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.
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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
Drug (Target) | Trial identifier | Study type | Subject number | Age | AD severity baseline | Study treatment duration | Primary endpoints | Key secondary endpoints | Adverse events | Status |
|---|---|---|---|---|---|---|---|---|---|---|
Crisaborole 2% ointment (PDE4) | NCT02118766, NCT02118792 | Parallel phase 3 RDBVCT | 759, 763 | ≥ 2 years | Mild–mod | 28 days | ISGA 0/1 (met) | Itch scores (met) | Application site pain | FDA approved age ≥ 2 years |
NCT03356977 | Phase 4 OL | 137 | 3 to < 24 months | Mild–mod | 28 days | Safety (met) | ISGA 0/1, EASI score, POEM (met) | Application site pain/discomfort/erythema | FDA approved age ≥ 3 months | |
Difamilast ointment (PDE4) | NCT02068352 | Phase 2 RDBVCT | 121 | 10 years–70 years | Mild–mod | 8 weeks | IGA 0/1 (met) | IGA, EASI, VAS pruritus (met) | AD flare (in 0.3% difamilast), pruritus | Completed |
NCT03018691 | Phase 2 RDBVCT, parallel group | 73 | 2–14 years | Mild–mod | 4 weeks | Safety (met) | IGA 0/1, EASI, VAS/VRS pruritus, POEM, %BSA (met) | Infrequent folliculitis | Completed | |
NCT03911401 | Phase 3 RDBVCT | 251 | 2–14 years | Mild–mod | 4 weeks | IGA 0/1 + ≥ 2 grade improvement (met) | EASI, VRS pruritus, POEM, BSA (met) | Infrequent folliculitis and impetigo | Approved in Japan age ≥ 2 years | |
Roflumilast cream (PDE4) | NCT04773587 | Phase 3 RDBVCT | 654 | ≥ 6 years | Not specified | 4 weeks | IGA 0/1 + ≥ 2 grade improvement | EASI-75, Itch NRS | NA | Completed, results not reported |
NCT04773600 | Phase 3 RDBVCT, parallel group | 683 | ≥ 6 years | Not specified | 4 weeks | IGA 0/1 + ≥ 2 grade improvement | EASI-75, Itch NRS | NA | Active, not recruiting | |
NCT04845620 | Phase 3 RDBVCT, parallel group | 650 (estimated) | 2–5 years | Not specified | 4 weeks | IGA 0/1 + ≥ 2 grade improvement | EASI-75 | NA | Active, recruiting | |
Tapinarof cream (AHR) | NCT02564055 | Phase 2b RDBVCT | 247 | 12–65 years | Moderate–severe | 12 weeks | IGA 0/1 + ≥ 2 grade improvement (met) | EASI-75, Itch NRS, %BSA (met) | Mild folliculitis | Completed |
NCT05014568 | Phase 3 RDBVCT | 400 (estimated) | ≥ 2 years | Moderate-Severe | 8 weeks | IGA 0/1 | EASI-75/EASI-90, Itch NRS, % BSA | NA | Active, recruiting | |
NCT05032859 | Phase 3 RDBVCT | 400 (estimated) | ≥ 2 years | Moderate–severe | 8 weeks | IGA 0/1 | EASI-75/EASI-90, Itch NRS, %BSA | NA | Active, recruiting | |
NCT05142774 | Phase 3 OL | 961 (estimated) | 2 to < 18 years | Moderate–severe | 48 weeks | Safety | IGA, % BSA, EASI-50/75/90, peak pruritus (PP)-NRS | NA | Active, recruiting | |
Ruxolitinib cream (JAK 1 and 2) | NCT03745638, NCT03745651 | Phase 3 RDBVCT | 631, 618 | ≥ 12 years | Mild–moderate | 52 weeks (8 + 44 extension) | IGA 0/1 + ≥ 2 grade improvement (met) | EASI-75, Itch NRS (met) | Nasopharyngitis, URTI, headache | Completed |
NCT04921969 | Phase 3 RDBVCT | 250 (estimated) | 2–11 years | Mild–moderate | 52 weeks (8 + 44 extension) | IGA 0/1 + ≥ 2 grade improvement | EASI-75, Itch NRS | NA | Recruiting | |
Delgocitinib ointment/cream (Pan JAK) | JapicCTI-173554 | Phase 3 | 158 | 2–15 years | 28 weeks ( 4 weeks + 24 open label extension) | %mEASI | mEASI-50/75, IGA 0/1, itch NRS, | Impetigo, nasopharyngitis, urticaria | Complete | |
JapicCTI-173555 | Phase 3 | 352 | ≥ 16 years | 52 weeks | Safety | %mEASI, mEASI-75, IGA 0/1, % I-NRS | Acne, eczema herpeticum, nasopharyngitis | Complete | ||
JapicCTI-184064 | Phase 3 RDBVCT | 2–15 years | Mild–severe | 52 weeks | %mEASI | mEASI-50/75, IGA 0/1, pruritus score | Folliculitis, acne, nasopharyngitis, influenza, impetigo, eczema herpeticum (favored unrelated) | Approved Japan | ||
Brepocitinib cream (JAK1/TYK2) | NCT 03,903,822 | Phase 2b RDBVCT | 240 | 12–75 years | Mild–moderate | 6 weeks | %EASI (all except 0.1% and 0.3% bid met) | EASI-75 (only 0.3% bid, 1% bid), IGA 0/1 (all except 1% qd, 0.3% qd, 0.1% qd), PP-NRS (all except 0.2%, 0.3%) | Nasopharyngitis, URTI, folliculitis, furuncle, herpes simplex, eczema herpeticum | Completed |
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.
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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).
Box 1: Crisaborole
Practical results of our authors’ experience with crisaborole suggests limited uptake due to minimal responses and localized discomfort at sites of application. Take caution before prescribing crisaborole for facial use given increased risk of discomfort at this site. Difamilast is not yet approved in the USA, but may prove beneficial given the lack of burning sensation associated with crisaborole. Crisaborole use is limited geographically as it is not approved outside the USA.
Aryl Hydrocarbon
Tapinarof is a small molecule aryl hydrocarbon receptor (AHR) agonist. When activated, the AhR/AhR nuclear translocator (ARNT) system promotes increased keratinocyte barrier gene expression [16]. The AhR/ARNT system decreases TH2 cytokines, oxidative stress, and is implicated in immunoregulation [17, 18]. A phase 2b RDBVCT in adolescents reported improved IGA 0/1 (53% versus 24%), Eczema Area and Severity Index (EASI) (60% versus 26%), and itch scores (30% versus 5%) in tapinarof versus vehicle [8]. Folliculitis and acne were reported [19]. Tapinarof has advanced to phase 3 trials that will include patients ≥ 2 years (NCT05014568, NCT05032859, NCT05142774).
Box 2: Tapinarof
Tapinarof is already on the market (FDA approved for psoriasis) and may be available for AD soon. Benefits include lack of burning sensation and few reported application site reactions. Watch for allergic contact dermatitis as this was reported in psoriasis trials [20].
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
Drug (Target) | Trial ID | Study type | Subject number | Age | Study treatment duration | Primary endpoint | Key secondary endpoints | Adverse events | Status |
|---|---|---|---|---|---|---|---|---|---|
Upadacitinib (JAK1) | NCT03569293, NCT03607422 | Replicate phase 3 RDBPCT (Measure Up 1 and Measure Up 2) | 847, 836 | 12–75 years | 16 weeks | EASI-75, vIGA-AD 0/1 (met) | WP-NRS4, EASI, ADerm-IS, ADerm-SS | Acne, URTI, nasopharyngitis, headache | FDA approved ages 12+, 2021 |
NCT03568318 | Parallel phase 3 RDBPCT (AD Up) | 968 | 12–75 years | 16 weeks + blinded extension (up to week 260) | EASI-75, vIGA-AD 0/1 | WP-NRS4, EASI | Nasopharyngitis, acne, and URTI | Active, not recruiting | |
Abrocitinib (JAK1) | NCT03349060, NCT03575871 | Parallel phase 3 RDBPCT (JADE MONO 1 and 2) | 387, 391 | ≥ 12 years | 12 weeks | IGA 0/1, EASI-75 (met) | PP-NRS4, PSAAD (met) | Nausea, vomiting, headache, acne, transient low platelets, elevated CPK, LDL/HDL | Completed |
NCT03796676 | Parallel phase 3 RDBPCT (JADE TEEN) | 285 | 12–17 years | 12 weeks | IGA 0/1, EASI-75 (met) | PP-NRS4, PSAAD | Nausea, vomiting, headache, acne, transient low platelets, elevated CPK, LDL/HDL | Completed | |
Baricitinib (JAK 1 and 2) | NCT03952559 | Phase 3 RDBPCT (BREEZE-AD-PEDS) | 465 (estimated) | 2–17 years | 16 weeks | IGA 0/1, PK | EASI, SCORAD, NRS4, PRISM, POEM, PGI-S-AD, CDLQI/IDQOL, WPAI-AD-CG, EQ-5D-Y, ADSS | NA | Recruiting |
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.
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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.
Box 3: Topical JAK Inhibitors
Topical JAK inhibitors have a reasonable safety profile and are not associated with application site burning/stinging. Use of topical JAK inhibitors is limited by approval for only limited BSA involvement (≤ 20%) and cost.
Oral JAK
JAK inhibitors have emerged as the first available oral targeted treatments for AD. Upadacitinib is a JAK1-selective inhibitor FDA approved for refractory moderate–severe AD in patients ≥ 12 years. In two phase 3 RDBPCTs (Measure Up 1 and 2) including patients ≥ 12 years, significant improvements in EASI-75 (80%/73% versus 70%/60% versus 16%/13%), validated IGA 0/1 (62%/52% versus 48%/39% versus 8%/5%), and itch scores were reported in upadacitinib 30 mg and 15 mg arms compared with placebo [33]. A phase 3b head-to-head trial (Heads Up) comparing 30 mg upadacitinib to dupilumab (DUPI) in adults showed slightly better improvement in EASI-75 scores in upadacitinib (71%) versus DUPI (61%) and significant improvement in pruritus score [34]. A phase 3 RDBPCT (AD Up) evaluating upadacitinib in combination with TCSs in patients 12–75 years reported improved EASI-75 (77% versus 65% versus 26%) and validated IGA-AD 0/1 (59% versus 40% versus 11%) in upadacitinib 30 mg versus 15 mg versus placebo, respectively (NCT03568318). This trial is now in a prolonged extension phase. A phase 1 OL study in children ages 2–12 years with severe AD is ongoing (NCT03646604).
Abrocitinib is a JAK1-selective inhibitor FDA approved for refractory moderate–severe AD in adults, but not adolescents. Safety and efficacy of abrocitinib were evaluated in two 12-week phase 3 RDBPCTs of subjects ≥ 12 years old with moderate–severe AD in JADE MONO-1 and JADE MONO-2 [35, 36]. Study arms abrocitinib 200 mg daily versus 100 mg daily versus placebo achieved IGA 0/1 (MONO 1: 43.8% versus 23.7% versus 7.9%; MONO 2: 38.1% versus 28.4% versus 9.1%) and EASI75 (MONO 1: 62.7% versus 39.7% versus 11.8%; MONO 2: 61.0% versus 44.5% versus 10.4%) by week 12. Subjects also achieved improvement in itch scores with abrocitinib compared with placebo. An additional phase 3 trial in adolescents evaluated abrocitinib + topical therapy (JADE-TEEN) [37]. Significant improvements in IGA (IGA 0/1: 46.2% versus 41.6% versus 24.5%), EASI-75 (72.0% versus 68.5% versus 41.5%), and itch scores were met in abrocitinib 200 mg and 100 mg versus placebo, respectively. A dose–response effect was stronger in JADE MONO-1 and MONO-2 compared with JADE-TEEN, possibly due to the concomitant topical therapy in JADE-TEEN. A phase 3 head-to-head trial of abrocitinib versus DUPI was completed in adults (JADE COMPARE) with a significant finding of decreased itch at week 2 in the 200 mg abrocitinib group compared with dupilumab. Otherwise abrocitinib was not noted to differ significantly from DUPI at week 16 [38]. An extension study (JADE EXTEND) of adult patients that had been randomized to the DUPI arm of JADE COMPARE demonstrated sustained response in patients who already responded to DUPI, and clinical benefit with skin clearance and itch relief in many patients who had failed to respond to DUPI [39]. Further studies are needed in pediatric patients, but these results suggest a role for oral JAK inhibitors in patients with AD refractory to DUPI. Similar treatment-emergent adverse events were noted in trials for upadacitinib and abrocitinib, including acne, headaches, herpes virus, upper respiratory infections, and nausea. Lab abnormalities were noted including transient thrombocytopenia, increased creatinine phosphokinase (CPK), and lipid levels, suggesting a role for lab monitoring. Serious adverse events (thromboembolic events and malignancy) were not noted, though long-term studies are needed to determine risk over time.
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Baricitinib is approved in Europe for moderate–severe AD in adults on the basis of the results of three phase 3 trials (NCT0333439, NCT03334422, NCT03435081). Two identical phase 3 trials (BREEZE-AD1 and BREEZE-AD2) of adults with moderate–severe AD in Europe, Asia, Latin America, and Australia demonstrated dose-dependent improvement in IGA, EASI score, and itch [40]. This response was again demonstrated in a phase 3 trial (BREEZE-AD5) of adults with moderate–severe AD in North America [41]. Changes in serum CPK and platelets were noted in these studies, but were transient.
Box 4: Oral JAK Inhibitors
Oral JAKs further expand options for patients who are needle-averse or unresponsive to other therapies, including topicals/biologics. Pruritus seems to respond quickly to JAK inhibitors (within 24 h of first dose). Side effects, including risk of nausea and acne, as well as more serious black box warnings, including infection, thrombosis, malignancy, and myelosuppression, should be thoroughly discussed with patients prior to JAK treatment. Lab monitoring is supported by abnormalities in CPK, lipid levels, LFTs, and CBC noted in studies, and testing should be completed before and during treatment per guidelines.
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
Drug and target | Study type and trial identifier | Subject number and ages included | AD severity baseline | Study treatment duration | Primary endpoint | Key secondary endpoints | Adverse events | Status |
|---|---|---|---|---|---|---|---|---|
Dupilumab IL-4Rα | Phase 3 RDBPCT (LIBERTY AD ADOL) NCT03054428 | 251, 12–17 years | Mod–severe | 16 weeks | IGA 0/1, EASI-75 (met) | EASI, NRS, % BSA, SCORAD, CDLQI, POEM | Conjunctivitis, injection site reactions | FDA approved age ≥ 12 years 2019 |
Phase 3 RDBPCT (LIBERTY AD PEDS) NCT03345914 | 367, 6–11 years | Severe | 16 weeks | IGA 0/1, EASI-75 (met) | EASI-75, %EASI, itch score, %BSA, SCORAD, CDLQI, POEM, DFI, PROMIS, TEAE, mean weekly TCS use | Injection site reactions, conjunctivitis | FDA approved age 6–11 years 2020 | |
Part A- Phase 2 Part B- Phase 3 RDBPCT (LIBERTY AD PRESCHOOL) NCT03346434 | 202, ≥ 6 months to 6 years | Mod–severe | Part A- 4 weeks Part B- 16 weeks | Part A- PK, safety Part B- IGA0/1, EASI-75 (met) | Part A- EASI, SCORAD, IGA0/1 Part B- EASI, NRS, %BSA, POEM, SCORAD, DFI, CDLQI, IDQOL | Nasopharyngitis, molluscum contagiosum, viral gastroenteritis, rhinorrhea, dental caries, conjunctivitis | FDA approved age ≥ 6 months to 5 years June 2022 | |
Phase 3 OL extension study (LIBERTY AD PED-OLE) NCT02612454 | 880, 6 months to 17 years | Mod–severe | 272 weeks | Safety, PK | IGA 0/1, EASI, BSA, SCORAD, CDLQI, IDQOL | Nasopharyngitis, URTI, AD, conjunctivitis | Active, not recruiting | |
Tralokinumab IL-13 | Phase 3 RDBPCT (ECZTRA), NCT02612454 | 301, 12–17 years | Mod–severe | 52 weeks | IGA0/1, EASI-75 | Itch NRS, SCORAD, CDLQI, EASI, POEM, pK | Viral URTI, conjunctivitis, headache, injection site reaction | Completed |
Phase 3, OL, extension study (ECZTEND) NCT03587805 | 1672, ≥ 12 years | 266 weeks | Safety | IGA0/1, EASI75 | NA | Active, not recruiting | ||
Phase 3, OL, single arm (INJECZTRA) NCT05194540 | 120 (estimated), ≥ 12 years | Mod–severe | 16 weeks | IGA 0/1, EASI-75 | Safety, treatment-emergent anti-drug antibodies | NA | Recruiting | |
Phase 2, single-blinded, randomized, parallel group (TRAPEDS 1), NCT05388760 | 53, 2–11 years | Mod–severe | 52 weeks | PK | Safety, anti-drug antibodies, SCORAD, POEM, EASI | NA | Recruiting | |
Lebrikizumab IL-13 | Phase 3 RDBPCT (Advocate 1), NCT04146363 | 424, ≥ 12 years | Mod–severe | 52 weeks | IGA 0/1, EASI-75 | IGA 0/1, itch NRS, EASI, % BSA, DLQI, sleep loss score, PROMIS | Conjunctivitis, injection site reactions, nasopharyngitis | Completed |
Phase 3 RDBPCT (Advocate 2), NCT04178967 | 445, ≥ 12 years | Mod–severe | 52 weeks | IGA 0/1, EASI-75 | IGA 0/1, itch NRS, EASI, % BSA, DLQI, sleep loss score, PROMIS | Conjunctivitis, injection site reaction, nasopharyngitis, headache, nausea | Completed | |
Phase 3 RDBPCT (Adhere), NCT04250337 | 228, ≥ 12 years | Mod–severe | 16 weeks | IGA 0/1, EASI-75 | EASI, itch NRS, % BSA, sleep loss score, SCORAD, CDLQI | Headache, conjunctivitis | Completed | |
Phase 3, OL, single arm (Adore), NCT04250350 | 206, 12–17 years | Mod–severe | 52 weeks | Safety | IGA 0/1, EASI, % BSA, PROMIS, CDLQI, PK | NA | Completed, results not published | |
Phase 3 RDBPCT (Adhere-J), NCT04760314 | 280, ≥ 12 years | Mod–severe | 16 weeks | IGA 0/1, EASI-75 | EASI, itch NRS | NA | Active, not recruiting | |
Phase 3 parallel assignment (Adjoin), NCT04392154 | 1000, ≥ 12 years | Mod–severe | 100 weeks | Safety | IGA 0/1, EASI-75 | NA | Recruiting | |
Phase 3 RDBPCT, NCT05149313 | 312, ≥ 12 years | Mod–severe | 52 weeks | EASI-75 | IGA, itch NRS, % BSA, SCORAD, CDLQI | NA | Recruiting | |
Phase 3 OL, NCT05369403 | 120, ≥ 12 years | Mod–severe | 24 weeks | EASI-75 | IGA 0/1, EASI, itch NRS, sleep loss scale, skin pain NRS, CDLQI, SCORAD | NA | Not yet recruiting | |
Phase 3 OL, NCT05372419 | 80, ≥ 12 years | Mod–severe | 24 weeks | EASI-75 | IGA 0/1, EASI, itch NRS, sleep loss scale, skin pain NRS, CDLQI, SCORAD | NA | Not yet recruiting | |
Nemolizumab IL-31Rα | Two phase 3, long-term, JapicCTI-173740, JapicCTI-183894 | 215, 88, ≥ 13 years | Mod–severe | 52 weeks | pruritus VAS, itch NRS, EASI, sIGA, ISI | DLQI, POEM, mean quantity of topical agents | Nasopharyngitis, AD, inc CPK, contact derm, influenza, urticaria, acne | Completed |
Phase 2 OL, NCT04921345 | 70, 2–12 years | Mod–severe | 52 weeks | PK | EASI, IGA, BSA, PP-NRS, sleep disturbance NRS, cDLQI/iDLQI, POEM | NA | Recruiting | |
Phase 2 OL, NCT03921411 | 20, 12–17 years | Mod–severe | 24 weeks | PK, safety | Completed, results not published | |||
Phase 3 RDBPCT, NCT03985943 | 750, ≥ 12 years | Mod–severe | 16 weeks | IGA 0/1, EASI-75 | PP-NRS | NA | Active, not recruiting | |
Phase 3 RDBPCT, NCT03989349 | 750, ≥ 12 years | Mod–severe | 16 weeks | IGA 0/1, EASI-75 | PP-NRS | NA | Active, not recruiting | |
Phase 3, long-term, NCT03989206 | 1700, ≥ 12 years | Mod–severe | 200 weeks | Safety | IGA 0/1, EASI-75, SCORAD, DLQI, POEM | NA | Recruiting | |
Benralizumab IL-5Rα | Phase 2 RDBPCT, NCT04605094 | 194, ≥ 12 years | Mod-severe | 16 weeks (+ 36-week extension) | IGA 0/1 | EASI-75/90, serum anti-drug antibody, peak pruritus score, DLQI and CDLQI | NA | Active, not recruiting |
Box 5: Dupilumab
Now approved for patients as young as 6 months, DUPI has a great safety profile with the benefit of no required lab monitoring. Administration via injection may limit use in needle-averse patients. DUPI associated conjunctivitis can often be managed with eye drops.
Anzeige
Tralokinumab
IL-13 may play a greater role in peripheral TH2 inflammation than IL-4. This led to emergence of IL-13 inhibitors for AD treatment [52]. Tralokinumab is an IgG4 mAb that binds to IL-13, preventing activation of the receptor. It was approved for adults with moderate–severe AD in early 2022 after proving safety/efficacy in ECZTRA 1 and ECZTRA 2 phase 3 trials [53]. Adverse events were similar to DUPI [54]. A RDBPCT of tralokinumab monotherapy in adolescents (ECZTRA 6) demonstrated improved IGA and EASI-75 versus placebo (NCT03526861). Additional pediatric trials are active (NCT03587805, NCT05388760).
Box 6: Tralokinumab
Not yet broadly available for pediatric patients, tralokinumab is FDA approved for adults with AD. The recent ECZTRA 6 trial may lead to FDA approval for adolescents soon. IL-13 inhibitor safety/efficacy appears similar to DUPI. It is unclear if there will be a unique role for IL-13 inhibitors compared with DUPI.
Lebrikizumab
Lebrikizumab is a mAb that inhibits IL-13 signaling by blocking IL-13Rα. A phase 2b trial in adults demonstrated dose-dependent improvement in EASI, IGA0/1, and itch. A total of 12 patients who failed to respond to previous DUPI treatment were randomized to receive lebrikizumab. Five of these 12 achieved EASI-75 at week 16 [55]. Several phase 3 trials including adolescents met primary endpoints (NCT04146363, NCT04178967, NCT04250337) with further active and planned phase 3 trials (NCT04760314, NCT04392154, NCT05149313, NCT05369403, NCT05372419).
Box 7: Lebrikizumab
IL-13Rα inhibitors may be as effective as IL-13 inhibitors. Several phase 3 trials that included adolescents met primary endpoints for improvement in AD. Like IL-13 inhibitors, it remains unclear if there is a unique role for IL-13Rα inhibitors compared with DUPI.
Nemolizumab
IL-31 is a pruritogenic cytokine involved in AD pathogenesis. Nemolizumab is an anti-IL-31 receptor α-chain (IL-31Rα) mAb that has shown promising results in phase 2/3 adult trials. Reduced itch in particular was noted, with a lesser improvement in dermatitis [56]. Two recent phase 3 long-term studies in Japanese adolescents demonstrated improved itch with a durable response. Improved EASI, sleep, and life quality were noted by week 16 and persisted through end of treatment [57]. IL-31 expression is increased in children, and nemolizumab may have greater efficacy in this population [56]. Ongoing phase 2/3 trials in adolescents and children are forthcoming (NCT03921411, NCT04921345, NCT03985943, NCT03989349, NCT03989206).
Box 8: Nemolizumab
Nemolizumab has demonstrated greater effect on pruritus than dermatitis in AD. Trials are ongoing in pediatric patients. The role of nemolizumab in AD treatment remains unclear.
Benralizumab
Upregulated TH2 cytokines in AD include IL-5, which promotes eosinophil activation and IgE production. Benralizumab is a mAb targeting IL-5 receptor α chain (IL-5Rα). A phase 2 RDBPCT in adults was completed (NCT03563066) and a phase 2 trial in adolescents is ongoing (NCT04605094).
Box 9: Benralizumab
Benralizumab is in early trials. Pending further studies, benralizumab (like DUPI and lebrikizumab) may have a role in treatment of hypereosinophilic-syndrome-associated AD [58].
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
Drug | Target | Route | Dosing | Boxed warning | Price, USD | Lab monitoring | Special/practical consideration |
|---|---|---|---|---|---|---|---|
Tacrolimus | CNI | Topical | Children ≥ 2 years 0.03% ointment twice daily Adolescents ≥ 16 years 0.1% ointment twice daily | Black box warning regarding risk of malignancy (lymphoma and skin) and recommend against use in children < 2 years | $2.80–$11.59 per gram (generic versus brand) | NA | Burning sensation at sites of application may limit use |
Pimecrolimus | CNI | Topical | Children ≥ 2 years and adolescents 1% cream twice daily | Black box warning regarding risk of malignancy (lymphoma and skin) and recommend against use in children < 2 years | $10.15–11.96 per gram (generic versus brand) | NA | Less local burning sensation than tacrolimus |
Crisaborole | PDE4 | Topical | Infants ≥ 3 months, children, and adolescents 2% ointment twice daily | NA | $13.84 per gram | NA | Burning/stinging, especially when used on face |
Ruxolitinib | JAK1/2 | Topical | Children ≥ 12 years and adolescents 1.5% cream twice daily | Black box warning regarding serious infections (herpes zoster and opportunistic), mortality, malignancies (lymphoma and others), MACE, thrombosis | $39 per gram | CBC as clinically indicated | Approval for use is limited to no more than 20% BSA twice a day for 8 weeks |
Dupilumab | IL-4/13 | Injection | Infants ≥ 6 months to children < 6 years: weight-based dosing using prefilled syringes every 4 weeks; 5 to < 15 kg inject 200 mg q4 weeks, 15 to < 30 kg inject 300 mg q4 weeks Children ≥ 6 years and adolescents < 18 years: weight-based dosing using prefilled syringe (age ≥ 6 years) or prefilled pen (age ≥ 12 years); 15 to < 30 kg inject 600 mg once followed by 300 mg q4 weeks, 30 to < 60 kg inject 400 mg once followed by 200 mg q2 weeks, ≥ 60 kg inject 600 mg once followed by 300 mg q2 weeks | NA | $1015–$2030 per mL | NA | Loading dose not necessary in children < 6 years Often need to fail topical treatments (± phototherapy) prior to insurance approval |
Upadacitinib | JAK1 | Oral | Children ≥ 12 years and adolescents weighing ≥ 40 kg: 15 mg orally once daily (may increase to 30 mg once daily if response inadequate) | Black box warning regarding serious infections (TB, invasive fungal, bacterial, viral including herpes zoster, other opportunistic pathogens), mortality, malignancies (lymphoma and others), MACE, thrombosis | $226 per pill | Prior to treatment: viral hepatitis serologies, TB screen, pregnancy test Baseline and periodically: CBC with differential (monitoring lymphocytes, neutrophils, hemoglobin) LFTs, lipids 12 weeks after initiation and periodically during treatment | Check medication interactions as there are multiple potential interactions Animal studies suggest fetal harm in cases of in utero exposure; unclear risk in humans |
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.
Acknowledgements
Funding
LCS salary and time was supported [in part] by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. No additional funding or sponsorship was received for the publication of this article.
Medical Writing and/or Editorial Assistance
N/A.
Author Contributions
KK, IN, LCS all contributed to the concept and design, planning, writing, review and revision of the manuscript.
List of Investigators (if applicable)
N/A.
Prior Presentation (if applicable)
N/A.
Disclosures
Katherine Kondratuk, Ilka Arun Netravali, and Leslie Castelo-Soccio have nothing to disclose.
Compliance with Ethics Guidelines
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.
Data Availability
N/A.
Other Acknowledgements
N/A.
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