An Overview of Atopic Dermatitis Disease Burden, Pathogenesis, and the Current Treatment Landscape: Recommendations for Appropriate Utilization of Systemic Therapies

J Clin Aesthet Dermatol. 2025;18(3):51–66.

by George Martin, MD; Lakshi Aldredge, MSN, ANP-BC, DCNP, FAANP, FSDNP; Douglas DiRuggiero, DMSc, MHS, PA-C, Melodie Young, MSN, A/GNP-C; and Eric Simpson, MD, MCR

Dr. Martin is with Dr. George Martin Dermatology Associates in Kihei, Hawaii. Ms. Aldredge is with the VA Portland Health Care System in Portland, Oregon. Dr. DiRuggiero is with the Skin Cancer and Cosmetic Dermatology Center in Rome, Georgia. Ms. Young is with Mindful Dermatology in Dallas, Texas. Dr. Simpson is with the School of Medicine at Oregon Health and Science University in Portland, Oregon.

FUNDING: Medical writing support was provided by Krista Mills, PhD, of Alphabet Health (New York, NY), supported by LEO Pharma Inc, according to Good Publication Practice guidelines (https://www.ismpp.org/gpp-2022). The authors received no honoraria related to the development of this publication.

DISCLOSURES: Dr. Simpson reports grants and/or personal fees from AbbVie, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, FortéBio, Galderma, Incyte, Kyowa Kirin, LEO Pharma, MedImmune, Menlo Therapeutics, Merck, Novartis, Ortho Dermatologics, Pfizer, Pierre Fabre Dermo Cosmetique, Regeneron, Sanofi, Tioga, and Valeant. Ms. Aldredge served as a speaker/consultant for AbbVie, Amgen, Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dermavant, Galderma, Incyte, LEO Pharma, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi, and UCB. Ms. Young has served as a speaker/consultant for AbbVie, Amgen, Arcutis, Boehringer Ingelheim, Dermavant, Galderma, Janssen, Lilly, LEO Pharma, Sanofi, Sun, and UCB, and served as a clinical investigator for Abbvie, Amgen, Celgene, Janssen, Lilly, Merck, Novartis, and Pfizer. Dr. Martin has served as a paid consultant to AbbVie, Almirall, Bausch Health, Bristol Myers Squibb, Dermavant, Galderma, LEO Pharma, Lilly, Pfizer, and UCB; has served on the scientific advisory board for AbbVie, Almirall, Bausch Health, Bristol Myers Squibb, Dermavant, DUSA/SUN, Horizon, Incyte, Janssen, LEO Pharma, Lilly, and UCB; has received speaking fees from Almirall, Dermavant, Incyte, LEO Pharma, and UCB; and is a stockholder of Doc Martin’s of Maui (Sunscreen Co.). Dr. DiRuggiero has served on the speakers’ bureau and medical advisory boards for Abbvie, Amgen, Arcutis, Bristol Myers Squibb, Dermavant, EPI Health, Galderma, Incyte, LEO Pharma, Lilly, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi, Sun Pharma, and UCB.

ABSTRACT: Objective: To review the disease impact, immunopathogenesis, and treatment landscape of atopic dermatitis (AD), including recommendations for appropriate utilization of systemic treatments. Methods: A PubMed search for relevant articles on AD and the treatment landscape was conducted using the key words “atopic dermatitis,” “biologic,” “therapeutic inertia,” “Janus kinase (JAK) inhibitor,” and “systemic treatment.” Results: AD is a common, chronic inflammatory skin disease that can have a profound negative impact on quality of life. With recent advancements and approvals of systemic treatments, it is now possible to offer targeted therapy to patients with moderate-to-severe AD. When topical treatments are no longer sufficient for managing AD, recently published AD management guidelines recommend that providers consider/offer advanced systemic treatments. Limitations: More data are needed on the use of systemic treatments in special populations, including head-to-head comparisons of available systemic treatments in these populations. Conclusion: An increased awareness of the immunopathogenesis, diagnosis, and treatment landscape of AD is needed amongst healthcare providers (HCPs). Special consideration of diagnosis and treatment options should be given to certain populations, including patients of different ages, those who may be pregnant or become pregnant, are biologic-experienced, and/or have comorbidities. Of note, HCPs should be aware of the clinical presentation in patients with skin of color. Therapeutic inertia can prevent HCPs from intensifying treatment when needed, and HCPs should know when it is appropriate to offer systemic treatments, including biologics and JAK inhibitors.

Keywords: Atopic dermatitis, biologic, therapeutic inertia, JAK inhibitor, systemic treatment

Introduction

Atopic dermatitis (AD) is a common, relapsing, chronic inflammatory disorder of the skin that can affect up to 20 percent of children and 10 percent of adults globally.^1–4 In the United States, the prevalence of AD is approximately 18 percent in school-aged children and seven percent in adults.^4,5 Disease onset most commonly manifests in infancy and childhood, though adult-onset occurs in 20 to 25 percent of adult patients with AD.^6,7 

AD is characterized by pruritus, eczematous lesions, quality of life (QoL) impairment, and various associated comorbidities.² In a population-based cross-sectional study of 602 adults with AD, of the patients who reported AD severity, 53.1 percent had mild, 38.8 percent moderate, and 8.1 percent severe AD.² In this study, the presence of AD resulted in a limited lifestyle, avoidance of social interaction, and impacted activities in 51.3 percent, 39.1 percent, and 43.3 percent of participants, respectively.² In a cross-sectional, international epidemiologic study in pediatric patients with AD, the proportion of mild AD ranged from 35.8 to 72.3 percent, moderate 24.0 to 55.0 percent, and severe 0.9 to 14.9 percent.⁸ 

Important hallmarks of this fluctuating disease include skin barrier impairment, chronic pruritus, a dysfunctional immune response, and dysbiosis of the skin microbiome.⁹ Immune dysregulation in AD is primarily driven by Type 2 cytokines such as interleukins (IL)-4 and IL-13,^10–12 with contributions from other Th1 (eg, IFN-g), Th2 (eg, IL-31), Th17 (eg, IL-17), and Th22 (eg, IL-22) cytokines, especially in more chronic disease.¹³ With the currently available treatment options for AD, it is important for the health care provider (HCP) to recognize when to offer a patient systemic treatment, especially in individuals with moderate-to-severe AD whose symptoms are not controlled by basic skin care management and traditional first-line therapies.¹⁴ Studies suggest many patients with moderate-to-severe AD are not offered advanced treatments that could provide significant QoL benefit.¹⁵ This article provides an overview of the disease impact on patients, immunopathogenesis, and treatment landscape of AD, including a comparison of and rationale for biologics and Janus kinase (JAK) inhibitors, followed by a discussion of the use of systemic treatment in special populations. 

Burden of disease and unmet needs

As the most common chronic inflammatory skin disease, AD can significantly impair QoL. AD can deprive children of a normal childhood due to a daily impact on playing, changing clothes, and isolation.¹⁶ Work and/or school productivity can be negatively impacted, with the degree of impairment correlating with increasing disease severity.^17,18 In adults, AD can be associated with a substantial burden of health care and direct and/or indirect cost of care.¹⁹ QoL, work, and/or school productivity can be further negatively impacted by sleep disturbances and fatigue associated with AD. In two cross-sectional studies, fatigue scores were positively correlated with disease severity in adults and adolescents with AD.^20,21 AD can present a significant economic burden to both society and individuals, which can comprise up to 10 percent of the annual household income, correlating with disease severity.^22,23

Unfortunately, even with many new treatments available for moderate-to-severe AD, many patients remain undertreated. Overuse and/or overprescribing of topical and oral steroids continues to be an issue with AD treatment even though new systemics and biologics are available.¹⁵ Therapeutic inertia (TI) is considered to be the failure of the HCP to initiate or intensify treatments when there are recommendations that exist and the provider is aware and has the ability to recommend them.²⁴ Studies in TI in dermatologists managing moderate-to-severe AD are limited. However a recent study showed that TI (those who stated that they do not favor the rapid initiation of a new systemic treatment or the optimization of an existing treatment in patients with uncontrolled moderate-to-severe AD) was demonstrated in 25.6 percent of 90 surveyed dermatologists in France.²⁴ 

To overcome TI, the HCP’s understanding of the patient’s disease burden, treatment options, and shared decision-making becomes an integral part of patient care.²⁵ To make a decision whether to start a patient on systemic or biologic treatments, the HCP should consider the latest treatment recommendations by professional dermatological associations.^26–28 In a survey of 840 adults with AD, some of the highest-rated qualities patients thought were important in a HCP were trust in the provider, comfort in discussing all aspects of the condition, not being rushed during visits, and the provider initiates treatment conversations.²⁵ Some of the factors with the highest percentage of unmet needs in shared decision-making were having a provider with the same race/ethnicity as the patient, open-ended or multiple recommendations from a HCP about the treatments they or their child may take, and receiving information about treatment options beforehand.²⁵ 

Immunopathogenesis of AD

The role of Type 2 inflammation.AD pathogenesis is primarily driven by Type 2 inflammation which involves numerous cytokines and chemokines (eg, IL-13, IL-4, IL-5, IL-31, thymic stromal lymphopoietin [TSLP], thymus-and activation-regulated chemokine) as well as multiple cell types (eg, T-helper [Th]2 cells, type 2 innate lymphoid [ILC2] cells, mast cells, basophils, eosinophils).^10,29–31 (Figure 1). A recent study that investigated the key disease drivers between psoriasis, atopic dermatitis, and healthy controls found that in more than 31,000 genes, IL13 was the most dominant in AD samples.¹² In both lesional and non-lesional skin, 100 percent of samples had elevated IL-13, and 40 percent of samples had detectable levels of IL-4.¹² It was further demonstrated that IL-13 levels correlated with disease severity as measured by SCORing Atopic Dermatitis (SCORAD).¹² IL-13 has also been shown to have a significant role in driving skin barrier impairment and dysbiosis of the skin microbiome.^12,32–41 Newer systemic treatments that interfere with the Type 2 inflammatory pathway include dupilumab (blocks both IL-4 and IL-13 signaling), tralokinumab (specifically blocks the IL-13 cytokine), lebrikizumab (blocks a different epitope of IL-13 than tralokinumab), nemolizumab (blocks IL-31), and the JAK inhibitors upadacitinib and abrocitinib (block numerous cytokine pathways in addition to IL-4 and IL-13).^42–45

Diagnosis of AD

AD is diagnosed clinically, and biopsies are not usually needed.^46,47 To diagnose AD, clinical signs, morphology/distribution of skin lesions, and historical features are considered.⁴⁷ (Figure 2). A 2014 diagnostic guideline developed by an expert panel in accordance with the American Academy of Dermatology (AAD) addressed the diagnosis of both pediatric and adult AD of all severities by considering widely recognized diagnostic criteria such as the 1980 Hanifin and Rajka criteria.⁴⁷ In this commonly used guideline, essential features must be present in patients for accurate diagnosis of AD: pruritus and acute/subacute or chronic eczema, which takes a chronic or relapsing history, and typical morphology, including age-specific patterns into account.⁴⁷ These patterns include current or prior flexural lesions in any age group, sparing of groin and/or axillary regions, and involvement of the face, neck, or extensors in pediatric patients.⁴⁷ Important features to consider for diagnosis include an early age of onset (most commonly occurs at 3 to 6 months of age), history of atopy, elevated serum IgE levels, and xerosis.⁴⁷ Associated features to consider for diagnosis include atypical vascular responses, keratosis pilaris/pityriasis alba/hyperlinear palms/ichthyosis, ocular/periorbital changes, other regional findings such as perioral changes/periauricular lesions, and perifollicular accentuation/lichenification/prurigo lesions.⁴⁷ Other dermatoses that may mimic AD morphology that should be excluded are scabies, seborrheic dermatitis, contact dermatitis, ichthyoses, cutaneous T-cell lymphoma, psoriasis, photosensitivity dermatoses, immune deficiency diseases, and erythroderma of other causes.⁴⁷ 

AD is one of the most common dermatoses in patients with skin of color (SoC).⁴⁸ Diagnosis and assessing treatment efficacy can be more challenging in SoC patients due to differences in clinical presentation,⁴⁹ and available data on the efficacy of common treatments for AD in SoC patients is scarce.⁵⁰ Erythema can be more difficult to distinguish in SoC due to it commonly presenting as violaceous/brown/dark grey.⁵¹ AD involvement in the flexural regions is considered to be a major criteria for diagnosing AD (depending on age), but involvement in Black patients is dominant in extensor and/or truncal regions.^51,52 Lichenification is common in SoC patients,^51,52 and Asian patients typically develop more well-demarcated lesions, scaling, and lichenification than white patients.^51,52 Lesions also have more papular involvement with perifollicular accentuation in SoC.⁵¹ In short, in addition to classical criteria, when diagnosing AD in patients with SoC, lichenification, non-pink violaceous or brown erythema, extensor involvement, papular involvement on lesions, psoriasiform thickening and scaling, and dyspigmentation should be considered.⁵¹  

The AD treatment landscape

The objectives of successful AD treatment are to provide disease control by repairing the epidermal barrier, reducing chronic inflammation, and decreasing pruritus, which can improve QoL and prolong remission.⁵³ The approach to AD treatment involves therapy tailored to disease severity and patient QoL, which largely includes topical management for mild AD and systemic treatments for moderate-to-severe AD.^3,53,54 (Figure 3). 

Preventative management and topical treatment. Preventative management of AD flares include skin care (moisturizers, warm baths/showers using non-soap cleansers, and wet dressings), avoiding triggers and scratching if possible, and topical treatments to reduce inflammation/itch, including topical corticosteroids (TCS), topical calcineurin inhibitors (TCI, pimiclimus and tacrolimus), topical PDE4 inhibitors (crisaborole ointment and roflumilast 0.15% cream), topical JAK inhibitors (ruxolitinib cream),^27,53,54 and topical aryl hydrocarbon receptor (AhR) agonists (tapinarof cream).⁵⁵ Many clinical experts and patients will start with TCS or TCI first,⁵⁶ with low-to-medium potency commonly used for mild AD.^53,54 TCS function to reduce the release of inflammatory cytokines and impede antigen processing,⁵³ and are recommended to be applied daily for up to several weeks at a time for acute flares until the inflammatory lesions are significantly improved.⁴⁷ However, TCS may lead to adverse effects such as striae and skin atrophy, perioral and allergic contact dermatitis, and rosacea,^53,57 which can lead to poor adherence to TCS treatment and/or result in the patient seeking care from different HCPs.

TCI also reduce release of inflammatory cytokines through inhibition of calcineurin-dependent T-cell activation.⁵³ TCI do not cause skin atrophy and are suitable for areas of thin skin such as the face, neck, eyelids, skin folds, and outer genital skin.⁵⁸ However, TCI use may be limited by initial tolerability issues such as a burning sensation and pruritus.⁵⁹ Additionally, a boxed warning for use under the age of two has been issued for a theoretical increased risk of lymphoma.⁵³ 

Due to the limitations of treatment with TCS and TCI, novel non-steroidal alternatives continue to be developed. Crisaborole ointment is an FDA-approved non-steroidal phosphodiesterase-4 (PDE-4) inhibitor approved in patients ≥ three months of age.⁶⁰ PDE-4 converts cyclic adenosine monophosphate into adenosine monophosphate, which promotes expression of pro-inflammatory cytokines.⁶¹ Roflumilast cream (0.15%) is a novel once daily topical PDE-4 inhibitor recently approved for the treatment of mild-to-moderate AD in patients ≥ six years of age.⁶² Tapinarof is another topical cream recently approved for the treatment of AD in patients ≥ two years of age.⁵⁵ Tapinarof is an AhR-modulating agent that reduces Type 2 cytokine expression, reduces oxidative stress, and increases expression of skin barrier proteins.⁶³ 

Lastly, ruxolitinib cream 1.5% is a topical JAK1/2 inhibitor approved in patients aged ≥12 years for mild-to-moderate AD in non-immunocompromised patients whose disease is not adequately controlled with other topical prescription therapies or when other topical treatments are not advised.^64,65 Ruxolitinib cream has a limitation of use to no more than 20 percent body surface area, and carries a boxed warning stating serious infections leading to hospitalization or death, higher rate of all-cause mortality, lymphoma and other malignancies, higher rate of major adverse cardiovascular events, and thromboembolic events.^64,65 JAK inhibitors block signaling of multiple cytokines in the AD immune pathway as well as other pathways.⁶⁶ JAKs are intracellular kinases that transduce signals from cytokine receptors to the nucleus through the JAK-signal transducer and activator of transcription (STAT) pathway.⁶⁶ Cytokine receptors utilize various combinations of the four JAK proteins-JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2).⁶⁶ Binding of cytokines and interferons to their receptors activates JAKs and STATs which then regulate gene expression.⁶⁷ Inhibitors targeting one or more JAKs can repress signal transduction through their corresponding cytokine receptor families, subsequently dampening inflammation through these pathways.⁶⁷ 

Phototherapy. When topical treatments and basic management are insufficient alone, narrow-band ultraviolet (UV) phototherapy may be used in combination with topical agents for moderate-to-severe AD.^53,68 However, barriers to widespread use of phototherapy include distance, frequent travel to phototherapy site, and out-of-pocket costs.⁶⁹ UVB treatment is recommended for consideration by the American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology (AAAAI/ACAAI) joint task force guidelines if the patient is refractory, intolerant, or unable to use mid-to-high potency topical treatment and other systemic treatment.⁵⁶

Systemic treatment. Rationale. Patients should be considered candidates for systemic treatment if they are refractory, intolerant, or are unable to use topical therapies.^28,56 Some patients with severe AD may be controlled with TCS alone, but often require large quantities used frequently over long periods of time, which can lead to adverse effects, including skin atrophy, disease rebound, and topical steroid withdrawal.^70,71 In patients who have involvement with a larger body surface area, the feasibility of using different classes, potencies, and vehicles of topical treatment becomes an important consideration, especially for a disease that may require years of therapy.^28,71

In patients with SoC, post-inflammatory pigment changes are a concern, and hypopigmentation can develop after use of high potency TCS.^51,52,72 These pigment changes should be considered as a reason to intervene earlier to control symptoms and decrease the inflammation. 

Traditional immunosuppressants. Systemic oral corticosteroids are often prescribed, but can have significant adverse effects, including growth impairment in children, adrenal insufficiency, cutaneous manifestations such as acne, and increased susceptibility to infection.⁷³ The AAD 2024 and AAAAI/ACAAI joint task force guidelines strongly recommend against use of systemic oral corticosteroids,^27,56 and state they should be considered conditionally only if the patient is refractory, intolerant, or unable to use mid-to-high potency topical treatment and other systemic treatments.⁵⁶ Other immunosuppressants that have been traditionally utilized for the treatment of AD included in the AAD 2024 guidelines with varying levels of evidence include cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil, of which cyclosporine, methotrexate, and azathioprine are the most commonly used.²⁷ The benefit of these therapies primarily lies in their low cost relative to newer systemic agents.²⁷ They are limited, however, by their lack of FDA-approval for AD, potential renal, hepatic, and hematologic toxicities that require frequent lab monitoring, or other limitations in their use such as length of time on the drug, and safety concerns in pregnancy and patients of childbearing potential.²⁷ 

Biologics. There are currently four biologics (human IgG antibodies) that are FDA-approved for the treatment of moderate-to-severe atopic dermatitis: dupilumab and tralokinumab, and the recently approved lebrikizumab and nemolizumab. Dupilumab and tralokinumab are strongly recommended as first-line systemic treatments for moderate-to-severe AD by the AAD 2024 and AAAAI/ACAAI joint task force guidelines (which were published before the lebrikizumab and nemolizumab approvals)^27,56 and target the Type 2 inflammatory pathway in distinct ways. Dupilumab blocks IL-4Rα inhibiting downstream signaling of both IL-4 and IL-13.^74,75 Dupilumab was the first biologic approved for moderate-to-severe AD in patients aged of 6 months and older, and is FDA-approved for the treatment of additional conditions, including asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.⁷⁴ Tralokinumab specifically targets IL-13 and prevents it from binding to IL-13Rα1 and IL-13Rα2.^75–77 Tralokinumab is currently approved for the treatment of moderate-to-severe AD in adolescents and adults in multiple countries, with approval in patients ≥12 years of age in the US.^77–81 Network meta-analyses have found dupilumab to be somewhat more effective than tralokinumab at the 16-week timepoint;^27,56,82 however, a review of concomitant TCS trials as well as a matching-adjusted indirect comparison found similar response rates between tralokinumab and dupilumab beyond Week 16 at the Week 32 timepoint.^83,84 Open-label, ongoing extension studies of dupilumab and tralokinumab have shown sustained efficacy and favorable safety long-term for up to four years,^85–88 and a preliminary integrated analysis of 8 tralokinumab clinical trials in adults and adolescents showed favorable safety for up to 4.5 years.⁸⁹ Of note, the dupilumab 4-year study included a subgroup of patients who were administered dupilumab once-weekly (QW), which is a more frequent dosing than the approved administration every other week (Q2W).^74,87 In addition to reducing AD clinical severity, treatment with dupilumab for 16 weeks and tralokinumab for up to two years was found to shift the transcriptome of lesional skin toward a non-lesional profile and reduce levels of Type 2 serum biomarkers.^90,91 

Two new biologics, lebrikizumab and nemolizumab, recently gained approval in the US in 2024.^92,93 Lebrikizumab is approved in multiple countries including the US in patients ≥12 years of age and inhibits IL-13 signaling by binding to a different epitope than tralokinumab and preventing the formation of the IL-4Rα and IL-13Rα1 heterodimer receptor signaling complex.^45,94–97 In 52-week studies (including a 16-week induction period and 36-week maintenance period), treatment with lebrikizumab was associated with significant improvements in signs and symptoms of AD in adults and adolescents.⁴⁵ An integrated safety analysis of eight lebrikizumab clinical trials demonstrated a favorable, consistent, and similar safety profile between adults and adolescents.⁹⁸ Nemolizumab is approved in the US in patients ≥12 years of age, and in Japan in patients ≥13 of age, and inhibits IL-31 by selectively binding to IL-31Rα.^93,99 IL-31 has a key role in pruritus and is involved in epidermal barrier disruption in AD, and inhibition of IL-31 activity may prevent the downstream release of IL-4 and IL-13 from basophils.^100–102 In 68-week studies in patients with AD and moderate-to-severe pruritus, nemolizumab treatment in combination with TCS/TCI resulted in continuous improvement after Week 16 in pruritus, AD signs, and QoL.¹⁰⁰ Additionally, nemolizumab demonstrated a favorable safety profile, with the majority of adverse events being mild in severity.¹⁰⁰

While these biologics are not considered to be immunosuppressant, require no lab monitoring, and have no boxed warnings, age-appropriate immunizations are recommended prior to initiation, and development of potential complications should be monitored, as biologics can be associated with an increased risk in adverse reactions such as conjunctivitis in patients with AD.^74,77,92,93 In two pooled dupilumab trials for AD, rates of conjunctivitis were 9.7 percent in patients treated Q2W vs. 2.2 percent in placebo-treated patients.¹⁰³ A meta-analysis of real-world evidence of up to 52 weeks of treatment with dupilumab found conjunctivitis in 26.1 percent of patients treated with 300 mg of dupilumab Q2W.¹⁰⁴ In pooled tralokinumab trials, after 16 weeks of treatment, conjunctivitis was present in 7.5 percent of tralokinumab-treated patients vs. 3.2 percent in placebo-treated patients.¹⁰⁵ Real-world data on conjunctivitis in tralokinumab-treated patients are still needed. For both dupilumab and tralokinumab, most cases of conjunctivitis were mild¹⁰⁵ and recovered or resolved during the treatment period.¹⁰⁶ Studies of lebrikizumab also show higher levels of conjunctivitis (8.5% in lebrikizumab Q2W-treated patients vs. 2.5% in placebo Q2W-treated patients) suggesting conjunctivitis is a class-wide effect of the IL-4/IL-13 blockade in AD.^45,98 Conversely, conjunctivitis is not listed as a common adverse event for nemolizumab.⁹³

Dosing, required laboratory monitoring, advantages, and comparisons of biologic treatments can be found in Table 1.

JAK inhibitors. Available FDA-approved oral JAK inhibitors include abrocitinib and upadacitinib.⁶⁷ A long-term comparison study showed that abrocitinib and upadacitinib resulted in more rapid achievement of EASI-75 than dupilumab and tralokinumab (especially at the higher doses of the JAK inhibitors), but comparable response rates at later timepoints.¹⁰⁷ Additionally, in head-to-head studies assessing the efficacy and safety of upadacitinib vs. dupilumab in adults and adolescents with moderate-to-severe AD, upadacitinib was found to demonstrate more rapid achievement of skin clearance and little to no itch.^108,109

These JAK inhibitors received a boxed warning for serious infections, mortality, malignancy, major adverse cardiovascular events, and thromboembolic events.¹¹⁰ However, integrated safety studies have demonstrated a manageable tolerability, longer-term safety profile, and/or favorable benefit-risk profile with continuous use for at least one year.^111,112 in patients who do not have concerning comorbidities. Preliminary findings of up to five years of upadacitinib treatment for AD demonstrated similar safety to the 1-year analysis, with low rates of major adverse cardiovascular and venous thromboembolic events.¹¹³ The European Medicines Agency safety committee¹¹⁴ recommends that JAK inhibitors should be used in the following patients only if no suitable treatment alternatives are available: those aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past and those at increased risk of cancer.¹¹⁴ Additionally, abrocitinib¹¹⁵ and upadacitinib¹¹⁶ have been investigated and preliminarily shown to be efficacious in patients with SoC. Lastly, baricitinib is approved for adults with moderate-to-severe active rheumatoid arthritis, alopecia areata, and some patients hospitalized with COVID-19 in the US,¹¹⁷ and additionally approved in adults and adolescents with moderate-to-severe AD and juvenile idiopathic arthritis in Europe.¹¹⁸ The AAD 2024 guidelines state that JAK inhibitors are not considered to be first-line systemic therapy,²⁷ and the AAAAI/ACAAI joint task force guidelines recommend addition of a JAK inhibitor only if the patient is refractory, intolerant, or unable to use mid-to-high potency topical treatment and other systemic treatments.⁵⁶ It is recommended to receive all age-appropriate vaccinations, including prophylactic herpes zoster vaccinations in agreement with current immunization guidelines before initiating abrocitinib or upadacitinib.^119,120 

Dosing, required laboratory monitoring, advantages, and considerations of non-biologic systemic treatments can be found in Table 1.

Use of systemics in special populations. With a variety of therapeutic options available for the treatment of AD, treatment selection should take the patient profile and special populations into consideration.¹²¹ It is the responsibility of the HCP to understand the risks and benefits of available treatments and participate in shared decision-making and personalized medicine, as the patient begins to understand the available options. Special populations covered here include pediatric and older adult patients, pregnancy, biologic-experienced, and patients who have comorbidities. Systemic treatment considerations for special populations with AD can be found in Figure 3.

Use of systemics in pediatric and older adult patients. Pediatric and older adult patients can be at risk for different comorbidities, adverse effects, and drug-drug interactions, necessitating special treatment consideration for these patients.¹²¹ The recommended systemic treatments for pediatric patients 6 months to 12 years of age is dupilumab, and in ≥12 years of age is dupilumab, tralokinumab, or the JAK inhibitors upadacitinib and abrocitinib.²⁷ Lebrikizumab and nemolizumab are also approved for patients ≥12 years of age.^92,93

Older adult patients (≥60 years of age) can have a unique AD manifestation due to reduced skin barrier integrity, immune dysregulation associated with age, dampened innate immunity, and hypersensitivity to environmental irritants.¹²² Older adult patients tend to have more comorbidities and medications, and can have altered blood pressure and kidney function, osteoporosis, and cancer.^122,123 Major diagnostic criteria for older adults can include pruritus with bilateral and symmetrical eczematous lesions,¹²⁴ and diagnosis can be delayed up to 6 months due to the necessity of excluding other conditions.¹²³ Additionally, older patients often undergo drug cessation trials to address a new-onset eczematous eruption with little improvement and potential harm.¹²⁵ Analyses of clinical trial results have shown that tralokinumab, dupilumab, and lebrikizumab demonstrated a favorable efficacy and safety profile in older adults.^{123,126–128} 

Use of systemics in pregnant patients. AD is the most common skin disease among pregnant patients, both de novo and recurrent.¹²⁹ Atopic eruption of pregnancy usually occurs before the third trimester, and other skin disorders associated with pruritus/eczema during pregnancy need to be ruled out, such as scabies, contact dermatitis, pemphigoid gestationis polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, urticaria, and drug reactions.¹²⁹ For patients being treated for existing AD, pregnancy planning should be discussed with all women of child-bearing years who require systemic therapy, and medication-specific washout periods are advised before pregnancy.¹³⁰ Treatment options for AD may be limited and should be carefully considered during pregnancy, as there is limited evidence of safety during pregnancy for biologics, while JAK inhibitors may pose risks to pregnancy outcome and fetal wellbeing.^129,131 Small molecules can cross the placenta readily, while IgG antibodies can transfer across the placenta as early as 13 weeks of pregnancy and increase over the course of gestation, which may present a risk to the fetus.^132,133 One review of seven FDA-approved biologics (mostly including case reports/series and observational studies in a total of 313 pregnancies) for various atopic diseases such as asthma, chronic urticaria, and atopic dermatitis found that biologics did not worsen maternal or fetal outcomes, while worsening atopic disease was detrimental to pregnancy.¹³¹ JAK inhibitors, methotrexate, and mycophenolate mofetil should be avoided during pre-conception, pregnancy, and breastfeeding.¹³⁰ In a mapped consensus across dermatologists, obstetricians, and patients in North-western Europe, cyclosporine, short-course prednisolone, azathioprine, and dupilumab were deemed suitable during lactation, though evidence needed to form decisions on a treatment course is limited.¹³⁰ Phototherapy is also a suitable option during pregnancy.¹²⁹ 

Use of systemics in biologic-experienced patients. In patients who have previously been on dupilumab and have either a primary failure (not achieving disease control) or a secondary failure (developing an adverse event or losing disease control), evidence suggests that tralokinumab, lebrikizumab, or JAK inhibitors may be alternatives. In a case series of 6 patients with severe AD, dupilumab-refractory patients responded positively to treatment with either tofacitinib or upadacitinib.¹³⁴ Additionally, a study assessing the efficacy and safety of switching from dupilumab to upadacitinib in adult patients with moderate-to-severe AD found additional incremental improvements in clinical responses within four weeks of starting upadacitinib.¹³⁵ In multiple case series, tralokinumab has been shown to be efficacious in patients who showed inadequate response to treatment with dupilumab and/or JAK inhibitors.^136–144 In some patients who had progression of ocular surface diseases (OSD) associated with dupilumab, transitioning patients to tralokinumab was efficacious without worsening, and in some cases clearing, the OSD.^143,145,146 Sub-analyses and indirect comparison studies of lebrikizumab clinical trials have demonstrated that lebrikizumab is efficacious and safe in patients who were previously treated with dupilumab for up to 52 weeks.^147–149 More data are needed for outcomes in tralokinumab, lebrikizumab, and nemolizumab-experienced patients. 

Use of systemics in patients with AD and comorbidities. Data reporting the use of systemic therapies in patients with AD and comorbidities is limited. A scoping review and International Eczema Council Survey conducted in 2022 found that for AD patients with comorbid liver disease, renal disease, viral hepatitis, HIV, or history of malignancy, dupilumab was the systemic treatment that respondents would most often consider prescribing.¹⁵⁰ However, this review and survey would benefit from being updated to reflect newer systemic treatments, including abrocitinib, baricitinib, upadacitinib, tralokinumab, lebrikizumab, and nemolizumab.¹⁵⁰ Recent studies with dupilumab, tralokinumab, lebrikizumab, and abrocitinib have indicated promising safety and efficacy for the treatment of AD in patients with atopic comorbidities,^{105,106,151–155} and with dupilumab for other atopic comorbidities¹⁵³ in patients with comorbid asthma, hay fever, conjunctivitis, and food allergy. More studies on the efficacy and safety of systemic treatments in patients with AD who have comorbidities are needed, and treatment selection should be carefully considered for a benefit-risk ratio in these patients. 

Conclusion

AD is a prevalent disease that can have a major negative impact on QoL. Among HCPs, an increased awareness of AD clinical manifestations, immunopathogenesis, comorbidities, and available therapies is needed. Decision-making on treatments may be affected by age of the patient, cost, geographic location, and insurance, especially in SoC patients.¹⁷⁹ The patient profile and special populations should be taken into consideration, as adolescents, older adult, pregnant, biologic-experienced, and patients with comorbidities may need tailored treatment. The overall goal for management of AD is for patients to achieve remission, reduce the number of subsequent flares, and improve overall quality of life. 

Type 2 inflammation-inhibiting systemic treatments for AD are on the rise and offer more targeted therapy for patients whose disease is not adequately controlled by basic management and topical treatment.¹⁸⁰ In particular, the biologics dupilumab and tralokinumab are strongly recommended as first-line systemic treatments for moderate-to-severe AD, and block a combination of IL-4/IL-13 signaling or IL-13 signaling alone, respectively.^27,56 Two additional biologics–lebrikizumab (blocks IL-13 signaling) and nemolizumab (blocks IL-31 signaling)–were recently approved in the US for the treatment of moderate-to-severe AD in patients ≥12 years of age, increasing the available treatment options.^92,93 Two anti-OX40 monoclonal antibodies, amlitelimab and rocatinlimab, are currently in Phase 3 trials and have demonstrated favorable efficacy and safety in Phase 2b trials for moderate-to-severe AD.^181–184 In addition to abrocitinib and upadacitinib, a third JAK inhibitor, baricitinib, which targets JAK1 and JAK2, has shown favorable efficacy and safety in Phase 3 studies and is approved in AD patients ≥ two years of age with moderate-to-severe AD in Europe.^118,169 

There is not a lifelong commitment to one particular treatment; if a patient fails to respond to one treatment, it is the responsibility of the HCP to be knowledgeable about available alternatives and where the patient sits on the therapeutic ladder. Additionally, the HCP must always evaluate patient compliance before switching therapies. Inappropriate use of topical and/or oral corticosteroids can pose an increased risk of adverse events, and the HCP should be aware of when to initiate other approved systemic therapies and/or change to non-steroidal treatment alternatives. As such, HCPs should be wary of therapeutic inertia, which can disallow a patient from being prescribed a systemic treatment when appropriate, ultimately prolonging symptoms and possibly prompting the patient to switch providers. Here, we have provided an overview of AD and an update on the treatment landscape for HCPs caring for patients with AD. 

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