Section 2: "Immune System and Psoriasis"

Chapter 4: "Th17/IL-17, Immunometabolism and Psoriatic Disease: A Pathological Trifecta"

The burgeoning arena of immunometabolism provides evidence of the role of cellular as well as local (tissue)/systemic metabolic pathways in controlling immunity and inflammation. An intricate and elaborate network of various metabolic circuits, specifically glycolysis, fatty acid oxidation and synthesis, and amino acid metabolism, precisely generates metabolites that rewire the immune response. Psoriasis is a chronic progressive self-perpetuated "IL-17-centric" inflammatory disease characterized by the co-existence of autoimmune and autoinflammatory pathways. Metabolic responses, governed by oxygen levels, nutrient availability, growth factors, cytokines, AMP/ATP ratios, and amino acids, play a pivotal role in programming Th17 cell fate determination. Understanding the intricate interactions and complex interplay of molecular mechanisms responsible for Th17 cell metabolic rewiring, an important determinant of Th17 cell plasticity and heterogeneity, has the potential to reshape psoriatic therapeutics in ways currently unimagined. This chapter presents recent updates on major cellular and systemic metabolic pathways regulating differentiation of Th17 cells as well their crosstalk with intracellular signaling mediators. It also sheds light on how dysregulation of these pathways can be responsible for immune impairment and the development of psoriatic disease. A better understanding of these metabolic processes could unveil an intriguing leverage point for therapeutic interventions to modulate metabolic programming and Th17 cell responses in this multisystemic inflammatory disease.

Chapter 5: "Immune Markers in Psoriasis"

Psoriasis is a chronic inflammatory skin disorder with high immunological background caused by a complex interplay between an altered immune system, genetic factors, autoantigens, lifestyle, and environmental factors. Extensive literature in recent years has highlighted the crucial role played by the immune system in the pathogenesis of this pathology. Although it is unequivocally accepted that psoriasis is a T-cell-mediated autoimmune condition, both innate and specific immune cells are highly involved in its pathogenesis. The aberrant interactions between immune cells and resident hyper-proliferative keratinocytes are mediated by immune- and non-immune-related molecules that lead to amplification of the local immune responses that maintain the chronic inflammatory status. This chapter discusses the immune molecules residing in

the psoriatic tissue or appending to the blood circulation that can indicate the prognosis of this systemic autoimmune disease. It also focuses on residing or circulating immune cells that can pinpoint the clinical evolution of the psoriatic disease. All these data can be developed in immune marker patterns that aid psoriasis diagnosis and/or future (immune)therapies.

Chapter 6 "Immunomodulatory Effect of Methotrexate Abruptly Controls Keratinocyte Activation in Psoriasis"

In psoriatic skin, epidermal keratinocytes undergo deregulated inflammatory response that leads to prolonged expression of inflammatory mediators as well as abnormal keratins. Due to immune and genetic factors, keratinocytes get activated and cell balance gets disturbed. This activation is mainly due to deregulated inflammatory response. A vicious cycle of keratinocyte-immune response called the keratinocyte activation cycle leads to psoriasis in psoriatic skin. Epidermal keratinocytes undergo deregulated inflammatory response that leads to prolonged expression of inflammatory mediators as well as abnormal keratins. Methotrexate, an immunosuppressive agent, has been used as a standard drug to treat severe psoriasis. Acanthosis and abnormal terminal differentiation were mainly due to the mutation in epidermal keratins. In turn, disease severity and relapsing of psoriasis are mainly due to the mutation of hyperproliferative keratins. These novel keratin mutations in psoriatic epidermis might be one of the causative factors for psoriasis. Methotrexate strongly regulates the keratinocyte activation cycle by deregulated inflammatory markers and maintains a normal keratin phenotype on hyperproliferating keratinocytes, thereby controlling acanthosis in psoriasis patients.

Section 3: "Treatment of Psoriasis"

Chapter 7: "Topical Moisturisers for the Management of Psoriasis Vulgaris"

This chapter provides an overview of basic and tailored topical moisturizers and discusses how and why they form the backbone for the management of psoriasis. The discussion begins by describing the main characteristics of psoriasis and indicating how alterations in the skin's integrity and barrier function contribute to the initial development of psoriasis and subsequent changes in psoriasis phenotype. Next, the chapter addresses the evolution of topical moisturizers to more sophisticated and beneficial products and describes the key biophysical effects exerted on psoriatic skin by their active ingredients as well as the myriad benefits offered by fundamental and specialty ingredients. Furthermore, the chapter explains how topical moisturizer formulation modalities can help to improve compromised skin barrier function and alleviate the symptoms of psoriasis, cosmetically and/or therapeutically. It also discusses associated concerns and challenges.

Chapter 8 "Developing Novel Molecular Targeted Therapeutics for Topical Treatment of Psoriasis"

In mild-to-moderate as well as moderate-to-severe psoriasis, 70%–80% of patients start with topical agents and continue to use them with other active therapies. This group of patients can benefit from topical treatment with minimal systemic exposure. The expression levels of IL-23 and IL-17 are upregulated in psoriatic skin compared

with non-lesional skin. Epidermal proliferation and psoriasis are caused by overactive Th17 cells, which are promoted and stabilized by the activated IL-23 receptor, forming part of the positive feedback loop. FDA-approved biologics in IL-23/IL-17 axis (ustekinumab, guselkumab, risankizumab, tildrakizumab, ixekizumab, secukinumab, and brodalumab) demonstrated superior clinical efficacy in the systemic treatment of moderate-to-severe psoriasis, providing clinical proof of the IL-23/IL-17 axis as a major immune pathway underlying the pathophysiology of psoriasis. However, due to its large size and poor permeability to the skin, biologics are not suitable to deliver via topical route. Current topical treatments of mild-to-moderate psoriasis are corticosteroids and vitamin D analogues, which have limited efficacy with significant side effects so patients must avoid long-term use. This chapter reviews current molecular targeted therapeutics under development for topical treatment of psoriasis.

> **Shahin Aghaei, MD** Department of Dermatology and Dermatological Surgery, Iran University of Medical Sciences, Tehran, Iran

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Section 1

Clinical Criteria, Differential

Diagnosis and Comorbidities

Section 1
