Efficacy and safety of tildrakizumab for the treatment of moderate-to-severe plaque psoriasis over five years in patients living with obesity.

The distinct role and regulatory mechanism of IL-17 and IFN-γ in the initiation and development of plaque vs guttate psoriasis

Differences in the number of Foxp3+ regulatory T cells (Tregs) in lesional skin and peripheral blood and their functioning in plaque vs. guttate psoriasis have not been reported. To investigate whether there is a differential expression of Foxp3+ Tregs and a differential regulation of inflammatory cytokines in plaque vs. guttate psoriasis vulgaris. The number and the percentage of Foxp3+ cells in different phases of skin lesions of patients with plaque and guttate psoriasis vulgaris were assessed by immunohistochemical staining. The expression of Foxp3 and interleukin (IL)-17 protein in CD4 populations was measured by flow cytometry. Inflammatory cytokine production by transforming growth factor-beta1-induced Foxp3+ Tregs was assessed in an in vitro study. The cytokines in supernatant and serum were determined by enzyme-linked immunosorbent assay. The percentage of Foxp3+ CD3+ cells in the papillary layer was higher than in the reticular layer of dermis and in epidermis (P < 0.05). The numbers of Foxp3+ Tregs in skin lesions and peripheral blood were higher in plaque than in guttate psoriasis, whereas the percentage of IL-17+ CD4+ cells was higher in guttate than in plaque psoriasis (P < 0.05). The numbers of Foxp3+ cells were positively correlated with the Psoriasis Severity Index score of skin lesions (P < 0.0001), and the percentages of Foxp3+ CD4+ cells in peripheral blood were positively correlated with the Psoriasis Area and Severity Index score of patients (P < 0.05). The inhibitory functions of Tregs to IL-17 and IL-6 in guttate psoriasis and to tumour necrosis factor-alpha in plaque psoriasis were deficient. Differential expression and regulatory functioning for inflammatory cytokine production by Foxp3+ Tregs may imply a different immunopathogenesis for plaque and guttate psoriasis.

Psoriasis is a chronic inflammatory disease. Pustular, erythrodermic, and extensive plaque psoriasis are responsible for systemic complications. Systemic capillary leak syndrome is the complication with greater progression to death and occurs due to vascular changes. The aim of this study was to evaluate vascular changes through the expression of CD34 and ICAM-1 in plaque, pustular, and erythrodermic psoriasis. The sample consisted of seven patients with erythrodermic psoriasis, 24 with moderate-severe plaque psoriasis, 14 with mild plaque psoriasis and 13 with pustular psoriasis. Patients were submitted to physical examination and skin biopsy for histopathological examination and immunohistochemical analysis with anti-CD34 and anti-ICAM-1 antibodies. Subsequently, tissue fragments were organized by groups using the Tissue Macroarray (TMA) technique to perform immunohistochemistry. In 58 patients, analysis of vessels using anti-CD34 demonstrated vascular immunostaining in superficial dermis and between dermal papillae. There were more blood vessels in erythrodermic psoriasis, followed by plaque psoriasis. In erythrodermic psoriasis, there were small and few tortuous blood vessels with great dilatation, while plaque psoriasis presented larger vessels that were less dilated and more tortuous. There was an intense and localized expression of ICAM-1 in endothelial and lymphocytic cells in all groups, with significant differences. Vascular alterations are important in psoriasis, with an increase in the number of blood vessels and ICAM-1 overexpression, especially in erythrodermic form. Therefore, vascular changes and the expression of intercellular adhesion molecules could help to diagnose the erythrodermic form of psoriasis.

Secukinumab is effective in the treatment of recalcitrant palmoplantar psoriasis and palmoplantar pustular psoriasis in a daily practice setting

The key role of T cells in the pathogenesis of cutaneous psoriasis has been well described in the last decade and the knowledge of the relative role of the different subsets of T cells in psoriasis pathogenesis has considerably evolved. Now, it is clear that IL-17A-producing T cells, including Th17/Tc17, have a central role in the pathogenesis of cutaneous psoriasis and therapies blocking the IL-17A pathway show high clinical efficacy. By contrast, the contribution of IFNγ-producing T cells has progressively become less clear because of the lack of efficacy of anti-IFNγ antibodies in clinical studies. In parallel, the role of CD8+ T cells specific for self-antigens has been revived and increasing evidence now indicates that in psoriatic skin the majority CD8+ T cells are present in the form of epidermal tissue-resident memory T cells. In the last years it also emerged the possibility of a contribution of T cell recirculation in the pathogenesis of psoriasis and its systemic manifestations. The aim of this review is to define a hierarchy for the different subsets of T cells in the T cell-mediated inflammatory cascade in psoriatic skin. This analysis will possibly help to distinguish the subsets that initiate the disease, those involved in the establishment of the self-sustaining amplification loop that leads to the cutaneous clinical manifestations and finally the subsets that act as downstream players in established lesions. Specific T cell subpopulations finally will be considered for their possible role in propagating inflammation at distant sites and for representing a link with systemic inflammation and cardiovascular comorbidities.

Pathogenesis, multi-omics research, and clinical treatment of psoriasis

Psoriasis is a chronic skin disease that appears to be autoimmune in nature. Recently, it is thought that microbial pathogens of skin can affect the pathogenesis of psoriasis by inducing autoimmunity. Heat-shock proteins (HSPs) are known to play an important role in immune and inflammatory responses of the skin including psoriasis. Recent studies have suggested that Toll-like receptors (TLR) 2, 4 and gammadelta T-cell receptors (TCR-gammadelta) may recognize HSP60 as a ligand and consequently activate the immune system. The biopsy specimens of 12 of guttate psoriasis, 12 of plaque psoriasis and five of normal skin were studied using immunohistochemical staining. The expressions of HSP60, TLR2 and TLR4 were evaluated using an immunostaining-intensity-distribution (IID) index and TCR-gammadelta positive cells were counted. The expression of HSP60 was significantly higher in guttate and plaque psoriasis than in normal skin. The expression of TLR4 was higher in guttate psoriasis than in plaque psoriasis and normal skin. The expression of TCR-gammadelta was higher in guttate and plaque psoriasis than in normal skin, but there was no correlation found between the expression of HSP60 and TLRs 2 and 4, or between that of HSP60 and TCR-gammadelta. HSP60 may be related to the pathogenesis of both guttate and plaque psoriasis and TLR4 may be related to the pathogenesis of guttate psoriasis.

The data in clinical practice regarding the effectiveness and safety of brodalumab in psoriasis are scarce, especially at scalp and palmoplantar locations. The main objective was the percentage of patients achieving absolute PASI ≤3/ ≤1/ =0 for plaque psoriasis and the percentage of patients achieving an IGA 0-1/IGA 0 for the special locations at Week 52 of treatment. Observational retrospective multicentre study in 28 Spanish Hospitals that included adult patients with plaque psoriasis treated with brodalumab, from September 2018 until March 2021. A total of 200 patients were included. The mean baseline PASI was 10.97 (±6.28) with a mean basal scalp (n = 58) and palmoplantar (n = 40) IGA of 2.10 (±0.97) and 2.15 (±1.26), respectively. At Week 52, 93.98%/75.90%/68.67% of patients reached an absolute PASI ≤3/ ≤1/ =0 in plaque psoriasis (n = 83), with a percentage of patients achieving scalp (n = 27) and palmoplantar (n = 19) IGA 0-1/IGA 0 of 96.3%/88.9% and 100%/88.9%, respectively. Fifteen per cent of patients reported any adverse events with candidiasis being the most reported (6%), but only 6% of the adverse events required the withdrawal. Brodalumab demonstrated high PASI and IGA responses and was well tolerated in clinical practice in plaque, scalp and palmoplantar psoriasis.

Palmoplantar pustulosis is a chronic inflammatory disorder characterized by sterile pustules predominantly involving the palms and soles. Palmoplantar pustulosis has many similar aspects to psoriasis, either plaque and pustular type, namely familial occurrence between palmoplantar pustulosis and psoriasis, the appearance of the Köbner phenomenon, joint involvement, and nail involvement. Pustular psoriasis is classified into generalized and localized types, and there are a number of papers regarding palmoplantar pustulosis as an acral variant of localized pustular psoriasis. Many Japanese dermatologists consider palmoplantar pustulosis to be a distinct entity from pustular psoriasis, and the coexistence of palmoplantar pustulosis and psoriasis is rare. However, outside Japan, palmoplantar pustulosis is often considered to be palmoplantar psoriasis or palmoplantar pustular psoriasis, and extra-palmoplantar lesions are also considered to be psoriasis. The purpose of the current review is to compare the similarities and differences between palmoplantar pustulosis and generalized/localized pustular psoriasis. Japanese patients with palmoplantar pustulosis have a close relationship with focal infection, and the associated bone-joint manifestation exclusively involves the anterior chest wall. Furthermore, pediatric occurrence of palmoplantar pustulosis is extremely rare, and difference of genetic background between palmoplantar pustulosis and psoriasis has also been reported. Treatment of focal infection often results in dramatic effects on both cutaneous lesions and joint pain of palmoplantar pustulosis. Those findings suggest that palmoplantar pustulosis should be separately considered from either palmoplantar psoriasis or palmoplantar pustular psoriasis. The clinicopathological features and therapeutic approach of both diseases are discussed.

Psoriasis can be provoked or exacerbated by environmental exposures such as certain microbiomes. The distinction between plaque psoriasis (PP) and guttate psoriasis (GP) in the skin or pharyngeal microbiota is not yet clear. High-throughput sequencing using Illumina MiSeq was used in this study to characterize skin and pharyngeal microbial composition in patients with PP [large PP (LPP, n = 62), small PP (SPP, n = 41)] and GP (n = 14). The alpha- and beta-diversity of skin microbiota LPP was similar to that of the SPP group, but different from the GP group. There were no differences in pharyngeal microbiota among the groups. According to linear discriminant analysis effect size (LEfSe) analysis, Staphylococcus, Stenotrophomonas, Enhydrobacter, Brevundimonas, and Allorhizobium–Neorhizobium–Pararhizobium–Rhizobium were the dominant genera of skin microbiota in PP. Diversity of skin microbiota correlated with Psoriasis Area and Severity Index (PASI). Moderate-to-severe psoriasis and mild psoriasis have different microbiota compositions. The skin microbiota may be related to the pharyngeal microbiota. Furthermore, two microbiota-based models could distinguish psoriasis subtypes with area under the receiver-operating characteristic curve (AUC-ROC) of 0.935 and 0.836, respectively. In conclusion, the skin microbiota in patients with LPP is similar to that in patients with SPP, but displays variations compared to that of GP, no differences are noted between subtypes in pharyngeal microbiota. Skin microbiota diversity correlated with PASI.

Background:Durability over time varies according to the safety, tolerability and efficacy of a drug.1However, durability may vary between patient (pt) subgroups,1,2and physicians should consider pt characteristics when making treatment decisions. Certolizumab pegol (CZP) is an anti-tumour necrosis factor (anti-TNF) agent approved for the treatment of chronic inflammatory diseases, including rheumatoid arthritis (RA) and plaque psoriasis (PSO).3However, little is known about the impact of pt baseline characteristics on long-term CZP durability.Objectives:To investigate the durability of CZP and reasons for discontinuation over 3 years (yrs) in subgroups of pts with RA or PSO using pooled clinical trial data.Methods:27 RA and 3 PSO clinical trials were pooled for indication-specific analyses. Kaplan-Meier curves were calculated to estimate CZP durability for pt subgroups by age, gender, disease duration, prior anti-TNF use and geographic region. Reasons for CZP discontinuation were investigated.Results:6927 RA and 1112 PSO pts were included; mean ages were 53.0 yrs (standard deviation [SD]: 12.2 yrs) and 45.4 (13.0) yrs, respectively. 79.3% RA pts were female (of all patients, 19.4% were women of childbearing age [18–&lt;45 yrs; WoCBA]) compared with 33.5% (15.2% WoCBA) in PSO. Mean disease durations were 6.4 (6.9) yrs for RA and 18.4 (12.3) yrs for PSO. 18.5% RA and 13.3% PSO pts had prior anti-TNF use. Maximum CZP exposure was ~8 yrs for RA and ~3 yrs for PSO. At 1 yr, 63.4% of RA pts remained on CZP vs 80.3% PSO pts, decreasing to 49.2% RA pts and 70.1% PSO pts at 3 yrs (Table 1). Reasons for discontinuation, at any time during the trials, included lack of efficacy (RA 13.5%; PSO 1.8%), adverse events (RA 11.9%; PSO 8.1%), consent withdrawn (RA 6.7%; PSO 6.7%), lost to follow-up (RA 1.8%; PSO 4.3%), protocol violation (RA 1.7%; PSO 0.3%) and other (RA 9.2%; PSO 8.7%). In RA pts, CZP durability was lower in the elderly and in pts with disease duration &lt;1 yr. In PSO, durability was lower in pts with disease duration &lt;1 yr or prior anti-TNF use. Durability was lower in WoCBA pts than male pts aged 18–&lt;45 yrs for both indications. CZP durability was lower in Western Europe and North America compared to other regions.Table 1.CZP durability at 3 years,[a] by patient subgroup% patientsRAPSOAll49.270.1Age, yrs 18–&lt;4552.166.3 45–&lt;6549.468.3 ≥6543.369.4Gender Female49.364.1 Male48.269.2 WoCBA51.162.0 Male aged 18–&lt;45 yrs56.568.3Prior anti-TNF use Yes49.360.1 No49.668.5Disease duration, yrs &lt;143.239.6 1–&lt;552.663.6 5–&lt;1051.464.4 ≥1048.769.7Region Asia-Pacific58.5 Central Europe61.578.8 Eastern Europe54.2 Latin America57.1 N America36.653.9 W Europe33.867.7 Rest of the world66.3[a] For PSO, the 3 year analysis was calculated with Week 144 data. CZP: certolizumab pegol; N: North; PSO: psoriasis; RA: rheumatoid arthritis; TNF: tumour necrosis factor; W: Western; yrs: years.Conclusion:Overall, CZP durability was similar to that reported for other anti-TNFs with some differences between indication and subgroups.1Factors influencing durability included age, disease duration and geographic region. Gender differences were observed in the 18–45 yrs age group, however, both male and female CZP durability was higher than in older RA pts.

Palmo-plantar pustular psoriasis (PPPP) and palmo-plantar pustulosis (PPP) are chronic skin diseases with significant impact on quality of life. The purpose of this study was to study the efficacy of ustekinumab in PPPP and PPP and gain more knowledge on the pathophysiology and the role of the interleukin-23 (IL-23) signalling pathway in these diseases. Thirty-three patients with either PPPP (20) or PPP (13) and seven volunteers with normal palmo-plantar skin were recruited. Patients with PPP or PPPP were randomised (1:1) to receive either an anti IL-12/IL-23 antibody (ustekinumab 45mg) or placebo at day 0 and week 4 with subsequent placebo cross-over to ustekinumab at week 16. The primary endpoint was the proportion of patients randomized to ustekinumab achieving a 50% improvement in the Palmo-Plantar Pustular Area and Severity Index (PPPASI-50) as compared to placebo. Skin biopsies of the palms and soles of normal subjects and patients with PPP or PPPP were performed and analysed by RT-PCR and immunohistochemistry. There was no statistically significant difference in the proportion of patients randomised to ustekinumab as compared to those randomised to placebo achieving PPPASI-50 at week 16 for patients with PPPP (10%, 20%; P=1.000) or PPP (20%, 37.5%; P=1.000) respectively. Compared to normal subjects an 89-fold increase in IL-17A expression was found in palms/soles of patients with PPPP (P=0.006) and a 190-fold increase for patients with PPP (P=0.051). There were no statistically significant changes in cytokine expression at week 16 in the palms and soles of patients with PPP or PPPP. Taken together these results suggest that ustekinumab at a dose of 45mg has limited efficacy in PPPP and PPP. IL-17A may have a more important role than IL-23 in patients with PPPP and PPP. Conclusions are limited by the small sample size of this study.

This chapter describes the role of the nerve growth factor (NGF) and its receptor system in inflammatory diseases, such as in psoriasis, psoriatic arthritis (PsA), adjuvant-induced rat arthritis, and arthritic pain of osteoarthritis (OA). To understand the role of NGF/nerve growth factor receptor (NGF-R) in the pathogenesis of psoriasis and PsA, it is essential to know how NGF and its receptor system can influence the critical biological events associated with the disease process of psoriasis and PsA. Study of the joint and bone tissues obtained from surgical samples of inflamed psoriatic joint has demonstrated abundant osteoclasts at the pannus and bone junction. Like in other inflammatory diseases, adhesion molecules play a critical role in the pathogenesis of both psoriasis and PsA. A role of neurogenic inflammation in the pathogenesis of psoriasis is considered because of several critical observations. Extensive in vivo and in vitro studies are needed to make anti-NGF therapy totally safe for human use.

Psoriasis is a chronic inflammatory skin disease characterized by IL-17-dominant abnormal innate and acquired immunity, and the hyperproliferation and aberrant differentiation of epidermal keratinocytes, and comorbid arthritis or cardiometabolic diseases. This Special Issue presented updated information on pathogenesis, comorbidities, and therapy of psoriasis. The pathogenesis of psoriasis may involve the dysfunction of indoleamine 2,3-dioxygenase 2 or of UBA domain containing 1-mediated regulation of CARD14/CARMA2sh. The blood cells of psoriasis patients showed the enhanced oxidative stress/autophagy flux and decreased 20S proteasome activity. Elafin, clusterin, or selenoprotein P may act as biomarkers for psoriasis and comorbid metabolic diseases. The proteomic profile of psoriasis lesions showed the dysfunction of dermal fibroblasts; up-regulation of proinflammatory factors and signal transduction or down-regulation of structural molecules. The skin inflammation in psoriasis may populate certain gut bacteria, such as Staphylococcus aureus and Streptococcus danieliae, which worsen the skin inflammation in turn. The psoriasis-associated pruritus may be caused by immune, nervous, or vascular mechanisms. In addition to current oral treatments and biologics, a new treatment option for psoriasis is now being developed, such as retinoic-acid-receptor-related orphan nuclear receptor γt inhibitors, IL-36 receptor antagonist, or aryl hydrocarbon receptor agonist. Antimicrobial peptides and innate immune cells, involved in the pathogenesis of psoriasis, may be novel therapeutic targets. The pathomechanisms and responses to drugs in collagen diseases are partially shared with and partially different from those in psoriasis. Certain nutrients can exacerbate or regulate the progress of psoriasis. The articles in this Special Issue will encourage attractive approaches to psoriasis by future researchers.

T cells in psoriasis