The Shifting Paradigm in Moderate-to-Severe Atopic Dermatitis: Moving Beyond Topical Corticosteroids to Targeted Systemic Therapy

Clinical Brief | Medical Writing Portfolio Sample

Dr. Shakeel Zulfiqar

Abstract

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with persistent pruritus, sleep disturbance, psychological burden, and impaired quality of life. Although topical therapies remain foundational, they may be insufficient for patients with moderate-to-severe disease requiring sustained control.

Objective: To review the clinical rationale, mechanisms of action, efficacy, safety considerations, and practical selection of targeted systemic therapies for moderate-to-severe AD.

Discussion: Biologic therapies targeting interleukin (IL)-4 and IL-13 provide pathway-specific treatment options, whereas oral Janus kinase (JAK) inhibitors offer rapid improvement in skin disease and pruritus for appropriately selected patients. Treatment selection requires consideration of clinical-trial endpoints, ocular adverse events, patient preferences, comorbidities, and the regulatory warnings associated with JAK inhibition. Long-term trial data provide valuable safety information but do not eliminate uncertainty about rare adverse events or replace individualized risk assessment.

Conclusion: Modern AD management requires more than repeated escalation of topical corticosteroids. Targeted systemic treatment should be selected through shared decision-making, with diagnostic reassessment when the presentation is atypical or unexpectedly refractory.

Keywords: atopic dermatitis; dupilumab; tralokinumab; lebrikizumab; upadacitinib; JAK inhibitors; biologic therapy; systemic treatment.

1. Clinical Case: When Topical Treatment Is No Longer Enough

A 34-year-old woman presents with persistent, widespread eczematous lesions and severe pruritus despite an appropriately optimized topical regimen, including topical corticosteroids and a topical calcineurin inhibitor. Her Eczema Area and Severity Index (EASI) score is 28, and her peak-pruritus numerical rating scale (PP-NRS) score is 9 out of 10. She reports frequent nocturnal awakening and difficulty maintaining her usual work performance.

She has no known cardiovascular risk factors or history of malignancy and prefers oral treatment to injections. She asks whether an oral JAK1 inhibitor would be appropriate and what safety assessment would be required before treatment.

This scenario illustrates a common clinical challenge: determining when persistent disease warrants systemic therapy and how to balance the need for symptom control against treatment-specific risks.

2. The Therapeutic Gap: Reassessing Disease Before Escalation

Atopic dermatitis results from interactions among epidermal barrier dysfunction, immune dysregulation, genetic susceptibility, and environmental factors. Type 2 inflammation, particularly signaling mediated by IL-4 and IL-13, contributes to inflammatory activity and barrier impairment. Persistent itch and scratching further damage the epidermis, reinforcing the itch–scratch cycle.

Topical corticosteroids remain effective anti-inflammatory treatments for many flares, while topical calcineurin inhibitors can be useful at selected sites and in appropriate maintenance strategies. Nevertheless, extensive disease, repeated flares, treatment burden, and inadequate sustained control can make topical treatment alone impractical or insufficient.

Before classifying disease as treatment-refractory, clinicians should reassess the diagnosis, adherence, application technique, treatment potency, and potential aggravating factors. Allergic contact dermatitis may coexist with AD, and patch testing may be appropriate when the distribution, exposure history, or clinical course suggests contact allergy.

Persistent or atypical eczematous eruptions in adults also warrant consideration of alternative diagnoses, including cutaneous T-cell lymphoma (CTCL), particularly mycosis fungoides. Features that may raise suspicion include an unusual distribution, progressive lesions, morphologic variation, or an unexpectedly poor response to appropriate treatment. When suspicion persists, skin biopsy and clinicopathologic correlation are important. Repeat biopsies, immunophenotyping, and T-cell receptor clonality studies may be considered in selected cases; no single test should be interpreted independently of the clinical findings.¹⁰

Diagnostic reassessment should not unnecessarily delay appropriate systemic treatment in patients with well-established AD and substantial disease burden. Rather, it helps ensure that treatment escalation addresses the correct underlying condition.

3. Targeted Systemic Therapies: Mechanisms and Clinical Rationale

3.1 Biologics targeting type 2 inflammation

Dupilumab is a monoclonal antibody directed against the IL-4 receptor alpha subunit (IL-4Rα), inhibiting signaling mediated by both IL-4 and IL-13. These cytokines have central roles in type 2 inflammation and contribute to epidermal barrier dysfunction and inflammatory activity.¹

Tralokinumab and lebrikizumab target IL-13. Although both act on the same cytokine, their molecular characteristics and clinical-trial programs differ. Their efficacy and safety should therefore be assessed using the evidence specific to each agent rather than assuming identical clinical effects.²˒³

These biologics offer targeted treatment without the broader intracellular kinase inhibition associated with oral JAK inhibitors. Conjunctivitis and other ocular surface events are recognized adverse events with dupilumab, tralokinumab, and lebrikizumab. Patients with pre-existing ocular disease or new persistent ocular symptoms may require clinical assessment and appropriate ophthalmic management.

A switch between biologics may be reasonable when efficacy, tolerability, or patient preference warrants it. In a small retrospective study of 39 patients treated with tralokinumab, six of seven patients who had previously experienced conjunctivitis with dupilumab had no recurrence after switching.⁹ This finding is encouraging but is based on a small subgroup and does not establish that tralokinumab has definitively superior ocular safety. Larger comparative studies are needed to clarify the relative ocular safety profiles of these agents.

3.2 Oral JAK1 inhibition

Upadacitinib and abrocitinib are oral JAK1 inhibitors. JAK–signal transducer and activator of transcription (STAT) pathways transmit signals from multiple cytokine receptors. Inhibiting JAK1 can therefore affect several inflammatory pathways implicated in AD, including signaling associated with IL-4, IL-13, and IL-31.⁴

The range of affected pathways provides a biological rationale for the rapid improvement in itch and skin disease observed with JAK1 inhibitors. However, JAK inhibitors carry important warnings concerning serious infections, malignancy, major adverse cardiovascular events (MACE), thrombosis, and mortality.⁶˒⁷

The regulatory safety concerns arose substantially from ORAL Surveillance, a randomized safety trial of tofacitinib in patients with rheumatoid arthritis aged 50 years or older who had at least one additional cardiovascular risk factor. The trial identified increased risks of certain cardiovascular and malignancy outcomes compared with tumor necrosis factor inhibitors.⁸ The US Food and Drug Administration subsequently required boxed-warning updates for several JAK inhibitors, including upadacitinib, because of concerns about potentially shared class risks.⁶

These findings require careful interpretation. The magnitude of risk in an individual with AD cannot simply be assumed to be identical to that observed in the rheumatoid arthritis population. Nevertheless, the regulatory warnings remain clinically important and should inform treatment selection and patient counseling.

4. Comparative Efficacy: Interpreting Week-16 Outcomes

EASI-75 denotes at least a 75% reduction from baseline in EASI score. It is a useful measure of improvement in disease extent and severity, but it does not independently capture every clinically important outcome, including itch, sleep, quality of life, or complete skin clearance.

Interpretation: These figures describe outcomes within individual clinical trials; they are not evidence of a definitive ranking among treatments. Differences in trial populations, study design, rescue-treatment rules, statistical methods, baseline disease characteristics, and placebo response can affect observed percentages. Direct comparisons require appropriately designed head-to-head trials or carefully conducted comparative analyses.

Efficacy should also be assessed across multiple domains. For a patient whose main treatment goal is rapid relief of severe itch, the time course of pruritus improvement may be particularly relevant. For another patient, sustained control, injection frequency, ocular tolerability, or the ability to maintain treatment over the long term may carry greater weight.

5. Durability of Response and Long-Term Evidence

The treatment objective extends beyond initial improvement: patients need sustained disease control with an acceptable burden of adverse events and monitoring.

Long-term extension studies provide additional information about durability and safety, but their results require careful interpretation. A favorable response during an initial treatment period does not guarantee continued response in every patient, and analyses restricted to patients who remain on treatment may not represent the experience of all patients who initiate therapy.

An integrated safety analysis of upadacitinib in AD included data from three phase 3 clinical trials, with more than 9,000 patient-years of exposure across up to six years of treatment. The reported incidence rates of adjudicated MACE and venous thromboembolic events (VTEs) were low, and the investigators identified no new important safety signal over the observation period.⁵

These data derive from integrated clinical-trial exposure and are not a substitute for a dedicated, adequately powered cardiovascular outcomes trial in an AD population. Trial eligibility criteria and participant characteristics may also limit the generalizability of these findings to patients with greater comorbidity burdens in routine clinical practice. The analysis included patients who continued treatment, and its findings cannot exclude rare or delayed adverse events.⁵

Long-term safety findings should therefore complement, rather than replace, the current prescribing information and an individualized assessment of treatment risks.

6. Safety Assessment Before JAK1 Inhibitor Treatment

For a patient considering upadacitinib, the decision should be based on disease severity, previous treatment response, alternative options, patient preferences, and relevant risk factors.

6.1 Baseline assessment

Before treatment, clinicians should review the current prescribing information and assess for factors that may alter the benefit–risk balance. Relevant considerations include:

  • Active or recurrent serious infections and tuberculosis risk.

  • Viral hepatitis status and other infection-related risks, as clinically indicated.

  • Complete blood count and liver function, with additional laboratory evaluation according to the product label and clinical context.

  • Pregnancy status and reproductive considerations when relevant.

  • History of cardiovascular disease, thromboembolism, malignancy, and smoking.

  • Current medications, vaccination status, and potential contraindications or interactions.

Screening and laboratory requirements should follow the applicable product label and clinical guidelines. Treatment should not be initiated or continued when label-defined laboratory abnormalities or active conditions make treatment inappropriate.⁷

6.2 Communicating the boxed warning

Patients should understand that JAK inhibitors have warnings concerning serious infections, malignancy, MACE, thrombosis, and mortality.⁶˒⁷ These warnings do not mean that every patient will experience these outcomes or that risk is uniform across populations. They do, however, require an informed discussion before treatment.

Particular caution is warranted in patients who are current or former smokers, have established cardiovascular disease or other cardiovascular risk factors, have a history of thrombosis, or have current or previous malignancy. Clinicians should assess the individual benefit–risk balance and advise patients about symptoms requiring prompt medical assessment, including features suggestive of serious infection, venous thromboembolism, or acute cardiovascular events.

The six-year AD trial analysis of upadacitinib provides useful long-term exposure data, but it does not negate regulatory warnings or establish that the drug is free from cardiovascular, thrombotic, or malignant risks.⁵–⁷

6.3 Age-specific dosing

For patients aged 65 years and older with AD, the FDA review recommended approval of the 15 mg once-daily dose of upadacitinib only. This recommendation reflected increased risks of serious infections and malignancies observed with the 30 mg dose in this subgroup, together with uncertainty about the additional benefit of the higher dose in older patients.⁸ Dose selection should follow the applicable prescribing information and account for the patient's clinical response and individual risk profile.⁷˒⁸

For eligible adults younger than 65 years, dosing and any escalation should also follow the current product label, clinical response, and individual safety considerations. The lowest effective dose consistent with adequate disease control is an important principle when balancing long-term benefit and risk.

7. Applying the Evidence to the Clinical Case

Returning to the 34-year-old woman with severe itch, an EASI score of 28, and substantial sleep and occupational impairment, systemic treatment is a reasonable consideration after confirming the diagnosis and ensuring that topical treatment has been appropriately optimized.

Her preference for an oral treatment is relevant but should not determine the decision in isolation. Shared decision-making should compare the potential benefits of a JAK1 inhibitor with those of biologic therapy, including speed of symptom improvement, route and frequency of administration, ocular adverse events, monitoring requirements, and uncertainties surrounding rare long-term risks.

Her lack of known cardiovascular risk factors or malignancy is reassuring but does not remove the need for baseline screening, risk assessment, and informed consent. If upadacitinib is selected, the clinician should explain the boxed warning, arrange the appropriate pretreatment evaluation, and review treatment response and tolerability regularly.⁷

If the patient prioritizes avoiding JAK inhibitor-associated warnings and accepts injectable therapy, a biologic targeting IL-4/IL-13 signaling may be an appropriate alternative. Conversely, a strong preference for oral treatment and the need for rapid itch relief may support consideration of a JAK1 inhibitor when the individualized benefit–risk assessment is favorable. The available evidence does not support a single universally preferred systemic treatment for every patient with moderate-to-severe AD.

8. Clinical Takeaways

  • Confirm the diagnosis before escalation. Reassess adherence, aggravating factors, contact allergy, and alternative diagnoses when disease is atypical or unexpectedly refractory.

  • Match treatment to the patient's priorities. Skin clearance, itch relief, sleep, treatment route, dosing frequency, comorbidities, and tolerability all matter.

  • Interpret efficacy figures in context. Week-16 trial response rates are useful reference points, not a definitive cross-treatment ranking.

  • Discuss JAK inhibitor risks transparently. Regulatory warnings, individual risk factors, screening, and ongoing monitoring are essential parts of informed treatment selection.

  • Interpret extension studies cautiously. Longer follow-up adds useful evidence but cannot eliminate uncertainty about rare or delayed adverse events.

  • Use shared decision-making. The best treatment is the option that offers a favorable individualized benefit–risk balance and is acceptable to the patient over time.

Conclusion

The management of moderate-to-severe atopic dermatitis has moved beyond reliance on topical corticosteroids alone. Biologics targeting IL-4/IL-13 pathways and oral JAK1 inhibitors provide distinct systemic options for patients whose disease remains inadequately controlled with topical treatment.

Selecting among these therapies requires accurate diagnosis, a clear understanding of trial endpoints, realistic interpretation of long-term evidence, and transparent communication about safety. Individualized treatment selection and continued reassessment remain central to achieving durable disease control.

References

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  2. Wollenberg A, Blauvelt A, Guttman-Yassky E, et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2021;184(3):437-449. doi:10.1111/bjd.19574.

  3. Silverberg JI, Guttman-Yassky E, Thaçi D, et al. Two phase 3 trials of lebrikizumab for moderate-to-severe atopic dermatitis. N Engl J Med. 2023;388(12):1080-1091. doi:10.1056/NEJMoa2206714.

  4. Guttman-Yassky E, Teixeira HD, Simpson EL, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 2021;397(10290):2151-2168. doi:10.1016/S0140-6736(21)00588-2.

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  6. US Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Published September 1, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death. Accessed October 14, 2026.

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  8. US Food and Drug Administration. Multidisciplinary Review and Evaluation: RINVOQ (upadacitinib), NDA 211675/S-004. FDA. https://www.fda.gov/media/155983/download. Accessed October 14, 2026.

  9. Kreeshan FC, Chircop O, Clayton TH, Hunter HJA, Warren RB. Real-world clinical experience of tralokinumab in a tertiary centre: an alternative for patients with conjunctivitis on dupilumab? Dermatol Ther (Heidelb).2025;15(8):2275-2279. doi:10.1007/s13555-025-01446-7.

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