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Summary: Background: 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. Objectives: To determine whether anakinra (an IL‐1 receptor antagonist) delivers therapeutic benefit in PPP. Methods: 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. Results: 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. Conclusions: No evidence for the superiority of anakinra was found. IL‐1 blockade is not a useful intervention for the treatment of PPP. What is already known about this topic?Treatment options for palmoplantar pustulosis include superpotent corticosteroids, phototherapy, acitretin, methotrexate and ciclosporin. However, these have poor evidence for benefit and there is a risk of toxicity with long‐term use.Anakinra is a recombinant interleukin (IL)‐1 receptor antagonist that blocks the activity of IL‐1α and IL‐1β, two cytokines repeatedly linked to neutrophil activation and extravasation.A therapeutic benefit of anakinra has been shown in neutrophilic dermatoses and conditions that manifest with skin pustulation. What does this study add?Anakinra was not significantly superior to placebo at 8 weeks in objective investigator‐assessed and patient‐reported measures.A greater proportion of participants in the anakinra group strongly agreed that the treatment was worthwhile.The safety profile of anakinra was consistent with previous studies.This is one of the largest randomized controlled trials for this rare condition, providing important data on its natural history and change in disease severity over time. Linked Comment: S.N. Lo and J.F. Thompson. Br J Dermatol 2022; 186:205–206. Plain language summary available online [ABSTRACT FROM AUTHOR]

Angiolymphoid hyperplasia with eosinophilia is a rare benign vascular lesion most commonly affecting the head and neck region. This article reports a case of a 26-year-old white woman with rapidly enlarging nodules of the upper lip and cheek treated successfully with oral corticosteroids and cetirizine. Morbidity and cosmetic deformity associated with radical surgery to the face and possible consequences of radiation treatment were avoided. There were no long-term complications. [ABSTRACT FROM AUTHOR]

Summary: Background: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. The multicentre prospective BLISTER (Bullous Pemphigoid Steroids and Tetracyclines) trial randomized 253 patients with BP to compare the benefits and harms between initial treatment with doxycycline or prednisolone. Objectives: To analyse distinct autoantibody profiles for the prediction of the disease course in a well‐characterized cohort of BP sera. Methods: One hundred and forty‐three patients of the BLISTER trial consented to participate in this serological study. Sera taken at baseline were analysed by (i) indirect immunofluorescence, (ii) anti‐BP180 NC16A (16th noncollagenous domain) and anti‐BP230 enzyme‐linked immunosorbent assay and (iii) immunoblotting with various substrates. Results were then linked with clinical parameters including age, Karnofsky score, number of blisters, related adverse events and mortality. Results: Disease activity correlated with immunoglobulin (Ig)G anti‐BP180 levels but not with levels of anti‐BP230 IgG and anti‐BP180 IgE. High levels of both anti‐BP180 IgG and anti‐BP230 IgG were associated with a low Karnofsky score. The presence of anti‐BP230 IgG was more frequent in older patients. Those with higher total IgE serum levels suffered from fewer adverse events. Higher IgG anti‐BP180 levels were associated with an increased 1‐year mortality rate. Conclusions: Analysis of the autoantibody profile is not only of diagnostic relevance but may also be helpful in predicting the course of the disease. What's already known about this topic? Serum levels of immunoglobulin (Ig)G autoantibodies against BP180 correlate with disease activity in bullous pemphigoid (BP).Reports about the correlation of serum anti‐BP180 IgE with disease severity are inconclusive.Karnofsky score is a predictor of death in BP but to date has not been shown to be related to serum autoantibody levels. What does this study add? High serum anti‐BP180 IgG levels are associated with an increased mortality in BP.Patients with BP with a lower Karnofsky score show higher serum levels of anti‐BP180 and anti‐BP230 IgG.High levels of total serum IgE appear to be related to a lower number of treatment‐related adverse events.Patients with BP with high anti‐BP180 IgG may be at risk of fatal outcomes, while in those with high total IgE, fewer adverse events can be expected. Linked Comment: Hashimoto and Tsuruta. Br J Dermatol 2018; 179:820–821. Plain language summary available online Respond to this article [ABSTRACT FROM AUTHOR]

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: Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs., Objectives: To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging., Methods: A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data., Results: PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six., Conclusions: Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2., (© 2020 British Association of Dermatologists.)

Background: Survival in mycosis fungoides (MF) is varied and may be poor. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) study is a web-based data collection system for early-stage MF with legal data-sharing agreements permitting international collaboration in a rare cancer with complex pathology. Clinicopathological data must be 100% complete and in-built intelligence in the database system ensures accurate staging., Objectives: To develop a prognostic index for MF., Methods: Predefined datasets for clinical, haematological, radiological, immunohistochemical, genotypic, treatment and quality of life are collected at first diagnosis of MF and annually to test against survival. Biobanked tissue samples are recorded within a Federated Biobank for translational studies., Results: In total, 430 patients were enrolled from 29 centres in 15 countries spanning five continents. Altogether, 348 were confirmed as having early-stage MF at central review. The majority had classical MF (81·6%) with a CD4 phenotype (88·2%). Folliculotropic MF was diagnosed in 17·8%. Most presented with stage I (IA: 49·4%; IB: 42·8%), but 7·8% presented with enlarged lymph nodes (stage IIA). A diagnostic delay between first symptom development and initial diagnosis was frequent [85·6%; median delay 36 months (interquartile range 12-90)]. This highlights the difficulties in accurate diagnosis, which includes lack of a singular diagnostic test for MF., Conclusions: This confirmed early-stage MF cohort is being followed-up to identify prognostic factors, which may allow better management and improve survival by identifying patients at risk of disease progression. This study design is a useful model for collaboration in other rare diseases, especially where pathological diagnosis can be complex., (© 2018 British Association of Dermatologists.)

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.

Mutations in the three genes (LAMA3, LAMB3, and LAMC2) that encode the three chains (alpha 3, beta 3, and gamma 2, respectively) of laminin 5, a protein involved in epidermal-dermal adhesion, have been established as the genetic basis for the inherited blistering skin disorder, Herlitz junctional epidermolysis bullosa (H-JEB). In this study, we performed mutational analysis on genomic DNA from a child with H-JEB and identified a nonsense mutation in the alpha 3 chain gene (LAMA3) consisting of a homozygous C-to-T transition resulting in a premature termination codon (CGA-->TGA) on both alleles. The parents were shown to be heterozygous carriers of the same mutation. Direct mutation analysis was used to perform DNA-based prenatal diagnosis from a chorionic villus biopsy at 10 weeks' gestation in a subsequent pregnancy. The fetus was predicted to be genotypically normal with respect to the LAMA3 mutation.

Objective: To determine whether there is a reduction in human forearm skin capillary density in essential hypertension., Subjects and Methods: We compared the number of capillary loops in the forearm skin of 12 patients with established, uncomplicated essential hypertension (mean blood pressure 180/109 mmHg) with that in carefully matched control subjects, using intravital capillaroscopy and fluorescein angiography., Results: There was a significant reduction in forearm skin capillary density in the hypertensive patients compared with the normotensive subjects. This represents a reduction by approximately 20% in capillary density. Capillary density was inversely correlated with blood pressure in the hypertensive patients alone (r = -0.4, P < 0.05) and in the whole group., Conclusion: The present study demonstrates a reduction in capillary density in the forearm of patients with essential hypertension. If this rarefaction in the forearm is also present in other vascular beds, it could result in an approximately 20% increase in peripheral resistance, which might play an important additional role in determining blood pressure.