Speaker: Antti Lauerma

Various allergic skin diseases include allergic contact dermatitis, atopic dermatitis, acute urticaria/ angioedema, drug-induced skin allergies, food-induced atopic dermatitis, insect venom reactions, vasculitis purpura (IgG-mediated), and cutaneous mastocytosis. A recent study aimed to update the old nomenclature, categorizing skin diseases into different types of allergic reactions. According to new nomenclature, Type I immediate reactions include acute urticaria/ angioedema, venom and drug allergies, and atopic dermatitis (AD), Type III reactions involve vasculitis, Type 4 reactions encompass AD, allergic contact dermatitis, toxic epidermal necrolysis, Stevens Johnson syndrome, and erythema multiforme. T2 Type IVb includes Drug rash with eosinophilia and systemic symptoms (DRESS) and AD, while Type IVc involves AD and Acute generalised exanthematous pustulosis (AGEP). There are currently no diseases categorized under Type epithelial reactions, although irritant dermatitis may be included in the future. Histamine-driven disorders causing nonspecific skin reactions are classified under metabolic reactions.

IL-31 signaling is of paramount importance in dermatology, particularly in conditions marked by intense itching, such as prurigo nodularis and AD. It has profound impact of pruritus on quality of life, often leading to depression and anxiety. Initial discovery of IL-31's role in pruritic atopic skin, identified through RT-PCR in 2006, revealed its overexpression in comparison to non-pruritic psoriasis skin, linking it directly to dorsal root ganglia and the brain-skin axis. Despite the long process of drug development, recent advancements have led to the development of nemolizumab, a promising IL-31 antagonist effective in treating pruritus associated with AD and prurigo nodularis. However, drug development faces significant challenges, with the majority of candidates failing in clinical trials due to adverse effects. The patients suffering from conditions like prurigo nodularis experience profound distress as the relentless itching perpetuated by IL-31 exacerbates nerve proliferation, creating pruritic centers. Thus, the advent of effective IL-31 antagonists offers hope for alleviating the torture of chronic itch, improving patients' quality of life.

Two drugs approved for prurigo nodularis, Dupilumab and Nemolizumab (an IL-31 antagonist), offer promising treatments, with others like Batzoluvimab in development. The Congress of Allergy and Clinical Immunology focuses on immunological aspects, particularly autoinflammation, which includes autoimmune and autoinflammatory disorders. Autoinflammatory diseases, characterized by recurrent inflammation episodes and high titres of autoantibodies and antigen-specific T cells, are often polygenic or monogenic. While autoimmune, allergic, and autoinflammatory classifications aid disease understanding, interactions between innate and adaptive immunity are recognized. Neutrophilic dermatoses, including diseases with pustules like subcorneal pustular dermatosis, pustular psoriasis and SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) syndrome, suggest potential autoinflammatory origins, as neutrophils, not staphylococci, drive pustule formation.

Pustular psoriasis, the most severe subtype among psoriatic conditions, manifests as a systemic disease-causing fever and significant morbidity if left untreated, with mortality rates ranging from 3 to 8%. The major cytokine implicated in its pathogenesis is IL-36, leading to a vicious cycle involving neutrophils and IL-23, IL-17, and TNF-α interactions. Treatment options include traditional psoriasis therapies like methotrexate and IL-17/IL-23/TNF-α inhibitors, with IL-36 inhibitors emerging as the most effective albeit costly option. A recent study in the Journal of Experimental Medicine highlights the role of IL-26 in pustular psoriasis, showing its involvement in inflammation distinct from psoriasis vulgaris. Neutrophils express and release IL-26, which activates pro-inflammatory chemokines and cytokines, suggesting a crucial role of IL-26 in driving autoinflammation in pustular psoriasis.

IL-26 has an intriguing role in forming complexes with bacterial DNA, indicating a connection between innate immunity, the microbiome, and neutrophilic inflammation. Unlike pathogens, commensal bacteria are required for this process, emphasizing the significance of bacterial DNA. This interaction creates a new vicious cycle, exacerbating the IL-36 pathway and worsening pustular psoriasis. While IL-26 antagonists are patented, their potential therapeutic application in pustular psoriasis and other diseases beyond dermatology warrants further investigation over the next 15 years.

European Academy of Allergy and Clinical Immunology (EAACI), 2024 31st May-3rd June, Valencia