What is the role of topical non-corticosteroids for atopic dermatitis/eczema?

Atopic Dermatitis and Treatment with Topical Non-corticosteroids

Atopic dermatitis, also referred to as “atopic eczema,” is the most common form of eczema in which an individual has an overactive immune system, causing the skin to become pruritic and dry. Globally, it is found to affect up to 20% of children and 3% of adults. Clinical manifestations of atopic dermatitis include erythema, dry patches, rashes that may ooze or weep clear fluid and bleed when scratched, and hardening and thickening of the skin. Depending on the individual’s age, the appearance and the location of the rash varies; however, during a flare-up, these symptoms can appear anywhere on the body. For instance, in infants and up to 2 years of age, these rashes are often located on the face, scalp, and flexural surfaces of the skin where skin touches upon bending of the joints (i.e. inside the elbows and behind the knees). During childhood between 2 years of age to puberty, atopic dermatitis can exist on elbows and knees, neck, and ankles. In adolescents and adults, it may appear on the hands, neck, elbows and knees, skin around the eyes, and the ankles and feet. It is important to note that pruritus from atopic dermatitis may lead to a viscous itch-scratch cycle, which further compromises the epidermal barrier, leading to the skin’s water loss, dryness, microbial colonization, and secondary infection. Thus, adherence to both pharmacological and non-pharmacological therapy is crucial in managing atopic dermatitis and to prevent complications.

The cause of atopic dermatitis is unknown, however there is an understanding that loss of moisture negatively affects the protective layer of the skin, making it more susceptible to dryness that can lead to damaged and inflamed skin. Scratching as a result of inflammation and dryness further destroys the skin barrier, putting the individual at risk for bacterial infection. Changes in skin barrier that may result in atopic dermatitis include genetic mutations, immune system dysfunction, environmental triggers such as exposure to tobacco smoke, air pollutants, particular fragrances and compounds found in skin products and soaps, and genetics. Those with a family history of this skin condition are at a higher risk of developing atopic dermatitis. Genetically, a defect in the keratin protein and structural components (i.e. ceramides, filaggrin, lipids) that support the epidermal barrier and natural moisturization of the skin may lead to increased trans-epidermal water loss. Further, epidermal barrier dysfunction contributes to greater allergen absorption into the skin and microbial colonization, resulting in skin infection. One of the important proteins that play a role in atopic dermatitis is filaggrin (FLG). Filaggrin is a protein important in providing epidermal structure and helps with the formation of corneocytes, which are differentiated keratinocytes that compose most of the stratum corneum, the outermost layer of the epidermis. They are essential for skin barrier function. Mutations in the gene encoding FLG may result in atopic dermatitis due to epidermal dysfunction and reduced barrier function. Moreover, it has been shown that inflammation and cellular responses in atopic dermatitis lead to the downregulation of FLG expression, further disrupting the skin barrier. Cutaneous immune dysregulation induced by mechanical injury (i.e. scratching or atopic skin trauma) can result in atopic dermatitis. This results in the formation of Th2 CD4 helper cells followed by inflammatory cytokines (IL-4, IL-5, IL-13, IL31) which downregulate filaggrin and antimicrobial peptides, recruit eosinophils, and disrupt the skin barrier.

Medications used to treat atopic dermatitis include topical prescription steroids of varying strengths, calcineurin inhibitors, PDE4 inhibitors, and janus kinase (JAK) inhibitors. The goal of therapy is to restore the skin’s barrier function, provide proper skin hydration, control itching, and prevent or treat skin infections. Topical corticosteroids are considered first-line therapy for the management of atopic dermatitis, however it is associated with serious adverse side effects, which include skin atrophy, telangiectasia, striae, and systemic absorption affecting the hypothalamic-pituitary adrenal axis. There exists a risk of relapse upon abrupt discontinuation. Due to patient and caregiver concerns of topical corticosteroid use, nonadherence is an issue. Thus, alternative topical non-corticosteroids that can be used are topical calcineurin inhibitors, pimecrolimus and tacrolimus. These are immunosuppressive agents that suppress T-cell activation and reduce cytokine production at the dermatitis site. Advantages of topical calcineurin inhibitors compared to topical corticosteroids include less skin atrophy and ocular adverse effects. Disadvantages are costliness and side effects of burning and stinging at the application site. There is a black box warning for potential malignancy risk.

It is FDA-approved for the treatment of atopic dermatitis as the following:

• Tacrolimus 0.1% ointment: Children ≥ 16 years of age and adults (mod-severe)

• Tacrolimus 0.03% ointment, Pimecrolimus 1% cream: Children ≥ 2 yrs of age and adults (mild to mod)

-Applied twice a day

-AE:burning and stinging

Another medication is the PDE4 inhibitor that was FDA approved in 2016, crisaborole. Phosphodiesterase 4 is an intracellular mediator of inflammation. It degrades cAMP, and as a result of decreased cAMP, it leads to production and release of proinflammatory cytokines and chemokines (IL-2, IL-4, and IL-31). PDE4 is overexpressed in atopic dermatitis resulting in inflamed skin. Crisaborole is a PDE4 inhibitor thereby decreasing cytokine production as well as preventing and treating atopic dermatitis flares. It is indicated for the use of mild to moderate atopic dermatitis in children 2 years and older when topical corticosteroids cannot be used or not effective. It is available as a 2% ointment and is applied twice a day with a thin layer. It clears lesions and improves pruritus. Adverse effects include pain, burning, and stinging at the application site.

Cytokines following the chemical signal pathway, janus kinase-signal transducer and activators of transcription (JAK-STAT) pathway, play a role in inflammation in atopic dermatitis. Thus, JAK inhibitors target the JAK-STAT pathway, thereby blocking immune signals and inhibiting cytokine-induced inflammation. Topical JAK inhibitors on the market work by blocking JAK1 and JAK2, which are enzymes involved in cytokine-induced inflammation that result in inflamed, itchy skin. JAK inhibitors reduce itch, rash, and skin redness. Opzelura (Ruxolitinib 1.5%) cream is a topical selective JAK inhibitor indicated for short-term and non-continuous treatment of atopic dermatitis in non-immunocompromised adults and pediatric patients 12 years of age and older in which other topical prescription therapies failed or is contraindicated.

It is important to manage atopic dermatitis not only to improve skin barrier and prevent flare-ups and complications (i.e. bacterial skin infection), but also to improve the individual’s quality of life.

References

“Atopic Dermatitis.” National Institute of Arthritis and Musculoskeletal and Skin Diseases, 9 Jan. 2023, www.niams.nih.gov/health-topics/atopic-dermatitis.

Brian S Kim, MD. “Atopic Dermatitis Treatment & Management.” Medical Care, Consultations, Diet, 13 Feb. 2023, emedicine.medscape.com/article/1049085-treatment.

McPherson, Tess. “Current Understanding in Pathogenesis of Atopic Dermatitis.” Indian Journal of Dermatology, Dec. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5122281/.

Papier, Ariana, and Lindsay C Strowd. “Atopic Dermatitis: A Review of Topical Nonsteroid Therapy.” Drugs in Context, 3 Apr. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC5886549/.

“What Are Topical Treatments for Eczema and How Should They Be Used?” National Eczema Association, 4 Mar. 2022, nationaleczema.org/eczema/treatment/topicals/.

“What Is Eczema?” National Eczema Association, 2 Dec. 2022, nationaleczema.org/eczema/.

Eczema is also known as atopic dermatitis and is a term that is used generally for a wide range of skin inflammation types. Albeit it is most common in young children and infants, eczema can occur at any age. It presents in crusty and scaly skin rashes in which blisters can develop. The rash itself is itchy, red, dry, and sore. Common sites for atopic dermatitis are behind the knees and ears, elbows, the face (particularly one’s cheeks), and the hands and feet. There are certain causes or “triggers” of eczema which include but are not limited to allergens (such as certain soaps and perfumes), pollution, environmental irritants, stress or even changes in the weather. In summary, the causes of atopic eczema remain unknown but are seemingly multifactorial and is a chronic inflammatory skin eruption that typically starts early in life. The basic treatment of eczema (non-pharmacological treatment) include hydration and the use of moisturizers/emollients.

Pharmacological treatment includes but is not limited to topical steroids such as triamcinolone acetonide 0.1% cream (and occasionally oral steroids but only if needed), antihistamines (for itching/pruritus), or even immunosuppressant calcineurin inhibitors but only if if the use of topical steroids with hydration are not adequate. Topical calcineurin inhibitors (TCIs) work by altering the immune system and there are two types that have been developed for treating atopic eczema. One example is tacrolimus ointment (Protopic) which is for moderate to severe eczema and the second example is pimecrolimus cream (Elidel) which is for mild to moderate eczema. Improvement in eczema flare-ups should be seen in two weeks and six weeks respectively for these two examples of TCIs. An alternative to topical steroids is Eucrisa (crisaborole) ointment. This medication is manufactured by Pfizer and it’s initial U.S. approval was in 2016. It is unique in the sense that it is a non-steroidal treatment that serves as a very suitable alternative to patients who want to avoid continuous use of steroids whether it is topical or oral. The one major downside to Eucrisa is that it is a significantly pricier alternative to topical steroids as it is only available as a brand name medication now.

Indications and Usage- Eucrisa is a phosphodiesterase 4 inhibitor (also known as a PDE4 inhibitor) indicated for topical treatment of mild to moderate atopic dermatitis in adult and pediatric patients who are 3 months of age and older.

Dosage and Administration- Apply a thin, uniform layer of Eucrisa twice daily to affected areas, preferably once in the morning and once in the evening. Eucrisa is available solely as a 2% strength white to off-white ointment.

Mechanism of Action- Crisaborole is a phosphodiesterase 4 inhibitor (PDE4 inhibitor). PDE4 inhibition will result in an increase of intracellular cyclic adenosine monophosphate (cAMP) levels. The specific possible mechanism(s) by which crisaborole exerts its therapeutic action for the treatment of atopic dermatitis has not yet been well defined.

Adverse Reactions- Application site pain (which is defined as skin sensations such as burning or stinging) have been observed in 4% of patients in clinical trials.

References-

Eucrisa- Package Insert.

http://labeling.pfizer.com/ShowLabeling.aspx?id=5331

Lee, Hyun Ji, Son, Wook Sag, et al. A Comprehensive Review of the Treatment of Atopic Eczema. Allergy, Asthma, and Immunology Research. 2016, May. 8 (3): 181-190.

RxPrep NAPLEX Review 2021. Chapter 39: Common Skin Conditions. Page 578.

Many parents are concerned with the side effects of topical corticosteroids, especially for children as they are more prone to develop systemic side effects when potent corticosteroids are used on their sensitive skin, enhancing capacity for absorption. Topical corticosteroids that are needed to be administered over large surface areas, in large quantities, and used for prolonged periods of time, another alternative is preferred.

One of the topical-corticosteroids to treat atopic dermatitis/ eczema is Eucrisa. This was approved on December 14, 2006, for the treatment of mild to moderate eczema/atopic dermatitis in patients two years of age and older. While the mechanism of action of the drug for atopic dermatitis is not known, it is a phosphodiesterase 4 (PDE-4) inhibitor.

Trial:

The safety and efficacy of Eucrisa were established in two placebo-controlled trials with a total of 1,522 participants ranging in age from two years of age to 79 years of age, with mild to moderate atopic dermatitis. Overall, participants receiving Eucrisa achieved greater response with clear or almost clear skin after 28 days of treatment.

https://nationaleczema.org/eczema/treatment/topicals/steroidsfaq/

https://www.fda.gov/news-events/press-announcements/fda-approves-eucrisa-eczema

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228634/