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Background:\ud Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1.\ud \ud Objectives:\ud To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP.\ud \ud Methods:\ud This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks.\ud \ud Results:\ud A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator’s global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [–1·65, 95% confidence interval (CI) –4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI –26·44 to 32·33; favouring anakinra), total pustule count (–30·08, 95% CI –83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was –3·80 (95% CI –10·76 to 3·16; P = 0·285). No serious adverse events occurred.\ud \ud Conclusions:\ud No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Background\ud The ‘treat to target’ paradigm improves outcomes and reduces costs in chronic disease management but is not yet established in psoriasis.\ud \ud Objectives\ud To identify treatment targets in psoriasis using two common measures of disease activity: Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA).\ud \ud Methods\ud Data from a multicentre longitudinal U.K. cohort of patients with psoriasis receiving systemic or biologic therapies (British Association of Dermatologists Biologics and Immunomodulators Register, BADBIR) were used to identify absolute PASI thresholds for 90% (PASI 90) and 75% (PASI 75) improvements in baseline disease activity, using receiver operating characteristic curves. The relationship between PGA (clear, almost clear, mild, moderate, moderate–severe, severe) and PASI (range 0–72) was described, and the concordance between absolute and relative definitions of response was determined. The same approach was used to establish treatment response and eligibility definitions based on PGA.\ud \ud Results\ud Data from 13 422 patients were available (58% male, 91% white ethnicity, mean age 44·9 years), including over 23 000 longitudinal PASI and PGA scores. An absolute PASI ≤ 2 was concordant with PASI 90 and an absolute PASI ≤ 4 was concordant with PASI 75 in 90% and 88% of cases, respectively. These findings were robust to subgroups of timing of assessment, baseline disease severity and treatment modality. PASI and PGA were strongly correlated (Spearman's rank correlation coefficient 0·92). The median PASI increased from 0 (interquartile range 0–0, range 0–23) to 19 (interquartile range 15–25, range 0–64) for PGA clear to severe, respectively. PGA clear/almost clear was concordant with PASI ≤ 2 in 90% of cases, and PGA moderate–severe severe was concordant with the National Institute for Health and Care Excellence PASI eligibility criteria for biologics in 81% of cases.\ud \ud Conclusions\ud An absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat‐to‐target management strategies in psoriasis.

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.

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.

Summary Background Patients with psoriasis and clinicians are concerned that infliximab may be associated with a risk of serious infections. Objectives To compare the risk of serious infections associated with infliximab in patients with chronic plaque psoriasis against a cohort on nonbiologic systemic therapies. Methods A prospective cohort study was performed using data from the British Association of Dermatologists Biologic Interventions Register (BADBIR). Infliximab was compared with nonbiologic systemic therapies, inclusive of any exposure to methotrexate, ciclosporin, acitretin, fumaric acid esters, psoralen‐ultraviolet A or hydroxycarbamide. Serious infections were those associated with hospitalization, the use of intravenous antimicrobial therapy and/or those that led to death. Propensity score inverse probability treatment weights were used to adjust for potential confounding from a priori identified covariates. Cox proportional hazards models were calculated to obtain hazard ratios (HRs). Results In total, 3843 participants were included for analysis up to October 2016. The incidence rates were significantly higher in the infliximab cohort (47·8 per 1000 person‐years) [95% confidence interval (CI) 35·7–64·0], compared with 14·2 per 1000 person‐years (95% CI 11·5–17·4) in the nonbiologic systemic cohort. Infliximab was associated with an overall increase in the risk of serious infection compared with nonbiologics [adjusted HR (adjHR) 1·95, 95% CI 1·01–3·75] and methotrexate only (adjHR 2·96, 95% CI 1·58–5·57) and a higher risk of serious infection in the first 6 months of therapy (adjHR 3·49, 95% CI 1·14–10·70). Conclusions Infliximab is associated with an increased risk of serious infections compared with nonbiologic systemic therapies in patients with psoriasis in the U.K. and the Republic of Ireland., What's already known about this topic? Randomized clinical trials are not sufficiently powered to investigate the risk of serious infection in patients with psoriasis who are undergoing treatment with infliximab.Published observational studies have used different methods to adjust for confounding and different comparators.Previous studies also lacked the adequate sample size to obtain a precise estimate of the risk of serious infection for infliximab. What does this study add? Using methods that better address bias and confounding, our study suggests that infliximab is associated with a higher risk of serious infections compared with nonbiologic systemic therapies in patients with psoriasis.Patients should be counselled on the risk of serious infection before infliximab is prescribed. Linked Comment: Puig. Br J Dermatol 2019; 180: 257–258. Plain language summary available online Respond to this article

Binary brush structures consisting of poly(cysteine methacrylate) (PCysMA) “corrals” enclosed within poly(oligoethylene glycol methyl ether methacrylate) (POEGMA) “walls” are fabricated simply and efficiently using a two-step photochemical process. First, the C–Cl bonds of 4-(chloromethyl)phenylsilane monolayers are selectively converted into carboxylic acid groups by patterned exposure to UV light through a mask and POEGMA is grown from unmodified chlorinated regions by surface-initiated atom-transfer radical polymerisation (ATRP). Incorporation of a ratiometric fluorescent pH indicator, Nile Blue 2-(methacryloyloxy)ethyl carbamate (NBC), into the polymer brushes facilitates assessment of local changes in pH using a confocal laser scanning microscope with spectral resolution capability. Moreover, the dye label acts as a radical spin trap, enabling removal of halogen end-groups from the brushes via in situ dye addition during the polymerisation process. Second, an initiator is attached to the carboxylic acid-functionalised regions formed by UV photolysis in the patterning step, enabling growth of PCysMA brushes by ATRP. Transfer of the system to THF, a poor solvent for PCysMA, causes collapse of the PCysMA brushes. At the interface between the collapsed brush and solvent, selective derivatisation of amine groups is achieved by reaction with excess glutaraldehyde, facilitating attachment of aminobutyl(nitrile triacetic acid) (NTA). The PCysMA brush collapse is reversed on transfer to water, leaving it fully expanded but only functionalized at the brush–water interface. Following complexation of NTA with Ni2+, attachment of histidine-tagged proteorhodopsin and lipid deposition, light-activated transport of protons into the brush structure is demonstrated by measuring the ratiometric response of NBC in the POEGMA walls.