Systemic and Long-Term Atopic Dermatitis (AD) Treatment

Chronic atopic dermatitis (AD) is characterized by recurrent or persistent inflammation, with cycles of improvement followed by relapse.⁷ When the disease remains uncontrolled despite topical and systemic therapies, it is considered refractory, though patient behavioral factors such as poor adherence and sleep disturbance should be evaluated before making this diagnosis.⁸ The severity of AD is assessed through both physical signs of atopic dermatitis and its psychological impact, including effects on daily activities, sleep, and mood.^3,11 Moderate to severe AD typically presents with dry skin, frequent itching and redness, noticeable impact on everyday life, and disturbed sleep.^3,11 According to the AAD guidelines, topical therapies are recommended across the severity spectrum, systemic treatments are reserved for moderate to severe cases when topical regimens have failed.^3,5

AD involves multiple inflammatory pathways and diverse T-cell subsets.  While many current treatments have made great strides in improving patient outcomes in AD, there still exists an unmet need. Many treatments take an approach of selectively targeting type 2 inflammatory drivers, addressing only part of the immune activity involved in AD.⁵ This approach rarely leads to therapy-free remission, meaning disease control persists only with continuous dosing.⁵ AD complexity stems from immune system dysregulation, with heterogeneous inflammation impacting cytokines like IL-4, IL-13, and IL-31.^4,6 This heterogeneity varies across populations, ethnicities, and age groups, highlighting the need for individualized treatment strategies.^4,6

Available systemic treatments include targeted biologic agents that address specific cytokine pathways,⁴ JAK inhibitors that interrupt the JAK/STAT signaling pathway,⁵ and conventional immunosuppressants requiring intense monitoring due to serious side effects.¹⁰ Guidelines advise against long-term corticosteroid use beyond 90 days due to increased adverse events risk.^12,13 Despite the significant progress made with these options, over 50% of adults identify flare recurrence as the most challenging disease aspect, while more than 55% report inadequate control while on treatment.^14,15 Long-term adherence remains problematic due to treatment burden and complexity.¹⁴

Treatment goals should evolve toward achieving sustained disease stability without frequent or burdensome intervention, addressing the unmet need for lasting control while reducing patient burden.^5,9

Understanding Chronic and Refractory Atopic Dermatitis

Chronic AD is characterized by recurrent or persistent inflammation, with periods of relative improvement followed by relapse.⁷

In cases where the disease remains uncontrolled despite topical and/or systemic therapies, AD is considered refractory.⁸ It is important to consider the patient’s behavioural habits before diagnosing refractory AD, as treatment failure is complex and may be impacted by poor adherence, sleep disturbance, and other factors.⁸  For those patients who have confirmed refractory AD, other interventions can be tried.⁸

Today, thanks to ongoing research into immune profiles, therapy choice could potentially be informed by knowledge of the underlying heterogeneity in immune profiles, enabling a targeted approach to resolve the immune dysregulation that underpins AD – rather than treating the inflammation alone, as with corticosteroids.^4-6,9,10

Learn more about the initiating phase of immune dysregulation, known as the inflammatory prequel.

Current Paradigm for Systemic Treatment in Moderate–Severe Atopic Dermatitis

To determine the severity of atopic dermatitis, the AAD and NICE guidelines advise assessing both the severity of the physical signs of AD as well as its psychological impact on the patient (e.g., impact on daily activities, sleep and mood).^3,11 Some key signs of moderate to severe atopic dermatitis include:¹¹

• Areas of dry skin with frequent itching and redness
• Noticeable impact on everyday life
• Frequently disturbed sleep

While topical therapies are recommended for mild to severe chronic atopic dermatitis treatment, systemic treatments are recommended for moderate to severe atopic dermatitis when optimized topical regimens have not led to sufficient management of the condition.^3,5

For example, corticosteroids for atopic dermatitis are usually only recommended for acute management: in particular, guidelines specifically advise against using corticosteroids for long-term management – despite their efficacy profile, short-term safety profile and relatively low cost – because of the increase in risk of experiencing adverse events after long-term use (more than 90 days).^12,13

View the guidelines for atopic dermatitis treatment at a glance.

Systemic Atopic Dermatitis Treatments and Targets

AD is a complex condition caused by dysregulation in the immune system.⁴ It displays heterogenous underlying immune inflammation, impacting various effector molecules such as cytokines that impair skin barrier function, including IL-4, IL-13, and IL-31.⁶

Accordingly, wide heterogeneity in the specific immune processes among different populations can be observed by comparing patients from different regions and ethnicities, ages, and other factors, highlighting a need for individualized, targeted treatment strategies.^4,6

Targeted Biologic Agents

The distinct immune profiles in patients with AD can lead to varied responses to therapies aimed at specific interleukins, opening the door for biological agent selection that specifically targets different cytokine pathways, blocking their activity and thereby reducing the specific inflammatory signalling prevalent in the individual’s AD.⁴

Janus Kinase (JAK) Inhibitors

JAK inhibitors interrupt the JAK/STAT signaling pathway, which includes JAK1, JAK2, JAK3 and TK2: all of which mediate cytokine signaling. Therefore, by inhibiting this pathway, these agents can inhibit multiple cytokines involved in AD, i.e. IL-4, IL-13, IL-31, IL-17 and IL-22.⁵

While targeting different signalling pathways with select agents may be beneficial, it is important to remember that selective signalling inhibition still may not address full disease heterogeneity.⁴

Conventional Immunosuppressants

Systemic treatments for atopic dermatitis include conventional systemic immunosuppressants, which inhibit a plethora of immune processes including T cells and NK activation, antigen presentation by APCs, and production of IL-2 and GM-CSF.¹⁰

While immunosuppressants can provide relief to patients with AD that is difficult to manage, they require intense monitoring of clinical signs and symptoms as they can potentially lead to serious side effects, such as reduction of leukocytes and platelets in the blood, or leukopenia.¹⁰

Real-World Challenges and Patient Burden in Long-Term AD Management

Despite treatments being available, recurrence is common: over 50% of adults with atopic dermatitis identify recurrence of flares and worsening symptoms as one of the most challenging factors of the disease and face concerns about long-term use.^14,15 

Even with recent developments in the AD treatment landscape, many patients continue to struggle to achieve lasting control, with more than 55% of adults with the condition reporting inadequate disease control while on treatment.^14,15

Many current AD therapies help to manage acute inflammation and provide short-term symptom relief, but they often require continuous treatment to prevent recurrence, with long-term impacts on patients’ lives.^14,16

Learn more about the immune pathways driving T cell inflammation in AD.

Long-term treatment adherence can also be a challenge for patients with the perceived burden and the complexities of current therapies representing substantial impacts on their lives; as such, improving administration convenience and reducing dosing frequency represent unmet treatment needs.^5,17 Studies have shown that regular appointments and monitoring help treatment adherence and allow the opportunity to identify patients’ changing needs and support them accordingly.¹⁴

As a result, there remains unmet need for treatments that can provide sustained disease stability while reducing the burden of frequent treatment.^5,9

Explore more on unmet need and patient burden in AD.

Rethinking Atopic Dermatitis Treatment Goals

While systemic treatments remain essential additions to the AD management toolkit, practitioners should be aware of their patients’ continuing unmet needs.¹⁰ 

Emphasis should be placed on identifying the best available treatment for each patient’s needs, taking into consideration the characteristics of their atopic dermatitis, reactions to previous treatments, as well as their lifestyle.^10,14

Meanwhile, the long-term goal of AD treatment should be achieving sustained disease stability that is not dependent on frequent or burdensome intervention.^5,9

Abbreviations

AD, atopic dermatitis; AAD, American Academy of Dermatology; NICE, National Institute for Health and Care Excellence; IL-4, interleukin 4; IL-13, interleukin 13; IL-31, interleukin 31; JAK-STAT pathway, Janus kinase-Signal Transducer and Activator of Transcription pathway; APC, antigen presenting cell; IL-2, interleukin 2; GM-CSF, Granulocyte-macrophage colony-stimulating factor.

References

1. Silverberg JI, et al. J Eur Acad Dermatol Venereol. 2021;35(9):1797-1810.
2. Frazier W, Bhardwaj N. Am Fam Physician. 2020;101:590-598.
3. AAD Guidelines of Care for Atopic Dermatitis, 2025. Available at: https://www.aad.org/member/clinical-quality/guidelines/atopic-dermatitis (last accessed January 2026)
4. Rothenberg-Lausell C, et al. Ann Allergy Asthma Immunol. 2024;132(2):177-186.
5. Zhang L, et al. Front Immunol. 2025;16:1712757
6. Fyhrquist N, et al. J Allergy Clin Immunol. 2025;156(1):24-40.e4
7. Wollenberg A, et al. J Eur Acad Dermatol Venereol. 2020;34(12):2717-2744.
8. Izadi N, Leung DYM. Ann Allergy Asthma Immunol. 2018;120:23-33.
9. Prados-Carmona A, et al. Int J Mol Sci. 2025;26(23):11487.
10. Lugović-Mihić L, et al. Life (Basel). 2023;13(6):1419
11. NICE Eczema – atopic: Scenario: Assessment, 2025. Available at: https://cks.nice.org.uk/topics/eczema-atopic/management/assessment/ (last accessed January 2026).
12. Jang YH, et al. JAMA Netw Open. 2024;7(7):e2423563.
13. Drucker AM. Br J Dermatol. 2017;177(5):1158-1159.
14. Feldman SR, et al. J Dermatolog Treat. 2024;35 :2315145.
15. Data on File.
16. Frølunde AS, Vestergaard C. Indian Journal of Skin Allergy. 2023;2:45-50.
17. Tier HL, et al. Fermatol Ther (Heidelb). 2021 ;11 :415-431.