Dupilumab-Induced Immune Drift Phenomena in Atopic Dermatitis: Novel Insights into Mechanisms and Therapeutic Strategies

Abstract

Atopic dermatitis (AD) and psoriasis exhibit opposing T-cell polarization patterns and cytokine axes. Dupilumab, a monoclonal antibody targeting the interleukin-4/interleukin-13 (IL-4/IL-13) signaling pathway, has become a first-line biologic for moderate-to-severe AD. However, emerging clinical observations reveal that some patients with AD develop psoriasiform eruptions following biologic therapy, while certain patients with psoriasis may conversely develop eczematous lesions after corresponding biologic treatments. This paradoxical immune response has been termed the “immune drift phenomenon.” This review synthesizes current evidence regarding the immunological mechanisms, clinical manifestations, histopathological characteristics, temporal patterns, and therapeutic strategies associated with this phenomenon, with particular emphasis on comprehensive management approaches, including topical therapies, systemic medication adjustments, biologic switching, and targeted small-molecule agents. In particular, it is important to acknowledge the potential limitations of small-molecule inhibitors, such as Janus kinase (JAK) inhibitors, or combination biologic therapies for managing immune drift, including the current lack of robust long-term safety and efficacy data in this specific context. We aim to provide clinicians with evidence-based management recommendations while outlining future research directions.

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by Th2-dominant immune responses, with approximately 80% of patients demonstrating elevated serum immunoglobulin E (IgE) levels and a strong atopic predisposition.¹ Biomarker research confirms that the Th2 pathway serves as the primary driver in AD, although multi-axial immune involvement contributes to phenotypic variability and disease severity. Notably, Th1 pathways may predominate in chronic AD.^2,3 The condition typically follows a chronic relapsing course, with most cases manifesting early in life, commonly within the first two years after birth.

In contrast, psoriasis represents a chronic immune-mediated inflammatory dermatosis primarily driven by Th1 pathways. The complex interplay between the innate and adaptive immune systems leads to cutaneous inflammation and abnormal keratinocyte hyperproliferation, clinically presenting as well-demarcated erythematous plaques with silvery scales.^{4, 5} Like AD, psoriasis significantly compromises skin barrier function.

Dupilumab has demonstrated remarkable efficacy in improving AD symptoms through interleukin-4/interleukin-13 (IL-4/IL-13) pathway inhibition, with extensive clinical trials and real-world applications confirming its safety profile. However, global experience with dupilumab has revealed an increasing number of patients with AD developing psoriasiform lesions during or after treatment, a phenomenon attributed to a “paradoxical immune response.”⁶ Current evidence suggests this phenomenon occurs when suppression of specific immune pathways leads to compensatory activation of alternative pathways, resulting in novel disease phenotypes. In the context of dupilumab therapy for AD, Th2 pathway inhibition may disrupt the natural regulation of Th1/Th17 responses, thereby promoting psoriasiform eruptions.

This article will systematically examine this phenomenon through three dimensions: underlying mechanisms, clinical characteristics, and therapeutic strategies, while proposing personalized management recommendations.

CLINICAL AND RESEARCH CONSEQUENCES

This study is a narrative review. A comprehensive literature search was conducted in the PubMed database for articles published between January 2014 and December 2024. The search strategy employed a combination of Medical Subject Headings (MeSH) terms and relevant free-text keywords, including “psoriasis,” “psoriasiform,” “atopic dermatitis,” “eczema,” “eczematous,” “adverse reaction,” “paradoxical reaction,” “immune drift phenomena,” “dupilumab,” and “IL-4.” Boolean operators were utilized to optimize search precision, with the search restricted to titles and abstracts.

To focus on detailed clinical presentations, only case reports and case series were included; clinical trials, observational studies, and meta-analyses were excluded. Non-English publications and articles without accessible full texts were also omitted. All retrieved records underwent manual screening to assess their relevance to dupilumab-induced psoriasiform dermatitis (DAPs).

Following this process, 32 articles met the predefined inclusion criteria and were included in the final review (Appendix 1). Article selection was performed independently by BX, CZ, and XZ. All articles were reviewed by senior authors (CL, WZ, and KZ), who made the final decision in cases of disagreement among the initial selectors.

The reviewed studies collectively reported 65 cases, consisting of 51 adult patients (28 male, 23 female; age range: 22-92 years) and 14 pediatric cases (10 male, 4 female; age range: 4-18 years). Twelve patients (18.5%) had a previous personal and/or family history of psoriasis, and 10 patients (15.4%) had a personal and/or family history of allergic diseases. The mean time from the start of treatment with dupilumab to the onset of psoriasiform rash or psoriasis was 20.71 weeks for adults and 32.83 weeks for children. However, two additional cases of exacerbated flare-ups on top of primary psoriasis resulted in a mean time of 16 weeks.

The types of new-onset psoriasis included plaque psoriasis, pustular psoriasis, reverse psoriasis, erythrodermic psoriasis, guttate psoriasis, and palmoplantar pustulosis, and psoriatic dermatitis. Rashes appearing on the scalp could be accompanied by alopecia areata (3.1%). The most frequently occurring type was plaque psoriasis (66.2%), followed by pustular psoriasis (15.4%). Episodes of lesions may involve multiple sites throughout the body, including the scalp, face, trunk, extremities, intertriginous areas, and palms and toes, and may even overlap with sites previously affected by AD. The rash typically presented as erythema, plaques, scales, and pustules.

In the literature, diagnosis was typically confirmed by biopsy. In terms of treatment, adults were most likely to discontinue dupilumab. Treatment strategies included topical or systemic corticosteroids, topical calcineurin inhibitors, immunosuppressive agents, acitretin, other biologics such as ustekinumab, omalizumab, anakinra, as well as small-molecule targeted agents such as apremilast, upadacitinib, and baricitinib. The treated rashes effectively improved or even completely subsided (90.8%), with only four cases of recurrence after treatment (6.2%).

EXPLORATION OF THE MECHANISM OF THE IMMUNE DRIFT PHENOMENON

Genetic Predisposition Factors

Atopic dermatitis and psoriasis share a common genomic locus on chromosome 5q31.1-q33.1, with IL-13 demonstrating significant associations with both conditions.⁷ Notably, IL-13 serves as a hallmark cytokine in AD pathogenesis and exerts more substantial effects than IL-4. While most genetic analyses support the dichotomous nature of AD and psoriasis, emerging evidence reveals overlapping genetic loci and shared cytokines, although their precise pathophysiological roles remain incompletely understood.

The filaggrin gene (FLG) is a well-established genetic risk factor for AD development. Mutations or polymorphisms in FLG compromise skin barrier integrity, impairing critical physiological functions such as hydration, pH regulation, thermoregulation, elasticity, and melanin content.⁸ Genome-wide association studies highlight the complex genetic architecture of psoriasis, with HLA-Cw2 emerging as the predominant susceptibility allele.⁹

Th2 Suppression and Compensatory Activation of the Th1/Th17 Pathway

The precise immunopathogenesis of DAPs eruptions remains incompletely understood; however, current evidence points to a complex interplay of cytokine-mediated mechanisms within the immune system. At the core of this phenomenon lies the fundamental immunological dichotomy between AD and psoriasis (Fig. 1): while AD is characterized by Th2-dominant inflammation mediated primarily by IL-4, IL-13, and IL-31, psoriasis manifests as a Th1/Th17-polarized condition driven by interferon-gamma (IFN-γ), IL-17A/F, IL-22, and IL-23.¹⁰

Figure 1.

Mechanisms underlying dupilumab-induced psoriasiform eruptions.

Dupilumab exerts its therapeutic effect through selective blockade of IL-4/IL-13 signaling via IL-4Rα binding, effectively suppressing pathogenic Th2 responses in AD. However, this targeted inhibition appears to disrupt crucial immunoregulatory balances, precipitating several compensatory changes. By removing the natural suppressive effects of IL-4/IL-13 on Th1 and Th17 cells, dupilumab may lead to elevated levels of IFN-γ, IL-17, and IL-23. The chronic phase of AD is characterized by upregulation of Th1 cytokines, particularly IFN-γ, along with an imbalance in the proportions of Th1, Th2, and Th17 cells, leading to dysregulated interactions among them.^11,12

Clinically, IL-17 inhibitors (e.g., secukinumab, ixekizumab) used for psoriasis have been reported to induce eczema.¹³ Risk factors for this paradoxical reaction include advanced age, female sex, and a history of AD or hay fever. A preliminary study using immunohistochemistry compared stable late-stage psoriasis with eczematous eruptions and found that IL-10, IL-4, and IL-17A expression was higher in eczematous rashes induced by secukinumab, thereby promoting AD-like lesions.¹⁴ These findings support the concept that suppression of the Th1/Th17 phenotype in psoriasis shifts the immune balance toward the Th2 phenotype characteristic of AD.

Dysregulation of Other Inflammatory Cytokine Axes

Recent studies have revealed that IL-22, a cytokine primarily secreted by Th17 cells, is produced and amplified under the regulation of IL-23. As an important effector of the Th17 lineage, IL-22 often acts synergistically with IL-17A or IL-17F, participating in local tissue inflammatory responses by modulating innate immune-related genes in the skin and enhancing antimicrobial peptide expression.¹⁵ Furthermore, IL-22 suppresses the expression of FLG2, compromises skin barrier integrity, and promotes keratinocyte proliferation and migration, thereby contributing to the pathological progression of psoriasis.

Although the IL-4Rα inhibitor dupilumab can reduce systemic IL-22 levels and improve clinical symptoms, it may activate T cell oligoclonal expansion during treatment, leading to IL-22 mediated cutaneous inflammation, such as head and neck dermatitis.¹⁶ Studies suggest that local cytokine signaling and tissue specific responses may not be fully suppressed by IL-4Rα blockade, resulting in the persistence of IL-22 associated gene expression in the skin and thereby contributing to disease remodeling.¹⁷

Certain alarmins participate in type 1 or type 2 immune responses. IL 31, a pruritogenic cytokine primarily overexpressed by Th2 cells, activates the neuroimmune axis via actions on keratinocytes and sensory neurons in AD. This process promotes the itch–scratch cycle, which disrupts the skin barrier, facilitates allergen penetration, and perpetuates inflammation.¹⁸ Although IL 31 was historically considered to have minimal involvement in psoriasis, recent evidence indicates elevated serum IL 31 levels in patients with psoriasis and enhanced IL 31 transcription within pruritic lesions, implying a potential role in psoriasis associated pruritus.¹⁹

IL-33 induces Th2 immune activation, promoting the release of cytokines such as IL-4, IL-5, and IL-13, while also driving macrophage polarization and degranulation of basophils and eosinophils.²⁰ IL-33 further stimulates IL-31 secretion, which directly activates sensory neurons to elicit pruritus. Serum levels of IL-31 and IL-33 correlate closely with symptom severity and disease progression, underscoring their interconnected roles in the pathogenesis of inflammatory and allergic disorders.

A study of dupilumab-treated AD demonstrated effective suppression of IL-4- and IL-13-mediated inflammation, although pathways regulating IL-33 production were not significantly affected.²¹ Notably, keratinocyte-derived IL-33 may promote epidermal hyperplasia in psoriasis through autocrine signaling, while immune cells may further contribute to IL-33-mediated exacerbation of psoriatic pathology.

Recent studies suggest that inhibition of IL-4/IL-13 signaling may upregulate IL-36, a pro-psoriatic cytokine, directly driving abnormal keratinocyte proliferation and inflammatory infiltration.^22,23 IL-36, a known downstream target of both IL-17A and IL-17C, exhibits synergistic effects with IL-17A in inducing antimicrobial peptides. Mechanistically, blockade of IL-4/IL-13 signaling disrupts T-cell immune balance, which, through IL-17-mediated pathways, amplifies pre-existing IL-36-driven inflammation, ultimately contributing to the development of both plaque-type and pustular psoriasis.

Divergence in Immune Responses Between AD and Psoriasis Patients

The diversity of skin microbiota and the overgrowth of Staphylococcus aureus are both modulated by innate immune sensing. Emerging evidence suggests that keratinocytes play a role in the immune drift phenomenon.

In AD, IL-13 downregulates structural proteins in keratinocytes—such as loricrin and involucrin—which are critical for maintaining the stratum corneum barrier. Concurrently, dysregulation of innate immune genes (coagulase and β-defensins) increases susceptibility to cutaneous infections (S. aureus), further compromising the epidermal barrier and exacerbating AD pathogenesis.²⁴ Failure to properly regulate antimicrobial peptides (AMPs) in AD may also contribute to a loss of microbial diversity. Psoriasis is characterized by AMPs (LL-37, β-defensins, S100 proteins) secreted by damaged keratinocytes, which activate dendritic cells and play a pivotal role in plaque formation.¹⁰

A significant portion of innate immune dysfunction in AD can be attributed to a weakened epidermal barrier and dominant Th2-driven inflammation. Notably, dupilumab treatment not only restores microbial diversity in AD skin but also reduces pro-inflammatory pathogen-associated molecular patterns (PAMPs) through innate immune sensing, thereby mitigating chronic inflammation.²⁵

Interestingly, IL-13 inhibition may disrupt keratinocyte proliferation control, potentially promoting psoriasiform epidermal hyperplasia and parakeratosis. Emerging evidence links dysbiosis in both AD and psoriasis to IL-33/IL-31 signaling, suggesting that microbial imbalance may drive disease progression through immune dysregulation.¹⁹ However, the causal relationship between dysbiosis and these dermatoses remains unclear, and the molecular mechanisms by which microbiome shifts sustain chronic inflammation are still under investigation.

In AD, reduced S. aureus colonization is often accompanied by increased Malassezia or Streptococcus species, which may promote Th17 responses.⁸ Conversely, approximately 60% of patients with psoriasis exhibit S. aureus colonization, which may exacerbate disease severity by amplifying Th17-mediated inflammation and perpetuating keratinocyte hyperproliferation.²⁶

CLINICAL MANIFESTATIONS AND PATHOLOGICAL FEATURES

Clinical Characteristics

Current epidemiological data indicate that approximately 1.7–3.3% of patients may develop psoriasiform eruptions during treatment.^27,28 The most frequently reported subtypes are plaque-type psoriasis, followed by pustular psoriasis, while erythrodermic, guttate, and inverse psoriasis variants are considerably less common.

The characteristic presentation of psoriasiform eruptions includes well-demarcated erythematous plaques with adherent silvery-white scales, morphologically resembling classic plaque psoriasis. These lesions predominantly localize to the trunk, extensor surfaces of the extremities, and scalp. While classic AD lesions typically present with eczematous features (erythema, papules, exudation, and lichenification), some atypical psoriasis-like eruptions may demonstrate similar characteristics.

These manifestations can present as minimally scaled lesions dominated by erythema and are often clinically indistinguishable from subacute eczematous eruptions. In such cases, histopathological examination is usually required to confirm the diagnosis. Rare variants, including erythrodermic, pustular, or inverse psoriasiform eruptions, should be considered when both clinical presentation and histopathological findings meet diagnostic criteria for psoriasis.

Diagnostic complexity escalates when encountering atypical eruptions or cases exhibiting features of both AD and psoriasis, frequently leading to misdiagnosis. Notably, phenotypically overlapping cases between psoriasis and AD retain the fundamental molecular signature of psoriasis. Advanced genomic biomarkers now enable molecular-level differentiation between these disease entities, providing crucial diagnostic clarification.¹⁹

Onset Time

The immune drift phenomenon occurs in the majority of cases between 3 and 12 months after treatment initiation, although a minority of cases may manifest as early as 6 weeks.^29,30 Most reported cases suggest an association with improvement in AD, with some patients developing psoriasiform eruptions following significant amelioration of AD with dupilumab. This observation implies that the immune drift phenomenon may be linked to immune remodeling during the disease remission phase.

Histopathology

Histopathology serves as the gold standard for diagnosing most dermatological conditions, providing robust support for clinical assessments. However, the pathological manifestations of AD often evolve dynamically with disease progression.

The pathology of a typical AD rash is most evident in the acute or subacute phase, with the epidermis showing spongiosis, interstitial edema of keratin-forming cells, widening of the interstitial spaces of the forming cells, and visible blisters, along with parakeratosis and mild sphenoidal hypertrophy.³⁰ The dermis is infiltrated by perivascular lymphocytes; eosinophils are often present, and eosinophil degranulation is occasionally observed, suggesting an allergic reaction.

In the chronic phase, the epidermis shows significant stratum spinosum hypertrophy and hyperkeratosis with reticular, basket-like, or dense keratinization. The dermal papillae are fibrotic, and a chronic inflammatory infiltrate is present in the dermis, including lymphocytes and macrophages, with occasional mast cells, accompanied by vascular proliferation and fibrosis.

There are more blisters in the acute phase and irregular epidermal hyperplasia in the chronic phase. The diagnosis of AD can be made definitively with sufficient pathologic evidence in conjunction with clinical presentation and immune markers, particularly elevated IgE levels.

Psoriasiform eruptions associated with immune drift following dupilumab treatment for AD typically demonstrate distinct histopathological features. Epidermal changes include parakeratosis, the presence of typical or atypical Munro microabscesses, and acanthosis, while dermal alterations feature capillary dilation with neutrophilic and lymphocytic infiltration.³⁰ A notable characteristic is the relative paucity of eosinophils (<5 per histologic section), with composite patterns such as lichenoid or vascular changes serving as key diagnostic clues.³¹ These findings show significant overlap with classical psoriasis, contributing to diagnostic challenges.

While most biopsy specimens of psoriasis and eczematous dermatitis exhibit distinct features, a substantial proportion demonstrate clinicopathological overlap, often yielding indeterminate results that may align with eczematized psoriasis, hyperkeratotic eczema, or psoriasiform eczema.³² Common histological observations include spongiosis, parakeratosis, variable acanthosis, and mixed dermal inflammatory infiltrates.

Cases exhibiting prominent spongiosis, increased eosinophil counts, and reduced neutrophilic infiltration are more likely to represent AD-dominant pathology. This histopathological spectrum underscores the complex interplay between AD and psoriasiform reactions in the context of dupilumab therapy, necessitating careful clinicopathological correlation for accurate diagnosis and management.

OPTIMIZATION OF TREATMENT STRATEGIES

Therapeutic Options

In the absence of standardized treatment guidelines, therapeutic strategies are tailored based on disease severity. For moderate-to-severe cases, options include topical or systemic corticosteroids, with the addition of immunosuppressants or acitretin for refractory presentations. Alternatively, switching to other targeted therapies such as apremilast, ustekinumab, anakinra, or upadacitinib may be considered.³³

For mild and localized psoriasiform eruptions, the preferred treatment strategy combines corticosteroids (fluticasone propionate) with vitamin D3 analogs (calcipotriol), while calcineurin inhibitors (tacrocrolimus) may benefit select patients. Phototherapy, particularly narrowband ultraviolet B (UVB), can simultaneously improve residual AD symptoms and psoriasiform lesions.³⁴ Short-term adjunctive low-dose apremilast may help modulate Th17 activation, while traditional systemic agents such as methotrexate or cyclosporine can serve as bridging therapies. Importantly, all of these strategies can be implemented while continuing dupilumab treatment for primary AD control.

For moderate-to-severe cases, treatment typically involves medication adjustment or even discontinuation of the biologic agent triggering paradoxical immune reactions. Current literature reports that switching to alternative biologics or small-molecule targeted therapies after discontinuation represents a common therapeutic strategy.

Given the Th1-axis shift characteristic of immune drift phenomena, conversion to Th17 inhibitors such as ixekizumab or guselkumab has demonstrated efficacy in managing new-onset eruptions, with some studies achieving PASI 100.³⁵

Compared to biologics, Janus kinase (JAK) inhibitors exhibit broader specificity by targeting multiple cytokines while minimizing excessive suppression of any single cytokine that might lead to immune dysregulation. This mechanism makes them effective for the treatment of both AD and psoriasis, with promising applications for paradoxical skin conditions.³⁶ Notably, JAK inhibitors currently approved for AD may be particularly suitable, as they can reduce the production of IFN-γ, IFN-α, tumor necrosis factor (TNF), and Th2 cytokines.

A recent meta-analysis indicates that, in the treatment of psoriasis, JAK1 and JAK3 inhibitors are more effective than JAK1/JAK2 inhibitors, with JAK1 inhibitors showing the lowest efficacy. Notably, significant therapeutic effects are generally observed only after 16 weeks of treatment.³⁷ Adverse events associated with JAK inhibitors—including infections, gastrointestinal disorders, and dermatological conditions such as herpes zoster—have been reported with both oral and topical formulations. However, topical application does not demonstrate statistically significant adverse effects. Therefore, further high-quality, large-scale, multicenter prospective studies are required to better define the safety profile of JAK inhibitors.

Balancing Treatment Continuation Versus Discontinuation

The decision to continue or discontinue dupilumab should be based on multiple factors, including the therapeutic response of AD, the extent and severity of psoriasiform eruptions, and the presence of comorbidities.

In cases where new-onset psoriatic lesions are mild, limited, and manageable—particularly when AD remains inadequately controlled—continuing dupilumab may be the preferred option, provided the patient shows no severe symptoms such as joint involvement. However, close monitoring of psoriasis progression and prompt symptomatic management are essential.

Discontinuation should be considered if the disease condition worsens, with widespread or treatment-resistant psoriatic eruptions, or when continued dupilumab therapy offers minimal clinical benefit. Immediate cessation is particularly warranted if new-onset psoriasis is accompanied by psoriatic arthritis or other Th17-mediated diseases, to prevent disease progression, followed by an individualized treatment plan tailored to the associated conditions.

An alternative promising strategy involves combination therapy with dupilumab and other monoclonal antibodies. Some case reports have documented successful dual biologic therapy—concurrent use of biologics targeting psoriasis and AD—with observable efficacy.³⁸

Further studies have summarized case reports of dupilumab combined with other biologics such as guselkumab, secukinumab, adalimumab, benralizumab, and omalizumab, demonstrating either no or only mild adverse drug reactions over observation periods ranging from 2 to 22 months.³⁹ However, existing long-term safety and efficacy data still lack high-level evidence and have been documented only in a limited number of clinical case reports.

FUTURE RESEARCH DIRECTIONS IN INFLAMMATORY SKIN DISEASES

Emerging research highlights promising avenues for investigating shared pathogenic mechanisms between AD and psoriasis, particularly through overlapping cytokine pathways.¹⁹ Similarly, the OX40-OX40L axis is recognized as playing a pivotal role in chronic inflammatory diseases such as AD and psoriasis, in which sustained signal transduction promotes the proliferation of effector T-cell subsets, including Th1, Th17, and Th22 cells.⁴⁰

Future research should focus on establishing disease severity biomarkers and investigating gene expression profiles associated with Th1-to-Th2 pathway switching, as well as corresponding serum cytokine levels, which will provide mechanistic insights to guide clinicians in developing more patient-centered approaches for both current and future therapeutic investigations.

The growing recognition of immune drift phenomena underscores the need for innovative biologic development targeting common pathways in both diseases. Particularly promising is the exploration of dual-targeting agents capable of simultaneously modulating IL-4/IL-13 and IL-17 signaling, which may represent a paradigm shift in managing these complex inflammatory skin disorders. These research directions aim to bridge current knowledge gaps while translating mechanistic insights into clinically actionable strategies.

CONCLUSION

Dupilumab-induced psoriasiform eruptions represent a classic manifestation of immune drift phenomena, characterized by compensatory Th1/Th17 activation following Th2 suppression. Clinical management should be individualized: mild cases may be managed with adjunctive topical therapies, while moderate-to-severe cases may require switching to alternative biologics or targeted small-molecule drugs, with JAK inhibitors representing a preferred option for addressing immune drift phenomena. However, it is essential to emphasize that the use of JAK inhibitors is associated with known side effects, and that long-term safety and efficacy evidence for combination therapy with biologics remains insufficient. Future research should focus on risk prediction and precision medicine strategies to optimize long-term outcomes for patients with AD.

Ethics Committee Approval

Ethical approval was not required for this study since this is a review article.

Informed Consent

Written informed consent was not required for this study.

Conflict of Interest

The authors have no conflicts of interest to declare.

Financial Disclosure

This work was funded by National Natural Science Foundation of China [NSFC 82173437] and the Dongguan Social Science and Technology Development Program (20221800905522).

Use of AI for Writing Assistance

No use of AI-assisted technologies was declared by the authors.

Author Contributions

Concept – BX; Design – BX; Supervision – WZ, KZ, CL; Resource – BX, CZ, WZ; Materials – BX, CZ, WZ; Data Collection and/or Processing – XZ, CZ; Analysis and/or Interpretation – BX; Literature Review – BX, XZ, CZ; Writing – BX; Critical Review – WZ, KZ, CL.

Peer-review

Externally peer-reviewed.