The use of immune-targeted therapies, including TNF inhibitors, anti-interleukins (IL), and Janus kinase Inhibitors (JAKis), is rapidly expanding in the treatment of immune-mediated skin diseases (IMSDs). The highly efficacious nature of several of these biologics and JAKis may herald a therapeutic renaissance. In the past decade, numerous drugs in this category have received approval for use in pediatric IMSDs. Although emerging evidence suggests that these medications offer a favorable safety profile compared with conventional systemic therapies in pediatric populations, their use remains limited compared with the adult population [1]. This review provides a comprehensive, current clinical overview of all approved and emerging biologics and JAKis, including those undergoing phase III clinical trials, for treating common pediatric IMSDs, including atopic dermatitis (AD), psoriasis, and alopecia areata (AA).

To date, the US Food and Drug Administration (FDA) has approved four monoclonal antibodies and three JAKis for the treatment of AD in the pediatric population (Table 1).

IL-4/IL-13 inhibitor

Interleukin-4 (IL-4) and IL-13 are key driving cytokines in AD pathogenesis [2]. They share a heterodimeric receptor composed of IL-4Rα and IL-13Rα1 [3]. Dupilumab, a human monoclonal antibody, inhibits IL-4 and IL-13 by binding to IL-4Rα. Dupilumab is FDA- and European Medicine Agency (EMA)-approved for patients over 6 months of age with moderate-to-severe AD [4].

A randomized, double-blinded, phase III trial in patients with AD between 6 months and 6 years (LIBERTY AD PRE-SCHOOL) demonstrated significant improvement in patients with dupilumab compared with placebo. Higher incidence of conjunctivitis occurred in the dupilumab group than in the placebo group (5% versus 0%) [5]. Dupilumab has also shown good efficacy in several real-world studies in children with AD [6, 7]. In addition, long-term treatment with dupilumab showed acceptable efficacy, safety profile, and tolerability in a long-term extension phase [8]. Unlike other immunomodulatory drugs, dupilumab does not cause immunosuppression, and no laboratory exams are needed for the monitoring of dupilumab [9, 10].

More recently, the selective IL-13 antagonists, tralokinumab and lebrikizumab, have demonstrated promise in the treatment of adolescents with AD. Tralokinumab inhibits the binding of IL-13 to the IL-13Rα1 and IL-13α2 receptor chains. Lebrikizumab does not block 13α2 receptor chains but impairs the hetero-dimerization of IL-4Rα and IL13-Rα1, thereby inhibiting signal transduction [11]. Tralokinumab, a human monoclonal IgG4 antibody, received EMA approval in June 2021 and FDA approval in December 2021 for the treatment of AD in children aged 12–17 years old [11, 12]. The efficacy and safety of tralokinumab were assessed in a 52-week phase III trial involving 289 adolescents aged 12–17 years with moderate-to-severe AD. Tralokinumab demonstrated significant efficacy, with over 50% of patients achieving the primary endpoint at week 16. It also exhibited a favorable safety profile, with only one severe adverse event (AE) leading to treatment discontinuation [12].

Lebrikizumab demonstrated significant improvement among adolescents with AD in three phase III multicenter double-blind, placebo-controlled randomized clinical trials (RCTs) [13]. Its high efficacy and tolerability led to EMA approval in November 2023 and FDA approval in September 2024 for the treatment of moderate-to-severe AD in patients ≥ 12 years [14, 15].

IL-31 inhibitor

Nemolizumab is a humanized monoclonal antibody targeting the IL-31 receptor alpha chain. IL-31 is a prominent pruritogenic factor produced by infiltrating Th2 cells in AD, which is excessively expressed in skin lesions in AD and correlated with disease severity [16].

It was first approved in Japan in March 2022 for patients with AD over the age of 13 years [17, 18]. It was approved by FDA in August 2024 for the treatment of prurigo nodularis in adults [19]. Nemolizumab is the most recently approved biologic option for therapeutic management of pediatric AD. In December 2024, nemolizumab received FDA approval for moderate-to-severe AD in patients over 12 years of age [20].

Nemolizumab was initially developed for the treatment of AD-related pruritus and demonstrated significant pruritus improvement with monthly dosing in several randomized clinical studies among adults [21, 22]. A phase III study investigating nemolizumab in Japanese children aged 6–12 years old with moderate-to-severe AD demonstrated efficacy and safety. While there was a statistically significant decrease in itch, the mean difference in the eczema area and severity index (EASI) between the nemolizumab and placebo groups was not significant [23]. Two recently published phase III multinational RCTs (ARCADIA 1 and ARCADIA 2) demonstrated the efficacy of nemolizumab in combination with topical corticosteroids in adolescents and adults with moderate-to-severe AD [24]. Currently, a phase III randomized, double-blind, multicenter study is investigating the efficacy and safety of nemolizumab on approximately 1700 adolescent participants with AD (NCT03989206).

OX40-OX40L inhibitors

OX40 is expressed on activated T cells, while its binding partner, OX40L, is predominantly expressed on antigen-presenting cells. The binding of OX40L to OX40 amplifies both Th1 and Th2 pathways and promotes upregulation of proinflammatory cytokine production [25]. Monoclonal antibodies targeting OX40, including rocatinlimab and telazorlimab, as well as those targeting OX40 ligand (OX40L), such as amlitelimab, have demonstrated promising results in clinical studies of AD. These findings highlight the potential of OX40 signaling as a new therapeutic target in AD [26].

A phase II trial evaluating rocatinlimab on adults with AD demonstrated a significant improvement in EASI scores compared with placebo [4]. Several phase III trials evaluating rocatinlimab for the treatment of AD are currently underway, including four specifically focused on pediatric patients (NCT05704738, NCT05882877, NCT06224192, and NCT05633355).

Amlitelimab completed one phase II trial in January of 2023, although the results have yet to be published as of this writing (NCT0375430). Five phase III clinical trials are currently recruiting adolescents with moderate-to-severe AD to evaluate the efficacy and safety of amlitelimab in this group (NCT06407934, NCT06241118, NCT06181435, NCT06130566, and NCT06224348).

Telazorlimab demonstrated robust efficacy and a favorable safety profile in a double-blind, placebo-controlled phase II b trial involving adults with AD. At 16 weeks, EASI scores significantly improved in the two high-dose treatment groups (300 mg and 600 mg every 2 weeks) compared with the placebo group, while the low-dose group (300 mg every 4 weeks) showed no significant difference from the placebo group [27]. There are currently no ongoing phase II or III trials investigating telazorlimab in the management of AD.

Oral JAK inhibitors

The JAK-STAT pathway plays a crucial role in the pathogenesis of AD, impacting filaggrin expression and pruritus [28]. Currently, two oral and one topical JAKis are approved by the FDA for use in AD [2]. Furthermore, baricitinib is approved by the EMA (but not FDA) in adults and children over 2 years of age with moderate-to-severe AD [29].

Upadacitinib is a selective JAK1 inhibitor. Three phase III trials (Measure Up 1, Measure Up 2, and AD Up) demonstrated rapid and significant improvements in AD in patients aged 12 years and older [30, 31]. Upadacitinib received FDA approval in 2022 for the treatment of severe AD in patients over 12 years old [32]. Recent real-world research has also shown that upadacitinib significantly improves AD in pediatric patients [33, 34].

Abrocitinib, another selective JAK1 inhibitor, is the latest JAKi approved for the treatment of AD in the pediatric population. In January 2022, the FDA approved abrocitinib for the treatment of moderate-to-severe AD in adults, and in February 2023, it extended approval for adolescents aged 12 years and older [30]. The approval was based on three phase III clinical studies (JADE TEEN, JADE MONO-1, and JADE MONO-2) that demonstrated abrocitinib’s effectiveness in improving the clinical signs and symptoms in adolescents with moderate-to-severe AD [35,36,37]. Head-to-head trials indicate that abrocitinib provides comparable results to dupilumab in patients with severe AD and, potentially, a more favorable itch response at 200 mg daily dosing [38].

Baricitinib, a selective JAK1/2 inhibitor, has demonstrated substantial promise as a treatment for pediatric AD. Currently, one phase III clinical trial (BREEZE-AD-PEDs) is underway to evaluate the efficacy and safety of baricitinib in the management of AD in patients aged from 2 to < 18 years (NCT03952559). Over a 16-week period, statistically significant improvements in EASI-75 and itch scores were observed compared with placebo [39]. Demonstrating promising safety and efficacy in this phase III trial, baricitinib received EMA approval for the treatment of AD in children and adolescents aged 2–18 years with AD [29]. FDA approval for the treatment of pediatric AD with baricitinib is pending.

In 2021, the FDA mandated boxed warnings for all JAKis, highlighting potential risks such as cardiovascular AEs, infections, pulmonary embolism, malignancy, and thromboembolism [40]. According to an EMA statement issued in November 2022, JAKis should only be used when no suitable alternative treatments are available for specific patient groups, including those over 65 years of age, patients with a high risk of major cardiovascular events, patients at high risk of cancer, and patients who are heavy smokers [41]. Despite these concerns, second-generation JAKis, which offer increased selectivity, hold promise for reducing AEs while maintaining efficacy, compared with the first-generation JAKis [42].

Topical JAK inhibitors

Topical ruxolitinib (1.5% cream), a JAK1/2 inhibitor, was approved by the FDA for the treatment of moderate-to-severe AD for patients ≥ 12 years of age in September 2023 [43]. The efficacy and safety of ruxolitinib cream was demonstrated by two identical phase III trials (TRuE-AD1 and TRuE-AD2) demonstrating significant improvement in AD with minimal AEs [44, 45]. An additional phase III trial (TRuE-AD3) evaluating the safety and efficacy of topical ruxolitinib in children aged 2–12 years was recently completed and showed promise in this age group [44]. There is one ongoing phase III trial registered for the evaluation of ruxolitinib in pediatric AD (NCT05456529).

Delgocitinib, a JAK1/3 and tyrosine kinase 2 (TyK2) inhibitor, is currently only approved as a topical treatment for severe AD in adults in Japan. However, promising results from a phase III trial in Japanese infants aged 6–24 months by Nakagawa et al. suggest its potential for wider pediatric use in the future [46]. A phase IIb study of topical brepocitinib (JAK1/TyK2 inhibitor) in adolescents and adults with mild-to-moderate AD was recently completed with promising results [47].

JAKis are the cornerstone of immune-targeted therapy for AA. At the time of writing, ritlecitinib is the only FDA-approved JAKi for patients under 18 years of age (Table 1). There are currently three ongoing phase III trials investigating the efficacy and safety of JAKis in the treatment of pediatric AA (Table 2).

JAK inhibitors

Ritlecitinib

Ritlecitinib, an inhibitor of JAK3 and tyrosine kinase expressed in hepatocellular carcinoma (TEC), received FDA approval in June 2023 for treating severe AA in patients aged 12 years and older [48]. Its efficacy was demonstrated in a phase III RCT, which included 718 patients aged 12 years old and older (ALLERGO study) [49]. An additional integrated safety analysis found that long-term ritlecitinib use was well tolerated in adolescents with AA, with no new safety signals identified [50].

Baricitinib

Baricitinib was the first JAKi to receive FDA approval for the treatment of severe AA (SALT > 50%) in adults over 18 years of age. Two prior phase III randomized clinical trials involving 1200 adult patients with severe AA (BRAVE-AA1 and BRAVE-AA2) demonstrated efficacy in the treatment of severe AA [51]. Despite receiving FDA emergency use authorization during the coronavirus disease-2019 (COVID-19) pandemic for patients aged 2–18 years, baricitinib has not obtained FDA approval for the treatment of AA, or any other IMSDs, in pediatric patients [52]. The effectiveness and safety of baricitinib in pre-adolescents (< 12 years) and adolescents (12–17 years) have recently been studied in long-term cohorts [53, 54]. A large global phase III trial (BRAVE-AA-PEDs) investigating the safety and efficacy of baricitinib in the treatment of AA in pediatric patients is currently underway (NCT05723198).

Deuruxolitinib

Deuruxolitinib, a slective JAK1 and JAK2 inhibitor, was approved by FDA in July 2024 for adults with severe AA and joined baricitinib and ritlecitinib as the third JAKi approved for AA [55]. Two phase III clinical trials involving 1209 adult patients with moderate-to-severe AA demonstrated significant scalp hair regrowth as early as 8 weeks into treatment [55, 56].

Upadacitinib

Two cohorts have demonstrated the efficacy of upadacitinib in treating AA [57]. In addition, several cases of successful treatment of AA in adolescent patients with upadacitinib have been reported thus far [58]. It has been utilized off-label to treat concomitant AA and AD in children over 12 years of age [59]. A phase III trial (UP-AA) is currently evaluating the efficacy and safety of upadacitinib in the treatment of AA in adolescents and adults (NCT06012240).

Tofacitinib

Tofacitinib is a first-generation pan-JAKi, approved by the FDA for use in adults with moderate-to-severe ulcerative colitis, refractory psoriatic arthritis, and refractory rheumatoid arthritis [60]. In 2014, a seminal case report described a patient with simultaneous alopecia universalis and psoriasis who was treated with oral tofacitinib (15 mg/day) [61].

Despite promising results demonstrating the efficacy of oral tofacitinib in treating pediatric AA, it has not yet received regulatory approval for any dermatologic conditions [62,63,64]. Data on its efficacy in AA are currently limited to meta-analyses of case reports and case series [65, 66]. This lack of evidence could be linked to emerging data during the COVID-19 pandemic that suggested the potential for severe complications in patients receiving tofacitinib. Further research is necessary to elucidate the potential efficacy and safety profile of tofacitinib in pediatric AA.

Other medications

Dupilumab has been used to treat patients with both AA and AD owing to it its regulatory approval for moderate-to-severe AD in patients 6 months and older [67]. Several prospective investigational studies have demonstrated positive therapeutic effects of dupilumab in pediatric AA [67]. Conversely, cases of dupilumab-induced AA have also been reported in patients with AD [68, 69]. Currently, an ongoing phase II study (PEDAL) is investigating the efficacy and safety of dupilumab in the treatment of pediatric AA (NCT05866562).

Biologics, including TNF inhibitors, IL-23 inhibitors, and IL-17 inhibitors are the cornerstone of contemporary treatment for pediatric psoriasis. Four biologics are currently approved by the FDA for the treatment of pediatric psoriasis: etanercept, ustekinumab, secukinumab, and ixekizumab. Adalimumab is approved by the EMA but not the FDA for the treatment of patients with moderate-to-severe psoriasis aged between 4–17 years (Table 1). Several phase III trials are ongoing to evaluate the therapeutic effects and safety of IL-23, IL-17, TNF, and TyK2 inhibitors in pediatric populations with psoriasis (Table 2).

TNF inhibitors

Etanercept

Of the four FDA-approved TNF inhibitors for adults (infliximab, adalimumab, certolizumab, and etanercept), etanercept is the only approved agent for the pediatric population. As the first biologic drug approved by the FDA for pediatric psoriasis in 2016 for children aged 4 years and older, it has demonstrated significant efficacy in a multicenter, double-blind, placebo-controlled trial [70, 71].

Long-term administration of etanercept has shown sustained improvement in Psoriasis Area and Severity Index (PASI) scores in children, using a dosage of 0.8 mg/kg/dose, up to a maximum of 50 mg once weekly [72]. However, it is important to note that etanercept, as with other anti-TNF agents, can paradoxically induce psoriasis. Several cases of severe scalp psoriasis induced by anti-TNF therapies, primarily infliximab, have been reported in literature [73]. In pediatric studies evaluating etanercept, the most common AEs included mild injection site reaction, increased risk of upper respiratory tract infection, and headache [71]. Overall, minimal AEs have been observed in children, comparable to those reported in the adult population [74].

Adalimumab

Adalimumab, a fully human monoclonal antibody targeting TNF, was approved by the EMA in 2015 for the treatment of severe plaque-type psoriasis of children more than 4 years old, following an international multicenter phase III controlled trial [75]. In this trial, PASI-100 was achieved after 4 months of therapy in 18.4% of children treated with adalimumab compared with 2.7% of those treated with methotrexate (0.1–0.4 mg/kg weekly) [75]. Despite its efficacy, adalimumab is not currently approved by the FDA for pediatric psoriasis. Both adalimumab and etanercept have demonstrated lower rates of AEs compared with oral methotrexate in pediatric patients with plaque psoriasis [76].

Certolizumab

Certolizumab, a humanized IgG4 monoclonal antibody, is approved for the treatment of psoriasis in adults. Treatment with certolizumab is currently being evaluated in a phase III clinical trial in children aged 6 years and older with plaque psoriasis (NCT04123795).

IL-17 inhibitors

Two humanized IL-17 monoclonal antibodies, ixekizumab and secukinumab, are currently approved for the treatment of pediatric psoriasis in patients over 6 years of age [74]. Secukinumab was the first IL-17 inhibitor approved by the FDA for psoriasis in 2015, initially for chronic severe psoriasis in adults [77]. A 236-week phase III comparative clinical trial evaluated secukinumab in 162 patients aged 6–18 years, demonstrating superior efficacy and safety compared with etanercept [78]. These findings were further confirmed in another phase III trial involving pediatric patients [79]. Secukinumab received EMA approval in 2020 and FDA approval in 2021 for the treatment of pediatric psoriasis (over 6 years of age) [80].

In a phase III comparative study involving 676 patients, secukinumab demonstrated superior efficacy to ustekinumab in the treatment of psoriasis [81]. Recent data support the treatment benefits of anti-IL-17 medications in pediatric psoriasis, suggesting they may offer superior outcomes and faster response compared with anti TNF agents [82].

Ixekizumab obtained FDA approval for adult plaque psoriasis in 2016 and for children aged 6 years and older in 2020, following the IXORA-PEDS phase III rial conducted by Paller et al. [83].

Brodalumab, another IL-17 inhibitor, is currently FDA-approved only for adult psoriasis and has demonstrated greater efficacy compared with secukinumab in head-to-head trials [84]. A phase III clinical trial aimed at evaluating the efficacy and safety of brodalumab in adolescents aged 12 and 17 years old with moderate-to-severe psoriasis (NCT04305327) was initiated but terminated early in July 2023 owing to recruitment challenges.

Bimekizumab is an IL-17 inhibitor that received FDA approval for the treatment of moderate-to-severe psoriasis in adults on 18 October 2023 [85]. A phase III investigation is currently underway to evaluate the efficacy and safety of bimekizumab in pediatric patients aged 6–18 years with moderate-to-severe plaque psoriasis (NCT06425549).

Upper respiratory tract infection, nasopharyngitis, candida infections, and injection site reactions are the most frequently reported AEs associated with IL-17 inhibitors [86]. Treatment-emergent infections were reported in 74.0% of pediatric patients with moderate-to-severe plaque psoriasis treated with ixekizumab [87]. The FDA implemented a black box warning for brodalumab following the suicides of six patients across four clinical trials, although no direct causal link was determined [88]. Subsequent studies have demonstrated no evidence of an increased risk of suicidal ideation and behavior with increasing patient-years of brodalumab exposure [89]. Furthermore, induction or exacerbation of inflammatory bowel disease has been reported in patients treated with IL-17 inhibitors [90].

IL-12/23 inhibitors

Among the four FDA-approved agents in this class (ustekinumab, tildrakizumab, guselkumab, and risankizumab), ustekinumab is the only one approved for the pediatric population. The remaining three are currently undergoing phase III clinical trials in pediatric populations (Table 2).

Ustekinumab is a monoclonal antibody targeting the shared p40 subunit of IL-12 and 23. It is approved by the FDA and EMA for the treatment of pediatric patients aged 6 years and older. In the phase III CADMUS trial, ustekinumab demonstrated significant improvement compared with placebo in 110 patients aged 12–17 years [91]. Another phase III study, CADMUS Jr, found that 84% of patients aged 6–12 years old with moderate-to-severe psoriasis achieved PASI-75 at week 12, with clinical response and PASI scores maintained through week 52 [92]. Ustekinumab has also been anecdotally shown to be superior to TNF inhibitors in individuals with psoriasis and concomitant CARD14 mutation [93].

Three IL-23 inhibitors—tildrakizumab, guselkumab, and Risankizumab—are currently under evaluation for pediatric psoriasis in ongoing phase III trials. In addition, a novel orally administered IL-23 inhibitor, JNJ-77242113, recently completed a phase II study in adults with plaque-type psoriasis, achieving a PASI90 response in 60% of patients at the highest dose (100 mg twice daily) [94]. Three simultaneous phase III clinical trials are currently in the recruitment phase, including patients over 12 years old (NCT06295692, NCT06095115, and NCT06095102).

JAK inhibitors

Despite growing real-world data, no JAKi has been approved to date for the treatment of plaque-type psoriasis in the pediatric population, and data on their use in managing childhood psoriasis remain limited [82, 95]. In September 2022, deucravacitinib, an oral selective TyK2 inhibitor, obtained FDA approval for the treatment of moderate-to-severe adult plaque-type psoriasis [86]. As the only approved JAKi for psoriasis, deucravacitinib blocks IL-23 and type I interferon-signaling pathway [96]. In two phase III trials (POETyk PSO-1 and POETyk PSO-2) deucravacitinib demonstrated significant superiority over placebo with greater PASI improvement [97]. Five ongoing phase III and phase IV studies are currently assessing the efficacy and safety of deucravacitinib in psoriasis, including one study with pediatric patients (NCT04772079).

Zasocitinib (TAK-279), another Tyk2 inhibitor developed by Nimbus Therapeutics, has shown promising results. A phase II, placebo-controlled trial demonstrated favorable efficacy, safety, and tolerability in 259 adult patients with psoriasis [98]. Currently, three phase III trials are recruiting adult patients to investigate zasocitinib’s efficacy in adult psoriasis; however, no studies have been conducted on pediatric patients thus far.

The introduction of biologic agents and JAKis in recent years has revolutionized the treatment of IMSDs. As more immune-targeted therapies gain approval in the coming years, clinicians will face the significant challenge of selecting the most suitable treatment for each patient.

Currently, no formal guidelines exist to assist clinicians in choosing the appropriate biological agent, leaving the decision largely to individual discretion. Ongoing assessment of both approved and emerging biologics and JAKis, supported by head-to-head trials and long-term observational studies, is essential for developing formal guidelines for systemic treatment options. It is important to note that the cost of these treatments remains a significant barrier to patient access, primarily owing to inadequate insurance coverage in dermatology practice [99]. Quantifying the efficacy of these novel agents will be essential in convincing third-party payers to enhance support and improve patient access.

In recent months, the therapeutic landscape of AD has radically expanded with two anti-interleukins, lebrikizumab and nemolizumab, obtaining FDA approval. Yet, among FDA-approved immune-targeted agents for AD, dupilumab is the only biologic approved for children under 12 years of age. Unlike JAKis, biologics for AD do not carry black box warnings and have relatively tolerable AE profiles. However, the safety profile of biologics other than dupilumab has not been investigated in the long-term period. Thus, for patients who do not achieve satisfactory improvement with dupilumab or who develop AEs, such as conjunctivitis or facial erythema, other approved therapeutic agents could be considered as an alternative treatment option.

Baricitinib is currently undergoing phase III clinical trial (BREEZE-AD-PEDS) to evaluate its use in pediatric patients and is expected to receive FDA approvals for pediatric AD, with promising primary results [100]. In addition, the therapeutic potential of anti-OX40-OX40L therapies for AD is supported by underlying cellular inflammatory mechanisms. Although no medications in this category are currently approved, the significant results reported thus far warrant further investigation. Currently, nine phase III clinical trials are investigating the efficacy and safety of two anti-OX40-OX40L therapies, amlitelimab and rocatinlimab, in treating pediatric AD.

For AA, two ongoing phase III clinical trials, BRAVE-AA-PEDS and UP-AA, are investigating the use of baricitinib and upadacitinib, respectively, for the treatment of pediatric AA.

For psoriasis, three IL-23 inhibitors previously approved for use in adults (tildrakizumab, guselkumab, and risankizumab) are currently undergoing phase III trials in pediatric patients aged 6–18 years, with the potential for future approval for use in pediatric patients. In addition, a novel orally administered IL-23 inhibitor, JNJ-77242113, has shown promise in the treatment of plaque psoriasis, with three active phase III trials investigating its efficacy in patients aged 12 years and older. If these trials confirm its efficacy and safety, this class could establish the first standard for oral treatment of pediatric psoriasis.

This review offers a current, comprehensive overview of both existing and emerging biologics and JAKis used in treating common pediatric IMSDs, including regulatory approvals and recent trial data. The advancements in this field herald a promising future for the treatment of pediatric IMSDs. Dermatologists will be increasingly equipped and informed with a broad array of treatment options, enabling them to effectively manage pediatric IMSDs and improve patient outcomes.