A genome-wide meta-analysis of palmoplantar pustulosis implicates TH2 responses and cigarette smoking in disease pathogenesis.

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 TH2-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 TH2 responses and cigarette smoking.

Disease heterogeneity and molecular classification of inflammatory palmoplantar diseases.

BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non-pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE). OBJECTIVE: We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis. METHODS: We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples. RESULTS: Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell-associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity. CONCLUSION: A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.

Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis, Palmoplantar Pustulosis, and Neutrophilic Dermatoses: A GRAPPA 2023 Annual Meeting Update.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome and chronic nonbacterial osteomyelitis (CNO) are rare autoinflammatory/autoimmune conditions seen in adults and children. Although osteoarticular manifestations are the primary distinguishing features of SAPHO, over half of patients also have palmoplantar pustulosis (PPP). These and other associated disorders such as acne, inflammatory bowel disease, and hidradenitis suppurativa are characterized, at least in the early stages, by neutrophilic infiltration. The bone and skin manifestations exhibit both innate and adaptive immune responses and therefore share similar pathogenic molecules and overlapping treatment targets. At the Group for Research and Assessment for Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting, a 3-part presentation provided an overview of current efforts at establishing consensus on diagnosis/classification, treatment, and core outcome sets for SAPHO/CNO; an overview of PPP in SAPHO and as a standalone condition; and finally, an overview of the role of the neutrophil in these disorders.

Local injection of micro-dose guselkumab for palmoplantar pustulosis after partial failure of systemic ixekizumab treatment.

We present a palmoplantar pustulosis case partially resistant to systemic IL-17A inhibitor (ixekizumab) treatment, and then receiving a local injection of 0.1 mL micro-dose (1 mg) IL-23 inhibitor (guselkumab) every 4 weeks for four times. The paradoxical lesion disappeared rapidly following local injection and there was no recurrence after 8 weeks of drug withdrawal. This is the first clinical report on the treatment of palmoplantar pustulosis by local injection of micro-dose guselkumab.

Large language model may assist diagnosis of SAPHO syndrome by bone scintigraphy.

OBJECTIVE: In this study, we employed a large language model to evaluate the diagnostic efficacy of radiology reports of bone scintigraphy in the context of identifying SAPHO syndrome, and further examined the potential of such a model to augment the diagnostic procedure. METHODS: Imaging data and clinical information of 151 patients (105/46 women/men, mean age: 53.5 years) who underwent bone scintigraphy for suspected Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) syndrome between January 2007 and December 2022 were retrospectively reviewed. ChatGPT-4.0 was used as the large language model. The diagnostic performance of the large language model was verified by comparing the cases judged to have SAPHO syndrome that fulfilled Kahn's classification criteria based on a combination of concise radiology reports and skin lesions such as palmoplantar pustulosis, with cases diagnosed with SAPHO syndrome by rheumatologists based on all clinical information. RESULTS: The diagnostic accuracy of a large language model for analysing bone scintigraphy radiology reports in conjunction with information about skin symptoms, such as palmoplantar pustulosis, achieved a sensitivity of 83.5%, specificity of 69.4%, and an overall accuracy of 76.8%. CONCLUSION: This research indicates the prospective value of extensive language models in scrutinizing radiology accounts from bone scintigraphy for the diagnosis of SAPHO syndrome.

Modified pustulotic arthro-osteitis diagnostic guidance 2022 - Modified Sonozaki criteria - Secondary publication.

The concept of pustulotic arthro-osteitis (PAO) was first reported by Sonozaki et al. in 1979, with diagnostic criteria (Sonozaki criteria) proposed in 1981. These criteria have served as the gold standard for PAO diagnosis for over 40 years. In recent years, there has been an increasing emphasis on maximizing the quality of life of patients with PAO. This is achieved by striving for clinical remission, structural remission, and functional remission through early diagnosis and appropriate therapeutic intervention from an early stage. This article is an English translation of a summary of the 'Modified PAO Diagnostic Guidance 2022', edited by the Japan Ministry of Health, Labour and Welfare's Research Group on improvement of medical standard and quality of life of patients with spondyloarthritis and related diseases represented by ankylosing spondylitis and the Japan Spondyloarthritis Society. This guidance is intended to be helpful to both Japanese and global communities in rheumatology and spondyloarthritis.

Biologics as a novel treatment option for palmoplantar pustulosis: a comprehensive review.

Introduction: Palmoplantar pustulosis (PPP) is a complex inflammatory skin disease. Currently, no standardized treatments exist, and traditional systemic therapies often display limited effectiveness and substantial adverse effects. Biologics, however, have shown potential for enhanced clinical outcomes in psoriasis patients, thereby prompting this investigation into their applicability in PPP treatment. Aim: This study constitutes the first comprehensive review to assess the effectiveness and underlying mechanisms of biologics for PPP. Material and methods: We conducted a PubMed search to identify studies on biologics for PPP from 1992 onward. The review focused on assessing the efficacy of biologics targeting cytokines like IL-1, IL-8, IL-17, IL-12/23, IL-36, and TNF-α. Results: Biologics for PPP are generally less effective than for psoriasis. Secukinumab and guselkumab, IL-17 and IL-23 inhibitors respectively, have shown better results compared to other biologics in trials. However, the effectiveness of other biologics remains uncertain due to limited data. Conclusions: More research is needed to find effective treatments for PPP, and selecting the right biologic for each patient is challenging.

Local injection of micro-dose anti-interleukin-17A antibody for palmoplantar pustulosis: A real-world study.

Palmoplantar pustulosis (PPP), a chronic and stubborn skin disease, is mainly confined to the palms or/and soles, making it possible for localized use of therapeutic antibodies. In this real-world prospective cohort study, 8 patients with PPP received palms/soles injections of ixekizumab (0.8 mg in 0.1 ml) every 2 to 8 weeks due to the COVID-19 pandemic. The treatment endpoint was a 75% improvement from baseline in Palmoplantar Pustulosis/Psoriasis Area and Severity Index (PPPASI 75). At week 8, 75%, 50% and 12.5% of 8 patients reached PPPASI 50, PPPASI 75 and PPPASI 90. At week 12, 100%, 75% and 25% of 8 patients reached PPPASI 50, PPPASI 75 and PPPASI 90. This is the first study to evaluate the efficacy and safety of local injection of micro-dose ixekizumab for PPP in real clinical practice. A high proportion of patients rapidly achieved PPPASI 75, and maintained long-term efficacy with satisfactory safety.

Utility of nailfold capillary assessment for predicting pustulotic arthro-osteitis in palmoplantar pustulosis based on a prospective cohort study.

BACKGROUND: Pustulotic arthro-osteitis (PAO) is 1 of the most serious comorbidities associated with palmoplantar pustulosis (PPP). Risk factors of PAO development are not well-known. OBJECTIVE: To evaluate the clinical significance of nailfold capillary (NFC) changes in patients with PPP. METHODS: We conducted a prospective cohort study in a population of 102 PPP patients. Correlations of NFC abnormalities, including nailfold bleeding and enlarged capillaries, with the prevalence of PAO, the incidence of new PAO, and serum levels of cytokines were analyzed. RESULTS: Detailed examination revealed that of 102 PPP patients, 52 without PAO and 50 with PAO. Both nailfold bleeding and enlarged capillaries were significantly more frequent in patients with PAO (50.0% vs 92.0%, P < .0001; 50.0% vs 94.0%, P < .0001). In addition, PPP patients without PAO were prospectively observed before they developed PAO (mean 28 months [1-52 months]). Multivariate analysis suggested that these NFC abnormalities were predictors of PAO development (hazard ratio 3.37, 95% confidence interval 1.13-10.07; 3.37, 1.13-10.07) and guselkumab prevent PAO development (0.093, 0.012-0.76). The degree of NFC abnormalities correlated with the severity of PAO and serum cytokine levels. LIMITATIONS: All participants were Japanese. CONCLUSION: NFC abnormalities could be predictors of PAO in PPP patients, and their degree indicators of disease severity.

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 characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although 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 (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy RESULTS: Bulk RNA-Seq 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-Seq in peripheral blood mononuclear cells of healthy and affected individuals. Memory CD4+ T cells of PPP patients were skewed toward a TH17 phenotype, a phenomenon that was particularly significant among cutaneous lymphocyte-associated antigen-positive skin-homing cells. We also identified a subset of memory CD4+ T cells that expressed both TH17 (KLRB1/CD161) and TH2 (GATA3) markers, with pseudotime analysis suggesting that the population was the result of TH17 to TH2 plasticity. Interestingly, the GATA3+/CD161+ cells were overrepresented among the peripheral blood mononuclear cells of affected individuals, both in the single-cell RNA-Seq data set and in independent flow cytometry experiments. Dual-positive cells were also detected in patient skin by immune fluorescence microscopy. CONCLUSIONS: PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.

Pustular psoriasis: Molecular pathways and effects of spesolimab in generalized pustular psoriasis.

BACKGROUND: The IL-36 pathway plays a key role in the pathogenesis of generalized pustular psoriasis (GPP). In a proof-of-concept clinical trial, treatment with spesolimab, an anti-IL-36 receptor antibody, resulted in rapid skin and pustular clearance in patients presenting with GPP flares. OBJECTIVE: We sought to compare the molecular profiles of lesional and nonlesional skin from patients with GPP or palmoplantar pustulosis (PPP) with skin from healthy volunteers, and to investigate the molecular changes after spesolimab treatment in the skin and blood of patients with GPP flares. METHODS: Pre- and post-treatment skin and blood samples were collected from patients with GPP who participated in a single-arm, phase I study (n = 7). Skin biopsies from patients with PPP (n = 8) and healthy volunteers (n = 16) were obtained for comparison at baseline. Biomarkers were assessed by RNA-sequencing, histopathology, and immunohistochemistry. RESULTS: In GPP and PPP lesions, 1287 transcripts were commonly upregulated or downregulated. Selected transcripts from the IL-36 signaling pathway were upregulated in untreated GPP and PPP lesions. In patients with GPP, IL-36 pathway-related signatures, TH1/TH17 and innate inflammation signaling, neutrophilic mediators, and keratinocyte-driven inflammation pathways were downregulated by spesolimab as early as week 1. Spesolimab also decreased related serum biomarkers and cell populations in the skin lesions from patients with GPP, including CD3+ T, CD11c+, and IL-36γ+ cells and lipocalin-2-expressing cells. CONCLUSIONS: In patients with GPP, spesolimab showed rapid modulation of commonly dysregulated molecular pathways in GPP and PPP, which may be associated with improved clinical outcomes.

Involvement of Molecular Mechanisms between T/B Cells and IL-23: From Palmoplantar Pustulosis to Autoimmune Diseases.

Palmoplantar pustulosis (PPP) is a disease that causes recurrent blisters and aseptic pustules on the palms and soles. It has been suggested that both innate and acquired immunity are involved. In particular, based on the tonsils and basic experiments, it has been assumed that T and B cells are involved in its pathogenesis. In addition, the results of clinical trials have suggested that IL-23 is closely related to the pathogenesis. This review describes PPP and the genetic background, the factors involved in the onset and exacerbation of disease and its relation to the molecular mechanism. In addition, we describe the usefulness of biological therapy and its implications in relation to the importance in pathology, the pathogenesis of PPP, the importance of the role of the IL-23-Th17 axis and IL-36 in PPP. Furthermore, we describe an animal experimental model of PPP, the efficacy and mechanism of action of guselkumab, an anti-IL-23 antibody, the latest research, and finally the possibility for it to be effective for other autoimmune diseases.

A randomized prospective study of different dose regimens using the 308-nm excimer laser in the treatment of palmoplantar pustulosis.

The objective of this study was to evaluate optimal treatment regimen of 308-nm excimer laser for palmoplantar pustulosis (PPP). 77 patients with PPP were randomly assigned to receive low dose (2-fold of MED as initial dose), medium dose (4-fold of MED as initial dose) and high dose group (6-fold of MED as initial dose) and the MED of each patient depended on the ultraviolet light sensitivity of individual's skin which ranged from 0.1 to 0.25 J/cm2 . All group received 308-nm excimer laser treatment three times weekly for 8 weeks. Clinical evaluation based on the Palmoplantar Pustular Psoriasis Area and Severity Index (PP-PASI) and Dermatology Life Quality Index (DLQI) score. All treatment groups achieved satisfied efficacy at the end of the treatment period with more obvious reduction of PP-PASI score in high dose group (16.05 ± 4.26) than low and medium dose group (23.67 ± 7.16, p < 0.01; 22.04 ± 5.74, p < 0.01). Improvement of DLQI score was greatest at week 4 for all patients in each group, while DLQI improved more quickly in high/medium dose group than low dose group. Adverse effects of erythema, blistering and erosions were more common with the higher dose regimen. High dose of 308-nm excimer laser could achieve a better efficacy in PPP treatment, reduce the severity of the disease in patients and improve the life quality of patients. Meantime, the incidence of adverse reactions should be aware of and it's necessary to evaluate the skin and lesion type before the dose selection.

Safety and efficacy profile of oral cyclosporine vs oral methotrexate vs oral acitretin in palmoplantar psoriasis: A hospital based prospective investigator blind randomized controlled comparative study.

Palmoplantar psoriasis (PPP) is a variant of psoriasis which affects only 5% body surface area, but has a devastating impact on affected individual's quality of life. There are few studies assessing efficacy of individual drugs, and few comparative studies of efficacy of two drugs in the literature, however randomized control trial comparing all three drugs against each other has not been done. A total of 75 patients of PPP were enrolled for study and randomly divided into three groups A, B, C of 25 each and assigned for treatment with cyclosporine (CSA) (2.5-5 mg/kg/d), methotrexate (MTX)(7.5-15 mg/week), and acitretin (ACT) (25-50 mg/d), respectively. Modified psoriasis area and severity index (PASI), psoriasis severity scale, visual analogue scale, physician global assessment, and PPQOL were used for monitoring response to therapy and improvement in quality of life up to end of study, and thereafter monthly follow-up was done to find duration of remission for next 90 days. Side effects if any were recorded. There was a statistically significant difference in modified PASI for CSA, MTX, and ACT. The mean modified PASI at baseline was 12.8 ± 4.8 for CSA, 12.57 ± 3.8 for MTX, and 11.92 ± 3.28 for ACT (P = .75). Mean modified PASI reduced to 2.91 ± 1.8 for CSA, 6.57 ± 2.2 for MTX, and 4.7 ± 2.2 for ACT at week 5 (P = <.01). Mean modified PASI further reduced to 0.095 ± 0.35 for CSA, 2.12 ± 1.4 for MTX, and 0.78 ± 0.97 for ACT at end of study (P = <.01). However, average duration of remission was 9 weeks for ACT group, followed by 6.47 and 3 weeks for CSA and MTX group, respectively. Adverse events were comparatively more in ACT group as compared to MTX and CSA groups. PPP affects quality of life tremendously and warrants systemic treatment for the same. CSA provides fastest resolution of lesions and have highest efficacy. MTX and ACT have similar efficacy, but ACT provides longer duration of remission.

Dysbiosis of Oral Microbiota Associated with Palmoplantar Pustulosis.

BACKGROUND: Dysbiosis of oral microbiota is implicated not only in oral inflammatory lesions, but also in a variety of extraoral diseases. The etiology of palmoplantar pustulosis (PPP) remains unclear; however, it has been suggested that chronic inflammation caused by periodontopathic bacterial infection may play a role. OBJECTIVES/METHODS: To determine whether patients with PPP have altered diversity and composition of oral microbiota, we conducted the 16S rDNA analysis using saliva samples collected from 21 outpatients with PPP and 10 healthy individuals. RESULTS: We found that the proportion of bacteria in the phylum Proteobacteria was significantly lower in PPP patients (p = 0.025). At the genus level, patients with PPP had a significantly lower abundance of Neisseria (p = 0.014), which best accounted for the observed decrease in Proteobacteria. We also identified multiple minor genera and species that were represented at a significantly higher level in the PPP group, several of which have been associated with periodontal diseases. CONCLUSION: Our results suggest a possible link between PPP and dysbiosis of oral microbiota, particularly the lower abundance of Neisseria, the most predominant genus of Proteobacteria in healthy oral microbiota. Probiotics that improves oral dysbiosis may be beneficial for patients with PPP as an adjunctive therapy.

Molecular Aspects of Pruritus Pathogenesis in Psoriasis.

Psoriasis is a chronic, systemic inflammatory disease with a genetic background that involves almost 3% of the general population worldwide. Approximately, 70-90% of patients with psoriasis suffer from pruritus, an unpleasant sensation that provokes a desire to scratch. Despite the enormous progress in understanding the mechanisms that cause psoriasis, the pathogenesis of psoriasis-related pruritus still remains unclear. In order to improve patients' quality of life, development of more effective and safer antipruritic therapies is necessary. In turn to make it possible, better understanding of complexed and multifactorial pathogenesis of this symptom is needed. In this article we have systematized the current knowledge about pruritus origin in psoriasis.

Pustular Psoriasis and Associated Musculoskeletal Disorders.

Pustular psoriasis (PsO) is an uncommon variant of PsO that may present in a generalized or localized fashion with or without musculoskeletal or systemic inflammatory involvement.Generalized pustular PsO (GPP) presents as a widespread acute or subacute pustular eruption that may be familial and is often associated with severe flares and systemic inflammation. The palmoplantar pustulosis variant is localized to palms and soles, whereas acrodermatitis continua of Hallopeau is localized to the nail apparatus. Patients with pustular PsO may have overlapping plaque PsO and may develop psoriatic arthritis (PsA). Pustulosis is also a feature of both synovitis, acne, pustulosis, hyperostosis, osteomyelitis (SAPHO) syndrome and chronic non-bacterial osteomyelitis. At the 2020 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting, members were given an overview of the cutaneous features of pustular PsO, SAPHO, and recent insights into the genetics of GPP, leading to new targeted drug therapies and the development of validated endpoints.

Palmoplantar pustulosis treated with oral rinse using ozone nanobubble water: A case series.

Neither the etiology nor a reliable treatment for palmoplantar pustulosis has been clearly established. Ozone nanobubble (ONB) water, which is treated with nanosized ozone gas particles and has strong antimicrobial activity, has attracted attention as a future therapeutic option for palmoplantar pustulosis. Oral rinsing, particularly in the periodontal areas, with 10 to 20 mL ONB water for a couple of minutes per night, was prescribed to seven palmoplantar pustulosis patients, comprising five female and two male patients, for 6 months. Skin lesions were observed to be completely cured within a treatment period of approximately 3 to 4 months in six patients; the exception case was the one suspected of having pyorrhea. Rinsing the periodontal area with ONB water resulted in very effective suppression of skin lesions and showed promise as a new treatment method for palmoplantar pustulosis, which suggested the involvement of oral bacteria.

Pustular Psoriasis: The Dawn of a New Era.

Pustular psoriasis is a clinically heterogeneous entity of different, orphan disease subtypes, among which the most clearly defined are generalized pustular psoriasis, palmoplantar psoriasis, and acrodermatitis continua of Hallopeau. Although phenotypically and genetically distinct from psoriasis vulgaris, these subtypes may be associated with plaque psoriasis lesions, establishing the rationale for their inclusion in the psoriasis spectrum. Unlike psoriasis, however, their genetic background is thought to be mainly monogenic, as shown by the recent identification of mutations in 3 different genes of the skin innate immune system; IL36RN, CARD14 and AP1S3. These major advances in the understanding of the disease pathogenesis have led to the design and ongoing development of tailored therapeutic approaches, which are highly necessary given the refractory nature of pustular psoriasis in response to most available antipsoriatic drugs.

Clinical and genetic differences between pustular psoriasis subtypes.

BACKGROUND: The term pustular psoriasis indicates a group of severe skin disorders characterized by eruptions of neutrophil-filled pustules. The disease, which often manifests with concurrent psoriasis vulgaris, can have an acute systemic (generalized pustular psoriasis [GPP]) or chronic localized (palmoplantar pustulosis [PPP] and acrodermatitis continua of Hallopeau [ACH]) presentation. Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations. OBJECTIVE: We sought to characterize the clinical and genetic features of pustular psoriasis through the analysis of an extended patient cohort. METHODS: We ascertained a data set of unprecedented size, including 863 unrelated patients (251 with GPP, 560 with PPP, 28 with ACH, and 24 with multiple diagnoses). We undertook mutation screening in 473 cases. RESULTS: Psoriasis vulgaris concurrence was lowest in PPP (15.8% vs 54.4% in GPP and 46.2% in ACH, P < .0005 for both), whereas the mean age of onset was earliest in GPP (31.0 vs 43.7 years in PPP and 51.8 years in ACH, P < .0001 for both). The percentage of female patients was greater in PPP (77.0%) than in GPP (62.5%; P = 5.8 × 10-5). The same applied to the prevalence of smokers (79.8% vs 28.3%, P < 10-15). Although AP1S3 alleles had similar frequency (0.03-0.05) across disease subtypes, IL36RN mutations were less common in patients with PPP (0.03) than in those with GPP (0.19) and ACH (0.16; P = 1.9 × 10-14 and .002, respectively). Importantly, IL36RN disease alleles had a dose-dependent effect on age of onset in all forms of pustular psoriasis (P = .003). CONCLUSIONS: The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP.