Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense pruritus, skin barrier dysfunction, and type 2 immune dysregulation. Several biologics have been approved since the approval of dupilumab in 2017. However, current guidelines provide limited guidance on biologic sequencing, treatment non-response, and switching strategies.

Methodology: A focused narrative review of guidelines published between January 2017, and January 2026 was conducted using PubMed/MEDLINE, EMBASE, guideline-specific databases, and official dermatology society websites. Evidence from phase III clinical trials, real-world registries, and network meta-analyses was also incorporated and they were categorized into four evidence levels.

Results: Current guidelines recommend dupilumab as the first-line biologic therapy for moderate to severe AD. IL-13-selective biologics such as tralokinumab and lebrikizumab represent an effective alternative, particularly for patients with ocular surface disease, while nemolizumab may be beneficial in pruritus-dominant disease. However, no currently appraised guideline provides a validated second-line biologic sequencing following dupilumab non-response.

Conclusion: Current guidelines fall short in addressing biologic sequencing for treatment-experienced AD patients. A mechanism-informed, phenotype-guided framework has been provided as a Level IV conceptual model to support clinical decision making until evidence from head-to-head trials, standardized definitions, and biomarker-driven treatment strategies become available.

AAD: American Academy of Dermatology AD: Atopic dermatitis; BAD: British Association of Dermatologists; BNMA: Bayesian network meta-analysis; CRSwNP: Chronic rhinosinusitis with nasal polyps; DLQI: Dermatology Life Quality Index; EADV: European Academy of Dermatology and Venereology; EASI: Eczema Area and Severity Index; EoE: Eosinophilic esophagitis; IGA: Investigator Global Assessment; IL: Interleukin; JAK: Janus kinase; MACE: Major adverse cardiovascular events; NMA: Network meta-analysis; OSD: Ocular surface disease; PEDISTAD: PEDIatric STudy in Atopic Dermatitis; POEM: Patient-Oriented Eczema Measure; PP-NRS: Peak Pruritus Numeric Rating Scale; RCT: Randomized controlled trial; SUCRA: Surface Under the Cumulative Ranking Curve; VTE: Venous thromboembolism.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease characterized by intense pruritus, epidermal barrier dysfunction, and type 2 immune dysregulation. It is most common in around 10-15% of children and 4–8% of adults worldwide, which represents a major public health issue that significantly affects the quality of life and psychological well-being [1–3]. AD is often associated with other medical conditions such as asthma, allergic rhinitis, food allergy, anxiety, and depression, reflecting its systemic and multifactorial nature [4,5].

To manage moderate to severe AD, the use of topical corticosteroids, calcineurin inhibitors, and broad immunosuppressants such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil has been known for decades. These therapies have offered some relief from symptoms in many patients; however, their long-term use was hampered by variable efficacy, toxicity concerns, and inadequate disease control [6,7]. A major breakthrough in therapeutics was marked by the approval of Dupilumab in 2017, demonstrating significant clinical efficacy superior to conventional immunosuppressants, thereby transforming the treatment scenario and reshaping subsequent guideline development [3,8].

Subsequent approvals of additional targeted biologics, including IL-13 inhibitors tralokinumab and lebrikizumab, as well as anti-IL-31Rα monoclonal antibody nemolizumab, have expanded the therapeutic armamentarium for AD [7,9]. Furthermore, emerging agents targeting OX40, OX40 ligand (OX40L), and IL-33 are in advanced stages of clinical development [9,10]. This proliferation requires clinicians to navigate not only agent selection but biologic sequencing, a domain where practice consistently outpaced guideline development.

Current international guidelines provide robust first-line recommendations but offer limited structured guidance on questions encountered daily in practice, such as What constitutes primary versus secondary non-response? When and to which agent should a clinician switch? How should comorbidities such as conjunctivitis, eosinophilic esophagitis, or cardiovascular disease influence sequencing? What evidence supports second- and third-line biologic use?

This review appraises guideline recommendations from the AAD (2023), EADV (2022), BAD (2023), and Asia-Pacific AD guidelines with a specific focus on biologic sequencing, identifies gaps between recommendations and real-world clinical needs, and proposes a mechanism-informed framework for managing biologic-experienced patients.

A targeted literature search was conducted using PubMed/MEDLINE, EMBASE, guideline-specific databases (GIN, NICE, AAD Guidelines Central), and official society websites. The primary search window was between January 2017 and December 2024, including the dupilumab approval era.

Priority was given to guidelines from major international dermatological societies, including the American Academy of Dermatology (AAD), European Academy of Dermatology and Venereology (EADV), and British Association of Dermatologists (BAD), together with pivotal peer-reviewed clinical studies relevant to biologic therapy in atopic dermatitis (AD). Sources were selected based on their scientific relevance rather than exhaustive retrieval, representing an inherent limitation in designing the review.

The evidence discussed in this review was categorized into four major levels: Level I, including phase II–III randomized controlled trials (RCT) and meta-analyses; Level II comprised Bayesian network meta-analyses; Level III included prospective registries and multicenter observational studies; and Level IV considered as expert consensus statements, position papers, and narrative reviews [11,12].

Major phase III clinical trials that inform about recent biologics use in AD are reviewed, including LIBERTY AD SOLO 1 and 2, ECZTRA 1 and 2 for tralokinumab, ADvocate 1 and 2 for lebrikizumab, and ARCADIA 1 and 2 for nemolizumab [13,14].  Real-world evidence from large observational studies and registries, including EUROSTAD, TARGET-DERM, BioDay, and PEDISTAD, was also incorporated to complement the trial dataset and improve clinical applicability [6,15,16]. Although a formal systematic review methodology was not employed, a structured, selective approach was used to include the most clinically relevant guidelines, major trials, and real-world examples relevant to biologic sequencing in AD.

The Approved Biologic Landscape in Atopic Dermatitis 

Dupilumab: The Anchor Agent

Dupilumab is a monoclonal antibody (mAb) that simultaneously inhibits IL-4 and IL-13 by blocking the IL-4 receptor alpha (IL-4Rα) subunit. In phase III trials of LIBERTY AD SOLO 1 and 2 have demonstrated EASI-75 responses in 44–51% of patients at week 16 compared with 12–15% for placebo-treated patients (Level I) [8]. Further, long-term extension studies showed sustained efficacy and safety up to three years [17]. It is currently approved for patients spanning from ≥6 months to adulthood, which makes it the broadest approved range biologic for AD [6,18]. Registered data demonstrate a high adult drug survival rate reaching 80–90% at 3 years, substantially higher than conventional systemic agents such as cyclosporine (20–37%) [3,19]. Ocular surface disease (OSD) remained the most recognized adverse effect, reported to affect 8–11% of patients in clinical trials, whereas real-world registries have mentioned the rates reaching up to 40% in selected populations [3].

Tralokinumab and Lebrikizumab: The IL-13 Selective Agents 

Tralokinumab and lebrikizumab selectively target IL-13 signaling without affecting IL-4 pathways. In ECZTRA 1 and 2 phase III trials, it has achieved Investigator’s Global Assessment (IGA) 0/1 responses in 15.8–22.2% of patients at 16 weeks [13,20].

Lebrikizumab has demonstrated a higher response rate for ADvocate 1 and 2 clinical trials, with IGA 0/1 responses in 29.1–43.1%, with the lowest conjunctivitis rates of any approved agent [21]. Both of these agents (tralokinumab and lebrikizumab) are approved for adult and adolescent patients aged ≥12 years.

In comparison with dupilumab, IL-13 selective agents appear to have fewer adverse effects, including OSD. Bayesian NMA ranked dupilumab the highest among effective biologics (SUCRA 96%), whereas lebrikizumab was ranked fourth (SUCRA 75%) and tralokinumab tenth (SUCRA 48%), indicating lebrikizumab as the most dupilumab-comparable alternative pending head-to-head data [22,23].

Nemolizumab: Targeting the Itch-Barrier Axis

Nemolizumab targets IL-31Rα to modulate the neuroimmune pathways involved in pursuits and skin barrier dysfunction. In the ARCADIA 1 and 2 phase III trials, nemolizumab significantly reduced the pruritus numerical rating scale (PP-NRS) score, with itch relief observed within the first week of treatment, along with improvements in EASI and IGA outcomes [24] It received FDA approval in 2024, covering both AD and prurigo nodularis in patients aged ≥12 years.

Pediatric phase III data in children aged 6–12 years have shown significant antipruritic efficiency compared to placebo from day 2 of treatment [25,26]. Nemolizumab may be particularly useful in patients with pruritus-dominant AD phenotype; combinatorial use with IL-4/IL-13 biologics is mechanistically plausible, but valid evidence is still lacking [3,19]. Table 1 summarizes the currently approved biologic therapies for atopic dermatitis, including their molecular targets, mechanisms of action, efficacy outcomes, and major adverse events.

Table 1: Comparative overview of approved biologic agents for moderate-to-severe atopic dermatitis

Comparative Appraisal of International Guidelines 

First-Line Biologic Selection: Points of Consensus

Current guidelines, including AAD (2023), EADV (2022), BAD (2023), and Asia Pacific expert consensus groups, have converged on a fundamental recommendation: the first-line biologic agent for adult patients with moderate-to-severe AD who have an inadequate response to, or are intolerant to, conventional systemic immunosuppressants [1,6,28]. This consensus is largely based on dupilumab's robust and long-term efficacy, long-term safety dataset among approved AD biologics, and approval in the broadest age range, including children as young as 6 months [6,19].

The AAD 2023 guideline has provided dupilumab with a strong recommendation (Level I) based on high certainty evidence and positions tralokinumab and lebrikizumab as conditional effective alternatives, based on robust phase III clinical trials [6]. Likewise, the EADV 2022 guideline endorses dupilumab as preferred first-line biologics, while IL-13-selective agents are recognized as appropriate alternatives for patients with dupilumab-associated OSD or in situations where selective IL-13 may be clinically advantageous [1].

Currently available international guidelines differ in the level of detail provided for biologic sequencing, non-response treatment definitions, special population management, and the role of the newer biologic agents. A comparative summary of key recommendations from different international guidelines is presented in Table 2.

Table 2: Comparative overview of international guideline recommendations for biologics and sequencing in atopic dermatitis. Information provided in this table is a synthesis of guidelines recommendations and expert consensus provided in AAD 2023 (6), EADV 2022 (28), BAD 2023 (29) and Asia Pacific guidance (30).

Sequencing After Biologic Non-Response: The Critical Gap

Despite increasing therapeutic opportunities, none of the currently available guidelines provide a structured, evidence-based algorithm for biologic sequencing after dupilumab non-response. Use of alternative biologics has also been acknowledged in the AAD guidelines; however, they do not define standardized criteria for primary or secondary non-response [6]. The EADV guideline proposes personalized switching, but relies primarily on expert opinion due to the absence of comparative prospective evidence [1]. Similarly, the BAD guidelines recommend assessments after 16 weeks of therapy but do not incorporate mechanistic or phenotype-based approaches [1]. The sequencing guidelines in the Asia-Pacific recommendations remain similarly limited.

An expert-level hypothesis (Level IV) suggests that patients with primary dupilumab non-response may have a signaling pathway inadequately suppressed by dual IL-4/IL-13 blockade that could also respond less favorably to selective IL-13 inhibition. However, this should not categorically exclude IL-13-selective agents after dupilumab primary failure; real-world data suggest intra-class switching for tolerability-driven discontinuation, such as conjunctivitis, rather than lack of efficacy [15,19]. Currently available guidelines do not adequately distinguish this major gap in clinical guidance.

Special Populations and Comorbidity-Guided Sequencing 

Dupilumab offers an additional approved indication beyond AD, including Eosinophilic Esophagitis (EoE), asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), prurigo nodularis, and alopecia areata, among others. Consequently, both AAD and EADV guidelines favor this biologic for patients with these comorbid conditions [1,6]. For patients with severe dupilumab-associated conjunctivitis, despite topical management, tralokinumab or lebrikizumab are recommended alternatives because of their reported lower OSD rates [1]. In contrast, nemolizumab may be very beneficial, particularly for pruritus-dominant disease, characterized by inflammatory phenotypes with significant sleep disruption; given its IL-31signaling inhibition along the neuroimmune itch pathway. However, formal guideline incorporation is anticipated in forthcoming updates (6,27,28).

Pregnancy and lactation remain areas with limited guideline-directed recommendations. Recent studies have documented a low risk of major adverse maternal or neonatal outcomes with dupilumab exposure during pregnancy. Available pharmacokinetic data suggested minimal transfer into breast milk, approximately 1.3% of the maternal plasma dose [31]. Nevertheless, product labeling recommends temporary discontinuation when appropriate; however, the AAD 2023 guidelines supports the use of dupilumab in pregnancy when expected benefits clearly outweigh the potential risks [6].

Toward a Practical Biologic Sequencing Framework 

Defining Response and Non-Response

The lack of standardized definitions for biologic treatment response and non-response is one of the major problems with the current atopic dermatitis guidelines. Primary non-response is conceptually defined as at least 50% improvement in the Eczema Area Severity Index (EASI-50) after 16 weeks of therapy with documented adherence. Secondary non-response refers to those patients who initially achieved EASI-50, but later reduced to more than 30% over at least 8 weeks [6,28]. Primary non-response more likely reflects mechanistic inadequacy to suppress the dominant inflammatory pathway, whereas secondary non-response may result from anti-drug antibody formation, disease phenotype shift, or comorbid diseases [15,28,32]. Mechanistic class switching is most recommended in case of confirmed primary non-response, whereas optimization strategies are reasonable in case of secondary non-response. However, this concept is largely based on expert opinion and observational evidence (Level IV), and prospective validation is required.

Phenotype- and Comorbidity-Informed Selection

The large number of biologic therapies for AD highlighted the importance of individualized treatment selection based on disease, some key phenotypic dimensions that include: 

1. Atopic comorbidity burden: the multi-indication approvals of dupilumab favor its use in patients with concurrent asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), or Eosinophilic Esophagitis (EoE) [33,34];
2. Patients with preexisting OSD: IL-13-selective agents such as tralokinumab or lebrikizumab is preferred for comparatively lower adverse effects [13,15].
3. Pruritus predominance: Nemolizumab is particularly useful for patients with severe PP-NRS (≥7) with sleep disruption [21,24].
4. Pediatric profile:  Dupilumab holds the broadest pediatric approval (starting from ≥6 months) [14,34].

In addition to these practical considerations, such as reimbursement policies, regional regulatory approvals, treatment accessibility, and future biosimilar availability, etc., are some other major determinants of biologic sequencing and long-term therapeutic sustainability [32].

Proposed Biologic Sequencing Framework 

Based on the preceding appraisal of current evidence and guideline limitations, a mechanism-informed, phenotype-guided biologic sequencing framework is proposed as a conceptual clinical model. It reflects expert consensus and theoretical reasoning, not an evidence-validated clinical guideline, and therefore, it should not be applied prescriptively; it represents expert-informed consensus pending prospective validation.

Step 1- Optimized conventional therapy (3-6 months): Topical corticosteroids along with calcineurin inhibitors with or without PDE4 inhibitors (crisaborole or roflumilast); assess for uncontrolled comorbid triggers before escalating to systemic therapy [28,35]

Step 2- First biologic: Dupilumab is preferred in all patients without contraindication. Tralokinumab or lebrikizumab are alternatives for patients with high conjunctivitis risk, dupilumab intolerance, or specific type 2 comorbidity profiles where selective IL-13 inhibition is preferred [13,21,28,35].

Step 3A- Primary non-response at 16 weeks ( First, evaluate adherence, concurrent infectious triggers, and adequacy of concomitant topical therapy before conclusion of failure. For confirmed dupilumab primary non-response cases, switching to an IL-13-selective agent remained supported by theoretical rationale and limited evidence [28]. Transition to Janus kinase (JAK) inhibitors may be considered for younger patients with appropriate cardiovascular, thromboembolic, and malignancy risk stratification [3,36].

Step 3B- Secondary non-response: Reassessment should include evaluating for anti-drug antibodies, adherence, and uncontrolled comorbid disease. Optimizing topical therapy and managing triggering factors may exacerbate the disease in some cases. Consider intra-class switching, such as from dupilumab to tralokinumab or lebrikizumab, may also be considered in selected cases. Reserve JAK inhibitors for refractory disease with adequate risk-benefit documentation [37].

Step 4 - Pruritus-dominant residual disease: In patients with persistent severe pruritus (PP-NRS ≥7) despite adequate lesional control on an IL-4/IL-13 pathway biologic, addition of nemolizumab may be considered. As a standalone first-line biologic in a specific pruritus-dominant, lesion-minimal phenotype, nemolizumab remains exploratory (Level IV), is not yet endorsed by any current major international guidelines,s and requires prospective validation before it can be regarded as established practice [24,27,28,35].

Step 5 - Pipeline agents: Several emerging biologic agents like Anti-OX40 (rocatinlimab), anti-IL-33 (itepekimab) and anti-OX40L (amlitelimab) are in advanced clinical development and may expand further for future sequencing strategies when approved based on available evidences [38,39].

The Interface of Biologics and JAK Inhibitors in Sequencing

Several JAK inhibitors, like upadacitinib, baricitinib, abrocitinib, etc., offer blockade of intracellular JAK-STAT signaling with higher short-term skin clearance than approved T2 biologics to modulate multiple inflammatory pathways [6,28]. Upadacitinib 30 mg achieved EASI-90 responses in approximately 60–62% of patients at 16 weeks in phase III studies [36,40]. The FDA’s 2021 Boxed Warning (major adverse cardiovascular events (MACE), venous thromboembolism (VTE), malignancy, infections) necessitates individualized risk stratification and documented informed consent before use. Current guidelines support biologic-first positioning in patients aged over 50 or with cardiovascular risk factors, a history of malignancy, or prior herpes zoster [1,3]. In contrast, JAK inhibitors may be considered in younger biologic-refractory patients without relevant comorbidities, after careful individual documentation of risk-benefit discussion [6,21,26].

Real-World Evidence and Its Implications for Sequencing

Real-world evidence has become an increasingly essential source of information to complement RCT findings with respect to persistence, efficacy, safety, and switching of the treatment regimen. Results from the EUROSTAD registry, which comprised a sample of over 3,000 biologic-naive AD patients with moderate-to-severe AD, indicated that 60% of patients had an EASI-75 response after treatment with dupilumab for 24 weeks [41]. Evidence from other real-world scenarios has helped shape biological switching approaches. A recently conducted Danish study, published in 2023, showed that switching from dupilumab to tralokinumab due to dupilumab-induced conjunctivitis was accompanied by great clinical success, as about 89% of patients reached the OSD remission stage while keeping their AD under control [42].

Long-term real-world effectiveness data from the Dutch BioDay registry have also provided important insights into treatment durability and patient-reported outcomes. A study involving a population of 1,223 patients followed up to 5 years confirms durable Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Numerical Rating Scale (NRS)-pruritus score improvements, with 73.5% of adults achieving well-controlled disease by composite PROM criteria, and work productivity impairment declining from 40.1% to 13.3–16.3% [43]. Itch-dominant phenotype and class I obesity predicted lower composite patient-reported outcome measures (PROM) response rates, directly informing phenotype-guided sequencing. Conjunctivitis affected 33.7% of patients, among them 69.7% experiencing moderate-to-severe disease [43].

The PEDISTAD registry, showing a 2-year observational study involving 379 children younger than 12 years of age, confirmed the superior effectiveness of dupilumab over methotrexate and cyclosporine, where the mean EASI declined from 20.9 to 8.6 with a lower rate of discontinuation (8.3% vs. 28.9% and 43.0%) than those observed in conventional immunosuppressants [44]. Formal pediatric sequencing guidance remains absent despite these differences [44].

Emerging real-world data indicate that dose-interval extension beyond the FDA-approved regimen for dupilumab may be feasible for select responders with sustained disease control. De Bruin-Weller et al. (2026) have reported that almost 83% of patients were able to maintain clinical effectiveness upon tapering to Q3W or Q4W regimens, where type 2 inflammation biomarkers such as TARC/CCL17 and PARC/CCL18 remained suppressed throughout the duration of follow-up [3]. Moreover, there was potential for significant healthcare cost savings, where the reduction in costs was predicted to approach €4 million over a period of 3.5 years in 401 patients. Similarly, Tralokinumab and lebrikizumab permit Q4W step-down after week-16 response [3]. This is an important consideration for biologic sequencing, since a patient with sustained disease control can be extended on interval therapy without changing to another class of biologics.

Indirect comparative evidence from a well-established network meta-analysis (NMA) by Drucker et al. (Level II evidence) identified dupilumab as the most consistently effective approved systemic biologic agent across multiple efficacy outcomes in moderate to severe AD [22]. More recently, Bayesian NMA by Babul et al. (2026), incorporating 17 RCTs and 6,366 patients, reported findings that broadly corroborate with previous analysis, ranking dupilumab highest across four predefined efficacy endpoints [23].

Strengths and Limitations of the Study

The strengths of this review lie in the integration of evidence across multiple levels (RCTs, registries, network meta-analysis) and an additional four-tier evidence grading made by the authors, which helps to assess claims effectively. One of the major limitations of the study is its review design. No attempt was made to use a comprehensive source selection, which may lead to selection bias. The lack of a formal systematic review protocol might introduce selection bias, but this approach was chosen to enable a focused, clinically oriented synthesis of rapidly evolving evidence. Another limitation of this study is that all of the proposed sequencing frameworks provide only Level IV evidence and have never been prospectively validated. Future AD guidelines should seek to reach the level of specificity achieved in psoriasis guidelines.

The introduction of biologic therapies has significantly transformed the management of moderate to severe AD, with current guidelines aligned with dupilumab as the preferred first-line biologic. However, despite the expanding therapeutic landscape, it falls substantially short on structured sequencing guidance for biologic-experienced patients. Defined non-response criteria, switching algorithms, and integrated real-world evidence remain absent. The mechanism-informed framework proposed herein offers a scaffold for clinical decision-making; urgent priorities include head-to-head biologic switching trials, standardized response definitions, and biomarker-driven stratification.

Declaration of Competing Interests

Conflict of Interest: The author declares that they have no conflict of interest.

Compliance with Ethical Standards

Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors.

Acknowledgments

The author declares no funding sources for this review. The author thanks colleagues in the Department of Dermatology for critical review of earlier manuscript drafts.

Author Qualification Statement

Ahmed M. Zahr Allayali is a dermatologist with clinical and academic experience in inflammatory dermatoses and systemic therapy for atopic dermatitis.

Contribution Details

Ahmed M. Zahr Allayali: Concepts; design; definition of intellectual content; literature search; data analysis and interpretation; manuscript preparation, editing, and review. Ahmed M. Zahr Allayali accepts full responsibility for the integrity of the work and is designated as guarantor.

Declaration of Competing Interests

The author declares no competing interests.

Funding

No external funding was received for this work.