Immunological Pathways in Hidradenitis Suppurativa: Current Concepts and Innovative Therapies

Hidradenitis Suppurativa is a chronic and disabling disease characterized by pustules, nodules, abscesses, and scaring. It affects natural body folds (inguinal, axillary, inframammary), perianal region and genitalia. Several comorbidities are related to this disease, such as: obesity, smoking, acne, folliculitis, and hyperandrogenism. Disorders in keratinization, systemic upregulation of complement (C5a) activation and changes in cutaneous microbiome stimulate the development of autoinflammatory state, promoting the increase of CD4+ T- helper lymphocytes (Th-17 and Th-1). These changes stimulate the expression of toll-like receptors type 2, enabling the NLR3 inflammasome and triggering of the caspase-dependent inflammatory cascade. Intralesional increase of dendritic cells, macrophage and neutrophil influx stimulate the production of pus, promoting necrosis and apoptosis of inflammatory cells undergoing a special type of cell death program, releasing proinflammatory cytokines (pyroptosis). In addition, patients affected with this condition presents an imbalance of IL-36 proinflammatory cytokines and decreased levels of its antagonist receptor IL-36Ra. Treatment is frustrating and includes the use of broad-spectrum antibiotics, surgical procedures, and oral retinoids. The first and only one biologic therapy approved is a TNF-α inhibitor (Adalimumab); other alternatives are under development, inhibiting IL-17 (Secukinumab, Bimekizumab and CJM112) IL-12 and IL-23 (Ustekinumab); and IL-1 (Anakinra, Canakinumab). Recent articles showed that liraglutide, a glucagon-like-1 pep-tide (GLP-1) agonist, could be used to treat one of the comorbidities associated with HS (insulin resistance). Finally, inhibition of IL-36 and C5a could be an option to treat this recalcitrant and exhausting disease. Highlights: Pathogenesis of HS involves genetic and environmental factors that trigger the innate immune response. Several cytokines participate in the inflammatory response of the skin. HS is chronic and relapsing causing a negative impact on patient's quality of life, expensive medical approaches, and huge number of comorbidities. New biological drugs, former medical treatments and cutaneous surgical interventions can be combined to better assist of patients suffering of HS. Keywords: Hidradenitis suppurativa; Biologics; IL-17; IL-1; IL- 23; C5a; Autoinflammatory diseases