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Background: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). Objective: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. Methods: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. Results: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. Conclusion: sThe identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN. What's already known about this topic? The genes IL36RN, CARD14 and AP1S3 have been implicated in pustular skin disease with IL36RN having a major role. Most studies have analysed variants in different genes separately. Significant subsets of patients with a pustular skin disease carry a single heterozygous mutation in IL36RN, leaving unanswered whether and how the variant is disease-contributing. What does this study add? Intragenic copy-number variants or noncoding mutations in carriers of single IL36RN mutations were not found. In total, 15% of patients with generalized pustular psoriasis (GPP) with IL36RN mutations carried variants in CARD14 or AP1S3, providing evidence for a complex inheritance. Lack of causal /disease-contributing variants in 64% of GPP patients suggests a role for other, not yet identified genes. Genotype-phenotype correlation did not reveal significant correlations aside from the presence of IL36RN mutations with age at onset. What is the translational message? This study of three genes provides evidence that the inheritance of GPP is more complex than previously understood. The role of known genes in GPP is rather limited, as almost two-thirds of patients do not carry a variant in any of these genes. In palmoplantar pustular psoriasis, the percentage of noncarriers is even lower. Further genetic studies will reveal the diseases' pathogenesis and provide a basis to use/develop more specific treatments. Linked Comment:Capon. Br J Dermatol 2018;178:589-590 Respond to this article

Background: Palmoplantar pustulosis (PPP) is arecalcitrant chronic inflammatory skin disease. Datarelevant for the medical care of patients with PPP arescarce. Thus, the aim of this work was to investigatethe disease burden, clinical characteristics, andcomorbidity of PPP patients in Germany. Patientsand Methods: PPP patients were examined in a crosssectionalstudy at seven specialized psoriasis centersin Germany. Results: Of the 172 included patients withPPP, 79.1% were female and 69.8% were smokers.In addition, 25.0% suffered from psoriasis vulgaris,28.2% had documented psoriatic arthritis, and 30.2%had a family history of psoriasis. In 77 patients themean Dermatology Life Quality Index (DLQI) was 12.2± 7.7 (mean ± SD). The mean Psoriasis PalmoplantarPustulosis Area and Severity Index (PPPASI) was 12.6 ±8.6. Mean body mass index was above average at 27.1± 5.5. The PPP patients had previously received anaverage of 2.6 ± 2.1 different anti-psoriatic systemicdrugs or UV-therapies. The systemic drugs that hadbeen used most frequently were corticosteroids in40.1% of patients, followed by acitretin (37.8%), andmethotrexate (27.9%). The PPPASI was 13.4 ± 8.9 inpatients without current systemic therapy and 10.4 ±7.9 in patients with systemic therapy. Conclusion: ManyPPP patients had a concomitant diagnosis of psoriasisvulgaris and/or psoriatic arthritis or had a familyhistory of psoriasis. Despite the fact that many of thepatients were using anti-psoriatic therapies, there wasstill a high burden of disease within this PPP cohort.This insufficient control of symptoms demonstratesthe urgent need for new PPP treatments.

Background: Psoriasis is one of the most common inflammatory skin disorders. There are only limited data on systemic treatment in children. Objective: To assess the safety and clinical efficacy of the treatment of six paediatric patients with fumaric acid esters (FAE, Fumaderm®) for psoriasis. Methods: Six patients aged 6-17 years were treated with FAE. Patients underwent regular assessment. Treatment efficacy was evaluated using the Psoriasis Area and Severity Index (PASI) and body surface area (BSA). Results: The mean duration of treatment was 17.8 months. PASI and BSA were determined after 12 weeks. All patients showed improvement in their skin condition, two achieving PASI75, one PASI90 and three PASI100 response. Proteinuria was encountered in one patient and two patients suffered from gastrointestinal discomfort. Treatment was discontinued due to remission in two patients. Conclusion: Treatment with FAE in paediatric patients is a valuable alternative option when systemic treatment is needed.

Liver cell transplantation (LCT) is a promising treatment approach for certain liver diseases, but clinical implementation requires methods for noninvasive follow-up. Labeling with superparamagnetic iron oxide particles can enable the detection of cells with magnetic resonance imaging (MRI). We investigated the feasibility of monitoring transplanted liver cells by MRI in a preclinical swine model and used this approach to evaluate different routes for cell application. Liver cells were isolated from landrace piglets and labeled with micron-sized iron oxide particles (MPIO) in adhesion. Labeled cells ( n = 10), native cells ( n = 3), or pure particles ( n = 4) were transplanted to minipigs via intraportal infusion into the liver, direct injection into the splenic parenchyma, or intra-arterial infusion to the spleen. Recipients were investigated by repeated 3.0 Tesla MRI and computed tomography angiography up to 8 weeks after transplantation. Labeling with MPIO, which are known to have a strong effect on the magnetic field, enabled noninvasive detection of cell aggregates by MRI. Following intraportal application, which is commonly applied for clinical LCT, MRI was able to visualize the microembolization of transplanted cells in the liver that were not detected by conventional imaging modalities. Cells directly injected into the spleen were retained, whereas cell infusions intra-arterially into the spleen led to translocation and engraftment of transplanted cells in the liver, with significantly fewer microembolisms compared to intraportal application. These findings demonstrate that MRI can be a valuable tool for noninvasive elucidation of cellular processes of LCT and—if clinically applicable MPIO are available—for monitoring of LCT under clinical conditions. Moreover, the results clarify mechanisms relevant for clinical practice of LCT, suggesting that the intra-arterial route to the spleen deserves further evaluation.

Antimicrobial peptides and proteins (AMP) are highly active molecules with a broad-spectrum of microbicidal activity. Human beta-defensins (hBD)-2 and hBD-3 were initially isolated from psoriatic-scale extracts, and other AMP have been identified in high concentrations in psoriatic skin explaining the uncommonness of skin infections in these patients. When a 71-year-old male patient suffering from a mild form of psoriasis (Psoriasis Area Severity Index PASI 4.4) presented a soft tissue infection (erysipelas) surrounding a psoriatic plaque of the elbow, we asked whether a local deficiency of AMP could be the reason for this infection. A detailed analysis of the expression and secretion levels of different classes of AMP was conducted. Induction of AMP was clearly shown by immunohistochemistry as well as by ELISA performed using skin-washing fluids. Therefore, other factors, for example deep penetrating injuries bypassing the keratinocyte innate defense system, must have caused the soft tissue infection.

The recognition of psoriasis as a systemic disorder with characteristic skin symptoms and associated diseases has changed treatment concepts substantially. The complexity of psoriasis disease not only requires appropriate therapy but also weight-loss and smoking cessation programmes as well as trigger factor elimination. The term 'management' may better reflect the aim for a holistic approach of disease control. Comorbidity and the presence of psoriatic arthritis are important denominators for drug selection. However, there is a lack of prospective data substantiating a benefit of associated diseases by antipsoriatic therapy. Securing success using treatment goals helps to establish an efficacious therapy and to control inflammation. A regular scoring of disease severity, patients' quality of life and assessment of other clinically relevant conditions are mandatory to closely follow the disease course. There is debate whether an early treatment may modulate the future course of psoriasis. Concepts of minimal disease activity have not been implemented in psoriasis yet. There is a lack of evidence how long any treatment should be given and when and how to terminate. Finally, outcome tools should specifically be tailored for psoriasis to evaluate disease-related items as well as the benefit of management from the patient's perspective.