Association of Clinical and Demographic Factors With the Severity of Palmoplantar Pustulosis.

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

Damaging alleles affecting multiple CARD14 domains are associated with palmoplantar pustulosis

No abstract available

Single-cell analysis implicates Th17-to-Th2 cell plasticity in the pathogenesis of palmoplantar pustulosis

Background Palmoplantar 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. Objective We sought to investigate the immune pathways that underlie the pathogenesis of PPP. Methods We 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 Results Bulk 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. Conclusions These 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. Clinical implications The simultaneous activation of Th17 and Th2 responses in PPP supports the therapeutic use of agents that inhibit multiple T-cell pathways

JUMPING TO CONCLUSIONS AND FACIAL EMOTION RECOGNITION IMPAIRMENT IN FIRST EPISODE PSYCHOSIS ACROSS EUROPE

Background Jumping 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. Methods Data 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. Results We 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). Discussion This 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

Single-cell analysis implicates Th17 to Th2 cell plasticity in the pathogenesis of palmoplantar pustulosis

Background: Palmoplantar 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. Objective: We sought to investigate the immune pathways that underlie the pathogenesis of PPP. Methods: We 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 Results: Bulk 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. Conclusions: These 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. Clinical implications: The simultaneous activation of Th17 and Th2 responses in PPP supports the therapeutic use of agents that inhibit multiple T-cell pathways

Association of clinical and demographic factors with the severity of Palmoplantar Pustulosis

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