and patient history.5,7 Primary diagnostic criteria are itchy skin plus 3 or more minor criteria. Generally, minor criteria include a history of itchy cheeks; previous eczema of cheeks, forehead, or outer limbs; and a history of atopic disease in a first-degree relative.5

Treatment

The key treatment for all stages of AD is once-daily bathing, then applying fragrance-free8 topical moisturizers or bath oils twice daily.5 When moisturization alone is insufficient, topical corticosteroids are first-line therapy for acute flares. For moderate AD maintenance, topical corticosteroid application can be used 2 to 3 times weekly.5,8 There is a risk of systemic absorption when treating AD long-term with corticosteroids. The lowest strength topical corticosteroid that is effective should be used. Potency selection should be cautiously undertaken regarding thin-skinned body areas, including the groin, face, neck, and body fold areas.8 High- to very-high-potency topical corticosteroids are not recommended for infants and children.5 Wet wrap therapy using topical corticosteroids may be used to treat moderate to severe AD flares, however evidence of effectiveness varies.8

Because AD is not histamine-mediated, antihistamines are ineffective for treating the pruritus in this condition but may help with sleep because of sedation.5 Short courses of a topical or oral antibiotic may be required because patients with AD are at higher risk for Staphylococcus aureus infection.5

Topical calcineurin inhibitors such as tacrolimus9 or pimecrolimus10 are recommended as a secondary therapy when treating mild to moderate AD short term. Cases that justify their preference include steroid-resistant AD, steroid-induced skin atrophy, continuous long-term steroid use, and use in thin-skinned areas.8 These topical agents work by inhibiting the calcineurin phosphatase enzyme and stopping overactive skin-damaging cytokines.5,8

The topical phosphodiesterase-4 inhibitor (PDE-4) crisaborole also limits cytokine activity and offers yet another alternative anti-inflammatory topical. It is indicated to treat mild to moderate AD in individuals aged 3 months or older.5,11  Topical roflumilast cream and difamilast ointment are currently in phase 3 trials.12,13

JAK inhibitors, an essential addition to AD therapy, suppress cytokine-induced inflammation by blocking the activity of interleukins. Ruxolitinib cream14 is the first topical JAK inhibitor for mild to moderate AD for those aged 12 years or older to be approved by the US Food and Drug Administration (FDA).15 Other FDA-approved JAK inhibitors for moderate to severe AD include oral abrocitinib16 and oral upadacitinib.17 Phase 3 trials are underway for oral baricitinib18 and oral and topical ivarmacitinib19 for moderate to severe AD.

Oral immunomodulators such as azathioprine, mycophenolate, cyclosporine, and methotrexate have been used off-label to treat severe AD but have substantial adverse effects and are not recommended in children, limiting their use.20

Notably, in 2017, the FDA approved the monoclonal antibody dupilumab21 for patients aged 6 years or older, offering an effective treatment option for children with severe AD.20 Monoclonal antibodies block inflammation mediated by interleukins 4, 13, and 31. Currently, the only other FDA-approved monoclonal antibody for AD is tralokinumab,22 yet several others are under phase 3 investigation, including rocatinlimab,23 lebrikizumab,24 and nemolizumab.25

A new class of topical agents called therapeutic aryl hydrocarbon receptor agonists improves skin barrier function and reduces the activity of T-helper type 2 cells, exerting an anti-inflammatory effect.5 Tapinarof and its alternative formulation, benvitimod, are in promising phase 3 trials.26

Narrow-band UVB phototherapy is first-line therapy to treat generalized body AD by increasing inflammatory cell death, inhibiting the activity of Langerhans cells, and reducing cytokine production.5,27

Multidisciplinary Management

Management of AD requires a variety of practitioners, including primary care physicians, dermatologists, allergists, and pharmacists, to increase the affordability of, the effectiveness of, and adherence to therapy. A multifaceted approach includes removing triggering factors (ie, allergens, stress), improving skin hydration and barrier function, using effective medications and adjunctive treatments, and team-based patient counseling.5

Conclusion

The American Academy of Dermatology is currently revising the 2014 AD treatment guidelines28-30 to incorporate new therapies, minimize treatment cost, and maximize patient outcomes. New biologic and topical nonsteroidal anti-inflammatory therapies have expanded effective treatments for refractory AD, persons of color, and young patients. Importantly, treatment for AD is developing and improving, giving hope to an underserved patient population.

References

1. Skin allergy. American Academy of Allergy, Asthma, and Immunology (AAAAI). Accessed June 23, 2022. https://www.aaaai.org/Conditions-Treatments/Allergies/Skin-Allergy

2. Raimondo A, Lembo S. Atopic dermatitis: epidemiology and clinical phenotypes. Dermatol Pract Concept. 2021;11(4):e2021146. doi:10.5826/dpc.1104a146

3. Davis DMR, Drucker AM, Alikhan A, et al. American Academy of Dermatology Guidelines: awareness of comorbidities associated with atopic dermatitis in adults. J Am Acad Dermatol. 2022;86(6):1335-1336.e18. doi:10.1016/j.jaad.2022.01.009

4. New study gives prevalence and severity insights to atopic dermatitis. Asthma and Allergy Foundation of America. October 3, 2018. Accessed June 23, 2022. https://www.aafa.org/media/2204/press-release-aafa-atopic-dermatitis-study-overview-released-3-october-2018.pdf

5. Mandlik DS, Mandlik SK. Atopic dermatitis: new insight into the etiology, pathogenesis, diagnosis and novel treatment strategies. Immunopharmacol Immunotoxicol. 2021;43(2):105-125. doi:10.1080/08923973.2021.1889583

6. Traidl S, Freimooser S, Werfel T. Janus kinase inhibitors for the therapy of atopic dermatitis. Allergol Select. 2021;5:293-304. doi:10.5414/ALX02272E

7. Davari DR, Nieman EL, McShane DB, Morrell DS. Current perspectives on the systemic management of atopic dermatitis. J Asthma Allergy. 2021;14:595-607. doi:10.2147/JAA.S287638

8. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116-132.:doi.10.1016/j.jaad.2014.03.023

9. Protopic. Prescribing Information. Astellas; 2000. Revised November 2011. Accessed June 23, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/050777s018lbl.pdf

10. Elidel. Prescribing information. Novartis; 2001. Revised January 2006. Accessed June 23, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021302s011lbl.pdf

11. Eucrisa. Prescribing information. Pfizer; 2016. Revised March 2020. Accessed June 23, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207695s007s009s010lbl.pdf

12. Arcutis Biotherapeutics. Pipeline roflumilast. Accessed June 23, 2022. https://www.arcutis.com/pipeline/#pipeline

13. National Center for Biotechnology Information. PubChem Compound Summary for CID 57855696, Difamilast. Accessed June 23, 2022. https://pubchem.ncbi.nlm.nih.gov/compound/57855696#section=Clinical-Trials

14. Opzelura. Prescribing information. Incyte; 2011. Revised April 2022. Accessed June 23, 2022. https://www.opzelura.com/prescribing-information.pdf

15. Incyte announces U.S. FDA approval of Opzelura (ruxolitinib) cream, a topical JAK inhibitor, for the treatment of atopic dermatitis (AD). News release. Incyte. September 21, 2021. Accessed June 23, 2022.  https://investor.incyte.com/news-releases/news-release-details/incyte-announces-us-fda-approval-opzeluratm-ruxolitinib-cream

16. Cibinqo. Prescribing information. Pfizer; 2022. Revised January 2022. Accessed June 23, 2022. https://cdn.pfizer.com/pfizercom/USPI_Med_Guide_CIBINQO_Abrocitinib_tablet.pdf

17. Rinvoq. Prescribing information. AbbVie; 2019. Revised January 2022. Accessed June 23, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211675s004lbl.pdf

18. National Center for Biotechnology Information. PubChem Compound Summary for CID 44205240, Baricitinib. Accessed June 23, 2022. https://pubchem.ncbi.nlm.nih.gov/compound/44205240#section=Clinical-Trials

19. National Center for Biotechnology Information. PubChem Compound Summary for CID 71622431, Ivarmacitinib. Accessed June 23, 2022. https://pubchem.ncbi.nlm.nih.gov/compound/Ivarmacitinib#section=ClinicalTrials-gov

20. Ghazal S, Ridha Z, D'Aguanno K, et al. Treatment guidelines for atopic dermatitis since the approval of dupilumab: a systematic review and quality appraisal using AGREE-II. Front Med (Lausanne). 2022;9:821871. doi:10.3389/fmed.2022.821871

21. Dupixent. Prescribing Information. Regeneron; 2017. Revised June 2022. Accessed June 23, 2022. https://www.regeneron.com/downloads/dupixent_fpi.pdf

22. Adbry. Prescribing information. Leo; 2021. Revised January 2022. Accessed June 23, 2022. https://www.leo-pharma.us/Files/Billeder/US Website Product PIs/AdbryPI.pdf

23. Amgen. Pipeline rocatinlimab. Published April 27, 2022. Accessed June 23, 2022. https://www.amgenpipeline.com/-/media/Themes/Amgen/amgenpipeline-com/amgenpipeline-com/PDF/amgen-pipeline-chart.pdf

24. Lilly's lebrikizumab combined with topical corticosteroids showed significant improvements in disease severity for atopic dermatitis. News release. Lilly. April 11, 2022. Accessed June 23, 2022. https://investor.lilly.com/news-releases/news-release-details/lillys-lebrikizumab-combined-topical-corticosteroids-showed

25. Galderma advances phase 3 clinical study with nemolizumab in moderate-to-severe atopic dermatitis. News release. Galderma. October 10, 2019. Accessed June 23, 2022. https://www.galderma.com/news/galderma-advances-phase-3-clinical-study-nemolizumab-moderate-severe-atopic-dermatitis

26. Furue M, Hashimoto-Hachiya A, Tsuji G. Aryl hydrocarbon receptor in atopic dermatitis and psoriasis. Int J Mol Sci. 2019;20(21):5424. doi:10.3390/ijms20215424

27. Rathod DG, Muneer H, Masood S. Phototherapy. In: StatPearls. StatPearls Publishing; May 8, 2022. https://www.ncbi.nlm.nih.gov/books/NBK563140/

28. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis: section 1. diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351. doi:10.1016/j.jaad.2013.10.010

29. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71(2):327-349. doi:10.1016/j.jaad.2014.03.030

30. Sidbury R, Tom WL, Bergman JN, et al. Guidelines of care for the management of atopic dermatitis: section 4. prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol. 2014;71(6):1218-1233. doi:10.1016/j.jaad.2014.08.038

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