FormalPara Key Summary Points

AD pathogenesis is heterogeneous; though T helper 2 (TH2) inflammation is common to all AD patients, the role of additional immune endotypes with specific potentially targetable cytokines, small molecules, and pruritogens have yet to be fully clarified.

Newly FDA-approved agents for pediatric AD include topical crisaborole (PDE4 inhibitor), topical ruxolitinib (JAK 1/2 inhibitor), oral upadacitinib (JAK 1 selective inhibitor), and injected dupilumab (anti-IL-4/13 monoclonal antibody), though phase 2 and 3 trials support the use of additional topical PDE4 inhibitors and an aryl hydrocarbon receptor agonist (tapinarof), topical and oral JAK inhibitors, and the injectable biologic treatments anti-IL-13 tralokinumab/anti-IL-13Rα lebrikizumab and anti-IL-31Rα nemolizumab in pediatric AD. Many of these medications are not universally available and cost may prohibit use.

Treatment selection for AD in pediatric populations depends on patient age/weight, body surface area affected, medical comorbidities, quality of life, and response to other treatments as well as cost and availability/approval of pharmacologic agents in the locality of the patient.

On the basis of current evidence and whether these medications in the pediatric AD arsenal are available, we recommend an approach of treating mild–moderate AD with topical corticosteroid or a steroid-sparing topical (topical calcineurin inhibitor, PDE4 inhibitor, or JAK inhibitor); dupilumab may be considered for refractory moderate–severe pediatric AD in patients who fail topical or other conventional therapy where it is approved and available. Systemic JAK inhibitors (such as upadacitinib) may be utilized for patients who fail to respond to dupilumab with refractory severe symptoms. The availability and ages of approval for these systemic agents vary across countries. Often concomitant use of topicals and systemic therapies is effective for moderate–severe disease.

Head-to-head trials including pediatric patients are necessary to further elucidate the role of emerging treatments in pediatric AD.

Introduction

Atopic dermatitis (AD) is a chronic dermatitis affecting 15–20% of children [1]. Though AD pathogenesis is heterogeneous, a “one-size-fits-all” often guides treatment [2]. Topical corticosteroids (TCS) and calcineurin inhibitors (CNIs) are typical first-line agents for mild–moderate AD with subsequent escalation to phototherapy or systemic immunosuppression with cyclosporine, azathioprine, methotrexate, or mycophenolate mofetil for refractory/severe cases [3]. New targeted treatments are now available. These treatments pose a challenge to practicing dermatologists as there are few head-to-head trials to guide treatment decisions. In this review, we discuss new/emerging therapeutics in pediatric AD and propose an updated treatment approach. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. The authors acknowledge that therapeutics discussed may not yet be approved for the same age groups in all countries or available in all countries.

Although knowledge of AD pathophysiology is expanding, the multifactorial nature is not fully understood. Barrier dysfunction, genetic factors, immune dysregulation, microbiome dysbiosis, and environmental exposures are implicated. Epidermal barrier disruption by external factors (allergens or irritants) promotes expression of immune alarmins interleukin (IL)-1β, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). IL-1β and IL-33 induce a T helper 2 (TH2) response with production of IL-4, IL-5, and IL-13 cytokines. These TH2 cytokines promote further TH2 polarization [4]. TSLP activates the TH2 pathway indirectly via stimulation of dendritic cell OX40 ligand (OX40L) expression, which activates T cells by binding OX40. IL-33 and OX40L stimulate production of pruritogenic IL-31. A cyclic inflammatory cascade whereby TH2 cytokines/chemokines promote further impairment of the epidermal barrier results. TH2 inflammation further weakens epidermal defenses by downregulating antimicrobial peptide (AMP) in response to environmental organisms, including Staphylococcus aureus [1, 5]. The TH2 activation pathway is common to all patients with AD. Increased TH17 signaling mediated by IL-36/IL-36 receptor and increased TH22 cells/IL-22 expression have been described. There is also emerging evidence that specific immune endotypes exist. Increased TH17 immunity was observed in infants, children, and Asian patients while increased TH1 immunity was observed in adults, but not pediatric patients [1]. The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway is shared by TH2, TH17, and TH1 cytokines. Itch pathways in AD are heterogeneous with potential for endogenous pruritogens (cytokines) or exogenous pruritogens (allergens, irritants, microbes) to stimulate unmyelinated nonhistaminergic dorsal root ganglia C-fiber neurons. IL-31, IL-33, and TSLP are direct pruritogens, while IL-4 and IL-13 indirectly upregulate the dorsal root ganglia signaling response [1, 5].

Topical Agents

Traditional topical treatments (TCSs and CNIs) risk potentially significant side effects, and CNIs still carry a black box warning of malignancy despite studies showing long-term safety in infants/children [6, 7]. Additional steroid-sparing agents are needed [8]. There are many topical treatments that completed or are in active trials for pediatric AD (Table 1).

Table 1 New and emerging topical treatments
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PDE4 Inhibitors

Elevated phosphodiesterase 4 (PDE4) in skin affected by AD results in decreased cyclic adenylate monophosphate (cAMP) levels and resultant increased proinflammatory cytokines. PDE4 inhibitors increase cAMP levels, thereby decreasing proinflammatory cytokines [9].

Crisaborole 2% ointment was the first PDE4 inhibitor studied for AD. Phase 3 randomized double-blind vehicle-controlled trials (RDBVCTs) (CrisADe CORE 1 and CrisADe CORE 2) of patients ≥ 2 years with mild–moderate AD demonstrated improved Investigator’s Static Global Assessment (ISGA) 0/1 scores with ≥ 2-grade improvement in 32.8%/31.4% of crisaborole-treated subjects compared with 25.4%/18% vehicle-treated subjects after 28 days [10]. This led to FDA approval for patients ≥ 2 years. A subsequent phase 4 open label (OL) study of infants ≥ 3 months–2 years (CrisADe CARE 1) demonstrated ISGA 0/1 with ≥ 2-grade improvement in 30.2% of patients, resulting in extended FDA approval for infants ≥ 3 months [11]. Application site reactions, though uncommon in original studies, were subsequently demonstrated in 32–50% of patients, with greater rates with facial application [12]. Crisaborole is not approved outside of the USA.

Difamilast is approved in Japan for AD patients ≥ 2 years with similar efficacy to crisaborole with few reports of application site discomfort [9, 13, 14]. There is an active phase 3 trial (NCT05372653) evaluating difamilast in infants ≥ 3 months–2 years.

Roflumilast (ARQ-151) failed to demonstrate a significant SCORing Atopic Dermatitis (SCORAD) improvement, but improved itch in a phase 2a adult trial [15]. One phase 3 RDBVCT of roflumilast including patients ≥ 6 years (INTEGUMENT I) was completed (NCT04773587), and additional phase 3 trials are active (NCT04773600, NCT04845620).

JAK Inhibitors

Topical JAK

The JAK family is composed of four cytoplasmatic tyrosine kinases: JAK1, JAK2, JAK3, and tyrosine kinase-2 (TYK2). Linked to transmembrane receptors, JAKs potentiate intracellular signaling of inflammatory mediators (interleukins/interferons) via STAT proteins [21, 22]. JAK phosphorylation causes STAT separation, dimerization, and translocation to the nucleus, where they induce gene transcription integral to immunity, proliferation, apoptosis, and differentiation [23]. Current understanding of AD emphasizes the role of TH2 IL-4, IL-5, IL-13, IL-31 and Th22 (IL-22) immune responses [24]. The JAK–STAT pathway mediates binding of key cytokines to promote inflammation and itch [4]. JAK1 is particularly important for TH2 cytokine signaling [25, 26]. Multiple JAK inhibitors have completed or are in active trials (Tables 1 and 2).

Table 2 New and emerging oral treatments
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Topical ruxolitinib (RUX) 1.5% is a JAK1/2 selective inhibitor. Two phase 3 trials (TRuE-AD1/AD2) in patients ≥ 12 years with mild–moderate AD demonstrated improvement in IGA 0/1 (54%/51% versus 15%/8%), higher rates of EASI-75 (62%/62% versus 25%/14%), and improved pruritus including itch reduction within 12 h of first application in RUX versus vehicle [27]. Results of TRuE-AD led to FDA approval in patients ≥ 12 years old in 2021. Notably, approval is limited to ≤ 20% BSA for 8 weeks. A subsequent phase 1 OL trial of RUX 1.5% cream revealed two patients of greater BSA involvement (45% and 90%) that exceeded the half maximal inhibitory concentration for JAK-mediated myelosuppression [28]. This study revealed potential benefit with use of topical RUX for higher % BSA, but demonstrated a risk of systemic absorption. Further research is needed to determine the upper limit of safe % BSA use. A phase 3 RDBVCT in children (TRuE-AD3) is recruiting (NCT04921969). Patients have found topical RUX to be an effective alternative with almost no reports of stinging/burning. Cost is the greatest hurdle to use.

Delgocitinib (DELGO) is a pan-JAK (JAK1/2/3 and TYK2) inhibitor approved in Japan for patients ≥ 2 years [29, 30]. Approval was based on a phase 3 RDBVCT in patients 2–15 years that demonstrated a decrease in the least squares mean percent change in modified EASI score with delgocitinib (−39.3% DELGO versus +10.9% vehicle) [31]. A phase 3 trial of patients ≥ 6–24 months was completed and topline results are positive [32]. In the USA, a phase 1 trial of delgocitinib was completed and included patients ≥ 2 years. Results are not available (NCT03826901), and there are no further active trials. Both topical RUX and delgocitinib are associated with minimal side effects. In the delgocitinib trials, two cases of eczema herpeticum were reported.

Topical brepocitinib (JAK1/TYK2) cream was evaluated in a phase 2 trial of adolescent patients ≥ 12 years (NCT03903822). In this study, patients using 1% brepocitinib cream once daily had an average decrease in their EASI score of −70%, compared with −44% using vehicle cream. Patients using 1% brepocitinib cream twice daily had an average decrease in their EASI score of −75%, compared with −48% using vehicle cream. Tofacitinib ointment (JAK 1/3, NCT 02,001,181, completed 2020) and ATI-502 solution (JAK 1/3, NCT03585296, completed 2021) completed phase 2 trials in adults, but do not have further trials at this time.

Biologics

Dupilumab

Dupilumab (DUPI) is the only FDA-approved biologic for pediatric AD. This humanized monoclonal antibody (mAb) binds to IL-4 receptor α (IL-4Rα), blocking IL-4/IL-13 signaling as the IL-4Rα chain is common to both IL-4R complexes: type 1 (IL-4Rα/γc; IL-4 specific) and type 2 (IL-4Rα/IL-13Rα1; IL-4 and IL-13 specific) [4]. Additional biologic agents are in trials (Table 3). Initially approved for adults, approval was expanded to include adolescents ≥ 12 years in March 2019 on the basis of the phase 3 RDBPCT (LIBERTY AD ADOL) [42, 43]. In this trial, more subjects achieved IGA0/1 (24% versus 2%), EASI75 (42% versus 8%), and reduction ≥ 4 in Peak Pruritus NRS (37% versus 5%) in the DUPI arm versus placebo, respectively [44]. The LIBERTY AD PEDS phase 3 RDBPCT of children age 6–11 years with severe AD evaluated DUPI + TCS versus placebo + TCS. More subjects achieved IGA0/1 (33% versus 30% versus 11%), EASI-75 (70% versus 67% versus 27%), and reduction by ≥ 4 of Peak Itch NRS (51% versus 58% versus 12%) in the DUPI every 4-week and 2-week regimen compared with placebo, respectively [45]. These results prompted expanded approval to ≥ 6 years old in 2020 [46]. Evaluating DUPI in subjects ≥ 6 months to < 6 years, the LIBERTY AD PRESCHOOL phase 2 results characterized appropriate DUPI safety/pharmacokinetics, and the phase 3 RDBPCT evaluating DUPI + TCS versus placebo + TCS found significantly more patients achieved IGA0/1 (28% versus 4%) and EASI75 (53% versus 11%) with DUPI versus placebo [48, 49]. A significant improvement in itch was also noted with DUPI [47]. This trial led to expanded FDA approval for children ≥ 6 months to 5 years in June 2022 [48]. Dupilumab-related adverse events included conjunctivitis, transient eosinophilia, and injection site reactions [44, 45, 47, 49, 50]. A phase 3 OL extension trial (LIBERTY AD PED-OLE) of patients ≥ 6 months is ongoing (NCT 02,612,454). Results from adolescent patients were recently published with findings relevant for a long-term safety profile consistent with the adult safety profile. Additionally, trial participants with clear/almost clear skin for 12 weeks were discontinued on DUPI with 56.7%, demonstrating recurrence and need to resume DUPI treatment to maintain AD control, which suggests a need to continue DUPI treatment to maintain efficacy [51]. With an excellent safety profile and high response rates, DUPI has become first line, when available, in refractory moderate–severe eczema. Head-to-head trials with JAK inhibitors are helping distinguish the role for these treatments, and further head-to-head trials against other biologics will be needed [34].

Table 3 New and emerging biologic treatments
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Other Experimental Agents

Microbial

Therapeutics targeting cutaneous dysbiosis have yielded mixed results. Omiganan, an antimicrobial peptide, demonstrated recovered dysbiosis in a phase 2 RDBVCT, but did not improve AD [59]. Roseomonas mucosa phase 1/2 trials demonstrated improved SCORAD, EASI, and pruritus scores, reduced S. aureus burden, and decreased TCS requirements [60, 61]. Targeted microbiome transplant (TMT) lotion containing Staphylococcus hominis demonstrated decreased S. aureus burden but did not improve dermatitis in a phase 1 trial. However, post hoc analysis of participants with S. aureus killed by S. hominis demonstrated improved eczema severity [62].

Orals

Oral small molecule inhibitors SCD-044 [sphingosine-1-P (S1P) receptor agonist] and RPT193 [chemokine receptor type 4 (CCR4) antagonist] completed adult trials but have not advanced to pediatric patients (NCT04684485 and NCT05399368).

Injectables

Anti-IgE mAb omalizumab was tested in a RDBPCT (ADAPT) that included pediatric patients with improved SCORAD and quality of life score compared with placebo [63]. There are no further active trials. OX40-targeting biologics completed phase 2 trials in adults, but have not advanced to pediatric populations (NCT03703102, NCT03568162, NCT03754309, NCT05131477). A trial of IL-36 inhibitor, spesolimab infusion, was completed (NCT03822832) in adults. Ustekinumab completed phase 2 trials in adults (NCT01806662, NCT01806662) and did not advance to further testing.

Approach to Treatment

Many new therapeutic modalities have emerged since the last published American Academy of Dermatology AD guidelines in 2013–2014, including JAK inhibitors and DUPI. New European guidelines include both JAK inhibitors and DUPI for age > 6 years in addition to older systemic agents like azathioprine, methotrexate, and ciclosporin/cyclosporine for children and adolescents with severe disease [64]. On the basis of current evidence, new European guidelines, and expert consensus [64, 65], our authors propose the following approach to treating pediatric patients with AD. Initial therapy should begin with topical treatments that include TCS and steroid-sparing agents. Options for steroid-sparing topicals are now expanded beyond calcineurin inhibitors (tacrolimus or pimecrolimus) to include PDE4 inhibitors (crisaborole, available in the USA) and a topical JAK inhibitor (ruxolitinib, available in the USA, and delgocitinib, available in Japan). Selection of a topical steroid or steroid-sparing agent should be based on BSA involvement, body location of AD, age of the patient, and accessibility for the patient (cost, local country approval, and availability) (See Table 4 for FDA-approved treatments). Often times, topical agents/therapies still play a role in patients with moderate-to-severe atopic dermatitis who are on systemic therapy. The authors do not have space to discuss these in detail. In cases of moderate–severe AD in which systemic treatment is necessary, DUPI can be included as a newer option (in those > 6 years old in Europe and other parts of the world and in those > 6 months in the USA). Conventional systemic medications, including ciclosporin/cyclosporine, methotrexate, and azathioprine, may still be considered on the basis of age, local approval, availability, and cost. For those patients who fail DUPI and/or these other conventional systemic therapies, oral JAK inhibitors may be an additional therapeutic option in older children [39]. Upadacitinib is the oral JAK inhibitor approved by the FDA and European Medicines Agency (EMA) in pediatric patients age ≥ 12 years. Other treatment options are in development, but further studies are needed in pediatric populations to determine safety/efficacy in these patients. Additionally, head-to-head trials against DUPI are needed to clarify the role of emerging systemic treatments for moderate-to-severe AD.

Table 4 FDA-approved treatments for pediatric atopic dermatitis
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Conclusions

As the pathomechanisms and immunologic profiles of AD are better understood, treatment tailored to specific immune endotypes may become the norm, especially when cost and accessibility improve. Though we have not reached this level of personalized medicine in pediatric AD, the approval of DUPI and JAK inhibitors for many age groups have already changed the treatment landscape of pediatric AD. Access to conventional therapies including cyclosporine, methotrexate, topical therapies (steroids, calcineurin inhibitors, and others), and light therapy still play a role for many of those living with atopic dermatitis. Additional systemic and biologic agents are in trials. Inclusion of pediatric patients in these trials, especially head-to-head trials, will be necessary to improve strength of guidelines for pediatric AD treatment choice in the future.