The surface receptor for advanced glycosylation end-products (RAGE) and its soluble (sRAGE) and endogenous secretory (EN-RAGE) forms belong to the superfamily of toll-like receptors and play important roles in inflammation and autoimmunity, directly or through binding with advanced glycosylation end-products (AGE) and advanced oxidation protein products (AOPP). We reviewed the literature on the role of RAGE in skin diseases. Research in this field is still rather limited (28 articles) but suggests the involvement of RAGE and RAGE-related pathways in chronic inflammatory diseases (lupus, psoriasis, atopic dermatitis, and lichen planus), infectious diseases (leprosy, Staphylococcus aureus-induced skin lesions), alterations of the repairing processes in diabetic skin, systemic sclerosis, and ulcers. These data prompt further research in this field, which not only will be useful to better understand the pathogenetic mechanisms of diseases, but is also likely to have intriguing clinical implications. Indeed, when their role in the complex and multifactorial inflammatory balance will be adequately defined, RAGE and related molecules could be used as markers of disease severity and/or response to treatment. Moreover, future promising therapeutic perspectives could be topical administration of some of these molecules (e.g., sRAGE) to modulate local inflammatory response and/or the development of anti-RAGE antibodies for systemic treatment.

Vitiligo is a chronic autoimmune dermatosis of which the pathogenesis remains scarcely known. A wide variety of clinical studies have been proposed to investigate the immune mediators which have shown the most recurrency. However, such trials have produced controversial results. The aim of this review is to summarize the main factors involved in the pathogenesis of vitiligo, the latest findings regarding the cytokines involved and to evaluate the treatments based on the use of biological drugs in order to stop disease progression and achieve repigmentation. According to the results, the most recurrent studies dealt with inhibitors of IFN-gamma and TNF-alpha. It is possible that, given the great deal of cytokines involved in the lesion formation process of vitiligo, other biologics could be developed in the future to be used as adjuvants and/or to entirely replace the treatments that have proven to be unsatisfactory so far.

Interleukin 31 belongs to the IL-6 superfamily, and it is an itch mediator already studied in several diseases, comprising atopic dermatitis, allergic pathologies, and onco-hematological conditions. This research aims to assess the role of this cytokine in the pathogenesis of these conditions and its potential therapeutic role. The research has been conducted on articles, excluding reviews and meta-analysis, both on animals and humans. The results showed that IL-31 plays a crucial role in the pathogenesis of systemic skin manifestations, prognosis, and itch severity. Traditional therapies target this interleukin indirectly, but monoclonal antibodies (Mab) directed against it have shown efficacy and safety profiles comparable with biological drugs that are already available. Future perspectives could include the development of new antibodies against IL-31 both for humans and animals, thus adding a new approach to the therapy, which often has proven to be prolonged and specific for each patient.

High-mobility Group Box 1 (HMGB1) is a nuclear protein that plays a key role in acute and chronic inflammation. It has already been studied in several diseases, among them melanoma. Indeed, HMGB1 is closely associated with cell survival and proliferation and may be directly involved in tumor cell metastasis development thanks to its ability to promote cell migration. This research aims to assess the role of this molecule in the pathogenesis of human melanoma and its potential therapeutic role. The research has been conducted on the PubMed database, and the resulting articles are sorted by year of publication, showing an increasing interest in the last five years. The results showed that HMGB1 plays a crucial role in the pathogenesis of skin cancer, prognosis, and therapeutical response to therapy. Traditional therapies target this molecule indirectly, but future perspectives could include the development of new target therapy against HMGB1, thus adding a new approach to the therapy, which has often shown primary and secondary resistance. This could add a new therapy arm which has to be prolonged and specific for each patient.

Interleukin (IL)-37 and IL-33 are among the latest cytokines identified, playing a role in several inflammatory conditions, spanning from systemic conditions to tumors to localized diseases. As newly discovered interleukins, their role is still scarcely understood, but their potential role as therapeutic targets or disease activity markers suggests the need to reorganize the current data for a better interpretation. The aim of this review is to collect and organize data produced by several studies to create a complete picture. The research was conducted on the PubMed database, and the resulting articles were sorted by title, abstract, English language, and content. Several studies have been assessed, mostly related to atopic dermatitis and immunologic pathways. Collective data demonstrates a pro-inflammatory role of IL-33 and an anti-inflammatory one for IL-37, possibly related to each other in an IL-33/IL-37 axis. Although further studies are needed to assess the safety and plausibility of targeting these two interleukins for patients affected by skin conditions, the early results indicate that both IL-33 and IL-37 represent markers of disease activity.

Atopic dermatitis and psoriasis are two of the most common chronic skin conditions. Current target therapies represent viable and safe solutions for the most severe cases of these two dermatoses but, presently, several limitations exist in terms of efficacy and side effects. A new class of products, epithelium-derived cytokines (TSLP, IL-25, IL-33), show an increasing potential for use in target therapy for these patients, and demonstrate a direct link between a generalized inflammatory and oxidative stress status and the human skin. A review was conducted to better understand their role in the aforementioned conditions. Of these three molecules, TSLP led has been most often considered in studies regarding target therapies, and most of the results in the literature are related to this cytokine. These three cytokines share common stimuli and are linked to each other in both acute and chronic phases of these diseases, and have been challenged as target therapies or biomarkers of disease activity. The results lead to the conclusion that epithelium-derived cytokines could represent a therapeutic opportunity for these patients, especially in itch control. Furthermore, they might work better when paired together with currently available therapies or in combination with in-development treatments. Further studies are needed in order to verify the efficacy and safety of the biologic treatments currently under development.