Defining the Potential for Disease Modification in Atopic Dermatitis

Abstract

Atopic dermatitis is a common inflammatory disorder affecting the skin, often associated with a strong disease burden and a long-term impact on patients’ quality of life. Although most treatments for atopic dermatitis have been mainly focusing on alleviating symptoms, emerging therapies and approaches may offer the potential to modify the disease course, thereby leading to off-treatment remission and prevention of comorbidities. However, a consensus on the definition of disease modification in atopic dermatitis is yet to be reached. The aim of this article is to review the concept of disease modification in atopic dermatitis and its different dimensions, including underlying pathophysiology, disease control, atopic and nonatopic comorbidities, subclinical biomarkers, and the importance of early therapeutic intervention. Ultimately, identifying therapies with long-lasting effects on atopic dermatitis progression could alleviate the global health burden of atopic diseases.

Key Points

Atopic dermatitis is a chronic inflammatory disease affecting the skin that can result in long-term life impairment. Treatments for atopic dermatitis have been primarily focusing on the management of signs and symptoms, but recent advances in the field may offer the potential to modify the disease course.

Disease modification in atopic dermatitis can be understood as any intervention that changes the disease trajectory by leading to off-therapy remission and potentially preventing the development of comorbidities. Recent studies suggest that early intervention may be a critical approach for disease modification in atopic dermatitis, as observed in other inflammatory disorders.

Identifying reliable biomarkers in atopic dermatitis may help determine whether therapies are modifying the disease course on a subclinical level.

Introduction

Disease modification refers to effects of treatments that not only alleviate signs and symptoms but also act on the pathophysiology of the disease, thereby altering its natural course [1]. The concept of disease modification is well established in fields such as neurodegenerative and rheumatologic disorders, where therapies aim to attenuate progressive and irreversible tissue degeneration [2, 3]. However, developing a definition of disease modification is more challenging for cutaneous inflammatory diseases, which are not characterized by structural or irreversible damage [3].

Atopic dermatitis (AD) is a chronic, relapsing inflammatory condition associated with persistent itch, disrupted sleep, visible skin lesions, and psychosocial distress, leading to impairment in daily functioning [4, 5]. The burdens of uncontrolled AD (atopic comorbidities, social stigma, loss of opportunity, mental health issues) accumulate over time and are potentially long lasting [6, 7] (Fig. 1). Disease modification in AD represents an important goal for the field [1], as it may help prevent or reduce this cumulative life course impairment and its impact on patients’ physical, emotional, and social well-being.

Fig. 1.

Model of cumulative burden of uncontrolled atopic dermatitis (AD), with physical, psychological, emotional, and social impairments affecting patients’ life trajectories.

AD is characterized by an overreactive type 2 immune response, which contributes to skin barrier dysfunction, inflammation, and pruritus [8, 9]. Newer targeted therapies that inhibit key elements in the type 2 immune pathway have shown promise, not only in alleviating symptoms but also in long-term disease control [10–20]. These advances offer the potential for disease modification, but clearer definitions and metrics are needed to evaluate such effects more rigorously. In this article, we aim to review the concept of disease modification in AD and discuss the ability of therapeutic interventions to modify the course of AD, based on current evidence and unmet clinical needs.

Proposed Definition of Disease Modification in AD

The definition of disease modification in AD has been proposed as any intervention that restores dysregulated molecular mechanisms and alters the natural course of the disease, leading to sustained remission after stopping systemic therapy [3, 21]. Sustained remission in AD can be defined as resolution of inflammation that is maintained without the need for ongoing therapy [3]. Any treatment that leads to a prolonged therapy-free remission in patients with AD could be considered a disease modifier.

As AD is often the first step of the atopic march, a progression of atopic diseases that usually begins in childhood, a disease-modifying therapy would potentially prevent the onset and/or further development of comorbidities. AD is often followed by other atopic conditions such as food allergy, asthma, and allergic rhinitis, which share a similar underlying immune dysfunction [22, 23]. The risk of developing other atopic diseases is higher in children who develop AD in their first year of life, who constitute two thirds of pediatric patients with AD [24].

Nonatopic comorbidities associated with AD include neurodevelopmental and mental health disorders [25–27], skin and systemic infections [28], immunological and inflammatory diseases [29], impaired bone health [30], and possibly cardiovascular diseases [31]. Anxiety and depression are widely observed in patients with AD [32], and an association has been observed between AD and attention-deficit hyperactivity disorder and/or autism spectrum disorder [33]. AD has also been associated with decreased bone mineral density [30, 34], increased risk of bone fractures [35, 36], and growth impairment in children and adolescents [37]. Causes of growth impairment may include sleep deprivation, effects of chronic inflammation on bone health, and use of immunosuppressant therapy.

The Importance of Early Intervention

Intervention at an early stage may be a critical approach for disease modification in AD. In other inflammatory disorders such as rheumatoid arthritis and Crohn’s disease, early intervention can impact the progression of the disease and lead to prolonged remission [38–42]. Similarly, preliminary data with AD suggest that early, proactive topical treatment can alter the long-term course of AD [43] and the development of food allergies [44, 45] in pediatric patients, with more promising results compared with the standard of care.

Emerging therapies, particularly those targeting key elements in the type 2 inflammatory pathway, may offer the potential to modify the underlying disease course in AD. In the ongoing LIBERTY AD PED open-label extension study [10, 11, 46], pediatric patients aged 6 months to 17 years with moderate-to-severe AD were treated with dupilumab for at least 40 weeks. Of these, about one third achieved an Investigator’s Global Assessment score of 0/1 (clear or almost clear skin), a stringent outcome in terms of efficacy, and maintained it for 12 weeks, after which treatment was stopped. After 3 months without therapy, about half of the patients who discontinued dupilumab maintained Investigator’s Global Assessment 0/1 and experienced no further flare or exacerbation. In other long-term studies of dupilumab, tralokinumab, and lebrikizumab in adults and adolescents with moderate-to-severe AD, a percentage of patients maintained efficacy responses for up to 38 weeks after drug withdrawal (placebo) [12–17]. Furthermore, off-therapy disease control has been observed in phase II trials of the anti-OX40 antibodies amlitelimab and rocatinlimab for 28 and 20 weeks, respectively [18, 19], and in a phase III trial of the Janus kinase (JAK)1 inhibitor abrocitinib for 40 weeks [20]. These results suggest that therapy-free disease control is possible after treatment. Prospective, adequately controlled, and long-term studies specifically designed with disease modification endpoints are further needed for a reliable inference regarding changes in the natural history of AD.

In a retrospective cohort study of pediatric patients with AD, dupilumab was associated with a reduced incidence of atopic comorbidities compared with other systemic therapy [47]. The risk of developing other atopic disorders was reduced by 46% in children younger than 6 years and by 36% in older children and adolescents. Similarly, in a population-based cohort study, pediatric patients with AD treated with dupilumab had a significantly lower risk of new-onset comorbidities compared with patients treated with other systemics, including gastrointestinal infection, mental health disorders, respiratory and urinary tract infections, urticaria, and skin and soft-tissue infection [48]. Although the observational nature of these studies does not allow casual inference, their results highlight the importance of early intervention and support dupilumab as a promising candidate for disease-modifying treatment in AD, with the potential to prevent both atopic and nonatopic comorbidities.

AD Biomarkers as a Potential Measure of Disease Modification

Given the long timelines involved in measuring the clinical aspects of disease modification, the use of biomarkers to predict long-term outcomes may help advance research in this field more efficiently. Although no biomarkers have been validated as indicators of an altered disease trajectory, identifying reliable markers of disease activity in AD may provide objective measures of response to treatment, and ultimately assess the potential for disease modification.

After skin barrier disruption, type 2 cytokines stimulate keratinocytes, dendritic cells, and endothelial cells to produce C-C motif chemokine ligand 17 (CCL17), which in turn amplifies the inflammatory response [49, 50]. Furthermore, dysregulated type 2 cytokines stimulate B cells to undergo class switching and release high levels of immunoglobulin E (IgE), which plays a key role in allergen sensitization [9, 51, 52]. As most patients with moderate-to-severe AD have elevated CCL17 and IgE serum levels, both CCL17 and total serum IgE have been considered acceptable severity biomarkers for AD. Increased levels of CCL17 have been associated with a higher risk of developing moderate-to-severe AD in infancy, suggesting that CCL17 could be a predictive biomarker for AD in early childhood [49, 53], and elevated IgE serum levels are often associated with a high probability and frequency of flares [54, 55].

On a subclinical level, biomarkers may help determine whether therapies are not only alleviating symptoms but also altering the disease course. In a real-world study of pediatric patients with AD and type 2 comorbidities (food allergy, asthma, allergic rhinitis), dupilumab decreased total IgE and allergen-specific IgE levels, suggesting that IgE reduction might be associated with a reduction of allergic sensitization [56, 57]. The frequency of type 2 memory B cells was strongly correlated with total IgE levels in pediatric patients with AD. Type 2 memory B cell and total IgE plasma levels were significantly decreased after 6 months of treatment with dupilumab, but not with cyclosporine or topical treatment [58]. Furthermore, real-world data showed that CCL17 levels increased or remained stable following treatment with JAK inhibitors (baricitinib, upadacitinib, abrocitinib), but substantially decreased with biologics targeting interleukin (IL)-4/IL-13 (dupilumab, tralokinumab) [59]. However, upadacitinib has been associated with a reduction in total eosinophil count in a real-world study [60], supporting total eosinophil count as a potential response marker in patients treated with JAK inhibitors. Further research is needed to clarify the mechanisms underlying these observations, and to determine whether changes in type 2 memory B cells, IgE, and CCL17 reflect off-therapy remission and/or prevention of comorbidities.

Regulatory T cells (Tregs) may also be involved in mechanisms of disease modification in AD. Functional Tregs normally suppress immune cell populations, including T helper and B cells, thereby reducing and potentially preventing excessive inflammation. In AD, the overexpression of IL-4 suppresses the differentiation of naïve T helper 0 cells to Tregs, which may contribute to skin inflammation [61, 62]. Treatment with rezpegaldesleukin, which stimulates production and function of Tregs, led to significant improvements in AD endpoints in a phase Ib clinical trial, suggesting that the restoration of Treg function may correlate with clinical improvement after treatment [63]. In another study, treatment with dupilumab for 6 months improved clinical symptoms of AD and was associated with an enhanced function of Tregs following IL-4Rα blockade [64]. Taken together, these findings suggest that the enhancement of Treg function may reflect a broader restoration of immune regulation, supporting their relevance as indicators of AD improvement at the molecular level.

Limitations

Several limitations should be considered for the proposed definition of disease modification in AD. In the absence of a true understanding of the mechanisms of remission or long-term controlled trials, it remains difficult to clearly separate deep disease control, extended drug effect, and genuine disease modification of the natural history of AD. International consensus initiatives, such as the International Eczema Council, are aiming to establish more robust criteria to define disease modification and remission states in AD [65]. Until such criteria are established, prolonged remission should be interpreted as suggestive of potential disease modification, rather than conclusive evidence.

Additionally, AD exhibits substantial variability in its natural course. Spontaneous remission occurs in a proportion of patients, particularly in pediatric populations. Therefore, long-term remission following treatment may partly reflect population characteristics rather than drug properties. Controlled age-stratified longitudinal studies are needed to distinguish treatment-induced disease modification from the background rate of this naturally remitting disease.

Concluding Remarks

Until now, the treatment of AD has focused primarily on the management of signs and symptoms. However, recent advances suggest that true disease modification may soon become a realistic goal. The potential for disease modification in AD can be assessed by determining a drug’s ability to reverse underlying pathophysiology, achieve clinical and subclinical control, and prevent the development of comorbidities. Ongoing research is aiming to identify treatments with long-term effects on disease progression, possibly leading to therapy-free remission. Pursuing this objective represents a critical opportunity to improve patients’ lives, not only by controlling signs and symptoms but also by preventing the cumulative life course impairment that often accompanies AD.

Declarations

Funding

Open Access funding was enabled and organized by Sanofi and Regeneron Pharmaceuticals Inc.

Conflicts of Interest

This article is based on content developed and presented by the authors at the 2025 Global ADVENT Forum. The ADVENT program is funded and facilitated by Sanofi and Regeneron Pharmaceuticals Inc. Eric L. Simpson has served as a principal investigator for and/or received grants from AbbVie, Acrotech, Amgen, Arcutis, ASLAN, Castle, CorEvitas, Dermavant, Dermira, Eli Lily, Incyte, Pfizer, Regeneron Pharmaceuticals Inc., Sanofi, Target, and Veriskin; and has received personal fees from AbbVie, Amgen, Arcutis, Astria Therapeutics, Castle, CorEvitas, Dermira, Eli Lilly, FIDE, Impetus Healthcare, Incyte, Innovaderm Recherches/Indero, Janssen, LEO, Numab Therapeutics AG, Pfizer, Recludix Pharma, Regeneron Pharmaceuticals Inc., Roche Products Ltd, Sanofi, and Sitryx Therapeutics. Amy S. Paller has served as an investigator for AbbVie, BioMendics, Dermavant, Eli Lilly, Incyte, Johnson & Johnson Innovative Medicine, Regeneron Pharmaceuticals Inc., and UCB; as a consultant for Abeona, Arcutis, BioCryst, Boehringer Ingelheim, Castle Creek, Chiesi, Dermavant, Johnson & Johnson Innovative Medicine, Krystal, LEO, Lilly, L’Oréal, MoonLake Immunotherapeutics, Pelthos, Quoin, Regeneron Pharmaceuticals Inc., and Sanofi; and as a data safety monitoring board member for AbbVie, Abeona, BioCryst, Daiichi Sankyo, and Galderma. Amy Paller is an Editorial Board member of the American Journal of Clinical Dermatology and was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Oscar Palomares has received speaker and/or consulting fees from AstraZeneca, GSK, Immunotek S.L., Novartis, Pfizer, Regeneron Pharmaceuticals Inc., and Sanofi. Thomas Bieber has received consultant fees from AbbVie, Affibody, Amagma, AnaptysBio, Anergis, AOBiome, Apogee Therapeutics, Arena Pharmaceuticals, Aristea, Artax Biopharma, Asana BioSciences, ASLAN Pharmaceuticals, Astria TX, Attovia Therapeutics, Bayer, BioVersys, Boehringer Ingelheim, Bristol Myers Squibb, BYOME Labs, Connect Biopharma, Daiichi Sankyo, Dermavant, DICE Therapeutics, Domain Therapeutics, DS Biopharma, EQRx, Galapagos, Galderma, Glenmark, GSK, Incyte, Innovaderm, Janssen, Kirin, Kymab, LG Chem, Medac, Micreos, MSD, Nektar Therapeutics, Novartis, Numab Therapeutics, OM Pharma, Overton, Pierre Fabre, Q32 Bio, RAPT Therapeutics, Samsung Bioepis, Sanofi, TIRmed Pharma, UCB, UNION Therapeutics, Upstream Bio, and Yuhan; and speaker fees and consultant fees from Almirall, LEO Pharma, Lilly, Pfizer, and Sanofi-Regeneron Pharmaceuticals Inc.

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Authors’ Contributions

All authors contributed equally to the conception, design, drafting, and critical revision of the manuscript. All authors approved the final version.