Personalized Immunomodulatory Therapy for Atopic Dermatitis: An Allergist's View

Abstract

The current standard medical therapy for atopic dermatitis (AD) mainly focuses on symptomatic relief by controlling skin inflammation with topical corticosteroids and/or topical calcineurin inhibitors. However, the clinical efficacy of pharmacological therapy is often disappointing to both patients and physicians. The terminology of AD contains a historical meaning of eczematous dermatitis caused by hypersensitivity reaction to environmental inhalant or food allergen. Complex interrelationships among genetic abnormalities, environmental triggers, skin barrier defects, and immune dysfunction resulting in a vicious domino-circle seem to be involved in the development and maintenance of AD. In the viewpoint of AD as an allergic disease, complete avoidance of clinically relevant allergen or induction of specific immune tolerance through administrations of allergen (allergen immunotherapy) can provide clinical remission by breaking the vicious domino-circle maintaining a chronic disease state. In recent clinical studies, monoclonal antibodies including the anti-interleukin-4 receptor antibody and anti-B cell antibody induced significant clinical improvements in patients with AD. The detailed characteristics of immune dysfunction are heterogeneous among patients with AD. Therefore, a personalized combination of immunomodulatory therapies to reduce hypersensitivity (allergen immunotherapy) and correct immune dysfunction (monoclonal antibody therapy) could be a reasonable therapeutic approach for patients with AD. Future immunomodulatory therapies for AD should be developed to achieve long-term treatment-free clinical remission by induction of immune tolerance.

Keywords: Allergens; Atopic dermatitis; Hypersensitivity; Immunomodulation; Therapeutics.

Fig. 1. One-way vertical flow pathogenesis model of atopic dermatitis.

This vertical model suggests that (1) environmental toxicants (e.g., volatile inorganic chemicals, air pollution, and food additives) induce immune dysfunction and hypersensitivity in genetically susceptible human subjects by decreasing the threshold for developing hypersensitivity reaction to environmental allergens and irritants; and (2) exposure to the allergens and/or irritants induces hypersensitivity reaction, chronic skin inflammation, skin barrier defect, and clinical manifestations of atopic dermatitis (pruritus and eczema). In this model, multiple modalities could be introduced to block multiple elements in the pathogenetic pathway for the treatment of atopic dermatitis. In addition, blocking the upper stream of the pathogenetic pathway of this model might be a more effective and fundamental therapeutic approach than blocking the lower stream of the pathogenetic pathway.

Fig. 2. "Domino theory".

A vicious domino-circle formed from negative interactions among multiple pathogenetic elements is essential for the development and maintenance of atopic dermatitis, and if one of the pathogenetic elements (e.g., environmental triggers, immune dysfunction, skin inflammation, or skin barrier defects) can be sufficiently controlled to break the vicious domino-circle, then clinical remission of atopic dermatitis could be possible.