Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs.

Psoriasis Pathogenesis and Treatment.

Fitzpatrickʼs Dermatology in General Medicine

Photobiomodulation (PBM) also known as low-level level laser therapy is the use of red and near-infrared light to stimulate healing, relieve pain, and reduce inflammation The primary chromophores have been identified as cytochrome c oxidase in mitochondria, and calcium ion channels (possibly mediated by light absorption by opsins) Secondary effects of photon absorption include increases in ATP, a brief burst of reactive oxygen species, an increase in nitric oxide, and modulation of calcium levels Tertiary effects include activation of a wide range of transcription factors leading to improved cell survival, increased proliferation and migration, and new protein synthesis There is a pronounced biphasic dose response whereby low levels of light have stimulating effects, while high levels of light have inhibitory effects It has been found that PBM can produce ROS in normal cells, but when used in oxidatively stressed cells or in animal models of disease, ROS levels are lowered PBM is able to up-regulate anti-oxidant defenses and reduce oxidative stress It was shown that PBM can activate NF-kB in normal quiescent cells, however in activated inflammatory cells, inflammatory markers were decreased One of the most reproducible effects of PBM is an overall reduction in inflammation, which is particularly important for disorders of the joints, traumatic injuries, lung disorders, and in the brain PBM has been shown to reduce markers of M1 phenotype in activated macrophages Many reports have shown reductions in reactive nitrogen species and prostaglandins in various animal models PBM can reduce inflammation in the brain, abdominal fat, wounds, lungs, spinal cord

Mechanisms and applications of the anti-inflammatory effects of photobiomodulation.

Psoriasis is a frequent chronic inflammatory skin disease, nowadays considered a major global health problem Several new drugs, targeting the IL-23/IL-17A pathway, have been recently licensed or are in clinical development These therapies represent a major improvement of the way in which psoriasis is managed, since they show an unprecedented efficacy on skin symptoms of psoriasis This has been made possible, thanks to an increasingly more accurate pathogenic view of psoriasis Today, the belief that Th17 cells mediate psoriasis is moving to the concept of psoriasis as an IL-17A-driven disease New questions arise at the horizon, given that IL-17A is part of a newly described family of cytokines, which has five distinct homologous: IL-17B, IL-17C, IL-17D, IL-17E, also known as IL-25 and IL-17F IL-17 family cytokines elicit similar effects in target cells, but simultaneously trigger different and sometimes opposite functions in a tissue-specific manner This is complicated by the fact that IL-17 cytokines show a high capacity of synergisms with other inflammatory stimuli In this review, we will summarize the current knowledge around the cytokines belonging to the IL-17 family in relation to skin inflammation in general and psoriasis in particular, and discuss possible clinical implications A comprehensive understanding of the different roles played by the IL-17 cytokines is crucial to appreciate current and developing therapies and to allow an effective pathogenesis- and mechanisms-driven drug design

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The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond

Cutaneous barriers and skin immunity: differentiating a connected network

Background Generalized pustular psoriasis (GPP) is a rare, debilitating, and often life-threatening inflammatory disease characterized by episodic infiltration of neutrophils into the skin, pustule development, and systemic inflammation, which can manifest in the presence or absence of chronic plaque psoriasis (PV). Current treatments are unsatisfactory and warrant a better understanding of GPP pathogenesis. Objective We sought to understand better the disease mechanism of GPP to allow improved targeted therapies. Methods We performed a gene expression study on formalin-fixed paraffin-embedded GPP (n = 28) and PV (n = 12) lesional biopsies and healthy control (n = 20) skin. Differential gene expression was analyzed using gene ontology and enrichment analysis. Gene expression was validated with quantitative RT-PCR and immunohistochemistry, and a potential disease mechanism was investigated using primary human cell culture. Results Compared with healthy skin, GPP lesions yielded 479 and PV 854 differentially expressed genes, respectively, with 184 upregulated in both diseases. We detected significant contributions of IL-17A, TNF, IL-1, IL-36, and interferons in both diseases; although GPP lesions furnished higher IL-1 and IL-36 and lower IL-17A and IFN-γ mRNA expression than PV lesions did. We detected prominent IL-36 expression by keratinocytes proximal to neutrophilic pustules, and we show that both neutrophils and neutrophil proteases activate IL-36. Suggesting another mechanism regulating IL-36 activity, the protease inhibitors serpin A1 and A3, which inhibit elastase and cathepsin G, respectively, were upregulated in both diseases and inhibited activation of IL-36. Conclusions Our data indicate sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration, and pustule formation, suggesting that the IL-1/IL-36 inflammatory axis is a potent driver of disease pathology in GPP.

IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis

Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice

Palmoplantar pustular psoriasis (PPP), a subtype of pustular psoriasis, is a stubborn disease involving the palms and/or soles that can cause marked physical discomfort, impaired quality of life, and psychiatric morbidity. 1 Acitretin, cyclosporine A, potent topical corticosteroids, and phototherapy are the common treat-ments for PPP but have no high-level evidence. PPP is usually resistant to treatment and recrudesces frequently. Furthermore, the consequent therapy-related adverse events increase the bur-den on patients, and therefore the lack of adequate treatment presently makes the therapy for PPP very challenging. The pathogenesis is clear, however, a previous study showed increased cutaneous expression of IL-17A but decreased expression of IL-23 in PPP, which is dif-ferent from psoriasis vulgaris. 2 Besides IL-17, IL-36 pathways are also involved in the pathogenesis of PPP. 3 The improvement in the understanding of these may aid in the dis-covery of new promising treatments.

Local injection of low‐dose ixekizumab for the treatment of palmoplantar pustular psoriasis

Local injection of micro-dose anti-interleukin-17A antibody for palmoplantar pustulosis: A real-world study.

Introduction: Although psoriasis and bullous pemphigoid are considered distinct disease entities, there have been a few reports of these conditions coexisting in the same patient. We report a rare case in which bullous pemphigoid developed in an untreated patient with chronic psoriasis. Case report: A 62-year-old man with a 15-year history of psoriasis vulgaris was admitted to our hospital with a 4-day-old eruption of vesicles and bullae on his trunk. After being diagnosed with coexistent psoriasis and bullous pemphigoid, he was treated with secukinumab and methotrexate. After 24 weeks of cumulative treatment, almost all skin lesions had disappeared. At a 12-week follow-up, the patient was devoid of skin lesions and was still being maintained on a lower dose of secukinumab. Discussion: The coexistence of psoriasis with bullous pemphigoid presents several therapeutic challenges. The lesions of our patient were well controlled with a combination treatment of secukinumab and methotrexate. Conclusion: The combination treatment of secukinumab and methotrexate might be a safe and effective option for treating coexistent psoriasis and bullous pemphigoid. 

Z. Yin

Papers

IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis

Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice

Local injection of low‐dose ixekizumab for the treatment of palmoplantar pustular psoriasis

Local injection of micro-dose anti-interleukin-17A antibody for palmoplantar pustulosis: A real-world study.

Coexistence of Psoriasis and Bullous Pemphigoid: Combination Treatment with Secukinumab and Methotrexate