Abstract
Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease with a multifactorial etiology that affects up to 20% of children and up to 7% of adults in the USA. Annual costs are estimated to be greater than $5 billion as of 2015 and have likely increased since. Mild cases can be managed with emollients and topical steroids or non-steroidal medications; however, moderate-to-severe AD is much more difficult to control and typically requires systemic therapy. While historically treatment has involved topical and oral corticosteroids and other immunosuppressive medications, advances in our understanding of the complex pathophysiology of AD has allowed us to develop more precisely targeted therapies for the condition. Specifically, because of the high prevalence and burden on quality of life, many new immunologic therapies are emerging or in development to treat this condition. This article summarizes the existing, upcoming, and failed immunologic-based medications for atopic dermatitis.
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Atopic dermatitis (AD) is a complex, potentially severe disease with numerous implicated signaling pathways that leads to difficult management. |
While historically treatment has involved topical and oral corticosteroids and other immunosuppressive medications, advances in our understanding of the complex pathophysiology of AD has allowed us to develop more precisely targeted therapies for the condition. |
Introduction
Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease that is often associated with other atopic disorders, namely asthma (50% of patients) and allergic rhinitis (75% of patients) [1]. AD is characterized by recurrent, poorly defined, pink-to-red erythematous patches often with exudate, blistering, crusting, scaling, and/or fissuring when uncontrolled, as well as lichenification at later stages. Patients often experience intense itch and discomfort and are at increased risk of superimposed infection due to impaired skin barrier and increased rates of Staphylococcus aureus colonization [2]. Patients also have high rates of concurrent allergic and non-allergic-mediated comorbidities [3]. AD most commonly presents in the first 5 years of life, with 30% of cases presenting in adolescence and 10% in adulthood. Up to 70% of children with AD will go into clinical remission before adolescence; individuals with a later presentation less frequently undergo spontaneous remission. AD has a prevalence of 10–20% in children and 3–7% in adults [1]. AD has a multifactorial etiology, including genetic, environmental, and immunologic factors, that contributes to its extremely varied phenotypes. While historically treatment has involved topical and oral corticosteroids and other immunosuppressive medications, advances in our understanding of the complex pathophysiology of AD has allowed us to develop more precisely targeted therapies for the condition. Some precise immunologic targets for AD include interleukin (IL)-4, IL-13, and IL-22. In contrast, Janus kinase (JAK) inhibitors of varying selectivity work more upstream and serve to block the widespread cytokine signaling that occurs in the disease [4]. The primary goal of this study is to describe AD therapy, including drugs that are newly approved, those undergoing clinical trials, and those that were unsuccessful, to characterize the currently available and emerging immune-modifying treatments for the cutaneous manifestations of AD.
Literature Search Methods
A review of PubMed, ClinicalTrials.gov, the Food and Drug Administration (FDA) Novel Drug Approvals site, and data from industry press releases related to atopic dermatitis was performed. The initial PubMed literature review was performed with the search terms “atopic dermatitis” AND “treatment” and studies were selected on the basis of relevance and publication between 2017 and 2024. Following this, the Food and Drug Administration (FDA) Novel Drug Approvals website was searched for AD therapies approved from 2015 to 2022. ClinicalTrials.gov was also searched for the status of included drugs. Key words included each drug (“tacrolimus”, “pimecrolimus”, “crisaborole”, “ruxolitinib”, “dupilumab”, etc.) combined with “atopic dermatitis”. Studies containing clinical trial data from both ClinicalTrials.gov and PubMed and articles highlighting expert perspectives on management or updates on current therapy of AD published within the last 5 years were included.
Pathophysiology
AD is a chronic inflammatory skin condition characterized by an impaired skin barrier [5]. Genetic involvement has been well characterized, with gene–gene and gene–environment links. Importantly, mutations in the filaggrin gene on chromosome 1 have been implicated in approximately 50% of all patients with AD [5]. This is often implicated in familial cases. Lack of normally functioning filaggrin leads to loss of skin hydration, protection from allergens, and antimicrobial activity. Other skin barrier components that have been implicated in AD include alterations in loricrin, another structural protein, and the dysregulation of keratinocyte differentiation. Changes in lipid and membrane ceramide metabolism also contributes to the various AD phenotypes, and all of these factors can be genetically or environmentally modified.
The molecular pathophysiology of AD is complex but includes Th2 cell-mediated inflammation. Involvement of Th1 and Th17 cell-mediated inflammation has also been identified [6]. Numerous cytokines, including IL-4, IL-5, IL-13, IL-13, IL-31, and IL-33 have been implicated in the pathogenesis of AD [7]. Chronic AD typically involves upregulation of tumor necrosis factor (TNF)-alpha and other proinflammatory cytokines such as IL-1, IL-6, IL-8, and IL-16 [6]. Th22 cell-mediated inflammation has also been more recently recognized in the pathogenesis of atopic dermatitis, as IL-22 disrupts normal keratinocyte differentiation and promotes epithelial hyperplasia. IL-22 levels have been shown to correlate with disease severity and response to therapy as well [6]. Because there are so many potential targets, it is difficult to standardize treatment with one therapy, as all patients respond differently. As such, it is important that we continue to discover therapies targeting different points in the AD pathway and more upstream targets for difficult to control cases.
Clinical Grading
Commonly used grading systems in AD clinical trials include Investigator’s Global Assessment (IGA) score, Eczema Area and Severity Index (EASI), and SCORing Atopic Dermatitis (SCORAD), which are measures of both the visible cutaneous symptoms and subjective discomfort of the patient [5]. Other grading systems include the Itch Numerical Rating Scale (Itch NRS), which is defined as the 7-day average of the worst level of itch intensity in the last 24 h when rated on a scale of 0–10. These scoring systems comprise the primary endpoints for the majority of the clinical trials discussed.
Current FDA-Approved Therapies by Target Molecule
Topical calcineurin inhibitors
Calcineurin inhibitors are among the older treatments for AD, with tacrolimus approved initially in 2000 and pimecrolimus in 2001. Tacrolimus and pimecrolimus are FDA approved as second-line topical therapy for moderate-to-severe AD. These drugs work by inhibiting proinflammatory cytokine production from T cells, which has both antiinflammatory and antipruritic effects. Tacrolimus and pimecrolimus are approved for individuals ≥ 2 years of age and should be used in a short-term and noncontinuous manner in non-immunocompromised individuals. These topical medications are safe for use on the face and intertriginous areas, unlike many corticosteroids [8].
Two multicenter, randomized, double-blind, vehicle-controlled phase III clinical studies were performed to evaluate safety and efficacy of tacrolimus for moderate-to-severe atopic dermatitis [8]. Patients were evaluated with the physician’s global evaluation of clinical response rather than with newer scoring tools. However, both the 0.1% and 0.03% strengths of tacrolimus showed significant efficacy, with at least 90% improvement in scoring compared with vehicle (p < 0.001). This was true for both pediatric and adult populations. The results for the 0.1% ointment were seen by week 1 for adults, and the results for the 0.03% ointment were seen by week 2 for pediatrics and week 3 for adults [8].
In addition, A 5-year, multicenter, open-label, randomized, parallel group study was performed to evaluate the safety of pimecrolimus 1% cream (PIM) and topical corticosteroids (TCS) over the first 5–6 years of life for the treatment of AD in children [9]. The results of the study suggest that PIM and TCS both had similar efficacy when used. Patients showed an improvement in AD severity, with an IGA ≤ 1 at year 5, in 88.7% PIM- and 92.3% TCS-treated infants and children (p < 0.001) [9, 10].
No screening is required prior to initiation of therapy. These are typically applied twice daily to affected skin as needed. Adverse events reported include localized burning or pruritus at application site, which typically improve with resolution of eczematous lesions. In addition, infection, impetigo, and nasopharyngitis were also seen [10]. The only absolute contraindication to therapy with calcineurin inhibitors is known hypersensitivity to tacrolimus, pimecrolimus, or their ingredients. Tacrolimus and pimecrolimus are not recommended in pregnancy (category C) or during breastfeeding. Tacrolimus and pimecrolimus should also be avoided on pre-malignant or malignant skin conditions. In addition, impaired skin barrier may increase systemic absorption, so use should be minimized in such patients [11].
Topical and Systemic PDE-4 Inhibitors
Crisaborole is a topical PDE-4 inhibitor FDA approved for mild-to-moderate AD. PDE-4 inhibition decreases the Th2 response with antiinflammatory effects via prevention of intracellular cyclic adenosine monophosphate degradation, which subsequently suppresses downstream release of cytokines [6]. Crisaborole is approved for individuals ≥ 3 months of age. Crisaborole is safe for use on the face and intertriginous areas, unlike many corticosteroids [6, 12].
Two phase III multicenter, randomized, double-blind, parallel-group, vehicle controlled clinical studies were conducted in the USA (AD-301 and AD-302), with a total of 1522 subjects, to assess the safety and efficacy of crisaborole in patients with mild-to-moderate AD [12]. Greater than 30% of patients were of skin of color (SOC). Outcomes assessed in the clinical trials include IGA score of 0/1 with at least two-grade improvement from baseline. Trial 1 noted IGA score improvement in 32.8% of patients in the treatment group compared with 25.4% in the vehicle group (p = 0.038). Trial 2 noted IGA score improvement in 31.4% of patients in the treatment group compared with 18.0% in the vehicle group (p < 0.001) [12]. Crisaborole was also found to improve subjective pruritus (p = 0.002) [12].
No screening is required prior to initiation of therapy. Crisaborole is typically applied twice daily to affected areas. Adverse events reported include stinging or burning at application site, which typically resolves within the first few days of treatment, and systemic absorption is negligible due to metabolization to inactive metabolites after penetration into the skin. There are no contraindications to crisaborole therapy aside from known hypersensitivity to the drug [12, 13].
There are a few PDE-4-targeting therapies undergoing study at this time which are listed in Table 1.
Topical and Systemic JAK Inhibitors
Ruxolitinib is a topical selective JAK1/2 inhibitor FDA approved for mild-to-moderate AD. The mechanism is inhibition of the JAK-signal transducers and activators of transcription (STAT) pathway, decreasing Th2 cell response, eosinophil activation, and proinflammatory cytokine secretion. Further, regulatory T-cell expression is increased by blocking this pathway, which further decreases inflammation. Ruxolitinib is indicated for short-term and non-continuous chronic treatment of AD in non-immunocompromised individuals ≥ 12 years of age when first-line prescription topical therapies have failed or are contraindicated. Other indications for ruxolitinib therapy include vitiligo [19].
Two double-blind, vehicle-controlled clinical studies were performed with a total of 1249 patients over 8 weeks to assess efficacy and safety in the Topical Ruxolitinib Evaluation in Atopic Dermatitis (TRuE-AD1 and 2) trials [20]. Greater than 20% of patients were of SOC, with fewer Asian patients compared with other ethnic groups [20]. Outcomes assessed in the clinical trials include IGA score of 0/1 with at least two-grade improvement from baseline. TRuE-AD1 noted IGA score improvement in 50.0% and 53.8% of patients in the ruxolitinib 0.75% and 1.5% cream treatment groups, respectively, compared with 15.1% in the vehicle group (p < 0.0001) [20]. TRuE-AD2 noted IGA score improvement in 39.0% and 51.3% of patients in the ruxolitinib 0.75% and 1.5% cream treatment groups, respectively, compared with 7.6% in the vehicle group (p < 0.0001) [20]. Both TRuE-AD1 and TRuE-AD2 noted improvement to EASI-75 score, with 56.0% and 51.5% of patients on 0.75% cream, 62.1% and 61.8% on 1.5% cream and 24.6% and 14.4% on vehicle, respectively (p < 0.0001) [20]. Both trials noted Itch NRS improvement, showing improvement in 52.2% and 50.7% of patients in the ruxolitinib 1.5% cream treatment group, respectively, compared with 15.4% and 16.3%, respectively, in the vehicle group (p < 0.05) [20]. A phase III randomized trial to assess efficacy and safety of topical ruxolitinib in children aged 2–12 years is currently underway.
No screening is required prior to initiation of topical therapy. Ruxolitinib is typically applied twice daily to the affected areas until resolution. The most common adverse events reported include nasopharyngitis, upper respiratory tract infection, headache, and application site burning or pruritus [20]. Use should be limited in patients undergoing immunobiologic therapy, other JAK inhibitor therapy, or other immunosuppressant use, as these groups were excluded from the trials [20]. Ruxolitinib has not been assigned a pregnancy category in the USA and should be avoided for 4 weeks prior to breastfeeding. There are no absolute contraindications to topical ruxolitinib therapy aside from known hypersensitivity to the drug or its ingredients [21].
Abrocitinib was FDA approved in January 2022 for individuals ≥ 12 years of age with moderate-to-severe, refractory AD. Abrocitinib is an oral selective JAK1 inhibitor that works by decreasing downstream IL-4 and IL-13 signaling without neutropenia and anemia, which are effects of JAK2 inhibition [22]. This medication is administered once daily with or without food.
A multicenter, double-blind, randomized, placebo-controlled phase III clinical trial (JADE-MONO-1) with a total of 387 patients from Australia, Canada, Europe, and the USA was performed to assess the efficacy and safety of abrocitinib. Greater than 20% of patients were of SOC. Outcomes assessed in clinical trials include IGA score of clear or almost clear skin (0/1) and/or at least a 75% improvement in EASI score [22].
Screenings recommended prior to initiation include testing for active or latent tuberculosis, viral hepatitis, comprehensive blood count (CBC), lipid panel, and comprehensive metabolic panel. CBC and lipids should be repeated 4 weeks after start and after any dose increase for monitoring. The recommended initial dose is 100 mg daily. If patients have an inadequate response after 12 weeks, the dose can be increased to 200 mg. Abrocitinib is renally excreted and can be given at a dose of 50 mg for patients with moderate renal impairment (estimated glomerular filtration rate (eGFR) 30–59) [23].
The most common AEs associated with abrocitinib include nasopharyngitis, nausea, headache, herpes simplex, increased blood creatinine phosphokinase, dizziness, urinary tract infection, fatigue, acne, vomiting, oropharyngeal pain, influenza, gastroenteritis, impetigo, hypertension, contact dermatitis, upper abdominal pain, abdominal discomfort, herpes zoster, and thrombocytopenia [23].
Abrocitinib is contraindicated in patients taking antiplatelet therapies, except for low-dose aspirin (≤ 81 mg daily), during the first 3 months of treatment. It is also contraindicated in patients who have a history of myocardial infarction, stroke, or thrombosis. It is also not recommended for use in patients with severe renal (eGFR < 30) or hepatic impairment. This medication cannot be taken with strong inhibitors or inducers of CYP2C19 and CYP2C9. There is no pregnancy data available, with current recommendations stating avoiding use while breastfeeding [23].
Upadacitinib was FDA approved in January 2022 for patients ≥ 12 years of age with moderate-to-severe, refractory AD. Upadacitinib is an oral nonselective JAK inhibitor that decreases downstream IL-4 and IL-13 signaling to decrease inflammation involved in AD. While upadacitinib is considered nonselective, its inhibition of JAK1 is greater than that of JAK2, JAK3, and tyrosine kinase 2 [24]. Other indications include rheumatoid arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. Of note, upadacitinib is indicated in patients as young as 2 years of age for psoriatic arthritis and with polyarticular juvenile idiopathic arthritis [25].
Two multicenter, double-blind, randomized, placebo-controlled phase III clinical trials (Measure Up-1 and 2) with a total of 847 patients from Australia, North America, South America, Europe, and Asia were performed to assess the efficacy and safety of upadacitinib. Greater than 20% of patients were SOC, mainly made up of Asian and Hispanic individuals. The primary efficacy points included IGA score of clear or almost clear skin (0/1) and/or at least a 75% improvement in the EASI score. Both Measure Up-1 and Measure Up-2 achieved an EASI-75 response at week 16, higher in the treatment groups compared with the placebo group. Both Measure Up-1 and Measure Up-2 achieved an IGA response at week 16, higher in the treatment group compared with the placebo group [24].
Laboratory screening for active and latent tuberculosis, viral hepatitis, anemia, white blood cell count, hepatic function, and pregnancy status, as well as updated immunizations, are recommended prior to initiation of treatment. The recommended initial dose is 15 mg once daily, and this may be increased to 30 mg daily if the response is inadequate [25].
Upadacitinib is not recommended for use with other JAK inhibitors, immunobiologic medications, or other immunosuppressants. It should also be avoided in individuals with cardiovascular disease or severe hepatic impairment. Use is not recommended with strong CYP3A4 inhibitors or inducers. Adverse effects and warnings include upper respiratory tract infections, acne, herpes simplex, headache, cough, folliculitis, nausea, abdominal pain, herpes zoster, fatigue, and changes to laboratory values (i.e., lymphocytes, neutrophils, hemoglobin, liver enzymes, lipids, creatine phosphokinase). Contraindications include allergy to upadacitinib or its ingredients and pregnancy. Live vaccines should be avoided when on upadacitinib. Upadacitinib is pregnancy class D, and use in breastfeeding is not advised [25].
JAK inhibitors come with hesitation among many providers to use these drugs due to safety concerns. The FDA-released warnings for JAK inhibitors include “increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions” [4]. When considering atopic dermatitis, however, these drugs are used for shorter periods, at lower doses, and can be via topical application when compared with use in other inflammatory conditions. Thus, further study will hopefully clarify the long-term safety profiles of these emerging therapies.
There are a number of emerging JAK inhibitors that are undergoing clinical trials, which are listed in Table 2.
Systemic IL-4R Inhibitors
Dupilumab is currently the only FDA-approved IL-4 inhibitor for AD and works as an antagonist of the IL-4 receptor alpha, which decreases the Th2 cell response by decreasing IL-4 and IL-13 signaling. Dupilumab is FDA approved for adults and children > 6 months of age with moderate-to-severe AD. Other indications for dupilumab use include prurigo nodularis, chronic rhinosinusitis, nasal polyposis, asthma, and eosinophilic esophagitis.
Two identical randomized, double-blind, placebo-controlled, parallel-group trials were performed with a total of 1379 patients to evaluate dupilumab in adults with moderate-to-severe atopic dermatitis in North America, Europe, and Asia (SOLO1 and SOLO2) [2]. Greater than 30% of participants were of SOC [2]. Outcomes assessed in clinical trials include IGA score of clear or almost clear skin (0/1) and reduction of at least two points from baseline and at least a 75% improvement in the EASI-75 score. Itch NRS reduction was also trended over 16 weeks [2]. SOLO1 showed reductions in IGA score of 38.0% and 37.0% in patients receiving dupilumab every other week and every week, respectively, compared with 10.0% in placebo (p < 0.001) [2]. SOLO2 showed reductions in IGA score of 36.0% and 36.0% in patients receiving dupilumab every other week and every week, respectively, compared with 8.0% in placebo (p < 0.001) [2]. SOLO1 showed reductions in EASI-75 score of 72.2% and 72.0% in patients receiving dupilumab every other week and every week, respectively, compared with 37.6% in placebo (p < 0.001) [2]. SOLO2 showed reductions in EASI score of 67.1% and 69.1% in patients receiving dupilumab every other week and every week, respectively, compared with 30.9% in placebo (p < 0.001) [2]. Both trials showed a significant reduction in Itch NRS score by 3–4 points (p < 0.001) [2]. Additional studies were performed in the pediatric and adolescent populations with similar efficacy and safety results as those in adults [30, 31].
No screening is required prior to initiation of therapy. Dupilumab is available in a 200 or 300 mg/mL pre-filled pen (age 12+ years) or pre-filled syringe (age 6+ months). The use of pens versus syringes is primarily based upon patient preference and insurance coverage. The dosing for dupilumab varies by age and weight. In pediatric patients 6 months–5 years, there is no initial loading dose. For pediatric patients 6–17 years of age, the loading and maintenance doses vary by weight, with monthly maintenance dosing for smaller children, and bimonthly maintenance dosing for children > 30 kg as well as adults, who typically receive 600 mg every 2 weeks [32].
The most common adverse events (AEs) included injection site reactions, exacerbation of atopic dermatitis, headache, conjunctivitis, nasopharyngitis, upper respiratory infection, oral herpes, other herpes simplex virus infection, and mild transient eosinophilia [2]. The only absolute contraindication to dupilumab therapy is hypersensitivity to any of its ingredients [32]. Dupilumab is thought to be safe in pregnancy and breastfeeding, though a pregnancy category has not been assigned. A previous report has suggested that dupilumab be assigned to pregnancy category B1 [33].
Emerging IL-4-related therapies are listed in Table 3.
Systemic IL-13 Inhibitors
Tralokinumab is a newer-to-market IL-13 inhibitor that was approved by the FDA in December 2021 for adults (18+ years) with moderate-to-severe atopic dermatitis and for adolescents 12–17 years of age in December 2023. IL-13 is implicated in skin barrier disruption, skin inflammation, increased risk of skin infections, itch signaling, and epidermal hyperplasia, and levels of IL-13 in lesional skin have been found to correlate with AD severity [36]. Blockage of IL-13 also leads to increased expression of filaggrin, an essential protein in epidermal barrier homeostasis, as IL-13 has been shown to downregulate filaggrin gene expression [37].
Tralokinumab is a human monoclonal antibody that works by blocking the binding of IL-13 to the IL-4 receptor alpha, preventing downstream JAK/STAT signal cascade. This leads to decreased inflammation via decreased T-cell transcription activation, immunoglobulin class switching to immunoglobulin E (IgE), and antigen presentation by B cells, as well as increased filaggrin expression.
Two 52-week, randomized, double-blind, placebo-controlled phase III clinical trials (NAME) were conducted to assess the safety and efficacy of tralokinumab. Greater than 30% of patients were of SOC. Outcomes assessed in clinical trials include IGA score of clear or almost clear skin (0/1) and/or at least a 75% improvement in EASI score [36].
No screening is required prior to initiation of tralokinumab, but it is recommended to complete all age-appropriate immunizations prior to initiating treatment. Dosing for tralokinumab includes a loading dose 600 mg subcutaneous (SC), followed by a maintenance injection of 300 mg SC every other week in adults. Pediatric dosing includes a loading dose of 300 mg SC followed by a maintenance dose of 150 mg SC every other week. Tralokinumab is available in a 150 mg/mL prefilled syringe. The most common AEs include upper respiratory tract infections (mainly reported as common cold), conjunctivitis, injection site reactions, and eosinophilia. Contraindications for the use are known hypersensitivity to tralokinumab [38].
Emerging IL-13-related therapies are listed in Table 4.
Other Target Molecules
Of note, there are a number of immune-modifying AD therapies in the pipeline with target molecules not previously FDA approved or mentioned above. These other emerging and terminated therapies are listed in Table 5.
Discussion
Atopic dermatitis (AD) is a highly prevalent disease with significant impact on patients’ quality of life. As a result, many clinicians and scientists have sought to identify new pathophysiologic targets to combat the disease. Drucker et al. studied the prevalence and impact of AD using the Children’s Life Quality (QoL) Index and found that among children aged 5–16 years, generalized eczema had the second largest impact on QoL, following only cerebral palsy, among all chronic diseases studied [1]. Further, adults with AD have been found to have higher rates of psychiatric comorbidities such as depression and anxiety [3]. Because of the widespread effects of AD, from physical discomfort to systemic symptoms and mental health implications, it is important to find effective treatments for the disease.
As it currently stands, the most common first-line therapy for AD is use of topical emollients or low potency topical corticosteroids for mild disease, with escalation to higher potency topicals or even oral corticosteroids with more severe disease. Further, many severe AD cases require treatment with systemic immunosuppressive medications with significant side effect profiles such as cyclosporine, azathioprine, or mycophenolate mofetil, which are all used off-label [22]. Another option for moderate-to-severe AD is phototherapy, which is limited by financial and geographic access and patient time, as phototherapy typically requires 2–3 sessions per week [6]. A conservative estimate of the annual costs of atopic dermatitis in the USA is $5.297 billion (in 2015 USD) [1]. Due to the prevalence and negative impact of AD, the financial burden of therapy, and the many adverse effects of long-term corticosteroid use, many scientists and pharmaceutical companies are working to develop the aforementioned targeted therapies on the basis of more recently studied immunologic targets.
FDA-approved second-line topical therapies include tacrolimus, pimecrolimus, crisaborole, and ruxolitinib; all but ruxolitinib are approved for pediatric use, with the latter only approved for adolescents ≥ 12 years of age. These medications serve as excellent steroid-sparing alternatives for long-term management of mild-to-moderate disease, particularly for patients with facial and intertriginous involvement where steroids are inappropriate. Ruxolitinib in particular is also limited by the current verbiage of “short-term” and “non-continuous” use, which affects insurance coverage. This will likely change as more long-term safety data are obtained and shared. When prescribing these drugs, which are typically considered to be second line therapies, it is important to have thorough documentation of previously failed therapies to obtain insurance coverage. Many drugs also have assistance programs to help patients, as the financial burden of many dermatologic medications is a major barrier to care.
For moderate-to-severe disease, systemic therapies are warranted, particularly in refractory cases or in cases with body surface area involvement that make topical application impractical. While dupilumab is approved for individuals as young as 6 months of age, tralokinumab, upadacitinib, and abrocitinib are only approved for adults. It is likely that tralokinumab will eventually be used in pediatric patients, as the IL-13 pathway is similar to IL-4 and is considered safe in this population. However, as upadacitinib and abrocitinib are JAK inhibitors, it is likely that the study of these in pediatric patients will be treated with hesitation until there is further study into the long-term safety of these drugs in adults.
Conclusions
Atopic dermatitis is a complex, potentially severe disease with numerous implicated signaling pathways that lead to difficult management. Fortunately, in recent years, there have been significant developments in our understanding of the multifaceted pathophysiology of AD, leading to the development of a number of medications for the treatment of this chronic condition. More than 40 immune system-modifying drugs are in the development pipeline, with promising results for patients. This review serves as an update for clinicians on the mechanisms and major phase III clinical trial results of approved therapies for AD and provides a summary of potential therapies in the development pipeline. While safety of many drugs, particularly JAK inhibitors, is still being examined, there are many drugs that will likely emerge in the near future.
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Conceptualization: all authors; literature search and data analysis: Hemali Shah, Francelia Eckembrecher, Daphne Eckembrecher; writing—original draft preparation: Hemali Shah, Francelia Eckembrecher, Daphne Eckembrecher; writing—review and editing: all authors; supervision: all authors. All authors have read and agreed to the published version of the manuscript.
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Shah, H., Eckembrecher, F.J., Eckembrecher, D.G. et al. Current and emerging immunobiologic therapies for atopic dermatitis. Drugs Ther Perspect 40, 226–237 (2024). https://doi.org/10.1007/s40267-024-01075-8
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DOI: https://doi.org/10.1007/s40267-024-01075-8