Key Summary Points
Why carry out this study? |
Mild atopic dermatitis (AD) has been traditionally managed with topical therapies; nonetheless, the latest systemic treatments open the way for discussions about early intervention. |
To date, conventional therapeutic strategies are primarily aimed at symptom relief, with systemic treatments to be reserved for moderate-to-severe cases. However, some patients still experience a significant disease burden. |
What was learned from the study? |
Proactive systemic treatment might nip the “atopic march” in the bud, as it might modify the natural course of AD and disrupt the recurrent cycles of flares and remissions. |
We suggest that early systemic intervention might be considered when pruritus is present even with no visible skin lesions, as it is a central driver of the “itch–scratch” cycle in AD, provided that the patient’s quality of life is severely affected. This approach aims to break that cycle and minimize subsequent skin damage and inflammation. |
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus, immune dysregulation, and compromised skin barrier function [1]. While topical therapies have long been the mainstay of disease management, the latest developments in the systemic treatment have put the issue of early intervention at the initial stages of AD in the spotlight [2].
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As yet, conventional strategies primarily target symptom management [3]. The treatment guidelines for AD consider the patient’s age and the disease severity, while they emphasize the notable variation in treatment approaches across AD patients. Systemic therapies are recommended for addressing moderate-to-severe cases of AD based both on severity scales and social/functional impairment; nonetheless, despite receiving systemic therapy for a duration of up to 12 months, some patients still face a substantial disease burden. This suggests the possibility of less-than-optimal treatment outcomes within this subset of patients, implying uncontrollable inflammation [4].
Moreover, it is suggested that the non-lesional skin in AD exhibits a subclinical immunologic activity, potentially contributing significantly to the overall inflammatory burden associated with this disease [5]. Consequently, a pivotal aspect to consider is the role of clinically “invisible” inflammation, contributing to a spillover effect in AD. While established objective assessment tools such as the Eczema Area Severity Index (EASI) and Scoring of Atopic Dermatitis (SCORAD) are valuable for quantitatively measuring the disease severity from a clinical point of view, they may not fully capture the actual inflammatory burden. This burden may derive from visible lesional skin and potentially undefined systemic components. Thus, solely relying on the evaluation of the visible AD lesions, as determined by physician-reported severity tools such as EASI or SCORAD, is likely to underestimate the actual disease activity. Notably, the notion of disease activity, including its definition and the systematic exploration of qualitative and quantitative evaluations, has yet to be comprehensively examined. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Accordingly, it should be expected that early systemic intervention, regardless of the age of onset of AD, might minimize systemic inflammation and the inflammatory burden on lymphoid organs that mediate IgE production, particularly in patients with extrinsic AD [2]. Even though literature data are very limited, a proactive systemic treatment might modify disease progression, leading to pruritus alleviation, enhanced quality of life, less reliance on intensive topical treatments, improved psychological well-being, and secondary complications prevention. Besides, the chronic nature of AD and its association with atopic comorbidities, namely allergic rhinitis and asthma, further highlight the need to target the disease at its inception [6]. A recent meta-analysis regarding adolescent and adult AD under dupilumab demonstrated that the inhibition of IL-4/IL-13 hampered the development of new or the deterioration of established allergic conditions in a large AD clinical trial database in a highly atopic population [7]. This knowledge adds an important therapeutic value for those individuals and constitutes an innovation for atopy management as a whole over time.
Building on this concept, early systemic treatment may intervene in the composite “atopic march” that drives AD progression. Such a therapeutic strategy could modulate the natural course, targeting the immune dysregulation and ultimately the inflammation that hallmarks the disease even in the incipient state. This approach aims to inhibit the escalation of inflammatory responses, before visible skin lesions develop, and disrupt the recurrent cycles of flares and remissions [8]. Based on the published literature, biologics may effectively diminish the atopic burden within affected individuals, indicating a potential disease modification and attenuation of the atopic march [9‐11]. Nonetheless, more extensive and long-term trials spanning diverse age cohorts and disease severity, are needed to validate this effect and substantiate whether biologics can consistently and durably rectify the inherent immune skew toward type 2 inflammation, the fundamental basis of the atopic march.
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Proposed possible time points for an early intervention in literature have been suggested to be [2]:
(a)
The presymptomatic stage where the use of emollients could remedy microbioma dysfunction. Possible evaluated outcomes could include subsequent prevalence of the comorbidities of the atopic march.
(b)
The stage of initial activation of the innate immunity. Treatment interventions on this stage within the current treatment landscape could include the effect of tezepelumab on alarmins, tapinarof on AhR, ruxolitinib on JAK, and roflumilast on PDE4 or OX40/OX40 ligand blockade on antigen presentation. Possible evaluated outcomes could include subsequent prevalence of comorbidities of the atopic march.
(c)
The stage of activation of the adaptive immune response. Treatment interventions on this stage could include current available topical and systemic treatments including monoclonals and JAK inhibitors. Possible evaluated outcomes could include non-atopic comorbidities such as cardiovascular associated conditions.
However, such outcomes require complex methodology and long-term design. The key point in early systemic treatment could be most likely pruritus, a hallmark symptom, and a central driver of the self-perpetuating “itch–scratch” cycle that characterizes AD [10]. The early systemic intervention would target the underlying triggers of itching and break the scratching cycle minimizing the subsequent skin damage and inflammation [12]. The comprehensive relief from pruritus alleviates immediate discomfort and helps patients regain their normal lives, unburdened by the relentless distress of itching-induced complications. Interestingly, patients with AD are willing to accept notable treatment-related risks in return for more significant or quicker alleviation of pruritus provided by systemic therapies [13].
Moreover, continuing pruritus-induced scratching frequently leads to secondary complications such as skin infections and lichenification [14]. Should pruritus be addressed at its root, the impetus for scratching would be reduced, preventing these complications, which, otherwise, would necessitate additional interventions to manage ensuing secondary issues.
The psychosocial burden of AD should not be underestimated, either, as it contributes to anxiety, depression, and social isolation [15]. This prompt approach opens the way for the patients with AD to actively engage in daily activities and regain a sense of normalcy, as they would no longer suffer from pruritus, sleep disturbances, and the visible presence of skin lesions [16]. This development bolsters self-esteem and enriches social interactions, resulting in improved overall welfare and optimum mental health of those patients.
In addition, a notable advantage of early systemic intervention lies in its potential to mitigate the need for intensive and protracted topical treatments. Although topical corticosteroids and immunomodulators are pivotal in AD management, prolonged use can incur certain risks [17]. Early systemic treatment administration offers the prospect of less frequent and short-term use of intense topical treatments, minimizing associated side effects. Such an approach promotes a safer, more patient-friendly therapeutic paradigm, sparing patients from prolonged exposure to potent topical agents.
The immediate and tangible improvements in symptoms achieved through early systemic intervention might motivate patients to adhere meticulously to their prescribed treatment regimens [18]. The noticeable relief from pruritus and visible improvements in disease progression foster increased engagement and commitment to therapy. This augmented adherence predicts sustained positive therapy outcomes and diminishes the risk of treatment discontinuation.
Besides immediate symptom relief, one of the most intriguing benefits of early systemic intervention lies in the lasting impact on the natural course of AD. As those therapies target the underlying inflammatory mechanisms, they may impart a disease-modifying effect, defined as a lower burden than that in non-treated patients [19]. This effect could translate into prolonged remission, less frequent and milder flares, and a more predictable disease profile over time. Such an effect would eventually redefine disease management paradigms.
Finally, early systemic treatment provides the right opportunity for healthcare professionals to engage patients in comprehensive disease management discussions [20]. Patients gain insights into their condition, treatment options, and lifestyle adjustments. This collaborative approach creates a sense of partnership between patients and attending physicians, empowering patients to actively participate in their care decisions, advocate for their needs, and implement strategies for sustainable long-term disease control.
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Identifying and detecting clinically relevant biomarkers is essential to this proposal for early systemic intervention implementation. Such an approach might prove beneficial in formulating intervention strategies targeted at averting the onset of AD and associated comorbidities in high-risk patients, specifically during the presymptomatic phase of the disease. Biomarkers offer promising avenues for stratification during the early, presymptomatic stages of the disease. Objective evaluation of the barrier function, such as electric impedance spectroscopy, can be valuable in this regard. Notably, both electric impedance spectroscopy and mucosal swabs provide non-invasive options for biomarker exploration, circumventing the need for skin biopsies. Furthermore, the measurement of thymus and activation-regulated chemokine, along with free sphingoid bases in tape-stripped material, has been proposed as a feasible approach for predicting the subsequent emergence of AD in a birth cohort [19]. Therefore, identifying the appropriate biomarkers could open a window in the precision medicine approach and provide evidence when the early intervention should be considered.
In conclusion, the multifaceted benefits of early systemic intervention in atopic dermatitis can potentially revolutionize the approach to disease management. By embracing a proactive stance that extends beyond surface-level symptom control, these interventions promise immediate symptom relief and long-term disease modification, reduced treatment burden, and overall improved well-being. The safety and efficacy of novel systemic treatments could offer us the transformative potential of early intervention in modifying the disease ab initio and reshaping the landscape of atopic dermatitis care. However, the issue will likely remain a matter of contention until patient stratification becomes feasible, given the current lack of predictive biomarkers for the onset and progress of AD at the presymptomatic stage of the disease.
Acknowledgements
Medical Writing and Editorial Assistance.
The authors did not receive any medical writing or editorial assistance for this article.
Declarations
Conflict of Interest
Efstratrios Vakirlis, Stamatios Gregoriou, Katerina Bakirtzi, Eleni Paschou, Aikaterini Tsiogka, Ilias Papadimitriou, and Eleni Sotiriou have nothing to disclose. Stamatios Gregoriou is an Editorial Board member of Dermatology and Therapy. Stamatious Gregoriou was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.
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Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
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