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Background: Palmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. Although the disease can present with concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets., Objectives: We sought to identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis., Methods: We performed a genome-wide association meta-analysis of 3 North-European cohorts (n = 1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the association signals. We also undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP., Results: We found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive (P < 5 × 10 -6 ) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and T H 2-mediated diseases such as atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP., Conclusions: The first genome-wide association study of PPP points to a pathogenic role for deregulated T H 2 responses and cigarette smoking., Competing Interests: Disclosure statement This work was supported by NIHR BioResource Centre Maudsley, National Institute for Health Research Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London. We gratefully acknowledge capital equipment funding from the Maudsley Charity (grant no. 980) and Guy’s and St Thomas’s Charity (grant no. STR130505). The work was also supported by the NIHR Manchester Biomedical Research Centre (grant no. NIHR203308). The Trøndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The APRICOT trial was funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership (grant no. EME 13/50/17). This study was supported by Boehringer-Ingelheim and by the Psoriasis Association (grant nos. BSTOP50/5 and PhD studentship ST3/20 to A.H.C.). Z.Q.L. was supported by the Talent Development Fund of KK Women’s and Children’s Hospital, Singapore. N.J.R. is an NIHR Senior Investigator and is also supported by NIHR Newcastle Biomedical Research Centre, NIHR Newcastle In Vitro Diagnostics Co-operative, and NIHR Newcastle Patient Safety Research Collaboration. The views expressed are those of the author(s) and not necessarily those of the NHS, Department of Health, or King’s College London. None of the funders was involved in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Disclosure of potential conflict of interest: F. Capon has received grants and consultancy fees from Boehringer-Ingelheim. A. D. Burden has received consultancy fees from Boehringer-Ingelheim. C. E. M. Griffiths has received research grants and/or honoraria from AbbVie, Almirall, Anaptysbio, Boehringer-Ingelheim, Bristol Meyers Squibb, Evelo, GlaxoSmithKline, Inmagene, Janssen, Lilly, ONO Pharmaceuticals, Novartis, Pfizer, and UCB. P. Baum and S. Visvanathan are Boehringer-Ingelheim employees. S. Wahie has had nonfinancial support (sponsorship to attend dermatology conferences) from Janssen, AbbVie, Novartis, Almirall, and UCB. J. N. Barker declares paid activities as an advisor and speaker for AbbVie, Amgen, Boehringer-Ingelheim, Bristol Myers Squibb, Johnson & Johnson, Lilly, and Novartis. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Economic evidence for vitiligo treatments is absent., Objectives: To determine the cost-effectiveness of (i) handheld narrowband ultraviolet B (NB-UVB) and (ii) a combination of topical corticosteroid (TCS) and NB-UVB compared with TCS alone for localized vitiligo., Methods: Cost-effectiveness analysis alongside a pragmatic, three-arm, placebo-controlled randomized controlled trial with 9 months' treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB-UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost-utility analyses measured quality-adjusted life-years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015., Results: The mean ± SD cost per participant was £775 ± 83·7 for NB-UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188-235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB-UVB compared with TCS was £173 (95% confidence interval 151-196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment., Conclusions: Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB-UVB only. Combination treatment would be considered cost-effective if decision makers are willing to pay £1932 per additional treatment success., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Evidence for the effectiveness of vitiligo treatments is limited., Objectives: To determine the effectiveness of (i) handheld narrowband UVB (NB-UVB) and (ii) a combination of potent topical corticosteroid (TCS) and NB-UVB, compared with TCS alone, for localized vitiligo., Methods: A pragmatic, three-arm, placebo-controlled randomized controlled trial (9-month treatment, 12-month follow-up). Adults and children, recruited from secondary care and the community, aged ≥ 5 years and with active vitiligo affecting < 10% of skin, were randomized 1 : 1 : 1 to receive TCS (mometasone furoate 0·1% ointment + dummy NB-UVB), NB-UVB (NB-UVB + placebo TCS) or a combination (TCS + NB-UVB). TCS was applied once daily on alternating weeks; NB-UVB was administered on alternate days in escalating doses, adjusted for erythema. The primary outcome was treatment success at 9 months at a target patch assessed using the participant-reported Vitiligo Noticeability Scale, with multiple imputation for missing data. The trial was registered with number ISRCTN17160087 on 8 January 2015., Results: In total 517 participants were randomized to TCS (n = 173), NB-UVB (n = 169) and combination (n = 175). Primary outcome data were available for 370 (72%) participants. The proportions with target patch treatment success were 17% (TCS), 22% (NB-UVB) and 27% (combination). Combination treatment was superior to TCS: adjusted between-group difference 10·9% (95% confidence interval 1·0%-20·9%; P = 0·032; number needed to treat = 10). NB-UVB alone was not superior to TCS: adjusted between-group difference 5·2% (95% CI - 4·4% to 14·9%; P = 0·29; number needed to treat = 19). Participants using interventions with ≥ 75% expected adherence were more likely to achieve treatment success, but the effects were lost once treatment stopped. Localized grade 3 or 4 erythema was reported in 62 (12%) participants (including three with dummy light). Skin thinning was reported in 13 (2·5%) participants (including one with placebo ointment)., Conclusions: Combination treatment with home-based handheld NB-UVB plus TCS is likely to be superior to TCS alone for treatment of localized vitiligo. Combination treatment was relatively safe and well tolerated but was successful in only around one-quarter of participants., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Chronic urticaria (CU) is a skin condition characterized by repeated occurrence of itchy weals and/or angio-oedema for > 6 weeks., Aim: To provide data demonstrating the real-life burden of CU in the UK., Methods: This UK subset of the worldwide, prospective, noninterventional AWARE study included patients aged 18-75 years diagnosed with H1-antihistamine (H1-AH)-refractory chronic spontaneous urticaria (CSU) for > 2 months. Baseline characteristics, disease activity, treatments, comorbidities and healthcare resource use were documented. Quality of life (QoL), work productivity and activity impairment were assessed., Results: Baseline analysis included 252 UK patients. Mean age and body mass index were 45.0 years and 29.0 kg/m 2 , respectively. Most patients were female (77.8%) and had moderate/severe disease activity (mean Urticaria Activity Score over 7 days was 18.4) and a 'spontaneous' component to their CU (73.4% CSU; 24.6% CSU and chronic inducible urticaria). Common comorbidities included depression/anxiety (24.6%), asthma (23.8%) and allergic rhinitis (12.7%). A previous treatment was recorded for 57.9% of patients. Mean Dermatology Life Quality Index score was 9.5, and patients reported impairments in work productivity and activity. Healthcare resource use was high. Severity of CSU was associated with female sex, obesity, anxiety and diagnosis. Only 28.5% of patients completed all nine study visits, limiting analysis of long-term treatment patterns and disease impact., Conclusions: Adult H1-AH-refractory patients with CU in the UK reported high rates of healthcare resource use and impairment in QoL, work productivity and activity at baseline. The differing structures of UK healthcare may explain the high study discontinuation rates versus other countries., (© 2020 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Importance: Although palmoplantar pustulosis (PPP) can significantly impact quality of life, the factors underlying disease severity have not been studied., Objective: To examine the factors associated with PPP severity., Design, Setting, and Participants: An observational, cross-sectional study of 2 cohorts was conducted. A UK data set including 203 patients was obtained through the Anakinra in Pustular Psoriasis, Response in a Controlled Trial (2016-2019) and its sister research study Pustular Psoriasis, Elucidating Underlying Mechanisms (2016-2020). A Northern European cohort including 193 patients was independently ascertained by the European Rare and Severe Psoriasis Expert Network (2014-2017). Patients had been recruited in secondary or tertiary dermatology referral centers. All patients were of European descent. The PPP diagnosis was established by dermatologists, based on clinical examination and/or published consensus criteria. The present study was conducted from October 1, 2014, to March 15, 2020., Main Outcomes and Measures: Demographic characteristics, comorbidities, smoking status, Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI), measuring severity from 0 (no sign of disease) to 72 (very severe disease), or Physician Global Assessment (PGA), measuring severity as 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe)., Results: Among the 203 UK patients (43 men [21%], 160 women [79%]; median age at onset, 48 [interquartile range (IQR), 38-59] years), the PPPASI was inversely correlated with age of onset (r = -0.18, P = .01). Similarly, in the 159 Northern European patients who were eligible for inclusion in this analysis (25 men [16%], 134 women [84%]; median age at onset, 45 [IQR, 34-53.3] years), the median age at onset was lower in individuals with a moderate to severe PGA score (41 years [IQR, 30.5-52 years]) compared with those with a clear to mild PGA score (46.5 years [IQR, 35-55 years]) (P = .04). In the UK sample, the median PPPASI score was higher in women (9.6 [IQR, 3.0-16.2]) vs men (4.0 [IQR, 1.0-11.7]) (P = .01). Likewise, moderate to severe PPP was more prevalent among Northern European women (57 of 134 [43%]) compared with men (5 of 25 [20%]) (P = .03). In the UK cohort, the median PPPASI score was increased in current smokers (10.7 [IQR, 4.2-17.5]) compared with former smokers (7 [IQR, 2.0-14.4]) and nonsmokers (2.2 [IQR, 1-6]) (P = .003). Comparable differences were observed in the Northern European data set, as the prevalence of moderate to severe PPP was higher in former and current smokers (51 of 130 [39%]) compared with nonsmokers (6 of 24 [25%]) (P = .14)., Conclusions and Relevance: The findings of this study suggest that PPP severity is associated with early-onset disease, female sex, and smoking status. Thus, smoking cessation intervention might be beneficial.

Background: Systematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo., Objective: To explore the clinical effectiveness and cost-effectiveness of topical corticosteroid monotherapy compared with (1) hand-held narrowband ultraviolet B light monotherapy and (2) hand-held narrowband ultraviolet B light/topical corticosteroid combination treatment for localised vitiligo., Design: Pragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up., Setting: Sixteen UK hospitals - participants were recruited from primary and secondary care and the community., Participants: Adults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area., Interventions: Topical corticosteroids [mometasone furoate 0.1% (Elocon ® , Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) plus dummy narrowband ultraviolet B light]; narrowband ultraviolet B light (narrowband ultraviolet B light plus placebo topical corticosteroids); or combination (topical corticosteroids plus narrowband ultraviolet B light). Topical corticosteroids were applied once daily on alternate weeks and narrowband ultraviolet B light was administered every other day in escalating doses, with a dose adjustment for erythema. All treatments were home based., Main Outcome Measures: The primary outcome was self-assessed treatment success for a chosen target patch after 9 months of treatment ('a lot less noticeable' or 'no longer noticeable' on the Vitiligo Noticeability Scale). Secondary outcomes included blinded assessment of primary outcome and percentage repigmentation, onset and maintenance of treatment response, quality of life, side effects, treatment burden and cost-effectiveness (cost per additional successful treatment)., Results: In total, 517 participants were randomised (adults, n  = 398; and children, n  =  119; 52% male; 57% paler skin types I-III, 43% darker skin types IV-VI). At the end of 9 months of treatment, 370 (72%) participants provided primary outcome data. The median percentage of narrowband ultraviolet B light treatment-days (actual/allocated) was 81% for topical corticosteroids, 77% for narrowband ultraviolet B light and 74% for combination groups; and for ointment was 79% for topical corticosteroids, 83% for narrowband ultraviolet B light and 77% for combination. Target patch location was head and neck (31%), hands and feet (32%), and rest of the body (37%). Target patch treatment 'success' was 20 out of 119 (17%) for topical corticosteroids, 27 out of 123 (22%) for narrowband ultraviolet B light and 34 out of 128 (27%) for combination. Combination treatment was superior to topical corticosteroids (adjusted risk difference 10.9%, 95% confidence interval 1.0% to 20.9%; p  = 0.032; number needed to treat = 10). Narrowband ultraviolet B light was not superior to topical corticosteroids (adjusted risk difference 5.2%, 95% confidence interval -4.4% to 14.9%; p  = 0.290; number needed to treat = 19). The secondary outcomes supported the primary analysis. Quality of life did not differ between the groups. Participants who adhered to the interventions for > 75% of the expected treatment protocol were more likely to achieve treatment success. Over 40% of participants had lost treatment response after 1 year with no treatment. Grade 3 or 4 erythema was experienced by 62 participants (12%) (three of whom were using the dummy) and transient skin thinning by 13 participants (2.5%) (two of whom were using the placebo). We observed no serious adverse treatment effects. For combination treatment compared with topical corticosteroids, the unadjusted incremental cost-effectiveness ratio was £2328.56 (adjusted £1932) per additional successful treatment (from an NHS perspective)., Limitations: Relatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase., Conclusion: Hand-held narrowband ultraviolet B light plus topical corticosteroid combination treatment is superior to topical corticosteroids alone for treatment of localised vitiligo. Combination treatment was relatively safe and well tolerated, but was effective in around one-quarter of participants only. Whether or not combination treatment is cost-effective depends on how much decision-makers are willing to pay for the benefits observed., Future Work: Development and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed., Trial Registration: Current Controlled Trials ISRCTN17160087., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 64. See the NIHR Journals Library website for further project information.

We report results of the studies relating to improved stability (40 days) of small sized microbial fuel cell (MFC) fabricated using agarose embedded paper-based proton exchange membrane. A fermentative bacterium Providencia rettgeri was isolated from rotten potato slurry and identified by 16S rRNA sequencing. The electroactivity of the bacteria was monitored via chronoamperometric and cyclic voltammetric studies using a three-electrode system which indicated the presence of bacterial redox mediator. The Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF) and UV-Vis absorption spectroscopy provided the evidence that Providencia rettgeri synthesized folate (vitamin B 9 ) during fermentation that was found to act for the first time as a redox mediator in an MFC. The paper based designed MFC fed with Providencia rettgeri yielded open circuit voltage of 787.9 mV with power and current density of 5.02 W/m 3 and 11.26 A/m 3 , respectively when measured across 10 kΩ. The microbial re-chargeable battery comprising of an assembly of parallelly aligned four units of MFCs when connected in series (total 16 MFCs), generated 1.5 V that was used for powering a red-light emitting device (LED)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552&#95;1565del;c.1552&#95;1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10 -6 and p = 3.6 × 10 -5 , respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10 -10 . Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (E max ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes., (© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Importance: High-cost biologic therapies have transformed the management of immune-mediated inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by measurement of circulating drug levels has been shown to be effective in various settings. However, limited evidence exists for this approach with the interleukin 12 and interleukin 23 inhibitor ustekinumab., Objective: To evaluate clinical utility of therapeutic drug monitoring for ustekinumab in patients with psoriasis., Design, Setting, and Participants: A prospective observational cohort of 491 adults with psoriasis was recruited to the multicenter Biomarkers of Systemic Treatment Outcomes in Psoriasis study within the British Association of Dermatologists Biologic and Immunomodulators Register from June 2009 to December 2017; samples from some patients were taken between 2009 and 2011 as part of a pilot study with the same inclusion criteria., Exposure: Serum ustekinumab level measured at any point during the dosing cycle using an enzyme-linked immunosorbent assay., Main Outcomes and Measures: Disease activity measured using the Psoriasis Area and Severity Index (PASI) score. Treatment response outcomes were PASI75 (75% reduction in PASI score from baseline [primary outcome]), PASI90 (90% reduction of PASI score from baseline), and absolute PASI score of 1.5 or less., Results: A total of 491 patients (171 women and 320 men; mean [SD] age, 45.7 [12.8] years) had 1 or more serum samples (total, 853 samples obtained 0-56 weeks from start of treatment) and 1 or more PASI scores within the first year of treatment. Antidrug antibodies were detected in only 17 of 490 patients (3.5%). Early measured drug levels (1-12 weeks after starting treatment) were associated with PASI75 response 6 months after starting treatment (odds ratio, 1.38; 95% CI, 1.11-1.71) when adjusted for baseline PASI score, age, and ustekinumab dose. However, this finding was not consistent across the other PASI outcomes (PASI90 and PASI score of ≤1.5)., Conclusions and Relevance: This real-world study provides evidence that measurement of early serum ustekinumab levels could be useful to direct the treatment strategy for psoriasis. Adequate drug exposure early in the treatment cycle may be particularly important in determining clinical outcome.

Background: Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection could improve patient outcomes and treatment cost-effectiveness., Objective: We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti-TNF-α) and ustekinumab (anti-IL-12/23)., Methods: This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables., Results: HLA-C*06:02-negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio [OR], 2.95; P = 5.85 × 10 -7 ), and the difference was greater in HLA-C*06:02-negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10 -5 ). Biologic-naive patients who were HLA-C*06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 × 10 -4 ). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1., Conclusion: This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis., (Copyright © 2018. Published by Elsevier Inc.)

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.

Background: The term pustular psoriasis indicates a group of severe skin disorders characterized by eruptions of neutrophil-filled pustules. The disease, which often manifests with concurrent psoriasis vulgaris, can have an acute systemic (generalized pustular psoriasis [GPP]) or chronic localized (palmoplantar pustulosis [PPP] and acrodermatitis continua of Hallopeau [ACH]) presentation. Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations., Objective: We sought to characterize the clinical and genetic features of pustular psoriasis through the analysis of an extended patient cohort., Methods: We ascertained a data set of unprecedented size, including 863 unrelated patients (251 with GPP, 560 with PPP, 28 with ACH, and 24 with multiple diagnoses). We undertook mutation screening in 473 cases., Results: Psoriasis vulgaris concurrence was lowest in PPP (15.8% vs 54.4% in GPP and 46.2% in ACH, P < .0005 for both), whereas the mean age of onset was earliest in GPP (31.0 vs 43.7 years in PPP and 51.8 years in ACH, P < .0001 for both). The percentage of female patients was greater in PPP (77.0%) than in GPP (62.5%; P = 5.8 × 10 -5 ). The same applied to the prevalence of smokers (79.8% vs 28.3%, P < 10 -15 ). Although AP1S3 alleles had similar frequency (0.03-0.05) across disease subtypes, IL36RN mutations were less common in patients with PPP (0.03) than in those with GPP (0.19) and ACH (0.16; P = 1.9 × 10 -14 and .002, respectively). Importantly, IL36RN disease alleles had a dose-dependent effect on age of onset in all forms of pustular psoriasis (P = .003)., Conclusions: The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background Hydroxychloroquine (HCQ), a 4-aminoquinolone antimalarial, is regarded as the oral therapy of choice for cutaneous and systemic lupus erythematosus (SLE). It is also licensed for rheumatoid arthritis (RA). Studies of HCQ-treated patients with SLE or RA have demonstrated a positive correlation between whole-blood HCQ levels and clinical response. Such studies have involved measuring whole-blood concentrations at any given time point after HCQ ingestion assuming that steady-state concentrations would undergo limited fluctuation over a daily interval because HCQ has a long half-life. This approach might not sufficiently take into account the potential intra-patient variation in HCQ blood levels that can occur over a 24-hour period. Such variation, if significant, could affect the credibility of any concentration-response relationship provided from these previous studies. Objectives The objectives of this report are to: (a) investigate the intra-patient variation in HCQ whole-blood levels and (b) suggest an optimum time for sampling patients for future studies. Methods Six patients were recruited with cutaneous lupus erythematosus who had each been on HCQ 200 mg twice daily for at least six months, so that they were at steady-state. Each patient was fasted overnight and had standardized meals and dosing schedule. Whole blood was sampled at seven time points over 24 hours. Whole-blood HCQ levels were measured with high-performance liquid chromatography using gradient elution, fluorimetric detection and chloroquine as an internal standard. The assay had a mean inter- and intra-day coefficient of variation of 10% and 5% respectively and a limit of detection of 5ng/ml. Results HCQ levels appeared to follow a biphasic pattern over the sampling period. Maximum levels were noted a median of four hours (range 2-6) after ingestion. Median intra-patient variation between trough and peak levels, 'Cmax' ((peak - trough)/trough × 100%), was 27% (range 8-150%). Conclusions This study demonstrated that whole-blood HCQ levels vary 27% (median, range 8-150%) within an individual over a 12-hour period. Drug levels might differ between individuals because of multiple factors, including variable adherence to medication. Measuring HCQ levels for assessment of drug adherence could be valuable in the 'real-world' clinical setting. This could be assessed by taking a blood sample at any time following HCQ ingestion. If patients were found to have very low or undetectable levels of HCQ, non-adherence to HCQ should be suspected.

Background: Pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment., Objective: We sought to estimate the effectiveness of topical therapies in the treatment of patients with PG., Methods: This was a prospective cohort study of UK secondary care patients with a clinical diagnosis of PG that was suitable for topical treatment (recruited between July 2009 and June 2012). Participants received topical therapy after normal clinical practice (primarily topical corticosteroids [classes I-III] and tacrolimus 0.03% or 0.1%). The primary outcome was speed of healing at 6 weeks. Secondary outcomes included the following: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality of life; treatment failure; and recurrence., Results: Sixty-six patients (22-85 years of age) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28 of 66 (43.8%) ulcers healed by 6 months. The median time to healing was 145 days (95% confidence interval, 96 days to ∞). Initial ulcer size was a significant predictor of time to healing (hazard ratio, 0.94 [95% confidence interval, 0.88-1.00); P = .043). Four patients (15%) had a recurrence., Limitations: Our study did not include a randomized comparator., Conclusion: Topical therapy is potentially an effective first-line treatment for PG that avoids the possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Background: Polymorphic light eruption (PLE) is approximately four times more common in women than in men and often begins in young adult life. It is hypothesized that patients with PLE have an inherent resistance to UVL-induced immunosuppression, which is a physiological phenomenon in normal healthy individuals. Consequently, in PLE there is a delayed-type hypersensitivity reaction to a UVL-modified skin antigen, which results in an inflammatory reaction and a variable rash. The female hormone, 17β-oestradiol, has been shown to inhibit UVL-induced physiological suppression of contact hypersensitivity responses. This has been postulated to account for the female preponderance of PLE. If 17β-oestradiol plays a significant part in the disease, one might hypothesize that the severity of PLE might reduce in women after menopause., Objectives: To compare the severity of PLE in pre-menopausal women with that in post-menopausal women., Methods: Eighteen pre-menopausal and 18 post-menopausal women with PLE had their Polymorphic Light Eruption Severity Index (PLESI) scored by a single investigator., Results: Pre-menopausal women (mean age 40 years; range 25-50) had a mean PLESI of 54.8 (range 0-86, SD 20.2). Post-menopausal women (mean age 63 years; range 53-78) had a mean PLESI of 36.8 (range 0-74, SD 18.2). A significant difference in mean PLESI values between pre- and post-menopausal women was noted (18.0; 95% CI 4.9-31.0; P = 0.008). At the time of the study, three subjects in the pre-menopausal group and one subject in the post-menopausal group were on oestrogen preparations. Even after excluding the four patients on oral oestrogens, there remained a statistically significant difference in the mean PLESI scores between the pre-menopausal and post-menopausal groups (55.10 vs. 36.64; difference of 18.46, 95% CI: 4.0-32.91; P = 0.014)., Conclusions: The severity of PLE was significantly less in post-menopausal women as compared with pre-menopausal women., (© 2014 European Academy of Dermatology and Venereology.)

A 61-year-old man presented with erysipelas-like cutaneous leishmaniasis.

Background: The recommended first-line oral therapy for discoid lupus erythematosus (DLE) is the antimalarial hydroxychloroquine. To the best of our knowledge, there is no published information regarding the long-term (i.e. > 6 months) response of DLE to hydroxychloroquine in clinical practice., Objectives: To describe the long-term clinical response of DLE to hydroxychloroquine after 6 months of use., Methods: A multicentre retrospective cohort study was conducted in patients with DLE who had received treatment with hydroxychloroquine. All patients were recruited and interviewed by a single investigator and response to hydroxychloroquine assessed by the same individual through a retrospective review of case notes using a specified protocol., Results: A total of 200 patients with DLE were recruited (F:M = 4 : 1) with a median age at diagnosis of 40 years (range 16-81) and median follow-up of 8 years (range 0·5-37). An adequate clinical response to hydroxychloroquine was recorded in 91 patients (45·5%) but nonresponse occurred in 85 patients (42·5%). The remainder of patients either had partial response or withdrew from therapy due to toxicity or were unclassifiable. Importantly, of those individuals that did respond to hydroxychloroquine within the first 6 months of use, almost one in five eventually lost their response, despite continued administration, after a median interval of 2 years. These patients often regained disease control if treated with a combination of hydroxychloroquine and mepacrine. Of those that did not respond to hydroxychloroquine within the first 6 months of use, almost one in 10 became eventual responders either after continued administration for up to 2 years or when rechallenged on hydroxychloroquine. The remaining nonresponders relied frequently on oral corticosteroid., Conclusions: In this cohort of patients with DLE, long-term clinical response to hydroxychloroquine occurred in less than 50% of patients. Nonresponders to hydroxychloroquine frequently required oral steroid to achieve disease control. These findings merit further investigation through a multicentre prospective study using a validated disease activity measure., (© 2013 British Association of Dermatologists.)

The recommended systemic therapy of choice for discoid lupus erythematosus (DLE) is the 4-aminoquinolone antimalarial hydroxychloroquine. There is limited published information on the likelihood of clinical response and, in particular, what factors influence outcome. We conducted a multicenter observational and pharmacogenetic study of 200 patients with DLE treated with hydroxychloroquine. The primary outcome was clinical response to hydroxychloroquine. We investigated the effects of disease attributes and metabolizing cytochrome P450 (CYP) polymorphisms on clinical outcome. Although the majority of patients responded to hydroxychloroquine, a significant proportion (39%) either failed to respond or was intolerant of the drug. Cigarette smoking and CYP genotype did not have any significant influence on response to hydroxychloroquine. Moreover, multivariate analysis indicated that disseminated disease (odds ratio (OR): 0.21; 95% confidence interval (CI): 0.08-0.52; P<0.001) and concomitant systemic lupus erythematosus (SLE; OR: 0.06; 95% CI: 0.01-0.49; P = 0.009) were significantly associated with lack of response to hydroxychloroquine. These findings suggest that baseline lupus severity and SLE are predictors of response to hydroxychloroquine. A prospective study is now required to further investigate the relationship between disease activity and response to hydroxychloroquine. This will have the potential to further inform the clinical management of this disfiguring photosensitive disease.

Intravascular lymphoma (IVL) is a subset of extranodal non-Hodgkin lymphoma, with an estimated incidence of <1 case per million people. It is characterised by extensive proliferation of lymphoma cells within small to medium-sized blood vessels. Most IVLs are B-cell tumours. IVL can present primarily in any organ system, including the skin. The disease is often disseminated at diagnosis. The overall mortality rate is thought to be >80%, and >50% of patients are diagnosed at postmortem examination. There is wide variability in the clinical appearance of cutaneous lesions, which may simulate inflammatory skin disease. Therefore, awareness by dermatologists is important to enable early diagnosis when cutaneous signs are present. We report two patients with unexplained systemic disease and a skin eruption, leading to the diagnosis of IVL, and outline the range of cutaneous features reported., (© The Author(s). CED © 2010 British Association of Dermatologists.)

Background: Discoid lupus erythematosus (DLE) is a disfiguring inflammatory skin disease. There is no specific tool for measuring disease severity., Objectives: To determine the features needed in a score measuring activity and damage in DLE and to investigate the score's reliability and its correlation with the physician's global assessment of disease severity and the patient-reported Dermatology Quality of Life Index (DLQI)., Methods: The content of the score was determined following a peer review, pilot work in patients and a preliminary inter-rater reliability study. The Score of Activity and Damage in DLE (SADDLE) measures severity of activity (erythema, scale, induration) and damage (scarring/atrophy and dyspigmentation) attributable to DLE. Summed scores range between 0 and 195. Inter- and intrarater reliability of the score was tested using six assessors and nine patients with DLE. Intraclass correlation coefficients (ICCs) > 0.7 were considered evidence of good inter- and intrarater agreement., Results: The mean +/- SD SADDLE score of nine patients in the inter-rater reliability study was 47 +/- 22 (range 14-102). There was good inter-rater agreement for the total score [ICC 0.82; 95% confidence interval (CI) 0.61-0.95] and for the activity and damage scales, the individual physical signs and the total scores at individual body sites. The total score demonstrated excellent intrarater reliability (ICC 0.98; 95% CI 0.86-1.00). Although there was poor inter-rater agreement for global assessments (ICC 0.28; 95% CI 0.06-0.66), a good correlation was demonstrated between total scores and global assessments (r = 0.7). A weaker positive correlation was observed between disease activity scores and DLQI (r = 0.4)., Conclusions: The SADDLE measures activity and damage in patients with DLE. It demonstrates good inter- and excellent intrarater agreement, over and above that for global assessment. It correlates well with global assessment scores. Further studies are required to investigate SADDLE's responsiveness to change with therapy.

Background: Pityriasis lichenoides (PL) is a skin disease that affects both children and adults. Anecdotally, it is said to run a more benign course in children, with a frequent tendency to self-resolution. However, to our knowledge, there have been no published studies comparing PL in both age groups., Objective: To evaluate the clinicopathological features, overall efficacy of treatments and disease outcomes in children and adults diagnosed with PL., Methods: A retrospective review of records was undertaken on all patients diagnosed with PL at two regional centres during an 8-year period (from 1998 to 2006). For each individual, data were collected on age, sex, number of lesions, lesional morphology and distribution, symptoms, histopathological features, treatment modalities (and response), overall follow-up and length of remission., Results: We recorded 25 children (median age 8 years, range 2-18) and 32 adults (median age 40 years, range 20-65) with PL. All the children and adults had more than 20 scaly, papular lesions. Children had greater lesional body involvement than adults. Lesions on the legs and trunk were present in 23 children (92%) compared with 19 adults (59%) (P < 0.01) and facial involvement was observed more commonly in children (n = 10, 40%) compared with adults (n = 8, 25%). Dyspigmentation was significantly more common in children (n = 18, 72%) compared with adults (n = 6, 19%) (P < 0.001). Topical corticosteroids were used by 16 children (64%) and 18 adults (56%) but only half in each group found these effective. Eight children (32%) were treated with erythromycin, with only two (25%) clearing, and one of these subsequently relapsing. In contrast, four adults (13%) received antibiotics, with three (75%) clearing and none relapsing thereafter. Ultraviolet B phototherapy was used in eight children (32%), with seven (88%) completely or almost clearing, but four (57%) subsequently relapsed. Fourteen adults (44%) received phototherapy; 10 (71%) completely cleared and only two of these (20%) subsequently relapsed. Strikingly, after a median disease duration of 30 months, only five children (20%) went into complete remission compared with 25 adults (78%) (P < 0.001)., Conclusions: This is the first study to compare PL in children and adults. Our findings suggest that, compared with adults, PL in children is more likely to run an unremitting course, with greater lesional distribution, more dyspigmentation and a poorer response to conventional treatment modalities.

Objectives: To prospectively determine the wound complication rate for dermatology inpatients undergoing diagnostic skin biopsies during their admission and to determine significant host and procedural risk factors., Design: Prospective assessment, by a single observer, of 100 postdiagnostic skin biopsy wounds in dermatology inpatients. The following data were recorded for each patient: age and sex, presence of comorbidities, smoking status, dermatologic diagnosis, use of immunosuppressive or antibiotic therapy, place of biopsy (whether in the operation theater or in the ward), grade of physician performing biopsy, biopsy site on the body, type of biopsy (whether elliptical incision, punch, shave, or curettage), and wound closure technique., Main Outcome Measure: Wounds were designated as having had no complication or as being complicated by infection, dehiscence, and/or hematoma., Setting: A dedicated dermatology inpatient ward in a university teaching hospital., Results: Wound complications occurred in 29 (29%) biopsies, 27 (93%) of which were the result of wound infection. Complications occurred significantly more frequently when biopsies were performed below the waist compared with above the waist (P < .02), in the ward compared with the outpatient operating theater (P < .001), in smokers compared with nonsmokers (P < .001), and in those taking corticosteroids compared with those who were not (P < .001). In addition, elliptical incisional biopsies developed complications more frequently when subcutaneous sutures were not used compared with when they had been used (P < .001)., Conclusions: This study has demonstrated a high rate of wound complications after diagnostic dermatologic surgery on dermatology inpatients with significant host and procedural risk factors. These findings are relevant for other centers with inpatient units where diagnostic biopsies are performed.

Photocontact allergic reactions to sunscreen chemicals are investigated by photopatch testing. It has generally been assumed that for photocontact allergy to be shown, the putative pro-allergen must be in the skin at the time of ultraviolet A (UVA) exposure. However, this assumption has not, to our knowledge, been tested. The objective of this study was to determine whether positive photocontact responses can still be elicited when sunscreen chemicals are exposed to UVA prior to application onto the skin. 3 patients known to have positive photocontact reactions to a total of 6 sunscreen chemicals were studied. For conventional photopatch testing, patch test strips were applied onto the back and removed 1 D later, and the area was irradiated with UVA (5 J/cm(2)). For pre-irradiated testing, patches were exposed to the same dose of UVA immediately before application onto the back and then removed 1 D later. Skin responses were visually assessed by a blinded investigator 1 and 2 D after patch test removal. The same photocontact responses of the same magnitude, as previously documented for each patient, were seen at each of the conventional UVA-exposed patch test sites. However, in no patient was a positive response elicited at any of the sites where pre-irradiated patches had been applied. This study shows that positive photocontact responses to sunscreen chemicals do not occur when the putative pro-allergen is irradiated prior to application onto the skin. This suggests that for a photoallergic reaction to occur, the sunscreen chemical needs to be within the skin when activated by UVA.

Background: In Europe, where sunscreens are classified as cosmetics, products may contain one or several of 27 permitted 'ultraviolet filters'. We were unable to find published data on the frequency of usage of individual ultraviolet (UV)-absorbing chemicals in currently available sunscreens., Aim: To record the active ingredients and labelling characteristics of sunscreens available in the UK., Methods: In 2005, two dermatologists visited seven retail outlets, which stocked a large range of sunscreens. Manufacturers were also contacted. For each product, the names of UV-protective ingredients and the labelling information, including sun protection factor (SPF), UVA protection and age group for which the product was marketed were recorded., Results: Data on 308 skin sunscreen products and 21 lip sunscreens were recorded. For skin products, the SPF ranged from 2 to 60. In total, 23 different UV-absorbing ingredients were found, 4 of which were found in > 25% of products. The child and baby skin sunscreens (n = 52) had a significantly higher median SPF of 40, compared with 15 for the remaining 256 adult products (P < 0.001). The number of UV-absorbing chemicals and the frequency of those commonly used did not differ substantially between child and adult products. Of skin sunscreens marketed for babies, 60% contained 2-6 UV-absorbing chemicals. Nearly half of the skin sunscreens contained at least one of nine UV-absorbing chemicals not available in patch testing formulations from commercial suppliers., Conclusions: The results of this survey indicate current sunscreen content and labelling, and are a benchmark from which new developments can be tracked. More standard sunscreen labelling, particularly separate listing of active ingredients, would be helpful. It was surprising to find UV-absorbing chemicals in products sold for use on babies.

Background: Treatment options for moderate-to-severe atopic eczema are limited. Although methotrexate (MTX) is a widely used and effective treatment for psoriasis, there have been no previous prospective trials of its use in refractory atopic eczema, despite a few small, retrospective reports suggesting that it is a well-tolerated and effective treatment., Objectives: We have assessed the safety and efficacy of oral MTX in 12 adults with moderate-to-severe atopic eczema in an open-label, dose-ranging, prospective trial using objective outcome measures., Methods: All patients had previously received other second-line therapies and had disease only partially responsive to potent topical steroids and emollients. During the 24-week MTX treatment period, unrestricted use of standard topical therapy was permitted. We used an incremental MTX dose regime, starting at 10 mg per week (following a 5-mg test dose) and increasing by 2.5 mg weekly until response was achieved or treatment was limited by toxicity. Disease activity [six area six sign atopic dermatitis (SASSAD) score] was assessed every 4 weeks during treatment and 12 weeks after stopping MTX. The primary endpoint was 24-week change in disease activity., Results: On average, disease activity improved by 52% from baseline (95% confidence interval 45-60%). There were significant improvements in quality of life, body surface area affected and loss of sleep and itch scores. Global response was rated as 'marked improvement' in five of 12 and six of 12 patients, by investigators and patients, respectively. In all patients, the majority of improvement in disease activity was seen by week 12, and, interestingly, patients who had not responded well over this period despite reaching a dose of 15 mg weekly failed to improve with further dose escalation. Only one patient withdrew due to minor adverse effects. MTX was well tolerated by the remaining 11 patients, all of whom completed treatment, achieving a median dose of 15 mg weekly. Importantly, eight of nine patients had a persistent improvement 12 weeks after stopping MTX, with mean disease activity remaining 34% below baseline., Conclusions: We have shown that MTX is an effective, well-tolerated treatment for moderate-to-severe atopic eczema, and response appears to compare favourably with other second-line therapies. A randomized, controlled trial is now warranted.

We describe three patients who presented with a total of four episodes of an inflammatory dermatosis associated with alcohol abuse. In each case, the rash had similar characteristic features. The patients responded promptly to emollients and topical steroids but not to zinc replacement therapy. Other nutrient deficiencies were not identified. In addition, long-term remission seemed to be dependent on a reduction in alcohol consumption. We postulate that this is a separate cutaneous manifestation of chronic alcohol misuse and that this syndrome may be more common than previously thought.