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Background\ud\udPalmoplantar pustulosis (PPP) is a severe inflammatory skin disorder, characterised by eruptions of painful, neutrophil-filled pustules on the palms and soles. While PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat.\udObjective\ud\udWe sought to investigate the immune pathways that underlie the pathogenesis of PPP.\udMethods\ud\udWe applied bulk- and single-cell RNA-sequencing methods to the analysis of skin biopsies and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy\udResults\ud\udBulk RNA-sequencing of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several Th2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-sequencing in peripheral blood mononuclear cells of healthy and affected individuals. We found that the memory CD4+T-cells of PPP patients were skewed towards a Th17 phenotype, a phenomenon that was particularly significant among CLA+ skin-homing cells. We also identified a subset of memory CD4+ T-cells which expressed both Th17 (KLRB1/CD161) and Th2 (GATA3) markers, with pseudo-time analysis suggesting that the population was the result of Th17 to Th2 plasticity. Interestingly, the GATA3+/CD161+ cells were over-represented among the PBMCs of affected individuals, both in the scRNA-seq dataset and in independent flow-cytometry experiments. Dual positive cells were also detected in patient skin by means of immune fluorescence microscopy.\udConclusions\ud\udThese observations demonstrate that PPP is associated with complex T-cell activation patterns and may explain why biologics that target individual T-helper populations have shown limited therapeutic efficacy.\udClinical implications\ud\udThe simultaneous activation of Th17 and Th2 responses in PPP supports the therapeutic use of agents that inhibit multiple T-cell pathways.

Background COVID-19 vaccination is efficacious at protecting against severe COVID-19 outcomes in the general population. However, vaccine hesitancy (unwillingness for vaccination despite available vaccination services) threatens public health. Individuals taking immunosuppression for psoriasis have been prioritised for COVID-19 vaccination, however there is a paucity of information on vaccine hesitancy in this population, including contributing factors. While global healthcare has been severely disrupted in the pandemic, the impact on access to psoriasis care and whether this may negatively influence vaccine uptake, is underexplored.Objectives To explore organisational and individual factors associated with COVID-19 vaccine hesitancy in individuals with psoriasis.Methods Individuals with psoriasis, identified through global patient organisations and social media, completed a cross-sectional self-reported online survey. The primary outcome was COVID-19 vaccine hesitancy. Logistic regression was used to examine the association between predictor variables (organisational and individual factors) and outcome.Results Self-reported data from 802 individuals with psoriasis across 89 countries were available (65.6% female, median age 51 years [IQR 37-61], 43.7% taking systemic immunosuppression). Eight percent (n=63) reported vaccine hesitancy. Those reporting vaccine hesitancy were younger, more likely to be of non-white ethnicity, non-UK resident, have a lower BMI, not taking systemic immunosuppression and with shorter disease duration compared to those not reporting vaccine hesitancy. The commonest reasons for vaccine hesitancy were concerns regarding vaccine side-effects, that the vaccine is too new or that psoriasis may worsen post-vaccination. Forty percent (n=322) reported that their psoriasis care had been disrupted by the pandemic. These individuals were younger, of non-white ethnicity, with shorter duration and more severe psoriasis. Disruption to psoriasis care was associated with vaccine hesitancy (unadjusted OR 2.97 (95%CI 1.23-7.13), p=0.015), although not statistically significant in the adjusted model.Conclusion A minority of individuals with psoriasis from our study reported COVID-19 vaccine hesitancy. Similar to general population trends, vaccine hesitancy in our psoriasis sample is most common in younger age and ethnic minority groups. Our data highlight patient concerns regarding COVID-19 vaccination, which are important to address during patient-clinician interactions to help optimise vaccine uptake and mitigate risks from the ongoing pandemic in individuals with psoriasis.What’s already known about this topic?The COVID-19 vaccine is highly efficacious at protecting against severe COVID-19 outcomes in the general population. Vaccine hesitancy (unwillingness to receive vaccination despite available vaccination services) poses a major threat to global public health and is more common in women, younger age and ethnic minority groups in the general population.Individuals with psoriasis taking systemic immunosuppression were considered at high risk of severe COVID-19 outcomes and prioritised for vaccination, however there is a paucity of information on vaccine hesitancy in this group, including contributing factors.While global healthcare has been severely disrupted by the COVID-19 pandemic, access to psoriasis care and its potential impact on vaccine hesitancy is underexplored.What does this study add?A substantial proportion (40%) of individuals with psoriasis reported disrupted access to psoriasis care during the COVID-19 pandemic. Disrupted care was most commonly reported in younger age and ethnic minority groups.COVID-19 vaccine hesitancy was reported by a minority (8%) of individuals with psoriasis. Those reporting vaccine hesitancy were younger and more likely to be of non-white ethnicity, in keeping with trends in the general population.The commonest reasons for vaccine hesitancy were concerns regarding vaccine side effects, that the vaccine is too new or that psoriasis may worsen post-vaccination. These concerns are important to address during patient-clinician interactions to help mitigate risks from the ongoing pandemic in individuals with psoriasis.Competing Interest StatementNothing to disclose: Dr Bechman, Ms Cook, Dr Dand, Prof. Langan, Dr. Norton, Dr. Tsakok, Dr. Yiu, Dr De La Cruz, Dr. Contreras, Ms. Vesty, Ms. Vincent, Mr. Bola Coker, Ms. Meynell, Dr. Lambert, Prof. Brown, Prof. Naldi. Prof. Barker reports grants and personal fees from Abbvie, grants and personal fees from Novartis, grants and personal fees from Lilly, grants and personal fees from J&J, from null, during the conduct of the study. Prof. Griffiths reports grants and personal fees from AbbVie, grants from Amgen, grants from BMS, grants and personal fees from Janssen, grants from LEO, grants and personal fees from Novartis, grants from Pfizer, grants from Almirall, grants and personal fees from Lilly, grants and personal fees from UCB Pharma, outside the submitted work. Prof. Jullien reports personal fees and non-financial support from Abbvie, personal fees and non-financial support from Novartis, personal fees and non-financial support from Janssen-Cilag, personal fees and non-financial support from Lilly, personal fees and non-financial support from Leo-Pharma, personal fees and non-financial support from MEDAC, personal fees and non-financial support from Celgene, personal fees from Amgen, outside the submitted work. Dr. Capon reports consultancy fees from AnaptysBio, grants from Boheringer-Ingelheim, outside the submitted work. Prof. Bachelez reports personal fees from Abbvie, personal fees from Janssen, personal fees from LEO Pharma, personal fees from Novartis, personal fees from UCB, personal fees from Almirall, personal fees from Biocad, personal fees from Boehringer-Ingelheim, personal fees from Kyowa Kirin, personal fees from Pfizer, outside the submitted work. Prof. Gisondi reports personal fees from Abbvie, Amgen, Eli Lilly, Janssen, Novartis, Pierre Fabre, Sandoz, UCB, outside the submitted work. Dr. Galloway reports personal fees from Abbvie, personal fees from Sanofi, personal fees from Novartis, personal fees from Pfizer, grants from Eli Lilly, personal fees from Janssen, personal fees from UCB, outside the submitted work. Prof. Weinmann has presented talks for Abbvie, Abbott, Bayer, Chiesi, Boehringer Ingelheim, Roche and Merck. Dr. Mason reports personal fees from LEO Pharma and Novartis, outside the submitted work. Ms. Moorhead reports personal fees from Abbvie, personal fees from Celgene, personal fees from Janssen, personal fees from LEO Pharma, personal fees from Novartis, personal fees from UCB, outside the submitted work. Dr. Puig reports grants and personal fees from AbbVie, grants and personal fees from Almirall, grants and personal fees from Amgen, grants and personal fees from Boehringer Ingelheim, personal fees from Bristol Myers Squibb, personal fees from Fresenius-Kabi, grants and personal fees from Janssen, grants and personal fees from Lilly, personal fees from Mylan, grants and personal fees from Novartis, personal fees from Pfizer, personal fees from Sandoz, personal fees from Sanofi, personal fees from Samsung-Bioepis, grants and personal fees from UCB, outside the submitted work. Dr. Mahil reports departmental income from Abbvie, Almirall, Eli Lilly, Janssen-Cilag, Novartis, Sanofi, UCB, outside the submitted work. Dr. Di Meglio reports grants and personal fees from UCB, personal fees from Novartis, personal fees from Janssen, outside the submitted work. Prof. Warren reports grants and personal fees from Abbvie, grants and personal fees from Celgene, grants and personal fees from Eli Lilly, grants and personal fees from Novartis, personal fees from Sanofi, grants and personal fees from UCB|, grants and personal fees from Almirall, grants and personal fees from Amgen, grants and personal fees from Janssen, grants and personal fees from Leo, grants and personal fees from Pfizer, personal fees from Arena, personal fees from Avillion, personal fees from Bristol Myers Squibb, personal fees from Boehringer Ingelheim, outside the submitted work. Prof. Smith reports grants from Abbvie, Sanofi, Novartis, and Pfizer and through consortia with multiple academic partners (psort.org.uk, BIOMAP-IMI.eu), outside the submitted work. Dr. Torres reports grants and personal fees from AbbVie, Almirall, Amgen, Arena Pharmaceuticals, Biogen, Biocad, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, LEO Pharma, MSD, Novartis, Pfizer, Samsung-Bioepis, Sandoz, during the conduct of the study. Dr. Waweru is on the Board of the International Federation of Psoriasis Associations who have received grants from Abbvie, Almirall, Amgen, Bristol Meyers Squibb, Boehringer Ingelheim, Celgene, Janssen, Leo Pharma, Eli Lilly, Novartis, Sun Pharma, Pfizer, and UCB, outside the submitted work. Mr. Urmston reports grants from Almirall, grants from Abbvie, grants from Amgen, grants from Celgene, grants from Dermal Laboratories, grants from Eli Lilly, grants from Janssen, grants from LEO Pharma, grants from T and R Derma, grants from UCB, outside the submitted work. Ms. McAteer reports grants from Abbvie, grants from Almirall, grants from Amgen, grants from Celgene, grants from Dermal Laboratories, grants from Eli Lilly, grants from Janssen, grants from LEO Pharma, grants from UCB, grants from T and R Derma, outside the submitted work. Prof. Spuls has done consultancies in the past for Sanofi 111017 and AbbVie 041217 (unpaid), received a departmental independent research grant for TREAT NL registry LeoPharma December 2019; is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of diseases such as psoriasis and atopic dermatitis, for which financial compensation is paid to the department/hospital; and is chief investigator of the

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_1565del;c.1552_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.

SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents. (DOCX 42 kb)

Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that clinically visible sterile pustules develop. Because of clinical co-incidence, PP is currently grouped with psoriasis vulgaris (PV). However, PP and PV are phenotypically different, respond differently to treatments, and seem to be distinct on the genetic level. In contrast to PV, the phenotypes of PP are not well defined. Descriptions of each form of PP are discordant among standard dermatology textbooks [1-5], encumbering the collection of phenotypically well-matched groups of patients as well as clinical trials. The European Rare and Severe Psoriasis Expert Network (ERASPEN) was founded to define consensus criteria for diagnosis, deeply phenotype large groups of PP patients, analyse the genetics and pathophysiology and prepare for prospective clinical trials. This work reviews historical aspects of these conditions, new genetic findings and presents our initial considerations on the phenotypes of PP and a consensus classification of clinical phenotypes that will be used as a baseline for further, prospective studies of PP. Generalized Pustular Psoriasis (GPP) is defined as primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques). GPP can occur with or without systemic inflammation, with or without PV and can either be a relapsing (>1 episode) or persistent (> 3 months) condition. Acrodermatitis continua of Hallopeau (ACH) is characterized by primary, persistent (> 3 months), sterile, macroscopically visible pustules affecting the nail apparatus. Palmoplantar pustulosis (PPP) has primary, persistent (> 3 months), sterile, macroscopically visible pustules on palms and/or soles and can occur with or without PV.