Unmet Educational Needs and Clinical Practice Gaps in the Management of Generalized Pustular Psoriasis: Global Perspectives from the Front Line.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening, neutrophilic, autoinflammatory skin disease characterised by recurrent flares of generalised sterile pustules and associated systemic features. Inconsistent diagnostic criteria and a lack of approved therapies pose serious challenges to GPP management. Our objectives were to discuss the challenges encountered in the care of patients with GPP and identify healthcare provider (HCP) educational needs and clinical practice gaps in GPP management. METHODS: On 24 July 2020, 13 dermatologists from 10 countries (Brazil, Canada, China, Egypt, France, Germany, Japan, Malaysia, the UK and the USA) attended a workshop to share experiences in managing patients with GPP. Educational needs and clinical practice gaps grouped according to healthcare system level were discussed and ranked using interactive polling. RESULTS: Lack of experience of GPP among HCPs was identified as an important individual HCP-level clinical practice gap. Limited understanding of the presentation and pathogenesis of GPP among non-specialists means misdiagnosis is common, delaying referral and treatment. In countries where patients may present to general practitioners or emergency department HCPs, GPP is often mistaken for an infection. Among dermatologists who can accurately diagnose GPP, limited knowledge of treatments may necessitate referral to a colleague with more experience in GPP. At the organisational level, important needs identified were educating emergency department HCPs to recognise GPP as an autoinflammatory disease and improving communication, cooperation and definitions of roles within multidisciplinary teams supporting patients with GPP. At the regulatory level, robust clinical trial data, clear and consistent treatment guidelines and approved therapies were identified as high priorities. CONCLUSIONS: The educational imperative most consistently identified across the participating countries is for HCPs to understand that GPP can be life-threatening if appropriate treatment initiation is delayed, and to recognise when to refer patients to a colleague with more experience of GPP management.

The real world impact of adalimumab on quality of life and the physical and psychological effects of moderate-to-severe psoriasis: a UK prospective, multicenter, observational study.

Psoriasis can adversely affect quality of life (QoL) and emotional well-being. In this UK prospective observational study we evaluated the 'real-world' impact of adalimumab on QoL and the physical/psychological effects of moderate-to-severe psoriasis. Hundred and forty-three biologic-naïve patients with moderate-to-severe psoriasis, receiving adalimumab in clinical practice, were included. Patients completed a series of questionnaires at baseline (adalimumab initiation), 4 and 16-weeks and 6-months post-adalimumab initiation during routine visits. The main outcome measure was the proportion of Dermatology Life Quality Index (DLQI) 'responders' at 16 weeks, defined as ≥5 point reduction from baseline or DLQI = 0.90% (95% CI = 80.8%-94.6%) of evaluable patients were DLQI responders at 16-weeks. There were significant improvements at 16 weeks in patient-reported measures of QoL, mental and physical well-being, cutaneous body image, anxiety, depression and psoriasis severity, which were maintained at 6-months. Adalimumab treatment was associated with improvements in patients' QoL and psychological functioning, which occurred contemporaneously with improvements in cutaneous disease.

Severity and management of psoriasis within primary care.

BACKGROUND: Scottish Intercollegiate Guidelines Network and National Institute of Health and Care Excellence guidelines stress the importance of assessing patients with psoriasis for psoriatic arthritis, comorbidities associated with severe disease and quality of life (QoL). The purpose of the study was to evaluate the primary care management of psoriasis in relation to disease severity and QoL from a patient's perspective. METHODS: A cross-sectional survey of adults (≥18 years) with psoriasis managed in primary care was conducted in Scotland over 1-year (2012-2013). Patients with psoriasis were identified and invited to participate in the online/telephone survey. The questionnaires included; Dermatology Life Quality Index (DLQI), Self-Administered Psoriasis Area and Severity Index (SAPASI), Psoriasis Epidemiology Screening Tool (PEST). The primary outcome measure was DLQI. Secondary outcomes included; demographics; comorbidities; involvement of different body sites; SAPASI and PEST scores. Relationships between measures were analysed using univariate analysis. RESULTS: The mean age of patients (n = 905) was 54.5 years (SD = 16.1), 436 (48.2 %) were men, and median DLQI and SAPASI scores were 4.0 and 6.0, respectively. Current psoriasis treatments were topical only (587, 64.9 %), oral medications or phototherapy (122, 13.5 %), biologics (26, 3 %) and none (156, 17.2 %). Despite SIGN recommendations, 256 of 391 patients (65.5 %) with a DLQI >5 (at least a moderate effect on QoL) had not seen a specialist during the past year. According to PEST scores, 259 patients (28.6 %) had symptoms suggestive of psoriatic arthritis requiring rheumatology referral. CONCLUSION: National recommendations are not being fully implemented in primary care in patients with psoriasis or psoriatic arthritis.

Effectiveness of Subcutaneous Methotrexate in Chronic Plaque Psoriasis.

BACKGROUND: Oral methotrexate (MTX) has been a first line systemic agent in the treatment of chronic plaque psoriasis (CPP) for more than 50 years. Parenteral MTX, administered as a subcutaneous (SC) injection has gained favour in recent years. The effectiveness of SC MTX has been proven in rheumatological conditions but there has been no assessment of its role in CPP. METHODS: We retrospectively reviewed case notes of 85 patients prescribed SC MTX for psoriasis in three dermatology centres in the UK (Betsi Cadwaladr University Health Board, Western Infirmary, Glasgow, and Salford Royal NHS Foundation Trust). Audit department approval was sought and granted. RESULTS: A total of 85 patients (44 male; 41 female; age range 14 - 78 years, mean 44 years; 79 Caucasian, 6 Asian) with CPP were identified. The average duration of psoriasis was 19 years [range 3 - 60 years]. Co-morbidities included depression, diabetes mellitus, hypertension, epilepsy, obesity, ischaemic heart disease, and hyperlipidaemia; 29 patients had no associated co-morbidities. Psoriatic arthritis was noted in 18 patients. Previous treatments included phototherapy (both narrow band ultraviolet B [TLO1] and psoralen and ultraviolet A [PUVA])(n=60), oral MTX (n=82), ciclosporin (n=37), acitretin (n=19), fumaric acid esters (n=20), hydroxycarbamide (n=6), mycophenolate mofetil (n=2), and repeated in-patient admissions (n=2). Oral MTX was stopped due to nausea (n=43), ineffectiveness (n=13) or partial response (n=11), headache (n=3), increased liver enzymes (n=2), and lethargy (n=2). The median number of systemic agents used prior to SC MTX was 3 (mean 2.65, range 1 to 6 agents). The weekly dose of SC MTX varied between 7.5mg to 30 mg (mean 18.5mg, median 20mg) and had been used for 2 months to 67 months (mean 14 months; median 9 months). Folic acid supplementation was used in every patient. The patients were reviewed between 6 weeks to 3 months once treatment was fully established. Using a pre-determined "adjective list" (where specific adjectives were used to denote those who responded or did not respond to treatment), patients were classified as "responders" (n=59) or "non-responders" (n=26). CONCLUSION: This study suggests that SC MTX is an effective option in patients with CPP who have failed oral MTX and could be a worthwhile consideration prior to commencement of a biologic agent. Furthermore, the SC route may be a viable first choice of MTX administration. A randomised controlled trial comparing oral and SC MTX is required to validate these findings.

Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans.

Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression.

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻8 and two loci with a combined P < 5 × 10⁻7). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻6). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.

Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial.

OBJECTIVE: To compare the efficacy, tolerability, and cosmetic outcome of photodynamic therapy (PDT) using topical methyl aminolevulinate with cryotherapy or topical fluorouracil for treatment of squamous cell carcinoma in situ. DESIGN: Randomized, placebo-controlled study, with follow-up at 3 and 12 months after last treatment. SETTING: Forty outpatient dermatology centers in 11 European countries. PATIENTS: Random sample of 225 patients with histologically confirmed squamous cell carcinoma in situ (lesion size, 6-40 mm) and no evidence of progression. INTERVENTIONS: Treatment with PDT with methyl aminolevulinate (160 mg/g; n = 96) or matching placebo cream (n = 17), cryotherapy (n = 82), or topical fluorouracil (5% cream; n = 30). Methyl aminolevulinate or placebo cream was applied for 3 hours before illumination with broadband red light (75 J/cm2, 570-670 nm). Treatment was repeated 1 week later. Cryotherapy was performed with liquid nitrogen spray. Fluorouracil was applied for 4 weeks. Lesions with a partial response at 3 months were re-treated. MAIN OUTCOME MEASURES: Clinically verified complete response of lesions; blinded and on-site assessment of cosmetic outcome (4-point rating scale). RESULTS: At 12 months, the estimated sustained lesion complete response rate with methyl aminolevulinate PDT was superior to that with cryotherapy (80% vs 67%; odds ratio, 1.77; 95% confidence interval, 1.01-3.12; P = .047), and better than that with fluorouracil (80% vs 69%; odds ratio, 1.64; 95% confidence interval, 0.78-3.45; P = .19). Cosmetic outcome at 3 months was good or excellent in 94% of patients treated with methyl aminolevulinate PDT vs 66% with cryotherapy and 76% with fluorouracil, and was maintained at 12 months. CONCLUSION: Methyl aminolevulinate PDT is an effective treatment option for squamous cell carcinoma in situ, with excellent cosmesis.

Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis.

The PSORS1 locus in the major histocompatibility complex region is the major genetic determinant for psoriasis vulgaris. Within the PSORS1 region reside at least three potential candidate genes for psoriasis susceptibility. Specific allelic variants of the genes HLA-Cw*6, HCR*WWCC, and CDSN*5 are strongly associated with psoriasis vulgaris and are in strong linkage disequilibrium with each other. We have genotyped the three psoriasis vulgaris susceptibility alleles of the PSORS1 locus in two clinical variants of psoriasis (guttate psoriasis and palmoplantar pustulosis) to study whether PSORS1 is also involved in the pathogenesis of these variants. We also asked whether these two clinical subgroups could help us to distinguish the causative gene within the high-risk PSORS1 haplotype. The association of guttate psoriasis with the three PSORS1 susceptibility alleles was similar and even stronger than seen with psoriasis vulgaris. Palmoplantar pustulosis, however, did not show association with any of the three candidate genes at this locus. Finally, no correlation with the age of onset for disease was observed. Our results show conclusively that psoriasis vulgaris and guttate psoriasis have a similar genetic basis for their association to PSORS1, whereas palmoplantar pustulosis appears to be a distinct disorder.