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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We have identified peroxidase I as a causative allergen for wheat-dependent exerciseinduced anaphylaxis developed as pollen food allergy syndrome(PFAS-WDEIA) due to crossreaction between wheat proteins and grass pollen allergens. The purpose of this study is to establish peroxidase I-specific IgE test and test its sensitivity and specificity to identify PFAS-WDEIA. Serum were obtained from 6 patients with PFAS-WDEIA, 18 patients with conventional WDEIA, 11 patients with hydrolyzed wheat protein allergy, 11 patients with hay fever, and 22 patients with red meat/crustacean allergy. Peroxidase I was purified upon chromatography steps, and peroxidase I-specific IgE test was established by CAP-FEIA system. Wheat, gluten and omega-5 gliadin-specific IgE were determined by CAP-FEIA system. Positive of peroxidase I-specific IgE test were 3 of 6 PFAS-WDEIA patients, but none of 18 conventional WDEIA, 11 hydrolyzed wheat allergy, 11 hay fever, nor 22 red meat/crustacean allergy patients. Sensitivity of peroxidase I-specific IgE test was 50% and its specificity was 100%, whereas, sensitivity of wheat-specific IgE test was 83.3% and its specificity was 74.2%, sensitivity of gluten-specific IgE test was 50% and its specificity was 79%, and sensitivity of omega-5 gliadin-specific IgE test was 0% and its specificity was 77.4%. Wheat peroxidase Ispecific IgE test is useful to identify patients with wheat-dependent exercise-induced anaphylaxis developed by sensitization to grass pollen.

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole exome sequencing of 19 unrelated cases, we identified one affected individual harbouring a homozygous splice-site mutation (c.2031-2A>C) in MPO. The same homozygous change was subsequently identified in a further subject suffering from acral pustular psoriasis, a disease phenotypically related to GPP. MPO encodes myeloperoxidase, an essential component of neutrophil azurophil granules. Of interest, the c.2031-2A>C allele was previously described as a genetic determinant of myeloperoxidase deficiency (MPOD), a condition which can causes recurrent infections. Here, a systematic literature review identified four individuals suffering from MPOD and pustular skin disease, further strengthening the link between MPO and pustular inflammation. A subsequent analysis of the UK Biobank cohort demonstrated that the c.2031-2A>C allele was associated with increased neutrophil abundance in the general population (P=5.1x10-6). The same applied to three further MPOD mutations for which genotype data was available, with two alleles generating p-values <10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor reduced cell apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO mutations as genetic determinants 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.