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).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.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).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.3-Dimensional Optical Clearing and Imaging of Pruritic Atopic Dermatitis and Psoriasis Skin Reveals Downregulation of Epidermal Innervation
While it has been known for more than 5 decades that nerve endings are found in the epidermis (Arthur and Shelley, 1959), it remains unclear how the cutaneous nervous system is altered in pruritic skin, as existing studies have yielded conflicting results. Although pruritic skin is commonly thought to be hyperinnervated (Taneda et al., 2011; Tominaga et al., 2009), several studies reported demonstrable reductions in nerve densities in itchy skin (Johansson et al., 1991; Maddison et al., 2008). One plausible explanation for this could be the disparate types of readouts used for nerve density analysis, for instance, counting the number of nerves per unit length (Kim et al., 2014) as opposed to measuring fiber length per epidermal unit area (Maddison et al., 2011) (Supplementary Table S1 online).Influenza Vaccination Rates in Adults with Psoriasis Compared to Adults with Other Chronic Diseases
Psoriasis is a chronic inflammatory skin disease affecting about 3% of the population (Rachakonda et al., 2014). Over the past decade, more evidence has been published suggesting that psoriasis is not just a disease of the skin, but a disease of systemic inflammation, predisposing patients to other medical comorbidities. Previous large, population-based studies have found that patients with psoriasis have higher rates of serious infections requiring hospitalization compared to adults without psoriasis, with lower respiratory tract infections, including pneumonia, being most common (Kao et al., 2014; Takeshita et al., 2018; Wakkee et al., 2011).Is CCR6 Required for the Development of Psoriasiform Dermatitis in Mice?
Intradermal injection of IL-23 and topical application of imiquimod (IMQ) are two widely adopted murine models of psoriasis. Both models result in psoriasiform dermatitis (PsD) in mice that resembles human psoriasis (van der Fits et al., 2009; Zheng et al., 2007). CCR6 is important for epidermal trafficking of IL-17/22–producing cells (Mabuchi et al., 2013) and is required for the development of PsD in the IL-23 injection model since CCR6-deficient knockout (CCR6KO) mice fail to show significant dermal inflammation (Hedrick et al., 2009).Proportion of CD4+CD49b+LAG-3+ Type 1 Regulatory T Cells in the Blood of Psoriasis Patients Inversely Correlates with Psoriasis Area and Severity Index
Psoriasis skin lesions are created through chronic T-cell activation and expansion of autoreactive, skin resident αβ T helper type 17 (Th17) cell clones (Matos et al., 2017), suggesting a defect in normal tolerance mechanisms. A previous study determined that although psoriasis patients have normal numbers of circulating regulatory T (Treg) cells (CD4+CD25+Foxp3+ T cells), psoriatic Treg cells were less effective at suppressing alloreactive T cells compared with Treg cells from healthy individuals (Bovenschen et al., 2011; de Boer et al., 2007; Sugiyama et al., 2005).SEB Stimulation Induces Functional Pathogenic Features in Th17 Cells from Psoriasis Patients
Psoriasis is a chronic inflammatory cutaneous disease in which CD4+ T-cell lymphocytes expressing IL-17 have been identified (Lowes et al., 2014), and IL-17 blockers have shown outstanding results in psoriasis treatment (Leonardi et al., 2012). Chronic inflammatory models have shown plasticity of T helper type (Th) 17 cells to acquire Th1 features. Conventional Th17 cells express RORγt and IL-17 but not IFN-γ, whereas after plasticity, Th17 cells express RORγt, T-bet, Runx1, and IFN-γ and lose IL-17 expression (Lee et al., 2012).Expression of PI3K Signaling Associated with T Cells in Psoriasis Is Inhibited by Seletalisib, a PI3Kδ Inhibitor, and Is Required for Functional Activity
The phosphoinositide 3-kinase (PI3K) pathway plays a key role in many cellular processes, including cell proliferation, survival, and protein synthesis, with the PI3K isoform, PI3Kδ, involved in normal T-cell development and function (Jarmin et al., 2008; Lucas et al., 2016; Vanhaesebroeck et al., 2012). Evidence to suggest that PI3K signaling might play a role in psoriasis comes from reports of increased expression of phosphorylated protein kinase B, mammalian target of rapamycin, and ribosomal protein S6 (pS6), which are downstream in the PI3K signaling pathway, in lesional psoriatic skin compared with nonlesional skin and healthy controls (Buerger et al., 2013; Madonna et al., 2012; Rosenberger et al., 2007).How Effective Is Tacrolimus in the Imiquimod-Induced Mouse Model of Psoriasis?
The imiquimod (IMQ)-induced mouse model has become a widely used standard to model human psoriasis since its introduction in 2009 and seems to mirror psoriasis in many pathogenetic, clinical, and histological features (van der Fits et al., 2009). Because of various advantages, the number of publications based on this model has increased exponentially in the past 7 years (Hawkes et al., 2017). However, van der Fits et al. already stated that the model’s response to antipsoriatic drugs still needs to be shown.Re: Quantitative Evaluation of Biologic Therapy Options for Psoriasis: A Systematic Review and Network Meta-Analysis
We thank Reich et al. for their correspondence on our paper (Jabbar-Lopez et al., 2017). They helpfully highlight the IXORA-S trial comparing ixekizumab with ustekinumab for moderate-severe plaque psoriasis (Reich et al., 2017). This was published after our search cutoff date and so was not included in our review.Objective Measures of Psoriasis Severity Predict Mortality: A Prospective Population-Based Cohort Study
A broad and growing body of literature suggests that psoriasis is associated with higher rates of major comorbidities, including mortality (Gelfand et al., 2007; Lee et al., 2017; Lindegard, 1989; Ogdie et al., 2014; Poikolainen et al., 1999; Salahadeen et al., 2015; Springate et al., 2017; Stern and Huibregtse, 2011; Svedbom et al., 2015). Most current literature does not adjust for major mortality risk factors such as obesity, and critically, to our knowledge there are no studies that evaluate how direct measures of psoriasis severity influence risk of death.Comment on “Quantitative Evaluation of Biologic Therapy Options for Psoriasis: A Systematic Review and Network Meta-Analysis”
We would like to provide additional context regarding interpretation of the recently published paper by Jabbar-Lopez et al. (2017). This report performed a systematic review of the literature and network meta-analysis (NMA) to compare six biologics licensed for the treatment of psoriasis with each other, methotrexate, or placebo in an attempt to inform patient and clinician decisions as well as to update the British Association of Dermatologists’ guidelines regarding prioritizations of biologic therapies in psoriasis.Characterization of Autoantigen Presentation by HLA-C*06:02 in Psoriasis
Psoriasis is a stubborn skin problem that is considered to be a T-cell-mediated chronic inflammatory skin disease and affects 2–3% of individuals worldwide (Harden et al., 2015). Studies have suggested that human leukocyte antigen C (HLA-C) is a strong susceptibility gene in psoriasis presenting autoantigens (Okada et al., 2014; Zhou et al., 2016).Response to Hjuler et al.
We want to thank Hjuler et al. (2017) for their comments on our article (Bissonnette et al., 2017). We agree that many unknowns remain on the mechanisms of atherosclerosis in patients with psoriasis. Our hypothesis was that adalimumab reduced vascular inflammation in patients with moderate-to-severe psoriasis. Measurement of vascular inflammation in the aorta and the carotids did not confirm this hypothesis. The target-to-background ratio was measured in an area that was localized between the beginning of the ascending aorta and the left subclavian artery, which includes the ascending aorta and the aortic arch.Using FDG-PET/CT to Detect Vascular Inflammation in Patients with Psoriasis: Where to Look? And for What??
We would like to commend Bissonnette et al. (2017) for their study, “TNF-α Antagonist and Vascular Inflammation in Patients With Psoriasis Vulgaris: A Randomized Placebo-Controlled Study” (Bissonnette et al., 2017).Topically Delivered Tumor Necrosis Factor-α–Targeted Gene Regulation for Psoriasis
Psoriasis is a highly visible, chronic, immune-mediated inflammatory skin disorder that affects 2–3% of the US population (Lowes et al., 2014). Tumor necrosis factor-α (TNF-α) and IL-17A synergistically up-regulate the production of other cytokines, chemokines, and antimicrobial peptides from keratinocytes and regional immune cells, initiating and perpetuating the immune activation of psoriasis (Chiricozzi et al., 2011; Di Cesare et al., 2009; Ettehadi et al., 1994; Harden et al., 2015; Lowes et al., 2005).Complement C3 Exacerbates Imiquimod-Induced Skin Inflammation and Psoriasiform Dermatitis
The complement system is pivotal in protection against pathogens, but it also plays important roles in bridging innate and adaptive immune responses (Scott and Botto, 2016) and in modulating local and systemic inflammation (Markiewski and Lambris, 2007). Activation of complement occurs through three different pathways (classical, alternative, and lectin), converges at C3 cleavage, and culminates in the formation of the membrane attack complex. The anaphylatoxic fragments, C3a and C5a, generated during the proteolytic cascade, recruit immune cells that can promote the removal of debris and pathogens, but they can also cause tissue damage (Markiewski and Lambris, 2007).The Involvement of Serum Amyloid A in Psoriatic Inflammation
Psoriasis vulgaris is a common inflammatory skin disorder that is characterized by abnormal epidermal proliferation and a cellular infiltrate including neutrophils and T cells (Nestle et al., 2009). The number of T helper (Th) type 1 and Th17 cells are particularly increased in psoriatic patients, and they are thought to play critical roles in the pathogenesis (Lowes et al., 2013; Nestle et al., 2009). In addition, psoriatic keratinocytes are morphologically abnormal and may influence infiltrating T-cell function by producing cytokines and chemokines (Lowes et al., 2013; Nestle et al., 2009).Presence of Hand Warts Is Associated with Subsequent Development of Cutaneous Squamous Cell Carcinoma in Psoriasis Patients Treated with Psoralen UVA (PUVA)
Squamous cell carcinoma (SCC) is the second most common type of skin cancer, with an estimated incidence of over 200,000 cases per year in the United States, causing significant morbidity and mortality (Weinstock, 1997). The prevalence of warts in the total US population aged 1–74 years is about 1%, with higher estimates of 3.3% (2.8– 3.8%) in those younger than 18 years old (Johnson and Roberts, 1978; Silverberg and Silverberg, 2013). Although factors such as UV light exposure, fair skin, and sex are well-established risk factors for developing cutaneous SCC (Lim and Stern, 2005), the role of human papilloma virus (HPV) infection remains controversial.IL-17 Responses Are the Dominant Inflammatory Signal Linking Inverse, Erythrodermic, and Chronic Plaque Psoriasis
Inverse and erythrodermic psoriasis are rare subtypes of psoriasis. Whereas the former is characterized by shiny erythematous nonscaly plaques in the body folds, the latter has widespread redness with fine scale, covering over 80% of the body surface area, and can be life threatening. Both are clinical subtypes of chronic plaque psoriasis and often coexist or evolve from plaque psoriasis (Boyd and Menter, 1989; Omland and Gniadecki, 2015), but the pathogenic mechanisms involved are unknown, and current treatments are frequently unsatisfactory (Rosenbach et al., 2010).
