Psoriasis
Psoriasis: Past, Present, and Future
Psoriasis is a chronic inflammatory disease of the skin, nails, and joints. In the last two decades, there has been enormous progress in our understanding of the genetics, immunology, and associated comorbidities (Figure 1). This has been accompanied by a marked improvement in the number of therapeutic agents and their effectiveness. Much of this progress has been outlined in numerous articles, commentaries and reviews in the Journal of Investigative Dermatology (JID) over the years (Figure 2). This commentary, which is part of the JID Collections, serves to outline how we have arrived at our present state of knowledge on psoriasis and provides an overview of some exciting future directions.Psoriasis Caught in the NET
A report in the June 2019 issue of the Journal of Investigative Dermatology reveals a role of neutrophil extracellular traps (NETs) in the induction of T helper type 17 cell responses and shows the relevance of this pathway in patients with psoriasis carrying a common risk variant in the TRAF3IP2 gene (Lambert et al., 2019). This work provides a new piece to the puzzle that links neutrophils to the T helper type 17–mediated pathogenesis of psoriasis.IL-17 May Be a Key Cytokine Linking Psoriasis and Hyperglycemia
Psoriasis is associated with the metabolic syndrome, an interconnected group of conditions characterized by significant morbidity and mortality, although the causal mechanisms are still under investigation. Ikumi et al. provide evidence of a link—involving IL-17—between psoriasis and hyperglycemia in humans and mice.Genetic Study on Small Insertions and Deletions in Psoriasis Reveals a Role in Complex Human Diseases
Genetic studies based on single-nucleotide polymorphisms have provided valuable insights into the genetic architecture of complex diseases. However, a large fraction of heritability for most of these diseases remains unexplained, and the impact of small insertions and deletions (InDels) has been neglected. We performed a comprehensive screen on the exome sequence data of 1,326 genes using the SOAP-PopIndel method for InDels in 32,043 Chinese Han individuals and identified 29 unreported InDels within 25 susceptibility genes associated with psoriasis.Defining a Minimal Effective Serum Trough Concentration of Secukinumab in Psoriasis: A Step toward Personalized Therapy
The armamentarium of psoriasis treatments has been reinforced by the introduction of biologics that target IL-17A (European Medicines Agency, 2015; Frieder et al., 2018), and at present, achieving complete skin clearance has become a realistic goal. However, in clinical practice, physicians encounter various levels of responses, including insufficient response or loss of response with anti–IL-17A treatment. This has led to physicians exploring off-label intensification regimens through trial and error, either by increasing the dose or by shortening the administration intervals (Beecker and Joo, 2018; Phung et al., 2018).Psoriasis Pathogenesis: Keratinocytes Are Back in the Spotlight
Psoriasis is a T helper type 17–mediated immune disease. Initial triggers that lead to T helper type 17 production and inflammatory cell recruitment into skin are being delineated. Autoantigens that stimulate T helper type 17 cells are also being identified. A new and important piece of the puzzle indicates that keratinocytes not only amplify inflammation, but that they are essential for a full-blown IL-17–mediated psoriatic phenotype in mice.Dysregulation of Akt-FOXO1 Pathway Leads to Dysfunction of Regulatory T Cells in Patients with Psoriasis
Psoriasis is a T lymphocyte–driven systemic inflammatory disease. Regulatory T cells (Tregs) are essential for establishing and maintaining immune tolerance. In this study, we found that patients with psoriasis and healthy controls had comparable percentages of circulating CD4+CD25+FOXP3+ Tregs, but psoriatic Tregs had reduced suppressive function. Thereafter, mRNA arrays were performed to study the gene expression profile of psoriatic Tregs. Psoriatic Tregs expressed high levels of a T helper type 1–like transcription factor and cytokines such as T-bet and IFN-γ.cis-Khellactone Inhibited the Proinflammatory Macrophages via Promoting Autophagy to Ameliorate Imiquimod-Induced Psoriasis
Psoriasis is a chronic inflammatory skin disease with unresolved pathogenesis. Studies on the pathogenesis of psoriasis have been extensively carried out, but treatments are still not satisfactory. In this study, we found improvement after treatment with cis-khellactone, a small molecular natural product, in imiquimod-challenged C57BL/6 mice. cis-Khellactone clearly reduced the level of cytokines in psoriatic skin, including IL-23, TNF-α, IL-1β, and IL-6, while limiting the inhibition of IL-17A, which is produced by T helper type 17 cells.HLA-C*01:02 and HLA-A*02:07 Confer Risk Specific for Psoriatic Patients in Southern China
Psoriasis is a complex, multigenic, immune-mediated skin disease characterized by heterogeneity across diverse ancestries; its prevalence varies from 0.09% to 11.4%, depending on the population of origin (Gibbs, 1996; Danielsen et al., 2013). In China, it is estimated that 0.47% of the population suffering from psoriasis (Ding et al., 2012), and the prevalence of psoriasis in northern China is higher than in southern China.Immunogenicity of Guselkumab Is Not Clinically Relevant in Patients with Moderate-to-Severe Plaque Psoriasis
In two pivotal phase 3 studies (VOYAGE-1 [ClinicalTrials.gov ID NCT02207231 ] and VOYAGE-2 [ClinicalTrials.gov ID NCT02207244 ]), patients (n = 1,829) with moderate-to-severe plaque psoriasis were randomized to subcutaneous guselkumab 100 mg (weeks 0 and 4, then every 8 weeks), placebo with guselkumab crossover at week 16, or adalimumab with guselkumab crossover at week 28 or week 52. The design of VOYAGE-2 incorporated a randomized withdrawal and retreatment period for patients who achieved ≥90% improvement in the Psoriasis Area and Severity Index (PASI90) score at week 28.Hyperglycemia Is Associated with Psoriatic Inflammation in Both Humans and Mice
Chronic low-grade inflammation can cause several metabolic syndromes. Patients with psoriasis, a chronic immunological skin inflammation, often develop diabetes. However, it is not clear to date how psoriasis leads to, or is correlated with, glucose intolerance. Here, we investigate whether psoriasis itself is correlated with hyperglycemia in humans and mice. In patients, the severity of psoriasis was correlated with high blood glucose levels, and treatment of psoriasis by phototherapy improved insulin secretion.Racial Differences in Perceptions of Psoriasis Therapies: Implications for Racial Disparities in Psoriasis Treatment
In the United States, black patients are less likely than white patients to receive biologic treatment for their psoriasis. We conducted a qualitative free-listing study to identify patient-generated factors that may explain this apparent racial disparity in psoriasis treatment by comparing the perceptions of biologics and other psoriasis therapies between white and black adults with psoriasis. Participants included 68 white and black adults with moderate to severe psoriasis who had and had not received biologic treatment.Imiquimod-Induced Psoriasis in Mice Depends on the IL-17 Signaling of Keratinocytes
The pathology of psoriasis strongly depends on IL-17A. Monoclonal antibodies blocking either the cytokine or its receptor are among the most efficient treatments for psoriatic patients. Keratinocytes can be activated upon exposure to IL-17A and tumor necrosis factor-α and secrete secondary cytokines and chemokines in the inflamed skin. In psoriasis and its imiquimod-induced mouse model, a strong skin infiltration of neutrophils and inflammatory monocytes can be observed. However, to date, it is not clear how exactly those cellular populations are attracted to the skin and how they contribute to the pathogenesis of the disease.IL-17 and IL-22 Promote Keratinocyte Stemness in the Germinative Compartment in Psoriasis
Psoriasis is an inflammatory skin disorder characterized by the hyperproliferation of basal epidermal cells. It is regarded as T-cell mediated, but the role of keratinocytes (KCs) in the disease pathogenesis has reemerged, with genetic studies identifying KC-associated genes. We applied flow cytometry on KCs from lesional and nonlesional epidermis to characterize the phenotype in the germinative compartment in psoriasis, and we observed an overall increase in the stemness markers CD29 (2.4-fold), CD44 (2.9-fold), CD49f (2.8-fold), and p63 (1.4-fold).Atopic Dermatitis Is an IL-13–Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis
Atopic dermatitis (AD) affects up to 20% of children and adults worldwide. To gain a deeper understanding of the pathophysiology of AD, we conducted a large-scale transcriptomic study of AD with deeply sequenced RNA-sequencing samples using long (126-bp) paired-end reads. In addition to the comparisons against previous transcriptomic studies, we conducted in-depth analysis to obtain a high-resolution view of the global architecture of the AD transcriptome and contrasted it with that of psoriasis from the same cohort.Mechanical Stretch Exacerbates Psoriasis by Stimulating Keratinocyte Proliferation and Cytokine Production
Psoriasis is a chronic inflammatory autoimmune skin disease that often occurs in rubbed areas undergoing a strong mechanical stretch, such as the elbows and knees. However, the pathologic role of mechanical tension in psoriasis remains unclear. In this study, we investigated the contribution of keratinocyte mechanical stretch to the clinical features of psoriasis. We found that keratinocyte proliferation and skin barrier-associated gene expression increased significantly after 24 hours of continuous stretching.Oral Health in Patients with Psoriasis—A Prospective Study
Psoriasis is associated with periodontitis, a chronic inflammation of the gingival tissue. However, data about periodontal and dental status of psoriasis patients are sparse. Therefore, we conducted a prospective study comparing psoriasis patients with control individuals. 100 psoriasis patients presenting at the outpatient service of a specialized psoriasis center and 101 nonpsoriatic control individuals were included in the study. Oral health was assessed with standardized measures including Bleeding on Probing, Community Periodontal Index, and dental parameters according to the DMFT index (a cumulative index in which teeth [T] are registered as decayed [D], missing [M], and filled [F]).Adalimumab in Psoriasis: How Much Is Enough?
Biologic therapies targeting tumor necrosis factor have revolutionized treatment of immune-mediated inflammatory diseases such as psoriasis, but optimal dosing and appropriate use of therapeutic drug monitoring are not yet fully understood. Wilkinson et al. explore these questions in a real-world psoriasis cohort on adalimumab monotherapy, defining a therapeutic range and finding value in early measurement for predicting clinical response.Caspase 1/11 Deficiency or Pharmacological Inhibition Mitigates Psoriasis-Like Phenotype in Mice
Inflammatory caspases, activated within the inflammasome, are responsible for the maturation and secretion of IL-1β/IL-18. Although their expression in psoriasis was shown several years ago, little is known about the role of inflammatory caspases in the context of psoriasis. Here, we confirmed that caspases 1, 4, and 5 are activated in lesional skin from psoriasis patients. We showed in three psoriasis-like models that inflammatory caspases are activated, and accordingly, caspase 1/11 invalidation or pharmacological inhibition by Ac-YVAD-CMK (i.e., Ac-Tyr-Val-Ala-Asp-chloromethylketone) injection induced a decrease in ear thickness, erythema, scaling, inflammatory cytokine expression, and immune cell infiltration in mice.Disinhibition of Touch-Evoked Itch in a Mouse Model of Psoriasis
Alloknesis, itch due to light mechanical stimulation, is frequently associated with dry skin and inflammatory skin disorders (e.g., atopic dermatitis, psoriasis). Recent studies have shown that mechanical itch is regulated by neuropeptide Y-positive spinal inhibitory interneurons that are innervated by low-threshold mechanoreceptors (LTMRs) (Bourane et al., 2015). LTMRs are divided into subtypes based on their action potential conduction velocities and their rates of adaptation to sustained mechanical stimulus (Woo et al., 2015; Zimmerman et al., 2014).A Western Diet, but Not a High-Fat and Low-Sugar Diet, Predisposes Mice to Enhanced Susceptibility to Imiquimod-Induced Psoriasiform Dermatitis
Psoriasis is a disease with systemic inflammation and accompanied by multiple comorbidities, including metabolic syndrome and obesity (Hwang et al., 2017; Tsai et al., 2017; Yu et al., 2017). Obesity is often observed in patients with psoriasis and may precede development of psoriasis (Debbaneh et al., 2014). Western diet (WD) plays a crucial role in the development of obesity in Western countries and is characterized by elevated amounts of fat and sugars, especially simple sugars such as sucrose (Jena et al., 2017).IL-36 Signaling Is Essential for Psoriatic Inflammation through the Augmentation of Innate Immune Responses
IL-36 cytokines are composed of three agonists, namely IL-36α, IL-36β, and IL-36γ, and a natural antagonist, IL-36Ra (Sims and Smith, 2010). IL-36 cytokines are abundantly expressed by the skin and other epithelial tissues, whereas the IL-36 receptor (IL-36R) is expressed by skin and immune cells, including dendritic cells (DCs) (Gabay and Towne, 2015; Vigne et al., 2011). Earlier studies have demonstrated that IL-36 cytokines play important roles in the development of psoriasiform inflammation by enhancing the function of T helper type 17 cytokines (Carrier et al., 2011; Tortola et al., 2012).Neutrophil Extracellular Traps Induce Human Th17 Cells: Effect of Psoriasis-Associated TRAF3IP2 Genotype
Psoriasis lesions are rich in IL-17–producing T cells as well as neutrophils, which release webs of DNA-protein complexes known as neutrophil extracellular traps (NETs). Because we and others have observed increased NETosis in psoriatic lesions, we hypothesized that NETs contribute to increased T helper type 17 (Th17) cells in psoriasis. After stimulating peripheral blood mononuclear cells with anti-CD3/CD28 beads for 7 days, we found significantly higher percentages of CD3+CD4+IL-17+ (Th17) cells in the presence versus absence of NETs, as assessed by flow cytometry, IL-17 ELISA, and IL17A/F and RORC mRNAs.A Transethnic Mendelian Randomization Study Identifies Causality of Obesity on Risk of Psoriasis
Psoriasis is a chronic disorder characterized by cutaneous and systemic manifestations. Epidemiological studies have reported increased comorbidity of psoriasis with numerous complex diseases such as metabolic clinical measurements (Greb et al., 2016; Naito and Imafuku, 2016). However, interpretation of the comorbidity remains controversial to date, because causal inference between correlated phenotypes is difficult when depending solely on epidemiological studies. Identification of causal inference between correlated phenotypes has significant clinical impacts, because modification of the causal phenotypes could benefit treatment of the outcome phenotypes.Impact of Secukinumab on Endothelial Dysfunction and Other Cardiovascular Disease Parameters in Psoriasis Patients over 52 Weeks
Psoriasis increases the risk of cardiovascular (CV) disease. Secukinumab, a fully human monoclonal antibody against IL-17A, shows significant efficacy in psoriasis, but effects on CV markers are unknown. CARIMA (Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated with Secukinumab) was a 52-week, randomized, double-blind, placebo-controlled, exploratory trial in patients with moderate to severe plaque psoriasis without clinical CV disease. Patients were randomly assigned to receive 300 mg or 150 mg secukinumab until week 52 or to receive placebo until week 12 and then 300 mg or 150 mg secukinumab until week 52.
