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.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.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.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.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.Online Care Versus In-Person Care for Improving Quality of Life in Psoriasis: A Randomized Controlled Equivalency Trial
This 12-month, pragmatic, randomized controlled equivalency trial evaluated whether an online, collaborative connected-health model results in equivalent improvements in quality of life compared with in-person care for psoriasis. Overall, 296 adults with physician-diagnosed psoriasis from ambulatory clinics were randomly assigned to either online or in-person care; all were analyzed for outcomes. In the online group, patients and primary care providers sought dermatologists’ care directly and asynchronously online.Biological Effects of IL-26 on T Cell–Mediated Skin Inflammation, Including Psoriasis
Psoriasis is a chronic inflammatory skin disease characterized mainly by epidermal hyperplasia, scaling, and erythema; T helper 17 cells have a role in its pathogenesis. Although IL-26, known as a T helper 17 cytokine, is upregulated in psoriatic skin lesions, its precise role is unclear. We investigated the role of IL-26 in the imiquimod-induced psoriasis-like murine model using human IL-26 transgenic mice. Erythema symptoms induced by daily applications of imiquimod increased dramatically in human IL-26 transgenic mice compared with controls.Potentiation of Psoriasis-Like Inflammation by PCSK9
Psoriasis is a systemic inflammatory disease, associated with metabolic disorders, including high level of low-density lipoprotein. PCSK9, which promotes the degradation of low-density lipoprotein receptors and, therefore, the increased concentration of circulating low-density lipoprotein, is also involved in inflammation. This study aims to examine the role of PCSK9 in psoriasis and to investigate the potential of topically applying small interfering RNA targeting Pcsk9 as a psoriasis treatment.Antagonization of IL-17A Attenuates Skin Inflammation and Vascular Dysfunction in Mouse Models of Psoriasis
Besides skin inflammation, patients with severe psoriasis suffer from an increased risk of cardiovascular mortality. IL-17A plays a central role in the development of psoriasis and might connect skin and vascular disease. The aim of this study was to clarify whether anti-IL-17A therapy could also ameliorate the vascular dysfunction associated with severe psoriasis. We analyzed three murine models with varying severities of psoriasis-like skin disease concerning their vascular function and inflammation: (i) K14-IL-17Aind/+ mice with keratinocyte-specific IL-17A overexpression and an early-onset severe psoriasis-like phenotype; (ii) homozygous CD11c-IL-17Aind/ind and heterozygous CD11c-IL-17Aind/+ mice overexpressing IL-17A in CD11c+ cells, leading to a delayed onset of moderate psoriasis-like skin disease; and (iii) the acute model of imiquimod-induced psoriasis-like skin inflammation.Psoriasis Plays a Wild CARD
Rare autosomal mutations in CARD14 have previously been linked to psoriasis susceptibility in humans, but their pathogenic role had not been shown. Mellett et al. generated mice harboring the patient-derived gain-of-function Card14ΔE138 mutation and showed that hyperactivation of CARD14 alone is sufficient to induce immunopathogenic mechanisms that are responsible for psoriasis, which is driven by the IL-17/IL-23 axis.Saturated Fatty Acids as Possible Key Amplifiers of Psoriatic Dermatitis
The association of obesity with psoriasis is well known, but the molecular link between these two entities is incompletely characterized. Herbert et al. report that dietary saturated fatty acids, rather than obesity itself, promote exacerbation of psoriasis in high fat diet-induced obesity. They also suggest that dietary manipulation could improve psoriasis.IL-22 Down-Regulates Cx43 Expression and Decreases Gap Junctional Intercellular Communication by Activating the JNK Pathway in Psoriasis
The roles of IL-22 in the pathomechanisms of psoriasis have been well demonstrated. Gap junctional intercellular communication (GJIC) is widely known for its involvement in multiple biological and pathological processes such as growth-related events, cell differentiation, and inflammation. Here, we show that IL-22 significantly decreased GJIC and down-regulated Cx43 expression in HaCaT cells. Cx43 overexpression markedly inhibited the proliferation of and increased GJIC in HaCaT cells, but the silencing of Cx43 exerted the opposite effects.
