Can We Do More for Topical Therapy in Pediatric Atopic Dermatitis?

Most recently in 2021, The National Center for Health Statistics reported a quarter of children in the United States possessed one or more allergic conditions.¹ These included seasonal allergy, food allergy, and eczema.¹ Pediatric atopic dermatitis (AD), also known as eczema, affects 1 in 10 children in the United States.¹ AD is characterized by itch, rash, and thickened skin, which may appear on any area of the body.² Its overall course may wax and wane with times of mild or severe skin disease.² Diagnosis is typically made by a pediatrician or pediatric dermatologist who will encourage the use of moisturizers as the mainstay of non-pharmacologic therapies.³

However, as eczema worsens families have the option of both topical and systemic therapies. Topical therapies are utilized as first line treatment options and are encouraged to be optimized prior to pursuing systemic therapies.³ Families of children with AD may feel more comfortable with topical therapies, so it is important to provide patients a thorough action plan outlining appropriate use of these medications.

Since the 1960s, topical corticosteroids (TCS) have been utilized in eczema, demonstrating its efficacy as well as cost-effectiveness. During active flares, twice daily application is recommended, and may be reduced to once or twice weekly in times of maintenance therapy.³ These agents act as immunosuppressants of skin inflammation.³ Rates of adverse effects (AEs) are low, however, thinning of the skin, hypopigmentation, and the appearance and leakage of small vessels under the skin are possible with inappropriate use.³

Keeping parents informed of TCS’ place in therapy for controlling flares is critical to better managing AD. TCS sparing agents such as topical calcineurin inhibitors (TCI) and crisaborole (Eucrisa, Pfizer Labs) play a role during times of less severe flares, combination, or maintenance therapy.3 Calcineurin inhibitors, such as tacrolimus or pimecrolimus, became available in the early 2000s, and provide an anti-inflammatory option in settings where there are concerns for TCS adverse effects.^3-5 Approved for patients 2 years of age and older, these agents carry boxed warnings for skin malignancy and lymphoma.^4,5 However, exact causal relationships have not been established.³ Twice daily application is encouraged during flares, and may be reduced to twice or 3 times weekly administration in stable disease.³ Although an effective therapeutic option for AD, TCS has AEs that can include incidence of a burning sensation on application.³ This presents as a barrier in children and can cause difficulty when encouraging continued use. Therefore, if intolerable, other therapies may be explored.

Crisaborole is a phosphodiesterase inhibitor introduced in 2016 for infants 3 months of age and older with mild to moderate atopic dermatitis.⁶ Twice daily administration is encouraged and may be reduced to once daily during remission.³ It presents as a favorable option in regards to its AE profile with less burning, pain, and irritation on application.³

Most recently, ruxolitinib (Opzelura, Incyte Corporation) cream, a topical janus kinase inhibitor (JAKi), was introduced in 2021 as a new approach for treating AD.⁷ Oral ruxolitinib for the treatment of myelofibrosis became the first FDA approved JAK inhibitor in 2011.⁸ These agents target the JAK-STAT pathway by modulating the expression of signaling molecules playing a key role in inflammation and autoimmune diseases.⁸ Topical ruxolitinib is approved for use in mild to moderate atopic dermatitis in children twelve years of age and older.⁷ Recommended application is at least twice daily where the affected area should not exceed greater than 20% total body surface area.⁷ Following a trial of 8 weeks, if signs and symptoms are not resolved; patients are to be reexamined by their provider.⁷ In phase 3 trials, significantly more patients achieved a global assessment of clear or almost clear with 1.5% ruxolitinib cream versus vehicle at week 8.⁷ Yet with this pathway, various AEs and precautions do exist. A boxed warning is present for serious infections, mortality, malignancy, major cardiovascular events, and thrombosis.⁷ Further, these warnings are highly associated with oral JAKs due to systemic absorption.³ Common AEs with topical ruxolitinib include application-site erythema, application-site pruritus, and local acne eruptions.⁷

Application of these agents begin by following the general recommendations to use a fingertip quantity. This is the standard unit for an adult and the equivalent of 0.5 g.⁹ However, this recommendation should be adjusted for infants, children, and adolescents. Specifically, infants require one-fifth of the adult dose, children two-fifths, and adolescents two-thirds.¹⁰ Additionally, families are encouraged to clarify application instructions with their clinicians, which may vary depending on the area affected and treatment formulation (eg, cream, ointment, or oil).

Understanding the importance of topicals assists parents in making informed decisions regarding treatment therapy. Frequency and consistency of application during flares and instruction for maintenance therapy is paramount. Prior to making a decision around systemic therapy, its key for clinicians to discuss which topical agents should be used at various states of eczema.

Prior to making a decision around systemic therapy, its key for clinicians to discuss which topical agents should be used at various states of eczema. Image Credit: © Марина Терехова - stock.adobe.com

Future innovations within the scope of pediatric eczema are anticipated. Currently, tapinarof (Vtama, Dermavant Sciences Inc) 1% cream and roflumilast (Zoryve, Arcutis Biotherapeutics Inc) 0.05% cream, are both FDA approved for plaque psoriasis and in phase 3 clinical trials for pediatric eczema.^11-14 These agents will hopefully provide additional options to further optimize topical therapy prior to parents and clinicians pursuing systemic agents.

References

1. Zablotsky B, Black LI, Akinbami LJ. Diagnosed Allergic Conditions in Children Aged 0–17 Years: United States, 2021; 2023. doi:10.15620/cdc:123250
2. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis. Journal of the American Academy of Dermatology. 2014;70(2):338-351. doi:10.1016/j.jaad.2013.10.010
3. Sidbury R, Alikhan A, Bercovitch L, et al. Guidelines of care for the management of atopic dermatitis in adults with topical therapies. Journal of the American Academy of Dermatology. 2023;89(1):e1-e20. doi:10.1016/j.jaad.2022.12.029
4. Elidel (pimecrolimus) [prescribing information]. Bridgewater, NJ: Bausch Health US, LLC; September 2020. Accessed November 8, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021302s018lbl.pdf
5. Protopic (tacrolimus) [prescribing information]. Madison, NJ: LEO Pharma Inc.; February 2019. Accessed November 8, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/050777s018lbl.pdf
6. Eucrisa Ointment 2% (crisaborole) [prescribing information]. New York, NY: Pfizer Labs; April 2023. Accessed November 8, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207695s007s009s010lbl.pdf
7. Opzelura (ruxolitinib) [prescribing information]. Wilmington, DE: Incyte Corporation; January 2023. Accessed November 8, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215309s001lbl.pdf
8. Shawky AM, Almalki FA, Abdalla AN, Abdelazeem AH, Gouda AM. A comprehensive overview of globally approved JAK inhibitors. Pharmaceutics. 2022;14(5):1001. doi:10.3390/pharmaceutics14051001
9. Oishi N, Iwata H, Kobayashi N, Fujimoto K, Yamaura K. A survey on awareness of the “finger-tip unit” and medication guidance for the use of topical steroids among community pharmacists. Drug Discoveries and Therapeutics. 2019;13(3):128-132. doi:10.5582/ddt.2019.01007
10. Nelson AA, Miller A, Fleischer AB, Balkrishnan R, Feldman SR. How much of a topical agent should be prescribed for children of different sizes? Journal of Dermatological Treatment. 2006;17(4):224-228. doi:10.1080/09546630600894998
11. Vtama (tapinarof) [prescribing information]. Long Beach, CA: Dermavant Sciences Inc; May 2022. Accessed November 8, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215272s000lbl.pdf
12. Zoryve (roflumilast) [prescribing information]. Westlake Village, CA: Arcutis Biotherapeutics Inc; October 2023. Accessed November 8, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215985s000lbl.pdf
13. Dermavant Reports Positive Topline Results from ADORING 2 Atopic Dermatitis Phase 3 Trial of VTAMA® (tapinarof) Cream, 1% Once Daily in Adults and Children as Young as 2 Years Old. Dermavant Sciences. https://www.dermavant.com/dermavant-reports-positive-topline-results-from-adoring-2-atopic-dermatitis-phase-3-trial-of-vtama-tapinarof-cream-1-once-daily-in-adults-and-children-as-young-as-2-years-old/.
14. Arcutis Announces Positive Results from INTEGUMENT-PED Pivotal Phase 3 Trial of Roflumilast Cream 0.05% for the Treatment of Atopic Dermatitis in Children Ages 2 to 5. News release. Arcutis. Accessed November 6, 2023. https://www.arcutis.com/arcutis-announces-positive-results-from-integument-ped-pivotal-phase-3-trial-of-roflumilast-cream-0-05-for-the-treatment-of-atopic-dermatitis-in-children-ages-2-to-5/