Psoriasis and metabolic syndrome: implications for the management and treatment of psoriasis.

Psoriasis is a chronic systemic inflammatory disorder associated with several comorbidities in addition to the characteristic skin lesions. Metabolic syndrome (MetS) is the most frequent comorbidity in psoriasis and a risk factor for cardiovascular disease, a major cause of death among patients with psoriasis. Although the exact causal relationship between these two disorders is not fully established, the underlying pathophysiology linking psoriasis and MetS seems to involve overlapping genetic predispositions and inflammatory pathways. Dysregulation of the IL-23/Th-17 immune signalling pathway is central to both pathologies and may be key to promoting susceptibility to metabolic and cardiovascular diseases in individuals with and without psoriasis. Thus, biological treatments for psoriasis that interrupt these signals could both reduce the psoriatic inflammatory burden and also lessen the risk of developing atherosclerosis and cardiometabolic diseases. In support of this hypothesis, improvement of skin lesions was associated with improvement in vascular inflammation in recent imaging studies, demonstrating that the beneficial effect of biological agents goes beyond the skin and could help to prevent cardiovascular disease. This review will summarize current knowledge on underlying inflammatory mechanisms shared between psoriasis and MetS and discuss the most recent clinical evidence for the potential for psoriasis treatment to reduce cardiovascular risk.

Transcriptomic changes during stage progression of mycosis fungoides.

BACKGROUND: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma, which in the early patch/plaque stages runs an indolent course. However, ~25% of patients with MF develop skin tumours, a hallmark of progression to the advanced stage, which is associated with high mortality. The mechanisms involved in stage progression are poorly elucidated. OBJECTIVES: We sought to address the hypothesis of MF cell trafficking between skin lesions by comparing transcriptomic profiles of skin samples in different clinical stages of MF. METHODS: We performed whole-transcriptome and whole-exome sequencing of malignant MF cells from skin biopsies obtained by laser-capture microdissection. We compared three types of MF lesions: early-stage plaques (ESP, n = 12) as well as plaques and tumours from patients in late-stage disease [late-stage plaques (LSP, n = 10) and tumours (TMR, n = 15)]. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to determine pathway changes specific for different lesions which were linked to the recurrent somatic mutations overrepresented in MF tumours. RESULTS: The key upregulated pathways during stage progression were those related to cell proliferation and survival (MEK/ERK, Akt-mTOR), T helper cell (Th)2/Th9 signalling [interleukin (IL)4, STAT3, STAT5, STAT6], meiomitosis (CT45A1, CT45A3, STAG3, GTSF1, REC8) and DNA repair (PARP1, MYCN, OGG1). Principal coordinate clustering of the transcriptome revealed extensive gene expression differences between early (ESP) and advanced-stage lesions (LSP and TMR). LSP and TMR showed remarkable similarities at the level of the transcriptome, which we interpreted as evidence of cell percolation between lesions via haematogenous self-seeding. CONCLUSIONS: Stage progression in MF is associated with Th2/Th9 polarization of malignant cells, activation of proliferation, survival, as well as increased genomic instability. Global transcriptomic changes in multiple lesions may be caused by haematogenous cell percolation between discrete skin lesions.

Intertriginous mycosis fungoides with T follicular helper cell phenotype progressing to Sézary syndrome.

This case report highlights the challenges in diagnosis and therapeutic options for an individual who initially presented with intertriginous mycosis fungoides with a T follicular helper cell phenotype, which later evolved to Sézary syndrome.

Position statement for a pragmatic approach to immunotherapeutics in patients with inflammatory skin diseases during the coronavirus disease 2019 pandemic and beyond.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, a novel RNA virus that was declared a global pandemic on 11 March 2020. The efficiency of infection with SARS-CoV-2 is reflected by its rapid global spread. The SARS-CoV-2 pandemic has implications for patients with inflammatory skin diseases on systemic immunotherapy who may be at increased risk of infection or more severe infection. This position paper is a focused examination of current evidence considering the mechanisms of action of immunotherapeutic drugs in relation to immune response to SARS-CoV-2. We aim to provide practical guidance for dermatologists managing patients with inflammatory skin conditions on systemic therapies during the current pandemic and beyond. Considering the limited and rapidly evolving evidence, mechanisms of action of therapies, and current knowledge of SARS-CoV-2 infection, we propose that systemic immunotherapy can be continued, with special considerations for at risk patients or those presenting with symptoms.

European dermatology forum: Updated guidelines on the use of extracorporeal photopheresis 2020 - Part 2.

BACKGROUND: Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multidisciplinary setting. It has confirmed recognition in well-known documented conditions such as graft-vs.-host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. MATERIALS AND METHODS: In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. RESULTS AND CONCLUSION: These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines were divided into two parts: PART I covers Cutaneous T-cell lymphoma, chronic graft-vs.-host disease and acute graft-vs.-host disease, while PART II will cover scleroderma, solid organ transplantation, Crohn's disease, use of ECP in paediatric patients, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.

European dermatology forum - updated guidelines on the use of extracorporeal photopheresis 2020 - part 1.

BACKGROUND: Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. It has confirmed recognition in well-known documented conditions such as graft-versus-host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. MATERIALS AND METHODS: In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. RESULTS AND CONCLUSION: These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines are divided in two parts: PART I covers cutaneous T-cell lymphoma, chronic graft-versus-host disease and acute graft-versus-host disease while PART II will cover scleroderma, solid organ transplantation, Crohn's disease, use of ECP in paediatrics practice, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.

Factors predicting persistence of biologic drugs in psoriasis: a systematic review and meta-analysis.

BACKGROUND: Long-term therapy for psoriasis is impaired by gradual loss of effectiveness and treatment discontinuation. Identifying factors that affect biologic drug survival may help in treatment optimization. OBJECTIVES: To identify factors that predicted biologic drug persistence or discontinuation in a real-life setting. METHODS: We identified studies of biologic persistence in psoriasis through a comprehensive, systematic literature search using predefined search criteria. Studies were screened by title and abstract then further by full-text review. Hazard ratio (HR) data were extracted for all available predictive factors (HRs > 1 denoted biologic discontinuation, and HRs < 1 denoted biologic persistence). A meta-analysis of HRs (random-effects model) was used to assess any predictive factor included in at least two studies. RESULTS: Sixteen cohort studies were included in the review, with a total of 32 194 patients. A meta-analysis was performed on 13 studies (n = 29 802): nine for female sex (n = 28 090), six for obesity (n = 9311) and six for psoriatic arthritis (n = 24 444). Obesity and female sex predicted treatment discontinuation, with HRs of 1.21 [95% confidence interval (CI) 1.10-1.32, I2 = 0%] and 1.22 (95% CI 1.07-1.38, I2 = 84%), respectively. Concomitant psoriatic arthritis predicted biologic persistence (HR 0.83, 95% CI 0.80-0.86, I2 = 0%). Female sex predicted biologic discontinuation due to side-effects, with a pooled HR of 2.16 (95% CI 1.39-3.35, I2 = 67%). Other reported predictive factors (smoking, metabolic syndrome, biologic naivety, age, Dermatology Life Quality Index, dyslipidaemia, high socioeconomic status and concomitant methotrexate) were insufficiently reported for meta-analysis. CONCLUSIONS: Our meta-analysis demonstrates that female sex and obesity predict biologic discontinuation, and concomitant psoriatic arthritis predicts biologic survival. What's already known about this topic? Ineffectiveness is the main factor that causes drug discontinuation during long-term treatment of psoriasis. It is unclear which factors and comorbidities impact drug persistence. What does this study add? Female sex and obesity predict biologic discontinuation due to ineffectiveness and adverse events. Concomitant psoriatic arthritis is associated with improved drug persistence.

Psoriasis and risk of myocardial infarction before and during an era with biological therapy: a population-based follow-up study.

BACKGROUND: Attention towards cardiovascular disease prevention in patients with moderate to severe psoriasis increased with the introduction of biological therapy. OBJECTIVE: To determine the risk of myocardial infarction (MI) following hospital-diagnosed psoriasis compared with the general population, in eras before and following the introduction of biological therapy. METHODS: We conducted a cohort study in Denmark utilising nationwide prospectively collected data from population-based registries. For the early era cohort, we identified subjects with first time hospital-diagnosed psoriasis between 1995 and 2002, and, for the late era cohort, those diagnosed between 2006 and 2013. Comparison cohorts from the general population were matched (10:1) on sex and birth year. All individuals were followed from date of psoriasis diagnosis (index date for matched controls) until incidence of MI, death, emigration or end of study (1 January 2002 for the early era cohort; 1 January 2013 for the late era cohort). We computed the cumulative MI incidence at 5 years of follow-up, and used Cox regression to compute HRs of MI comparing psoriasis subjects with general population subjects. RESULTS: For the early era, we identified 4302 psoriatic subjects and 43 791 general population subjects; and for the late era, 4577 psoriatic subjects (4% received biologic therapy) and 46 376 general population subjects. The cumulative incidence of MI among psoriatic subjects in the early era was 2.5% and it was 2.2% in the late era. The HRs comparing MI risk in the psoriasis and general population cohorts were 1.40 (95% CI: 1.09-1.80), for the early era, and 1.39 (95% CI: 1.10-1.75) for the late era, adjusting for educational level and use of cardiovascular drugs. CONCLUSION: The increased risk of MI among patients with hospital-diagnosed psoriasis, relative to the general population, remained unchanged during the initial years of increased attention towards cardiovascular disease prevention and availability of biologic therapy.

Long-term optimization of outcomes with flexible adalimumab dosing in patients with moderate to severe plaque psoriasis.

BACKGROUND: The recently updated dosing recommendation for adalimumab for moderate to severe plaque psoriasis states that patients with inadequate response to adalimumab every other week (EOW) after 16 weeks may benefit from an increase in dosing frequency to 40 mg every week (EW). OBJECTIVE: To determine the long-term efficacy of adalimumab in patients with psoriasis with flexibility to escalate and de-escalate between EOW and EW dosing. METHODS: Data from an open-label study in patients with psoriasis who had received adalimumab in phase 2/3 studies and their extensions were included. Patients initially received 40 mg adalimumab EOW for 24 weeks. From weeks 24-252, patients whose Psoriasis Area and Severity Index response was <50% (PASI 50) could have their dose-escalated to 40 mg EW and were re-evaluated at 6 and 12 weeks and then every 12 weeks thereafter. Patients who had their dose-escalated and achieved a PASI 75 response were de-escalated to EOW and could re-escalate to EW if response fell below PASI 50 again; no further de-escalation was allowed. Changes in PASI scores were reported at the last visit before dose escalation or de-escalation. RESULTS: By week 24, 64.1% of patients in the overall population (n = 1256) achieved ≥PASI 75 response, 40.3% ≥PASI 90 response and 21.7% PASI 100 response. Patients who had a

Safety, efficacy and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis.

BACKGROUND: Real-life data on newer biological and biosimilar agents for moderate-to-severe psoriasis are lacking. OBJECTIVES: To examine safety, efficacy and time to discontinuation (drug survival) of biologics (adalimumab, etanercept, infliximab, secukinumab and ustekinumab) and compare originators with biosimilars (i.e. Enbrel with Benepali, and Remicade with Remsima). METHODS: The DERMBIO registry contains data on all Danish patients with moderate-to-severe plaque psoriasis treated with biologics. We examined patients treated between 1 January 2007 and 31 March 2017. We used Kaplan-Meier survival curves and Cox regression to examine drug survival patterns. RESULTS: A total of 3495 treatment series (2161 patients) were included (adalimumab n = 1332; etanercept n = 579; infliximab n = 333; ustekinumab n = 1055 and secukinumab n = 196). Secukinumab had the highest number of PASI 100 (100% improvement from baseline Psoriasis Area and Severity Index) respondents, but also the lowest drug survival among all the biologics. Ustekinumab had the highest drug survival overall. There were no significant differences in discontinuation risk between originator and biosimilar versions of infliximab or etanercept. Treatment with higher than approved dosages was frequent for all drugs except for adalimumab and secukinumab. Adverse events (predominantly infections) were most frequent for secukinumab compared with the other agents. CONCLUSIONS: Ustekinumab was associated with the highest drug survival, and secukinumab with the lowest, although most patients on secukinumab were non-naïve. Switching from originator to biosimilar had no significant impact on drug survival, and the safety profiles were comparable. Adverse events occurred most frequently with secukinumab. Future studies are warranted to assess the long-term safety of novel biologics for psoriasis.

Associations between functional polymorphisms and response to biological treatment in Danish patients with psoriasis.

Biological agents including anti-tumor necrosis factor (anti-TNF; adalimumab, infliximab, etanercept) and anti-interleukin-12/13 (IL12/23; ustekinumab) are essential for treatment of patients with severe psoriasis. However, a significant proportion of the patients do not respond to a specific treatment. Pharmacogenetics might be a way to predict treatment response. Using a candidate gene approach, 62 mainly functional single-nucleotide polymorphisms (SNPs) in 44 different genes were evaluated in 478 Danish patients with psoriasis undergoing 376 series of anti-TNF treatment and 230 series of ustekinumab treatment. Associations between genetic variants and treatment outcomes (drug survival and Psoriasis Area Severity Index reduction) were assessed using logistic regression analyses (crude and adjusted for gender, age, psoriatic arthritis and previous treatment). After correction for multiple testing controlling the false discovery rate, six SNPs (IL1B (rs1143623, rs1143627), LY96 (rs11465996), TLR2 (rs11938228, rs4696480) and TLR9 (rs352139)) were associated with response to anti-TNF treatment and 4 SNPs (IL1B (rs1143623, rs1143627), TIRAP (rs8177374) and TLR5 (rs5744174)) were associated with response to ustekinumab treatment (q<0.20). The results suggest that genetic variants related to increased IL-1ß levels may be unfavorable when treating psoriasis with either anti-TNF or ustekinumab, whereas genetic variants related to high interferon-γ levels may be favorable when treating psoriasis with ustekinumab.

Effectiveness and safety of secukinumab in 69 patients with moderate to severe plaque psoriasis: A retrospective multicenter study.

Secukinumab (anti-IL17A) is effective as treatment for moderate to severe plaque psoriasis, but real-life data on effectiveness and safety lack. We aimed to present real-life data of all Danish patients treated with secukinumab (n = 69). At baseline, before initiation of treatment with secukinumab 300 mg (47.8%) or off-label treatment with secukinumab 150 mg (52.2%), the median PASI score was 7.1. A total of 66.7% (34/51) and 52.9% (27/51) of patients still on secukinumab at week 12 achieved a PASI (Psoriasis Area and Severity Index)-50 and PASI-75 of 66.7% and 52.9%, respectively. A total of 83.0% (44/53) and 60.4% (32/53) of the patients had a PASI-score < 5 and PASI-score < 2, respectively, after 12 weeks on treatment with secukinumab. A third of the patients had secukinumab discontinued due to limited clinical improvement or adverse events (n = 23) within a median of 92 days (interquartile range 51-212 days). Notably, the majority of the patients may represent a particularly difficult-to-treat group of patients, as 92.8% had been refractory to other biologic treatment. A total of 26.1% (n = 18) experienced adverse events. Secukinumab appears to be an effective treatment option with a favorable side effect profile in patients with plaque psoriasis who are refractory to or have side effects of traditional biologic drugs.

Characteristics of patients receiving ustekinumab compared with secukinumab for treatment of moderate-to-severe plaque psoriasis - nationwide results from the DERMBIO registry.

BACKGROUND: While safety and efficacy of ustekinumab and secukinumab, monoclonal antibodies approved for psoriasis, are described in clinical trials, data on their real-life application are lacking. OBJECTIVE: We compared the characteristics of patients initiating first-time treatment with secukinumab or ustekinumab. METHODS: All Danish patients with moderate-to-severe plaque psoriasis treated with biologics are recorded in the nationwide DERMBIO registry. We compared characteristics of patients starting first-time therapy with ustekinumab and secukinumab, respectively. RESULTS: We identified a total of 1037 and 142 first-time treatment series with ustekinumab and secukinumab. There was a male predominance in both groups, but patients initiating secukinumab were slightly older and with longer disease duration; in agreement with guidelines for biologic treatment in Denmark where ustekinumab has been first line for all with psoriasis without joint problems since 2012, and secukinumab first line for psoriasis with joint problems since July 2016. A total of (52.9% and 14.5%) patients receiving ustekinumab and secukinumab, respectively, were bio-naïve. The mean dermatology life quality index score was slightly higher for ustekinumab than secukinumab (11.6 vs. 10.0; P = 0.0769); the mean Psoriasis Area and Severity Index score were significantly higher (10.4 vs. 7.3; P < 0.0001) for ustekinumab. Prevalence of joint disease was markedly lover (22.7% vs. 44.4%) among patients receiving ustekinumab. CONCLUSIONS: We found significant differences in characteristics of patients starting therapy with ustekinumab and secukinumab in a real-life clinical setting. These findings may aid clinicians and researchers when interpreting efficacy data derived from clinical trials and biologic registries of patients with psoriasis.

A randomized, double-blind, placebo-controlled, dose-escalation first-in-man study (phase 0) to assess the safety and efficacy of topical cytosolic phospholipase A2 inhibitor, AVX001, in patients with mild to moderate plaque psoriasis.

BACKGROUND: Cytosolic phospholipase A2 (cPLA2α) is an enzyme suggested as a therapeutic target in inflammatory skin diseases. AVX001, a cPLA2α inhibitor, was investigated in a randomized, double-blind, placebo-controlled, split-design, first-in-man study in patients with mild to moderate psoriasis. OBJECTIVES: The primary objective was to evaluate cutaneous safety and tolerability of AVX001 in doses from 0.002% to 5.0%. Safety was assessed as local skin reaction adverse events (LSRAE) grades 3-4. The secondary objective was assessment of efficacy on modified PASI (mPASI) score compared with placebo. METHODS: Of 94 randomized men, 88 completed treatment with AVX001 and placebo. The treatment period was four weeks with two-week follow-up with assessment at screening, randomization and once weekly until study end. AVX001 and placebo were applied blinded at symmetrically affected areas once daily. RESULTS: AVX001 was safe with no grades 3-4 LSRAE. A 29% reduction in mPASI was seen at the 5% dose level at week four. Post hoc analysis of combined doses of 3% and 5% showed a clinical relevant effect with 31% reduction in mPASI (P = 0.058) and statically significant reduction of the infiltration (P = 0.036). The actively treated side showed improvement in mPASI score after one week of treatment, and the observed improvement continued throughout the four weeks of treatment. CONCLUSIONS: Treatment with AVX001 is well tolerated in doses up to 5%, and showed placebo-adjusted, clinical effects at a level of statistical significance. The improvement throughout the treatment period suggests that longer treatment could conceivably result in superior efficacy.

Ubiquitin-specific peptidase 2 as a potential link between microRNA-125b and psoriasis.

BACKGROUND: The extensive involvement of microRNA (miRNA) in the pathophysiology of psoriasis is well documented. However, in order for this information to be useful in therapeutic manipulation of miRNA levels, it is essential that detailed functional mechanisms are elucidated. miR-125b has previously been shown to be strongly associated with psoriasis, and presents as an obvious candidate for further investigation. OBJECTIVES: To elucidate the specific pathway and mechanism of interest in this association. METHODS: A three-step bioinformatical hypothesis-generation pipeline was performed to identify genes of interest. This pipeline was based on miR-125b binding, expression in psoriatic lesions and genome-wide association study-based evidence of involvement. The identified candidate gene was then carefully evaluated using luciferase binding assays, in vitro overexpression, small interfering RNA knock-down and downstream gene readouts. RESULTS: Based on our bioinformatical pipeline, ubiquitin-specific peptidase 2 was selected as a likely candidate for a mechanistic explanation for psoriasis association. After establishing a definite connection to miR-125b, we proceeded to show that modulation of nuclear factor kappa B-mediated inflammation is the likely mechanism through which this miRNA gene pair functioned. CONCLUSIONS: Shedding further light on the multifactorial causes of psoriasis is essential, if the goal is to progress towards finer control of therapeutic tools in disease management. Findings, such as the ones presented herein, are therefore necessary in order to achieve the future of personalized medicine.