Emollients

Moisturizers and emollients play a crucial role in improving barrier function, providing adequate hydration, reducing skin inflammation, decreasing the frequency of flares, and minimizing the need for topical corticosteroids (TCS). They also help maintain clinical remission achieved with other active treatments. Therefore, emollients are recommended for all cases of AD, regardless of severity or disease activity. They typically contain humectants, such as urea or glycerol, which promote hydration of the stratum corneum, and occlusives, such as lipids or petrolatum, which reduce water evaporation.^[2] Prescription emollient devices (PEDs) are specialized topical formulations designed to restore the skin barrier in AD by mimicking the natural lipid composition of the stratum corneum. They often contain:

1. Physiologic lipids (ceramides, cholesterol, and free fatty acids) in optimal ratios (3:1:1)

2. Anti-inflammatory agents (e.g., furfuryl palmitate and antioxidants)

3. Non-steroidal and non-immunosuppressive components.

Hebert (2022) conducted a real-world, post-marketing surveillance study evaluating a furfuryl palmitate-containing PED in 134 patients (pediatric to adult) with atopic or contact dermatitis over 28 days. The study reported a treatment success rate of 87.5%, with pruritus improving in 90.6%, skin irritation in 91.3%, and dryness in 90.9% of patients.^[3]

Ceramides

Ceramides are lipid molecules that make up a major component of stratum corneum and are essential for maintaining the skin’s barrier function and preventing transepidermal water loss (TEWL). In individuals with AD, ceramide levels are significantly reduced, leading to impaired barrier function, increased skin dryness, and susceptibility to allergens and irritants. This deficiency contributes to inflammation, pruritus, and the chronic-relapsing nature of the disease.

Topical formulations containing ceramides have been developed to restore the skin barrier and are now considered a key part of maintenance therapy in AD. These ceramide-based moisturizers replenish lost lipids, reduce TEWL, and improve hydration, thereby reducing flare-ups, the need for TCS, and extending the period of remission.

A systematic review and meta-analysis by Nugroho et al. (2023) analyzed five articles, which evaluated the efficacy of ceramide-containing moisturizers compared to other moisturizers in managing AD.^[4] Ceramide-containing moisturizers demonstrated a statistically significantly greater reduction in SCORing AD (SCORAD) scores. The mean difference was -0.98 (95% CI: -1.63 to -0.33; p = 0.003), indicating enhanced efficacy in reducing AD severity.^[4] Overall, ceramides offer a safe, effective, and steroid-sparing option in the long-term management of AD.^[5]

Cleansing

Cleansing should be a routine part of AD care, particularly in cases with prominent oozing. For crusted lesions, the skin should be gently cleansed to remove crusts, allergens, and contaminants. Non-irritant, non-allergenic products that help preserve skin barrier function and maintain optimal pH (5.5-6) and lipid metabolism are recommended. Non-soap aqueous cleansers or syndets are preferred. Daily short baths lasting less than 5 minutes using lukewarm water, followed by gentle drying with a soft cloth, are ideal.

Emollients should be applied immediately afterward while the skin is still damp to lock in moisture and enhance barrier repair [Table 1].^[6]

Bleach bath

Bathing in dilute bleach (sodium hypochlorite; NaOCl) is a common adjunctive treatment for AD. Administration of this treatment includes 1/4 to 1/2 cup of 5% to 6% bleach in a full bathtub (~40 gallons of water) for a final concentration of ~0.005%, applied for 10 minutes, 2-3 times per week. Ensure the bath duration does not exceed 10 minutes. Rinse thoroughly with fresh water afterward and apply moisturizer immediately.

By reducing the Staphylococcus aureus colonization, which is a common bacterium that exacerbates the inflammation in AD, it helps to:

1. Decrease inflammation triggered by bacterial toxins and superantigens

2. Improve skin barrier function by reducing bacterial-induced skin damage

3. Reduce flare frequency and severity of AD.^[7,8]

Wet wrap therapy

Wet wrap therapy is a useful treatment approach for moderate-to-severe AD. It involves the application of layers of bandages or cotton over topical medications, offering cooling, anti-inflammatory, and antipruritic effects. This method enhances skin hydration and provides a protective barrier against external allergens. Two standardized techniques are commonly followed. The first is the double-layer wet wrap, where an inner wet layer and an outer dry layer are applied over a topical cream or ointment. The second method involves applying diluted corticosteroids to the inner layer, followed by a dry outer layer. Both techniques typically begin with a 10-15-minutes bath and are recommended to be performed 2-3 times daily. While wet wrap therapy is effective, it can be time-consuming and requires thorough education for caregivers or parents. Potential drawbacks include skin maceration, folliculitis, and the risk of local or systemic corticosteroid side effects, especially if steroidimpregnated wraps are used for prolonged periods.^[9]

Janus Kinase (JAK) inhibitors

JAK inhibitors are a class of intracellular tyrosine kinase inhibitors that target JAK 1, 2, 3, and TYK2, acting by inhibiting the JAK-STAT signaling pathway. They have shown promise in the treatment of AD by reducing inflammation and improving skin barrier function.

Delgocitinib

Delgocitinib is the first topical pan-JAK inhibitor studied in AD. It works by inhibiting the activation of various inflammatory cells, including B- and T-cells, while also improving barrier function. Three randomized phase 3 trials have been conducted till date for evaluating the safety and efficacy of this drug. One of the studies (JapicCTI-184064), conducted on 2-5 5-year-old patients, showed improvement in modified eczema area and severity index (mEASI). mEASI 50 and mEASI 75 were achieved by 50.7% and 37.7% of the patients, respectively, in the first 4 weeks. Improvement in mEASI, Investigator’s Global Assessment (IGA), and pruritus numeric rating scale (NRS) scores were maintained through week 56.^[13] Adverse events were generally mild, with nasopharyngitis being the most common, followed by local side effects such as folliculitis and acne.

Ruxolitinib

Ruxolitinib is a first-generation, potent JAK 1/2 inhibitor currently FDA-approved for topical use in patients aged >12 years with mild-to-moderate chronic AD who are not immunocompromised. It primarily inhibits IL-33, Th2 proteins, and interferon-induced transmembrane protein 3. The drug is available as a 0.75% and 1.5% cream. A large phase 3 trial with both the formulations showed improvement of 40-50% in IGA score with 0.75% cream and around 50% improvement with 1.5% cream at week 8. EASI75 was achieved by around 50% of the patients on 0.75% cream, and around 60% on 1.5% cream. The adverse effects were mild, with the most common being a burning sensation, upper respiratory tract infections, nasopharyngitis, and influenza.^[14]

Tofacitinib

Tofacitinib is a JAK 1/3 inhibitor evaluated in a phase 2a randomized trial in adults for mild-to-moderate AD. Th2 immune response is central in pathogenesis of AD, and IL-4 is the key cytokine involved in Th2 differentiation. JAK 1/3 inhibition caused a decrease in IL-4, thereby decreasing the Th2 immunity and causing improvement of the disease.^[8] After 4 weeks of treatment, an improvement in EASI scores of 81.7% was observed compared to the vehicle. Additionally, improvements in the physician’s global assessment and body surface area (BSA) scores were noted after 3 months of use. Its safety profile was comparable to other drugs in the JAK inhibitor group.^[15]

Brepocitinib

Brepocitinib, a JAK 1/TYK2 inhibitor, was tested in a large-scale phase 2 study in patients with mild-to-moderate AD. It is available in 0.1%, 0.3%, 1%, and 3% cream formulations and was tried once and twice daily regimens. Improvements in EASI by around 70% and IGA scores by 29.7-44% were observed after 6 weeks of treatment.^[16]

Other JAK Inhibitors

Newer agents, such as ATI-1777, are soft JAK inhibitors that exert their effect only at the site of application and undergo rapid metabolism in systemic circulation, minimizing systemic exposure. These are currently in phase 2 trials, and a 74.4% reduction in mEASI in the drug group has been reported with no adverse events to date.^[17]

Ifidancitinib, a JAK 1/3 inhibitor, has completed phase 2 trials in patients over 18 years with moderate to severe AD. However, its use in pediatric patients has not yet been established.^[18] JAK inhibitors currently being tried in pediatric AD are shown in Table 3.

Phosphodiesterase-4 (PDE4) inhibitors

PDE4 inhibitors have recently emerged as a promising treatment for AD. They primarily act by increasing cyclic adenosine monophosphate levels, which negatively regulate pro-inflammatory cytokines such as IL-4, IL-5, IL-10, IL-13, and prostaglandin E2, all of which play a role in AD pathogenesis.

Crisaborole

Crisaborole is the first topical PDE4 inhibitor approved by the FDA for the treatment of mild-to-moderate AD in children aged 3 months and older. Clinical trials have demonstrated around 30% improvement in pruritus and ISGA scores, along with a favorable safety profile.^[19] The most commonly reported adverse effects include localized pain and a burning sensation at the application site.

Other PDE4 inhibitors

Topical roflumilast 0.15% cream has been evaluated in pediatric patients with AD and has shown significant improvement in pruritus, as evidenced by reductions in the NRS score. Further studies are needed to establish its long-term efficacy and safety.^[20] Various PDE4 inhibitors that are currently being used in pediatric AD are shown in Table 4.^[21,22]

Aryl hydrocarbon receptor (AhR) agonists

AhRs are highly expressed in the skin and play a crucial role in epidermal differentiation by upregulating proteins such as filaggrin and involucrin. Activation of these receptors helps maintain skin barrier function, homeostasis, and the skin’s response to external factors.^[23]

Tapinarof

Tapinarof is a novel AhR agonist with additional antioxidant properties. It also inhibits interleukins IL-17 and IL-22, which are involved in inflammation. A large-scale randomized controlled trial was conducted in patients aged 12-65 years with mild-to-moderate AD. The study evaluated the efficacy of 0.5% and 1% tapinarof cream. Around 50% improvement in IGA score in the 1% cream group and around 30% in the 0.5% group was observed after 3 months of treatment. EASI75 was higher (around 50-60%) in both groups.^[24]

Adverse effects were reported in approximately half of the patients, with nasopharyngitis being the most common. Less frequent side effects included folliculitis, acne, and disease flare-ups. Some patients experienced transient elevations in liver enzymes and electrocardiogram changes, which resolved following treatment. Overall, tapinarof appears to be a promising topical therapy for AD, offering a novel mechanism of action with a favorable efficacy and safety profile.^[25]

Transient receptor potential vanilloid 1 (TRPV1) antagonists

TRPV1 receptors play a crucial role in pruritus, barrier function, and inflammation. These receptors are overexpressed in AD lesions, where they contribute to the release of inflammatory molecules that exacerbate itching and skin irritation.^[26]

Asivatrep

Asivatrep, a TRPV1 antagonist, has demonstrated significant efficacy in managing AD symptoms. A phase 3 clinical study conducted in patients aged 12-70 years reported substantial improvement in IGA score by around 40% and EASI score by around 50% after 8 weeks of treatment. Adverse effects were minimal, with nasopharyngitis being the most common, similar to other topical agents. Importantly, no serious adverse events were reported, making asivatrep a promising new option for AD treatment.^[27]

Skin microbiome modulators

Cutaneous dysbiosis, or the imbalance of skin microbiota, is a hallmark of AD. Patients with AD often exhibit an overgrowth of S. aureus and a decreased presence of beneficial bacterial species. This microbial imbalance has been associated with more severe disease manifestations, elevated IgE levels, eosinophil counts, and lactate dehydrogenase levels, all of which contribute to disease exacerbation.^[28,29]

Roseomonas mucosa

Roseomonas mucosa, a Gram-negative bacterium commonly found in healthy skin, has been investigated for its role in restoring microbial balance. In a study involving children aged 9-14 years, twice-weekly topical application of Roseomonas mucosa resulted in significant improvements in SCORAD scores and pruritus symptoms. Reported adverse effects were mild, making it a promising adjunct therapy for AD.^[30]

Other microbiome-based therapies

Other beneficial bacterial species, including Staphylococcus hominis and Nitrosomonas eutropha, are currently being evaluated in phase 1 and 2 clinical trials. These studies have demonstrated encouraging improvements in EASI and SCORAD scores, although further research is needed to assess their long-term benefits and sustainability.^[31,32]

Antimicrobial peptide (AMP)-based treatments

Patients with AD also exhibit reduced production of AMPs, leading to increased susceptibility to infections. Indolicidin, an AMP derived from bovine neutrophils, has been synthesized into omiganan gel, which has both antimicrobial and immunomodulatory properties.^[33] Clinical improvement with omiganan gel was mild, with improvement of only 2.5% in BSA, SCORAD, and pruritus, but restoration of the skin microbiome and reduced infection rates were reported.^[34] However, due to its limited efficacy in reducing inflammation, it is unlikely to be used as a monotherapy.

Newer emollients and barrier repair therapies

Intensive daily moisturization is an essential component of AD management. Recent advances in non-medicated therapeutic emollients have introduced formulations that not only improve skin barrier function but also offer antipruritic, antioxidant, and immunomodulatory effects.

Key active ingredients

1. Ceramides: Restore lipid composition and strengthen the skin barrier.

2. Saponins: Possess anti-inflammatory and antioxidant properties.

3. Bacterial lysates (Aquaphilus dolomiae and Vitreoscilla filiformis): Modulate immune responses and support microbial balance.^[35,36]

Newer molecules

Many other molecules are being tried in the topical treatment of AD, but the results have not yet been published, and the trials are still ongoing. Their use in the pediatric age group has not yet been established [Table 5].^[38-41]

A concise table comparing the topical therapies in pediatric AD according to the European, American, and Korean guidelines, along with the level of evidence, has been depicted in [Table 6].^[42,43]