Update on Biologic Therapy for Atopic Dermatitis

Atopic dermatitis (AD) is the most prevalent chronic inflammatory skin disease in childhood, and is characterized by complex interactions between genetic susceptibility, epidermal barrier dysfunction, immune dysregulation, and environmental triggers. Recent advances in understanding its immunopathogenesis, particularly the central role of the Th2 axis and the neuroimmune circuitry of itch, have driven a paradigm shift in therapy from conventional symptomatic approaches to mechanism-based strategies. Conventional treatments, including emollients, topical corticosteroids, and calcineurin inhibitors, remain essential but are often insufficient in moderate-to-severe forms. The advent of biologics, most notably dupilumab, has revolutionized pediatric AD management, demonstrating sustained efficacy and safety across all age groups, including infants. Selective IL-13 inhibitors, such as tralokinumab and lebrikizumab, offer targeted options for children and adolescents who exhibit suboptimal responses or intolerance to dupilumab, while nemolizumab provides a complementary strategy by directly targeting the IL-31/IL-31RA axis to alleviate pruritus. Small molecules, including JAK inhibitors and topical PDE4 inhibitors, further expand the therapeutic armamentarium, although systemic risks necessitate careful monitoring in younger populations. Current evidence underscores the importance of balancing efficacy, safety, and long-term immunomodulatory consequences in clinical decision-making. As the therapeutic landscape continues to expand, head-to-head comparative studies and precision medicine approaches, including biomarker-guided treatment selection, will be crucial to optimize sequencing, combination strategies, and cost-effectiveness. Ultimately, novel biologics and targeted therapies hold the promise not only of durable disease control but also of modifying the natural history of AD, improving quality of life and potentially limiting progression along the atopic march.

INTRODUCTION

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, affecting over 200 million individuals worldwide, with prevalence rates reaching 15-25% in children and 3-7% in adults adults ¹. It primarily begins in childhood, with more than 85% of cases presenting before the age of 5 years ².

The healthcare and societal costs associated with atopic dermatitis are substantial, not only due to the complexity of pharmacological treatments, but also because of the significant impact on patients’ quality of life and that of their families, the psychological burden affecting the entire household, and the sleep, attention, and mood disturbances frequently observed in affected individuals ^3,4.

Onset typically occurs during the first year of life ⁵, but the condition may persist into adulthood, especially in cases of severe disease ⁶.

The pathogenesis of AD is a matter of debate. On one hand, immune dysregulation through a T2 inflammation may induce a defect of epithelial barrier with AD chronicity. On the other hand, genetic mutations, together with multiple environmental factors, contribute to immune dysregulation and structural impairment of the skin barrier, making the skin more susceptible to irritation and infection ⁷. In AD, the skin commonly exhibits a reduction in essential lipids and an increase in transepidermal water loss, promoting xerosis, inflammation, and pruritus. Chronic scratching, triggered by persistent itching, progressively leads to skin thickening and lichenification.

CLINICAL MANIFESTATIONS AND PATHOGENESIS OF ATOPIC DERMATITIS

AD is a chronic, relapsing disease characterized by eczema with age-dependent distribution. In infants (< 2 years), lesions typically affect the cheeks and scalp, but may involve the neck, trunk, and extensor surfaces, presenting with erythema, exudation, crusts, and intense pruritus. After 2 years of age, the disease evolves into chronic forms with lichenification, mainly in flexural areas (antecubital, popliteal fossae). In older children and adolescents, xerosis, crusted lesions, and involvement of hands, feet, and extensor surfaces are common ⁸.

AD arises from genetic predisposition, immune dysregulation, and environmental influences. Climatic conditions, stress, pollution, skin microbiota alterations, and urban lifestyle significantly affect disease risk (hygiene hypothesis) ^9,10. Environmental triggers, especially temperature extremes, low humidity, and indoor heating, worsen xerosis and barrier dysfunction, fuelling inflammation ¹¹. This complex interaction of external factors is defined as the exposome ¹².

Two main hypotheses underlie the pathogenesis of AD:

• Outside-in theory: primary skin barrier dysfunction due to mutations in genes such as filaggrin (FLG) leads to increased transepidermal water loss, impaired barrier stability, and enhanced allergen penetration ⁹. Barrier damage triggers release of chemokines (CCL17, CCL22) and alarmins (TSLP, IL-25, IL-33), which activate ILC2 and dendritic cells, inducing a Th2-skewed immune response (IL-4, IL-5, IL-13) ^9,10. These cytokines amplify inflammation and barrier impairment, perpetuating the disease. Staphylococcus aureus colonization further exacerbates chronicity ¹³.
• Inside-out theory: primary immune dysregulation drives AD ¹⁰. Genetic variants in cytokine-related genes (e.g., IL-4, IL-5, IL-13) lead to exaggerated Th2 responses, reduced filaggrin expression, impaired lipid metabolism, and weakened antimicrobial defence ¹⁴. Immune activation thus precedes and causes barrier impairment. ILC2 cells, activated by alarmins, sustain local inflammation even without prior barrier damage, supporting an immunocentric view ^14,15.

Both mechanisms are interconnected, with reciprocal amplification of barrier dysfunction and immune activation.

THE ITCH-SCRATCH CYCLE: AN INTEGRATED NEUROIMMUNOLOGICAL MODEL

Itch is a hallmark of AD, acting not only as the main clinical symptom but also as a driver of chronic inflammation. Scratching damages the skin barrier, facilitates allergen and microbe entry, and amplifies immune activation. Chronic itch also significantly impairs quality of life and contributes to psychological comorbidities.

Its pathogenesis is multifactorial, arising from interactions between the immune system, skin barrier, and the peripheral nervous system ¹⁶. The itch-scratch cycle is mediated by sensory neurons ¹⁷ and sustained by pruritogenic mediators including histamine, cytokines (IL-4, IL-13, IL-31, IL-33, TSLP), neuropeptides, and chemokines. Histamine, released by mast cells and acting via H₁ receptors, is mainly relevant in acute itch; in chronic AD its role is limited and H₁ antagonists show modest efficacy ¹⁸.

Mack and Kim (2018) ¹⁷, highlighted the neuroimmunological perspective: bidirectional communication among nerves, epithelial cells, and immune cells perpetuates chronicity. Th2 cytokines (IL-4, IL-13) not only drive inflammation but also sensitize itch-specific nociceptors ¹⁹.

Scratching, initially relieving through spinal inhibition, causes microtrauma that induces keratinocytes to release TSLP, IL-33, and IL-25. These activate innate immune cells (ILC2, dendritic cells), promoting a Th2 response (IL-4, IL-13, IL-31) ^20,21 that enhances sensory neuron excitability. IL-31, via Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signaling, directly activates receptors on keratinocytes and neurons. Meanwhile, nociceptors release neuropeptides (e.g., substance P), stimulating mast cells and amplifying inflammation.

This creates a self-perpetuating neuro-epithelial-immune loop: scratching worsens barrier damage, which amplifies inflammation, increases itch sensitivity, and leads to further scratching. This paradigm supports novel therapies such as JAK inhibitors, which block IL-31- and Th2-mediated cascades, effectively reducing pruritus ²². Furthermore, IL-4 and IL-13, acting through IL-4Rα, do not directly induce itch but enhance neuronal sensitivity to other pruritogens (IL-31, TSLP, histamine) ²³.

MOLECULAR ENDOTYPES OF ATOPIC DERMATITIS

In recent years, the clinical approach to AD has been enriched by a biological perspective. The concept of an endotype – defined as a subgroup of patients sharing specific immunological and molecular features regardless of phenotype – has emerged. This distinction is crucial to explain AD heterogeneity, variability in treatment responses, and disease progression ²⁴.

“Omics” studies (transcriptomics, proteomics, microbiomics) have identified several endotypes, mainly grouped into extrinsic/Th2-dominant, Th17/Th22-associated, and intrinsic/non-IgE mediated ²⁵. These differ in cytokine expression, barrier function, microbiome composition, genetic background, and therapeutic response, especially to biologics. Stratification enables more accurate classification and provides the foundation for personalized, targeted therapies, reducing disease burden.

The most relevant endotypes are extrinsic and intrinsic (Tab. I).

• Extrinsic (≈80%): early-onset, often more severe, with high total/specific IgE, eosinophilia, and Th2-driven inflammation (IL-4, IL-5, IL-13, IL-31). FLG loss-of-function mutations are frequent, leading to increased TEWL, allergen penetration, and reduced antimicrobial peptides, predisposing to Staphylococcus aureus colonization and infection ¹³. This endotype is strongly linked to atopic comorbidities (asthma, rhinitis, food allergies), consistent with the “atopic march” ⁷.
• Intrinsic (≈20%): later-onset, milder phenotype, with normal IgE levels and no systemic allergic sensitization. It involves Th1/Th17 responses (↑ IFN-γ, IL-17), relatively preserved barrier integrity, less pronounced TEWL, and lower susceptibility to bacterial colonization and allergic complications ²⁶.

THERAPEUTIC APPROACH TO ATOPIC DERMATITIS: FROM CONVENTIONAL THERAPIES TO BIOLOGICS

A critical component in the management of AD is the induction of remission through effective suppression of cutaneous inflammation and pruritus. Therapeutic interventions are stratified based on disease severity. Initial treatment typically involves conventional modalities, including emollients, topical corticosteroids, and calcineurin inhibitors. Patient and caregiver education regarding daily skin care and strategies to prevent flare-ups is essential to optimize long-term disease control.

Conventional topical treatments

Emollients are the cornerstone of AD therapy, and are essential in mild disease and as an adjunct in moderate-to-severe cases. They reduce inflammation, steroid dependency, and risk of relapse, acting through hydration and barrier repair. Both traditional formulations and occlusive agents show proven efficacy in alleviating pruritus, erythema, fissures, and lichenification ^27,28. Continuous use is recommended even during biologic therapy to maintain barrier function ²⁹.

Topical corticosteroids (TCS) remain the first-line treatment during flares, with potency selection based on age, site, and severity. Low-potency agents are advised for sensitive areas (face, folds), while medium/high-potency agents may be used for lichenified or thick skin under strict medical supervision. Vehicle choice is crucial: ointments for chronic lesions, creams for acute/moist areas ³⁰.

Once-daily application is generally as effective as twice-daily ³¹. A proactive strategy – intermittent low-potency TCS with daily emollients – reduces flares and prolongs remission ^32,33. Education on correct dosing using the “fingertip unit” (FTU) enhances adherence and prevents over/underdosing ³⁴.

Calcineurin inhibitors (TCI), including tacrolimus (0.03% and 0.1%) and pimecrolimus (1%), are preferred for sensitive areas, as they inhibit T-cell activation without causing skin atrophy. Tacrolimus 0.03% and pimecrolimus are approved from age 2, while tacrolimus 0.1% is approved for patients > 15 years ³⁵. TCIs are useful in facial/periorbital dermatitis and may reduce dupilumab-associated conjunctivitis ³⁶.

Topical PDE4 inhibitors, particularly crisaborole 2%, reduce production of inflammatory cytokines (TNF-α, IL-2, IL-4, IL-31) by increasing intracellular cAMP. Approved in Europe for mild-to-moderate AD in patients ≥ 2 years ³⁷, crisaborole has shown efficacy in improving clinical manifestations and pruritus in children and adolescents ³⁸. It is well tolerated, with most adverse events being mild local reactions. When used proactively with emollients, it reduces flares and the need for rescue corticosteroids ³⁹.

Systemic treatments

In patients with moderate-to-severe AD who remain refractory despite optimized topical therapy, systemic immunosuppressive agents have traditionally represented the next therapeutic step. Until 2017, the most recommended systemic options included cyclosporine, methotrexate, and azathioprine. These agents have broad immunomodulatory activity, and their long-term use is limited by potential adverse effects and the need for regular laboratory monitoring.

Cyclosporine is a calcineurin inhibitor and is effective in severe AD, but is recommended only short-term (≤ 12 months) due to nephrotoxicity, hypertension, and other cumulative toxicities ⁴⁰. Careful baseline and ongoing monitoring is required ⁴¹.

Methotrexate, a folate antagonist, shows efficacy within 12 weeks and is a viable alternative for refractory cases, particularly when biologics are not an option. Adverse effects include gastrointestinal symptoms and elevated transaminases; folic acid supplementation is recommended ⁴².

Azathioprine, a purine synthesis inhibitor, demonstrates efficacy comparable to methotrexate but with slower onset, often requiring > 12 weeks of therapy ^43,44.

Mycophenolate mofetil, another purine synthesis inhibitor, shows limited evidence but is generally well tolerated. Adverse effects include gastrointestinal complaints and, rarely, hematologic or genitourinary toxicity ⁴².

Given their modest efficacy, delayed response, and systemic risks, traditional immunosuppressants should be reserved for selected cases when modern targeted therapies are unavailable or contraindicated, with strict monitoring and minimization of treatment duration.

Small molecules

In recent years, the therapeutic landscape of AD has significantly expanded due to the introduction of targeted drugs, biologics, and small molecules capable of selectively modulating the immune pathways involved in the pathogenesis of the disease. The advent of these agents has marked a true revolution in the treatment of atopic dermatitis.

JAK and PDE4 inhibitors in AD

Several cytokines involved in AD pathogenesis interact with keratinocytes, immune cells, and peripheral sensory neurons, activating the JAK-STAT pathway, which drives the inflammatory response ⁴⁵. The JAK family includes JAK1, JAK2, JAK3, and TYK2, which are non-receptor tyrosine kinases associated with cytokine receptors. Upon activation, JAKs phosphorylate STATs, which dimerize and translocate to the nucleus to regulate inflammatory gene expression ⁴⁶.

JAK inhibitors (JAKi) are small molecules available for oral or topical use, selectively modulating JAK1, JAK2, or combinations thereof in a dose-dependent manner ⁴⁷. JAKi reduce inflammation, improve skin barrier function, and attenuate pruritus signaling.

Selective JAK1 inhibitors, such as upadacitinib and abrocitinib, provide rapid symptom improvement and quality-of-life benefits in moderate-to-severe AD, including adolescents ≥ 12 years. Phase III studies (Measure Up 1, Measure Up 2, AD Up) reported up to 70% EASI-75 response at week 16 with sustained efficacy up to 52 weeks ⁴⁸. Upadacitinib demonstrated superiority over dupilumab in itch reduction and skin clearance ⁴⁹.

Abrocitinib showed rapid pruritus relief from week 2 and durable response up to 48 weeks, with dose-dependent adverse events including nausea, headache, acne, herpes simplex, and increased creatine phosphokinase (CPK) ⁵⁰.

Baricitinib, a selective JAK1/JAK2 inhibitor approved for adults and children ≥ 2 years, effectively reduces lesion severity, pruritus, and maintains long-term efficacy up to 68 weeks ⁵¹. Its onset is slower than selective JAK1 inhibitors, but overall efficacy is comparable.

Ruxolitinib 1.5% cream, a topical dual JAK1/JAK2 inhibitor, is indicated for mild-to-moderate AD. Limited systemic absorption favors pediatric use, providing rapid itch reduction and lesion clearance with a favorable safety profile ⁵².

Long-term JAKi use requires clinical monitoring for dose-dependent adverse events, including infections and hematologic, hepatic, and lipid abnormalities. Risk assessment is necessary for cardiovascular, thromboembolic, and oncological events, with informed consent in patients with predisposing factors ⁵³.

Topical PDE4 inhibitors, such as crisaborole and difamilast, are effective non-steroidal treatments for mild-to-moderate pediatric AD. They reduce inflammation and pruritus, allow steroid-sparing therapy, and are safe for long-term use, including infants ^54,55. Rapid onset improves adherence, caregiver satisfaction, and disease control.

Biological drugs

Dupilumab (anti IL-4/IL-13)

Mechanism of action

Dupilumab is a human monoclonal antibody belonging to the IgG4 subclass, directed against the α-subunit of the interleukin-4 receptor (IL-4Rα), a receptor component shared by both type I (IL-4Rα/IL-2Rγ) and type II (IL-4Rα/IL-13Rα1) receptors ⁵⁶. By blocking IL-4Rα, dupilumab simultaneously inhibits the signaling pathways of IL-4 and IL-13, which are the key effector cytokines of the Th2 immune axis and central to the pathogenesis of AD ⁵⁷. Although dupilumab’s mechanism of action is limited to selective inhibition of these two cytokines, it results in a broader suppression of multiple downstream proinflammatory pathways, accompanied by improved skin barrier integrity and partial normalization of the altered epidermal microbiome ⁵⁸.

This drug has represented a therapeutic breakthrough in the treatment of AD: in 2019, both the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) approved dupilumab for the treatment of moderate-to-severe AD in adolescents (> 12 years) ⁵⁹, in 2020 for children aged 6 to 11 years, and in 2022 for infants from 6 months of age ⁶⁰ in the USA and 2023 in Europe ⁶¹. As of November 2024, the Italian Medicines Agency (AIFA) has approved reimbursement of this therapy by the Italian National Health Service for the treatment of severe AD in children aged between 6 months and 5 years who are eligible for systemic therapy. Until that time, in this age group, the drug could only be prescribed on a compassionate use basis. Between 2018 and 2019, the EMA and FDA approved dupilumab as add-on maintenance treatment in adults and pediatric patients aged 6 years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype or oral corticosteroid-dependent asthma. Dupilumab has been also indicated from FDA and EMA for patients with eosinophilic esophagitis older than 1 year and at least 15 kg of weight since January 2024. The FDA has approved dupilumab for children aged 1 year and older with eosinophilic esophagitis (EoE) ⁶².

Dupilumab has also been approved in USA and Europe for chronic rhinosinusitis with nasal polyposis, chronic spontaneous urticaria, prurigo nodularis, chronic obstructive pulmonary disease, and bullous pemphigoid, in patients older than 12 years ^{63 64}.

Clinical studies across different age groups: > 12 years, 6-11 years, and 6 months-5 years. Safety and adverse event profile

Long-term data confirm the good tolerability and sustained safety profile of dupilumab over time ⁶⁵.

Age group > 12 years

The multicenter study conducted by Cork et al. in 2020 ⁶⁶, involving adolescents with moderate-to-severe AD, demonstrated the long-term efficacy and safety of dupilumab, confirming its sustained clinical benefit and favorable tolerability profile.

In the phase III, randomized, double-blind, placebo-controlled, multicenter trial (LIBERTY AD ADOL), a total of 251 adolescents (aged 12-18 years) with moderate-to-severe AD were enrolled. Participants were divided into three groups: one-third received subcutaneous dupilumab every two weeks (200 mg for patients < 60 kg or 300 mg for those ≥ 60 kg), one-third received dupilumab every 4 weeks (300 mg), and the remaining third received placebo. At week 16, patients treated with dupilumab achieved significant clinical improvement, with an EASI-75 response rate more than 75% higher than that observed in the placebo group.

The safety profile of dupilumab was found to be favorable, with an overall incidence of adverse events comparable between the dupilumab and placebo groups: 72% in the biweekly dupilumab group, 64% in the monthly group, and 69% in the placebo group. The most common adverse events associated with dupilumab included conjunctivitis (reported in 10% of patients receiving the drug vs. 5% in the placebo group) and injection site reactions; however, these were self-limiting and of mild intensity. These findings confirm that dupilumab exhibits a good tolerability profile in the adolescent population, consistent with observations in adults, thus supporting its use as a safe and well-tolerated therapeutic option in this age group.

The LIBERTY AD PED-OLE study (Blauvelt et al. ⁶⁷) also assessed the long-term efficacy of dupilumab in 294 adolescents (aged 12-17 years) with moderate-to-severe AD. The clinical follow-up lasted 52 weeks, allowing for a thorough evaluation of sustained efficacy and long-term tolerability. By week 52, 42.7% of patients achieved clear or almost clear skin, and 93.1%, 81.2%, and 56.4% showed at least a 50%, 75%, or 90% improvement in EASI scores, respectively. From a safety standpoint, the results were consistent with those observed in previous studies and confirmed the favorable tolerability profile of dupilumab over the long term. Most adverse events – including upper respiratory tract infections, conjunctivitis, and injection site reactions – were of mild or moderate intensity and did not lead to treatment discontinuation. The absence of cumulative toxicity signals or new adverse effects further reinforces the value of dupilumab as a long-term treatment capable of providing sustained disease control without compromising patient safety.

Age group 6-11 years

A significant contribution to the understanding of the efficacy and safety profile of dupilumab in the 6-11 year age group is provided by the phase III randomized, double-blind, placebo-controlled study published by Paller et al. in 2020 ⁶⁸. The study enrolled 367 pediatric patients with severe AD inadequately controlled by topical treatments (involving ≥ 10% body surface area, an EASI score ≥ 21, and a Numerical Rating Scale (NRS) for itch ≥ 4). Patients were divided into three treatment groups: the first received dupilumab 300 mg every four weeks; the second received dupilumab every two weeks, with a dose of 100 mg for patients weighing < 30 kg and 200 mg for those ≥ 30 kg; the third group received placebo. The duration of treatment was 16 weeks.

The results demonstrated a marked clinical improvement in children treated with dupilumab compared to placebo. At week 16, 68.4% of patients receiving dupilumab every 2 weeks achieved a ≥ 75% reduction in EASI score from baseline, compared to 53.4% of patients treated monthly and only 27.1% in the placebo group. Benefits were also observed in subjective symptoms such as itch: a reduction of at least 4 points on the NRS was achieved by 51% of patients receiving dupilumab biweekly versus 12% in the placebo group. Concurrently, significant improvement in quality of life was recorded, assessed by the Children’s Dermatology Life Quality Index (CDLQI), along with a reduced need for topical corticosteroids in the dupilumab-treated groups, indicating better overall disease management.

From a safety perspective, dupilumab treatment was generally well tolerated. The overall incidence of adverse events was similar between the dupilumab and placebo groups (approximately 72-75%), with most events being of mild to moderate intensity. The most reported adverse events in patients treated with dupilumab were injection site reactions and conjunctivitis, with an incidence ranging from 6% to 10%. Notably, the incidence of skin infections, including impetiginization, was lower in the dupilumab-treated groups compared to placebo (6-7% vs. 13%), suggesting a potential protective effect related to improved skin barrier integrity.

In conclusion, the study demonstrates that dupilumab, in combination with topical corticosteroids, is significantly more effective than placebo in improving clinical parameters of severe AD in children aged 6 to 11 years. The drug was also shown to be safe and well tolerated in this age group, with a predictable and manageable adverse event profile.

Age group 6 months-5 years

In 2021, Paller et al. conducted the LIBERTY AD PRE-SCHOOL ⁶⁹ evaluating the efficacy and safety of dupilumab in 40 children aged ≥ 6 months to < 6 years. This study provided essential data supporting the safety and favorable pharmacokinetics of dupilumab in children under 6 years of age with severe uncontrolled AD.

Patients were divided into two cohorts (6 months-2 years and 2-6 years), both treated with dupilumab (3 mg/kg for patients < 15 kg, 6 mg/kg for those ≥ 15 kg). The results showed clinical improvement in both cohorts, with slightly higher responses in the older children and a safety profile consistent with previous studies. At week 4, a mean reduction of 44% in EASI score was observed, along with significant improvements in itch (assessed by NRS), sleep quality, and irritability, based on parental reports.

Regarding safety, dupilumab was well tolerated in both cohorts, with no serious adverse events or treatment discontinuations. The main adverse events reported were mild and self-limiting, including rhinitis, pharyngitis, transient skin rashes, and mild injection site irritation. No serious infections or clinically relevant signs of immunosuppression were observed.

Furthermore, another phase III, multicenter, randomized, double-blind, placebo-controlled study ⁷⁰, demonstrated the efficacy and safety of dupilumab in 162 children aged 6 months to 6 years with uncontrolled AD. Participants were divided into two groups: one group received subcutaneous dupilumab every four weeks (200 mg for patients < 15 kg and 300 mg for those ≥ 15 kg), while the control group received placebo at the same interval. The double-blind treatment period lasted 16 weeks, at the end of which both clinical efficacy endpoints and safety parameters were evaluated. At week 16, a ≥ 75% reduction in EASI score was achieved in 53% of children treated with dupilumab, compared to 11% in the placebo group. A substantial reduction in itch, assessed by caregiver-reported NRS, was also observed: a ≥ 4-point reduction occurred in 48% of patients receiving dupilumab versus 9% in the placebo group. Similar improvements were noted in sleep quality and irritability, which are critical parameters for the child’s psycho-physical development and family well-being.

Regarding safety, the overall incidence of adverse events was similar between dupilumab and placebo groups (64% vs. 74%). The most frequent adverse events were mild to moderate and included upper respiratory tract infections, injection site reactions, and conjunctivitis.

These data on the long-term safety and efficacy of dupilumab in children aged 6 months to 5 years with moderate-to-severe AD were further confirmed by the phase 3 open-label extension study, LIBERTY AD PED-OLE ⁷¹, published in 2024. The study included patients who had previously completed the LIBERTY AD PRE-SCHOOL trial, during which they received dupilumab for 16 weeks. In the extension phase, participants continued to receive the drug every 4 weeks, with dosing adjusted according to body weight (200 mg for children weighing 5 to 15 kg, and 300 mg for those between 15 and 30 kg), for a total duration of up to 52 weeks. The trial involved 142 children, of whom 60 completed the full year of treatment. Regularly administered dupilumab was associated with a favorable safety profile. Most adverse events (approximately 78% of patients) were mild to moderate and transient. The most common events were pharyngitis, cough, and fever. Regarding efficacy, data collected up to week 52 confirmed a clinically significant and sustained improvement over time. In all, 97% of patients achieved at least a 50% improvement in EASI score (EASI-50), 79% achieved a 75% reduction (EASI-75), and nearly 59% achieved a 90% reduction (EASI-90).

Overall, these results indicate that continuous use of dupilumab for one year in younger children with AD has a favorable tolerability profile and is associated with a clinically meaningful therapeutic response.

Efficacy on pruritus, skin lesions, sleep quality, and atopic comorbidities

Pruritus is considered one of the most debilitating symptoms of AD, negatively impacting not only patients’ quality of life but also sleep quality, psychological well-being, and daily activities. In adolescents, persistent pruritus is specifically associated with impaired academic, occupational, and social functioning. Therefore, reducing this symptom represents a primary therapeutic goal in the management of AD, on par with the reduction of skin lesions.

An integrated analysis of data from four phase III registration trials ⁷² provided a detailed evaluation of dupilumab’s effect on pruritus dynamics in a large adolescent patient population. The results demonstrated that dupilumab induces an early, significant, and sustained reduction in pruritus, measured using the NRS, a subjective 0-to-10 scale where patients rate the average itch intensity over the previous three days. Notably, patients treated with dupilumab reported clinically meaningful reductions as early as the first week of treatment. This effect further consolidated in the following weeks: by week 12, symptomatic response rates exceeded 55-60%, with a peak efficacy observed around week 16 and maintained long-term in patients on continuous therapy.

Importantly, the reduction in pruritus was found to be independent of the reduction in lesion extent, suggesting a direct effect of dupilumab on the pruritogenic mechanism.

From a pathophysiological perspective, the efficacy of dupilumab can be attributed to its targeted action on the IL-4 and IL-13 signaling pathways, cytokines directly involved in the generation of neuroinflammatory pruritus. Inhibition of this pathway leads to a reduction in peripheral nerve fiber sensitization and normalization of the cutaneous expression of pruritogenic mediators such as thymic stromal lymphopoietin (TSLP), confirming dupilumab’s dual action on both inflammatory and neurosensory levels.

The benefits on pruritus were accompanied by significant improvements in other related subjective parameters, including sleep quality, daytime irritability, academic or occupational concentration, and a decreased use of antihistamines.

Tralokinumab and lebrikizumab (anti-IL-13)

AD is a type 2 immunity (Th2)-driven allergic disease, in which upregulation IL-4 and IL-13 in lesional and non-lesional skin suggests a pivotal role of these cytokines in the pathogenesis. In particular, IL-13 has been recently clarified as the key cytokine leading the inflammation in the peripheral tissues, while IL-4 may have basically a central effect, in patients with AD ^73-75. Increasing evidence showed that IL-13 is locally overexpressed and impacts the biologic pathways of the skin areas affected by AD. IL-13 seems to hold a role in the inflammatory reaction underlying AD, recruiting inflammatory cells, altering the skin microbiome, and decreasing epidermal barrier function. Increases in of IL-13 associated chemokine mRNA and blood levels are associated with a more severe phenotype of the disease, while lower IL-13 levels have been related with a good therapeutic and clinical response ⁷⁶. The actual relative contribution of each of these two cytokines to AD pathogenesis needs to be clarified ^77,78.

Tralokinumab

Tralokinumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that selectively binds and specifically neutralizes IL-13, thus preventing it from binding to the IL-13Rα1 and IL-13Rα2 receptors ⁷⁹. Tralokinumab was approved in 2021 by the FDA and EMA for adults with moderate-to-severe AD. On September 2022 and December 2023, the EMA and FDA both expanded approval of tralokinumab in Europe and USA to patients aged 12 to 17 years with moderate-to-severe AD, not adequately controlled with topic therapies, and with no improvement or have developed intolerable adverse effects with dupilumab. The recommended dosage is an initial loading dose of 300 mg, followed by a 150 mg dose every 2 weeks. During treatment with tralokinumab, routine laboratory tests are not required ⁸⁰. Following the promising early and sustained results of phase II studies, testing the treatment with tralokinumab combined with topical corticosteroids in adults with moderate to severe AD, two 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, have been conducted on adults with moderate-to-severe AD with an inadequate response to topical treatments, randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks or placebo. Tralokinumab has been described as safe and effective monotherapy superior to placebo at 16 weeks of treatment and well tolerated up to 52 weeks of treatment in selected patients. In detail, at 16 weeks, the Investigator’s Global Assessment (IGA) score of clear to almost clear (IGA 0 or 1) was achieved in 15.8 and 22.2% of treated patients versus 7.1 and 10.9% on placebo; moreover 25.0 and 33.2% of treated patients achieved an EASI-75 vs. 12.7% and 11.4% on placebo. At 16 weeks, the trials found early improvements in pruritus, sleep interference, DLQI, SCORing Atopic Dermatitis and Patient-Oriented Eczema Measure, with a maintenance of the good response at week 52 in most of the subjects treated with tralokinumab treatment without any rescue medication. Adverse effects were seen in 76.4% and 61.5% of patients receiving tralokinumab and in 77.0% and 66.0% of patients receiving placebo, respectively, in ECZTRA 1 and ECZTRA ⁸¹.

The clinical trial ECZTRA 3 examined the combination of tralokinumab and TCS compared to a nonactive drug (placebo) plus TCS treatment for adults with moderate-to-severe AD not previously improved with topical treatments. Treated patients were injected with tralokinumab 300 mg or placebo every week for 16 weeks; in case of a good response, they continued the same treatment or were moved on to receive less-frequent dosing (once every 4 weeks) for a further 16 weeks to assess the best effective dose for the maintenance of the clinical result. TCS was provided to patients for treatment of signs and symptoms of AD and recorded in its use. The evaluation of extent and severity of eczema showed that significantly more tralokinumab-treated patients had a 75% reduction in the severity of their eczema, compared with placebo-treated patients: 56.0% vs. 37.7% ⁸². The most common side effects were mainly mild to moderate, described as upper respiratory infections, conjunctivitis, injection-site reactions, and eosinophilia. They mainly resolved by the end of the initial 16-week treatment period ^81,83.

A phase 3 clinical trial (Phase-3 ECZTRA-6) was recently conducted in 289 adolescents 12 to 17 years old with moderate to severe AD, enrolled by 72 centers across 10 countries in North America, Europe, Asia, and Australia. The aim of the study was to evaluate the efficacy and safety of interleukin-13-targeted treatment with tralokinumab as monotherapy. Patients were randomized (1:1:1) to tralokinumab (150 or 300 mg) or placebo every 2 weeks for 16 weeks. Patients receiving tralokinumab and meeting either primary endpoint at week 16 without use of rescue medication were considered responders and were re-randomized (1:1) to receive blinded maintenance treatment until week 52 for either every 2 weeks or every 4 weeks at their original dose (150 or 300 mg); adolescents in the placebo arm meeting the primary endpoint at week 16 without use of rescue medication continued to receive blinded placebo every 2 weeks until week 52. The remaining were transferred to open-label treatment with tralokinumab 300 mg every 2 weeks with optional use of weak to moderate potency TCS or TCI. Most of the patients treated with 300 or 150 mg of tralokinumab in monotherapy achieved an IGA score of 0 (clear) or 1 (almost clear) and 75% or more improvement in the EASI after 16 weeks, compared to placebo, with reported data of 21.4, 17.5 and 4.3% respectively (adjusted difference, 17.5% [95% CI, 8.4-26.6%]; P < .001 and 13.8% [95% CI, 5.3-22.3%]; P = .002, respectively). A higher number of patients achieved EASI 75 without rescue medication in the tralokinumab 150 mg (28.6%) and tralokinumab 300 mg (27.8%) arms vs. the placebo (6.4%) arm at week 16 (adjusted difference, 22.5% [95% CI, 12.4-32.6%]; P < .001 and 22.0% [95% CI, 12.0-32.0%]; P < .001, respectively). The most common adverse events were mainly local injection site reactions, upper respiratory tract infections, asthma flare, headache, and eosinophilia. The incidence of conjunctivitis was low and similar between the two tralokinumab arms vs. the placebo arm at week 16 and up to 52 weeks ⁸³. Even in adolescents tralokinumab-treated (150 mg or 300 mg) who did not achieve the high standard of clear/almost clear skin – IGA > 0/1 – after 16 weeks of treatment without rescue therapy, meaningful results were observed in both clinician-measured and patient-reported outcomes. The use of outcome measures of both efficacy and patient quality of life, in addition to IGA scores, can help the clinician in the evaluation of the response in adolescents with moderate-to-severe AD treated with tralokinumab ⁸⁴. The results from studies are consistent and suggest that tralokinumab is an effective and well-tolerated long-term treatment option for uncontrolled AD in adolescents. Tralokinumab is not FDA-approved for younger children (< 12 years old), although clinical trials are underway for children 2-12 years of age. A phase II single (Assessor) blinded, randomized, parallel-group, monotherapy trial has been started to evaluate the pharmacokinetics and safety of tralokinumab in children (6-12 years) with moderate-to-severe AD. An initial treatment period for 16 weeks will be followed by an open-label treatment period for 52 weeks and a long-term extension treatment period for up to 106 weeks. The outcomes will be evaluated using SCORAD, POEM, EASI and recording adverse effects ⁸⁵.

Lebrikizumab

Lebrikizumab is a humanized IgG4κ monoclonal antibody selectively binding and neutralizing soluble IL-13 with high affinity. IL-4Rα/IL-13Rα1 signaling complex and downstream type-2 inflammation is blocked, while IL-13 binding to the decoy receptor IL-13Rα2 (an endogenous regulatory pathway) is preserved. This targeted mechanism of action on IL-13 improves epidermal barrier function, reduces Th2 type inflammation, and has good effect on itch in AD ⁸⁶. Lebrikizumab is currently approved for adults and adolescents with moderate-to-severe AD, ≥ 12 years who weigh ≥ 40 kg both in the USA and Europe ^63,87.

A phase 2b randomized clinical trial in which lebrikizumab was used as monotherapy highlighted meaningful dose-dependent clinical improvement across EASI, IGA, and itch in adults, with a good safety profile. Based on phase II trials, the blockage of IL-13 with lebrikizumab in monotherapy can be sufficient to see satisfying clinical results in AD, with rapid onset, dose-dependent efficacy in adults ⁸⁸. At week 12, 82.4% adult patients achieved EASI-50 with lebrikizumab 125 mg every 4 weeks vs. 62.3% of placebo (P = .026); single dose of lebrikizumab did not reach any significant result in EASI-50 compared with placebo. Adverse effects were similar and mild-to-moderate in both groups ⁸⁹. The phase 3 trials ADvocate-1 and -2 confirmed the promising results in 52-week trials, in which lebrikizumab was used as monotherapy: IGA 0/1 improved up to 43% and EASI-75 up to 59% vs. placebo at week 16; the good response has been maintained to 1 year in responders prolonging the treatment ⁹⁰. Efficacy of lebrikizumab in adolescents is as consistent as in adults in recent phase 3 studies. Skin-clearance and itch outcomes (IGA/EASI) are comparable in adolescents older than 12 years treated at week 16 with further improvements by week 52. Paller’s team (in ADore study) showed that, at week 16, ≥ 2 point from the baseline of IGA was achieved in 62.6% of patients and EASI-75 in 81.9% of patients by week 52 ⁹¹.

Silverberg’s phase 3 trial (ADvocate program) also demonstrated that the primary outcome was achieved in 43.1% in the treated group vs. 12.7% of placebo group (P < 0.001), with a IGA score of 0 or 1 and a reduction at least of 2 points from the baseline at week 16; EASI-75 response occurred in 58.8% and 16.2%, respectively (P < 0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P < 0.001); EASI-75 response has been reported in 52.1% vs. 18.1%, respectively (P < 0.001). In trial 2, the primary outcome was seen in 33.2% of adolescents receiving the treatment vs. 10.8% in the placebo group (P < 0.001), similarly to an EASI-75 response of 52.1% and 18.1%, respectively (P < 0.001). Safety profile has been described as largely mild/moderate according with prior trials ⁹⁰.

Ongoing pediatric trials are assessing efficacy, safety and potential label expansion below 12 years. In particular, a randomized, double-blind study has started enrolling children from 6 months to < 18 years. Additional Phase 3/3b studies are currently ongoing to evaluate broader real-world efficacy of lebrikizumab and its use in special populations ⁹².

At variance from dupilumab, the available results suggest that IL-13 blockade via lebrikizumab or tralokinumab may not suffice to yield clinical benefit in uncontrolled asthma and EoE ¹⁹,⁹³.

Comparative data between selective anti IL-13 biologic drugs and dupilumab

Recent meta-analyses have indirectly shown a lower efficacy of tralokinumab than lebrikizumab in adults and adolescents at week 16 (IGA 0/1 up to 22.2% and 43%; EASI-75 25-33% and 52-59% vs. placebo respectively) and prolonged long-term responses for all. The results are comparable between lebrikizumab and dupilumab ^81,90. However, head-to-head active comparator studies are needed to evaluate the comparative efficacy of anti-IL-13 therapy alone vs. anti-IL-4/IL-13. Current phase III trials have been investigating the long-term safety and efficacy of lebrikizumab as monotherapy after 52 weeks treatment of moderate-to-severe AD. In terms of safety, IL-13 drugs and dupilumab can be considered safe; focusing on conjunctivitis as adverse effect, dupilumab showed a slightly higher incidence compared to placebo ^94,95.

Nemolizumab

Nemolizumab is a humanized monoclonal antibody that binds selectively to the α-subunit of the interleukin-31 receptor (IL-31RA). This blocks the IL-31-driven neuroimmune pathway, which is involved in the connection between cutaneous inflammation and itch. It produces a prompt antipruritic response by suppressing IL-31-induced activation of sensory neurons in both cutaneous tissue and dorsal root ganglia, thereby reducing the neural conduction of itch-related signals ⁹⁶. Blocking signalling of IL-31 not only has an antipruritic action, but also mitigates downstream immune responses, such as the release of inflammatory mediators, and promotes normalization of keratinocyte maturation and epidermal differentiation, facilitating restoration of skin barrier integrity ^96,97. Thus, it may help to prevent long-term barrier dysfunction and fibrotic remodelling. Moreover, inhibition of IL-31RA disrupts the self-perpetuating itch-scratch cycle, thereby reducing chronic pruritic stimuli and preventing further compromise of the skin barrier and potential fibrotic remodelling. This effect arises from the fact that IL-31-induced pruritus leads to scratching, which exacerbates inflammation and perpetuates the sensation of itch ⁹⁷.

Nemolizumab is approved by the EMA in Europe for patients aged ≥ 12 years with moderate-to-severe AD. In experimental models, including transgenic mice overexpressing IL-31 and rodents administered IL-31 via intradermal, intravenous, subcutaneous, or intrathecal routes, marked and persistent scratching behavior, often accompanied by AD-like skin lesions, has been consistently observed. These findings highlight the critical role of IL-31 in both the initiation and maintenance of this pathogenic cycle ^98,100. Conversely, IL-31RA-deficient mice do not exhibit pruritus or dermatitis in response to IL-31 exposure, underscoring the critical role of IL-31RA in mediating these neurocutaneous responses ⁹⁹. Moreover, therapeutic blockade of IL-31, either through monoclonal antibodies targeting the cytokine itself or its receptor, significantly reduces scratching behavior in murine models, demonstrating that disruption of this pathway mitigates itch-driven disease progression ^101,102. Collectively, these mechanistic insights illustrate that nemolizumab exerts a targeted neuroimmune effect, rapidly alleviating pruritus while simultaneously addressing immune-mediated epithelial dysfunction in AD ⁹⁶.

Kabashima et al. conducted a double-blind, randomized trial involving individuals with AD and moderate-to-severe pruritus unresponsive to standard topical therapy. Participants were randomized in a 2:1 ratio to receive nemolizumab (60 mg) subcutaneously or placebo every four weeks over a 16-week period, while continuing their baseline topical regimen. The primary efficacy endpoint was the percentage change in itch intensity from baseline to week 16, assessed using a visual analogue scale (VAS). Secondary outcomes included changes in the EASI, DLQI, Insomnia Severity Index (ISI), and overall safety. Nemolizumab treatment resulted in a statistically significant reduction in pruritus, accompanied by parallel improvements in EASI, DLQI, and ISI compared with placebo. Most adverse events were mild, with injection-site reactions more frequently reported in the nemolizumab group ¹⁰³. In adolescents with moderate-to-severe AD, a loading dose of 60 mg followed by 30 mg every 4 weeks led to substantial clinical improvements after 16 weeks, including reductions in EASI (-66.5% ± 32.5), pruritus (PP-NRS -43.2% ± 37.0), and sleep disturbance (Sleep NRS -53.5% ± 47.8). Pharmacokinetic exposure and exposure-response relationships were comparable to those observed in adult populations ¹⁰⁴. Additionally, in a multicentre, phase III trial involving Japanese children aged 6-12 years with AD and moderate-to-severe pruritus, administration of nemolizumab 30 mg every 4 weeks resulted in significantly greater improvement in mean weekly itch scores compared with placebo (least-squares mean difference -0.8; 95% CI -1.1 to -0.5; P < 0.0001). The therapeutic effect emerged as early as day 2 post-dosing, and the safety profile was consistent with that reported in older age groups ¹⁰⁵.

In the open-label phase of the NCT03921411 trial, Sidbury et al. evaluated nemolizumab in adolescents aged 12-17 years with moderate-to-severe AD. Treatment over 16 weeks was associated with marked improvements in pruritus, skin lesions, and sleep quality, while maintaining a pharmacokinetic and safety profile consistent with data in adults. Integrated pharmacokinetic/pharmacodynamic analyses further supported comparable exposure-response relationships between adolescents and adults, reinforcing the therapeutic relevance of nemolizumab across age groups. Moreover, nemolizumab therapy was associated with the downregulation of skin biomarkers implicated in AD-related inflammation, highlighting the central role of IL-31 in disease pathophysiology ¹⁰⁵.

In two phase 3 studies, ARCADIA 1 and ARCADIA 2 ¹⁰⁶, patients over the age of 12 with moderate-to-severe AD, associated pruritus, and inadequate response to topical steroids received nemolizumab 30 mg subcutaneously, which was significantly better than placebo in IGA score improvement, and EASI75 was achieved in ≥ 75% at week 16.

Liang et al. ¹⁰⁷ analyzed 6 randomized controlled studies involving 14 cohorts of participants. Nemolizumab significantly reduced pruritus and EASI scores in comparison with placebo, with no increased occurrence of adverse events.

Given the significant burden of pruritus and impaired quality of life in pediatric patients, nemolizumab represents a promising targeted therapy. Controlled pediatric trials are warranted to further establish the safety and efficacy of nemolizumab, in the management of moderate-to-severe AD in children and adolescents. A phase 2 trial on efficiency and safety of nemolizumab in children aged 2-11 with moderate-to-severe AD is ongoing.

OTHER BIOLOGICS

The OX40-OX40 ligand (OX40L) costimulatory axis is integral to the persistence and antigen-specific nature of pathogenic T-cell responses in AD, promoting propagation, differentiation, endurance and memory differentiation across Th2, Th1, Th17 and Th22 lineages, leading to chronic inflammation ¹⁰⁸. The OX40 co-stimulatory receptor is induced by OX40L after antigen stimulation, on various T cell subsets ¹⁰⁹. Studies in adults showed that targeting the OX40-OX40L axis may be helpful to control chronic T cell-mediated inflammation in AD. Rocatinlimab (formerly KHK4083) is a human, non-fucosylated IgG1 anti-OX40 monoclonal antibody engineered to enhance antibody-dependent cellular cytotoxicity and to reduce the burden of activated OX40-expressing T cells ¹¹⁰.

Amlitelimab (SAR445229 / KY1005) is a fully human, non-depleting IgG4 anti-OX40L monoclonal antibody that inhibits APC-T-cell co-stimulation at the ligand level without direct cytotoxic depletion of T cells ^111-113. In a phase 2b, multicenter, randomized, double-blind study that enrolled adults with moderate-to-severe disease, rocatinlimab produced statistically significant least-squares mean reductions in EASI at week 16 across all dose regimens (for example, -61.1% with 300 mg every 2 weeks vs. -15.0% for placebo) and demonstrated progressive improvement during the active-extension phase with durable responses maintained in the majority of responders during a 20-week off-treatment follow-up .The safety profile of rocatinlimab was characterized predominantly by transient, mostly mild-to-moderate injection/infusion-related reactions (notably pyrexia and chills after initial dosing), together with mild upper-respiratory symptoms and occasional aphthous ulcers; serious adverse events were uncommon and no deaths were reported in the phase-2b cohort ¹¹⁴. Another phase 1, single-center, open-label, repeated-dose study confirmed the safety and tolerability of rocatinlimab in patients with moderate to severe AD. In fact, there were no deaths or serious adverse events in the trial, nor any discontinuations due to adverse events. Only mild or moderate adverse events such as pyrexia and chills were recorded, with no clinically meaningful changes in laboratory values, vital signs, or electrocardiogram recordings ¹¹⁵.

In the STREAM-AD phase-2b program, amlitelimab met the primary endpoint with least-squares mean EASI reductions at week 16 of approximately -61.5%, -56.8%, -51.6% and -59.6% across the active dose groups vs. -29.4% with placebo, and clinically meaningful proportions of patients achieved IGA (Investigator Global Assessment) 0 (clear skin) /1(almost clear skin) and EASI-75. Amlitelimab produced rapid, broad pharmacodynamic effects with reductions in serum biomarkers linked to AD activity, including TARC (Thymus- and activation-regulated chemokine), IL-13, IL-31, IL-17A and IL-22, as well as decreases in lactate dehydrogenase, total IgE and blood eosinophils; these biomarker changes were sustained through week 52 in patients who continued treatment and in those who were withdrawn ¹¹⁶. Notably, both the rocatinlimab and amlitelimab programs reported clinically durable control after treatment discontinuation for substantial subsets of responders, an outcome consistent with mechanistic reduction or functional inhibition of antigen-specific pathogenic T cells rather than only transient symptomatic suppression ¹¹⁴,¹¹⁶.

In a phase 2 study in adults with moderate to severe AD, rademikibart, an anti IL-4 receptor alpha blocking IL-4 and IL-13 activities, was effective and tolerated after 2 and 4 weeks of treatment. The efficacy was maintained following 52 weeks of treatment ¹¹⁷.

In phase 1 and 2 studies in adults with moderate to severe AD, several monoclonal antibodies IL-4 and IL-13 by binding IL-13 receptor including cendakimab ¹¹⁸ and eblasakimab ^119,120 were effective and tolerated.

Among monoclonal antibodies that inhibit anti-IgE, in a randomized clinical trial omalizumab ¹²¹ showed significantly reduced eczematous skin lesions and enhanced quality of life in children with severe eczema unresponsive to standard treatment and elevated total serum IgE, while ligelizumab ¹²² showed no efficacy.

Benralizumab (anti-IL-5Rα receptor) ¹²³, bermekimab (anti-IL1α) ¹²⁴, fezakinumab (anti-IL-22) ¹²⁵, mepolizumab (anti-IL-5), monoclonal antibodies that inhibits IL-33, including melrilimab ¹²⁶, itepekimab ¹²⁷ and astegolimab ¹²⁸, risankizumab (anti-IL-23p19), secukinumab (anti-IL-17A) ¹²⁹, tezepelumab (anti- thymic stromal lymphopoietin) ¹³⁰, and ustekinumab (anti-IL-12/23p40) ¹³¹ have also been studied.

CONCLUSIONS

The therapeutic landscape for pediatric AD has undergone substantial evolution over the past decade, shifting from a predominantly symptomatic approach, centered on emollients, topical corticosteroids, and calcineurin inhibitors, toward a mechanism-based therapeutic strategy incorporating biologics and targeted small molecules. This paradigm shift reflects an enhanced understanding of disease pathophysiology, particularly the pivotal role of the Th2 immune axis, epidermal barrier dysfunction, and microbial dysbiosis in perpetuating chronic inflammation. This has led to treatments that directly interrupt the key cytokine pathways that drive disease activity.

The mechanisms of action of drugs used in AD are summarized in Table II. Biologics such as dupilumab, tralokinumab, and nemolizumab selectively target these cytokines, including IL-4, IL-13, and IL-31, demonstrating significant efficacy in reducing disease severity, alleviating pruritus, improving sleep quality, and addressing comorbid allergic conditions in pediatric patients. Likewise, small molecules, such as oral JAK inhibitors and topical PDE4 inhibitors, offer additional therapeutic options, with flexible routes of administration and potential utility in both acute and maintenance settings. PDE4 inhibitors, such as crisaborole and difamilast, provide steroid-sparing topical alternatives for mild-to-moderate disease, with favourable tolerability profiles suitable for prolonged use. While JAKi have shown high efficacy, their use in younger populations requires careful patient selection and monitoring due to potential systemic risks. In clinical practice, treatment selection should balance efficacy, safety, and the long-term implications of early immunomodulation. Among available agents, dupilumab has sustained efficacy and safety demonstrated across multiple age groups, including infants and durable disease control on long-term extension. Selective IL-13 blockades with tralokinumab and lebrikizumab expands the options for children and adolescents with moderate-to-severe AD, particularly for those who exhibit suboptimal response, intolerance, or practical limitations with dupilumab. Targeting the IL-31/IL-31RA axis with nemolizumab offers a complementary, mechanism-anchored approach focused on the neuroimmune circuitry of itch, a dominant and disabling morbidity in pediatric AD. This profile makes nemolizumab particularly attractive for pruritus-predominant endotypes or as an adjunct in partial responders to other biologics. As the therapeutic armamentarium expands, head-to-head trials and comparative effectiveness studies will be essential to optimize sequencing, combination strategies, and cost-effectiveness in real-world practice. Looking forward, novel biologics may not only achieve better durable symptom control but also modify the disease trajectory by limiting skin barrier damage and reducing progression along the atopic march toward asthma and allergic rhinitis. Integration of precision medicine approaches, including biomarker-driven treatment selection, holds promise for further refining outcomes. The expanding range of treatment options has the potential to improve quality of life for affected children and their families while minimizing long-term disease burden.

Ethical consideration

This article is a narrative review of the scientific literature focusing on novel therapeutic approaches for atopic dermatitis.

Funding

The author declares that no funding was received for this work.

Conflicts of interest statement

The author declares no conflict of interest.

Author’s contributions

All authors have read and approved the final version of the manuscript and agree with its submission to the journal.

History

Received: September 15, 2025

Published: January 23, 2026

Figures and tables

TABLE I. Main immunological endotypes of AD and therapeutic implications ⁷.

Endotypes	Immunological characteristics	Targeted therapies
Th2-dominant	↑ IL-4, IL-13, IL-31↑ IgE↓ Antimicrobial peptides	Dupilumab (anti-IL-4), Tralokinumab, Lebrikizumab (anti IL-13) and Nemolizumab (anti-IL-31)
Th17/Th22-associated	↑ Il-17/IL-22	Anti IL-22 (ongoing clinical trials)
Intrinsic/non-IgE mediated	IgE normal level↑ Th1/Th17	JAK inhibitors (Upadacitinib, Abrocitinib)

TABLE II. Mechanisms of action of drugs used in AD.

Drugs	Therapeutic target	Mechanism of action	Therapeutic indications
Pimecrolimus	Calcineurin	Calcineurin inhibition resulting in the interruption of T cell activation	Mild-to-moderate AD 54
Tacrolimus	Calcineurin	Calcineurin inhibition resulting in the interruption of T cell activation	Moderate-to-severe AD 134
Cyclosporin	Calcineurin	Calcineurin inhibition resulting in the interruption of T cell activation	Moderate-to-severe AD 135
Metotrexate	Dihydrofolate reductase	Reduces purine and pyrimidine synthesis, thereby inhibiting cell proliferation, including T lymphocytes, which play a central role in the pathogenesis of atopic dermatitis	Moderate-to-severe AD 136
Azathioprine	Purines	Antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and purines	Moderate-to-severe AD 137
Mycophenolate mofetil	Inosine monophosphate dehydrogenase (IMPDH)	Potent, selective, and reversible inhibitor of IMPDH, particularly the isoenzyme IMPDH II, which is highly expressed in activated lymphocytes	Moderate-to-severe AD 138
Upadacitinib	JAK1	Selective JAK1 inhibitor (systemic)	Moderate-to-severe AD 48
Abrocintinib	JAK1	Selective JAK1 inhibitor (systemic)	Moderate-to-severe AD 139,140
Ruxolitinib	JAK1/JAK2	Binds to JAK1/JAK2 with high affinity (topical)	Moderate-to-severe AD 141
Baricitinib	JAK1/JAK2	Bindsto JAK1/JAK2 with high affinity (systemic)	Moderate-to-severe AD 139
Dupilumab	IL-4Rα	Binds to IL-4Rα and inhibits IL-4 and IL-13 signaling	Moderate-to-severe AD 46
Tralokinumab	IL-13	Binds with high affinity to IL-13, inhibiting its interaction with receptors	Moderate-to-severe AD 143
Lebrikizumab	IL-13	Binds with high affinity to IL-13, inhibiting its interaction with receptors	Moderate-to-severe AD 144
Nemolizumab	IL-31Rα	Binds to the interleukin-31 receptor alpha (IL-31RA) targeting pruritus	Moderate-to-severe AD
Mepolizumab	IL-5	Antagonizes IL-5, reducing eosinophil levels	Moderate-to-severe AD 145
Benralizumab	IL-5Rα	Binds to the IL-5 receptor (IL-5R), blocking its signaling	Moderate-to-severe AD 146
Ustekinumab	IL-12	Blocks the binding of inflammatory cytokines to receptors on lymphocytes	Moderate-to-severe AD 147
Tezepelumab	TSLP	Inhibits Th2 activation and reduces keratinocyte differentiation	Moderate-to-severe AD 148
Fezakinumab	IL-22	Binds IL-22, preventing the formation of the IL-22/IL-22R complex	Moderate-to-severe AD 149
Sekukinumab	IL-17	Blocks receptors expressed on keratinocytes.	Moderate-to-severe AD 150
Crisaborole	PDE4	Inhibits PDE4, enzyme expressed in various immune cells involved in inflammatory responses, such as T lymphocytes, mast cells, and macrophages (topical)	Mild-to-moderate AD
Difamilast	PDE4	Inhibits PDE4, enzyme expressed in various immune cells involved in inflammatory responses, such as T lymphocytes, mast cells, and macrophages (topical)	Mild-to-moderate AD