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.

; for the ERASPEN consortium and the APRICOT and PLUM study team 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.

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BackgroundJumping to conclusions (JTC) is a well-established reasoning and data gathering bias found in patients with psychosis even at illness onset (First Episode Psychosis, FEP). Preliminary work in this field focused primarily on the association with delusions, although jumping to conclusions has also been found in non-deluded schizophrenia patients after remission, and in individual with at risk mental state.Moreover, psychotic patients tend to show impairments in social cognition, struggling in identifying, processing and interpreting social clues. Deficits in facial emotion recognition (FER) – a key component of the construct – represent a well-replicated finding in schizophrenia. Furthermore, deficits in global facial affect recognition have been found in FEP with the same severity as at further stages, especially for anger recognition. The present study aims to measure JTC and FER bias in a sample of FEP recruited across 5 European countries, compared with healthy controls.MethodsData on JTC (Beads task 60:40), FER (Degraded Facial Recognition task – DFAR) and socio-demographics have been analysed in a sample of 643 FEP and 1019 population controls recruited as part as the EU-GEI study across UK, Netherlands, France, Spain, and Italy.IQ scores were used to exclude cases and controls with current IQ<70 (N=171) from JTC analysis and a score <41 (N=384) on the Benton Facial Recognition test for the analysis on DFAR. Logistic regression model was applied to predict case/control status using 1) JTC and 2) DFAR as predictive variables controlling for age, gender and country.ResultsWe showed that the presence of JTC bias varies across different countries both in cases (χ2=23.77 p<0.001) and controls groups (χ2=14.01 p=0.007).Logistic regression analyses revealed JTC to be a significant predictor of case/control status (Adj OR=1.88 CI 95%=1.43–2.29 p<0.001).As well as JTC, FER differed over Europe in both groups (FEP, total: F=17.37, p<0.001; neutral: F=12.4, p<0.001; happy: F=25.62, p<0.001; frightened: F=8.78, p<0.001; angry: F=5.48, p<0.001. Controls, total: F=23.06, p<0.001; neutral: F=21.72, p<0.001; happy: F=21.74, p<0.001; frightened: F=14.14, p<0.001; angry: F=12.49, p<0.001).Logistic regression analyses revealed all DFAR scores, except for happy emotions, to be negatively associated with case/control status (total: B=-.0182 p=0.001; neutral: B=-.054 p=0.003; happy: B=-.0196 p=0.2; frightened: B= -.065 p<0.001; angry: B=-.030 p=0.04).DiscussionThis study supports the evidence that 1) FEP patients are more likely to present JTC and FER impairments than controls; 2) cognition and social cognition might represent transcultural features of psychotic disorders.