Eczema is more common in children, with an incidence rate of 12%–25%. The prevalence rate of eczema in children around 5 years old in China is as high as over 85% and shows an increasing trend year by year. Pediatric eczema is divided into seborrheic eczema, dry eczema, and wet eczema according to different symptoms, with manifestations including erythema, blisters, erosion, or desquamation. It can occur all over the body and is more common on the hands, feet, face, neck, and skin folds. Severe itching causes children to cry and fuss, which is a torment for parents. For adults, the characteristics of pruritus, erosion, ulceration, exudation, and recurrence easily lead to the affected skin becoming more prone to desquamation, cracking, and even localized skin peeling off in pieces after years of suffering, seriously affecting normal life and work.
Since the pathogenesis of eczema is not yet clear, it is generally believed to be related to the patient's own immune capacity, environmental factors, and psychological factors. These include genetics, immune abnormalities, changes in sex hormone levels, endocrine disorders and metabolic disturbances, impaired epidermal barrier, and intake or exposure to allergens.
In traditional Chinese medicine (TCM), the treatment of eczema mainly focuses on dispelling wind and clearing heat, as well as strengthening the spleen and eliminating dampness. TCM holds that eczema arises when the "spleen" system's ability to transport and transform water declines—this impairment further causes a simultaneous reduction in the coordination capacity of other systems such as the "liver" and "kidney" systems, which in turn leads to disorders of the immune mechanism, ultimately resulting in eczema.
Modern medicine also considers eczema as a series of allergic skin diseases caused by immune system disorders. For example, pediatric eczema patients often experience gradual improvement as they grow older. However, researchers have found that due to immune system disorders in patients, most pediatric eczema patients have a high probability of suffering from allergic rhinitis, asthma, and other diseases as they age [1].
Generally, the treatment of eczema often involves glucocorticoids, calamine lotion, or traditional Chinese medicine. Biological agents are usually used for moderate-to-severe eczema, mostly targeting human interleukins, such as dupilumab injection [2] and anti-human interleukin-8 mouse monoclonal antibody.
Through basic and clinical research, it has been found that immunoglobulin E (IgE) plays a crucial role in the development of atopic diseases such as eczema and can be used as a diagnostic marker for disease severity. IgE is the least abundant immunoglobulin subtype in the human body, accounting for only 0.002% of the total serum immunoglobulins (Ig). Although its concentration is much lower than that of other immunoglobulin subtypes of the same type, it can still continuously produce and maintain a relatively high concentration to participate in the progression of allergic diseases, affecting the health and even life safety of approximately 25% of the global population [3].
Basophils and mast cells are mainly involved in the early stage of allergic reactions. After cross-linking with IgE, these cells can rapidly release granules, further releasing substances such as histamine and 5-hydroxytryptamine to induce allergic reactions. The production of IgE is largely related to interleukin-4 (IL-4), which can promote the activation and proliferation of B cells, and specifically induce B cells to synthesize IgE with the assistance of T cells and monocytes, thereby increasing the probability of allergies [4].
IL-4 is mainly produced by activated CD4+ T lymphocytes and can reversely induce the differentiation of CD4+ T lymphocytes into Th2 cells, which then secrete more cytokines, leading to an imbalance between Th1 and Th2 cells and the occurrence of type 2 inflammatory responses. In addition, IL-4 and interleukin-13 (IL-13) can jointly induce differentiated eosinophils to migrate to inflammatory sites, and at the same time induce the conversion of IgM to IgE in B cells and activate the IgE-FcεRI signaling pathway. This further increases the release of bioactive substances from the binding of IgE to basophils, mast cells, etc., significantly aggravating allergic reactions [5]. All these bioactive mechanisms driven by IL-4 can exert their effects through its specific receptor, the interleukin-4 receptor (IL-4R). Among them, the alpha subunit of interleukin-4 receptor (IL-4Rα) is a common receptor subunit for both IL-4 and IL-13; blocking this target can simultaneously inhibit the driving mechanisms of both cytokines and the type 2 inflammatory pathway.
Drugs targeting IL-4Rα have a wide range of applicable indications, and various indications have been developed so far, such as atopic dermatitis, asthma, chronic spontaneous urticaria, and eosinophilic chronic rhinosinusitis with nasal polyps mentioned above [6]. Taking dupilumab as an example, it is a fully human monoclonal antibody targeting the alpha subunit of interleukin-4 receptor (IL-4Rα), used for the treatment of atopic diseases including eczema. It is also the world's first targeted biological agent approved for moderate-to-severe atopic dermatitis in adults, which can treat diseases related to type 2 inflammation at the mechanism level. In addition to atopic dermatitis, it has successively obtained approvals for indications such as asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and prurigo nodularis. Moreover, based on the experimental data of dupilumab, its mechanism of action also has a therapeutic effect on diseases such as chronic obstructive pulmonary disease (COPD).
Due to the complex driving mechanisms of IL-4 and IL-13, precise targeting of IL-4Rα or avoiding binding to other targets remains a safety issue that needs attention in drug development strategies. At present, there have been studies and patent applications for anti-IL-4Rα nanobodies in China [7]. The inherent advantages of nanobodies, such as precise targeting and small molecular size, may further provide effective treatment options for patients with eczema and other atopic diseases at the mechanism level.
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