The cellular microenvironment regulates CX3CR1 expression on CD8+ T cells and the maintenance of CX3CR1+ CD8+ T cells.

Expression levels of the chemokine receptor CX3CR1 serve as high-resolution marker delineating functionally distinct antigen-experienced T-cell states. The factors that influence CX3CR1 expression in T cells are, however, incompletely understood. Here, we show that in vitro priming of naïve CD8+ T cells failed to robustly induce CX3CR1, which highlights the shortcomings of in vitro priming settings in recapitulating in vivo T-cell differentiation. Nevertheless, in vivo generated memory CD8+ T cells maintained CX3CR1 expression during culture. This allowed us to investigate whether T-cell receptor ligation, cell death, and CX3CL1 binding influence CX3CR1 expression. T-cell receptor stimulation led to downregulation of CX3CR1. Without stimulation, CX3CR1+ CD8+ T cells had a selective survival disadvantage, which was enhanced by factors released from necrotic but not apoptotic cells. Exposure to CX3CL1 did not rescue their survival and resulted in a dose-dependent loss of CX3CR1 surface expression. At physiological concentrations of CX3CL1, CX3CR1 surface expression was only minimally reduced, which did not hamper the interpretability of T-cell differentiation states delineated by CX3CR1. Our data further support the broad utility of CX3CR1 surface levels as T-cell differentiation marker and identify factors that influence CX3CR1 expression and the maintenance of CX3CR1 expressing CD8+ T cells.

Psoriasis/Psoriatic Arthritis Patients' Long-term Treatment Patterns and Adherence to Systemic Treatments Monitoring Recommendations.

Limited information exists regarding treatment of patients with psoriasis/psoriatic arthritis in primary care. The aim of this study is to assess treatment patterns, adherence, persistence, and compliance in newly diagnosed patients with psoriasis/psoriatic arthritis from 2012 to 2018 in Stockholm, Sweden. In addition, laboratory monitoring before initiation of treatment and at recommended intervals was quantified for patients prescribed methotrexate or biologics. A total of 51,639 individuals were included, with 39% initiating treatment with topical corticosteroids and < 5% receiving systemic treatment within 6 months post-diagnosis. During a median (interquartile range) follow-up of 7 (4-8) years, 18% of patients received systemic treatments at some point. Overall, 5-year persistence rates were 32%, 45% and 19% for methotrexate, biologics, and other systemic treatments, respectively. Pre-initiation laboratory tests, as recommended by guidelines, were performed in approximately 70% and 62% of methotrexate and biologics users, respectively. Follow-up monitoring at recommended time intervals occurred in 14-20% and 31-33% of patients prescribed methotrexate and biologics, respectively. These findings highlight gaps in the pharmacological care of patients with psoriasis/psoriatic arthritis, including suboptimal adherence/persistence and inadequate laboratory monitoring.

Clinical characterisation at onset of childhood psoriasis - a cross sectional study in Sweden.

Epidemiological data in childhood psoriasis are accumulating. However, reliable information captured at onset is lacking. In a cross sectional study we recruited 109 children < 16 years within 12 months of psoriasis onset and explored the clinical characteristics. Pre-pubertal children, especially boys, more often had inverse involvement (OR = 2.8, 95% CI = 1.1, 7.1, p ≤ 0.05). HLA-C*06 was positively associated with facial lesions (OR = 3.8, 95% CI = 1.5, 9.7, p < 0.01) and guttate phenotype and was more common in pubertal children. A high PASI score was not associated with overweight or early age at onset, and gender did not influence disease onset. Psoriasis can be difficult to diagnose in children, especially in pre-pubertals. Thorough examination of facial and genital areas can help in establishing the diagnosis. Our published genetic data in combination with the clinical findings presented herein indicate that puberty may separate different populations of childhood psoriasis.

[Structured and regular workplace-based assessment and feedback of clinical competence for residents in dermatology]. / Strukturerad återkoppling på ST-läkares kliniska färdigheter.

Workplace-based assessment of clinical competence is essential as an educational tool for residents. The residents in dermatology and venereology at Södersjukhuset, Sweden, reported lack of feedback in an evaluation 2014. Therefore, a project to enhance the use of formative assessment methods was launched in 2018. All dermatologists were educated in formative assessment methods and feedback, certain clinical skills which should be assessed during the education was established, and a requirement to perform at least six formative assessments each year of residency was introduced. After two years, all residents had participated in a median of 7 (range 3-21) formative assessments the past year and reported regular use of assessment tools for clinical skills, good access to clinical teachers, and frequent feedback.

Occurrence of adverse events associated with the initiation of methotrexate and biologics for the treatment of psoriasis in routine clinical practice.

Background: Limited information exists on the risk of adverse events (AEs) attributed to methotrexate (MTX) and biologics for the treatment of psoriasis/psoriatic arthritis (PsA/PsO) in heterogeneous clinical practice and beyond the duration of clinical trials.Methods: An observational study of 6294 adults with incident PsA/PsO who initiated MTX or biologics in Stockholm from 2006-2021 was conducted. The risk of kidney, liver, hematological, serious infectious, and major gastrointestinal AEs was quantified and compared between therapies using incidence rates, absolute risks, and adjusted hazard ratios (HRs) from propensity-score weighted Cox regression.Results: Median follow-up was 4.3 (2-7) years. Users of MTX had a higher risk of anemia (HR 1.79 [95% CI, 1.48-2.16]), particularly mild-moderate anemias (1.93;1.49-2.50), and mild (1.46;1.03-2.06) and moderate-severe liver AEs (2.22;1.19-4.15) compared to biologics. Chronic kidney disease incidence did not differ between therapies (affecting 1.5% of the population in 5 years; HR:1.03;0.48-2.22). Acute kidney injury, serious infections, and major gastrointestinal AEs showed low absolute risks and no clinically meaningful differences between both therapies.Conclusion: The use of MTX for psoriasis patients in routine care was associated with a higher risk of anemia and liver AEs than biologics, but similar risks of kidney, serious infections, and major gastrointestinal AEs.

IL-22 Downregulates Peptidylarginine Deiminase-1 in Human Keratinocytes: Adding Another Piece to the IL-22 Puzzle in Epidermal Barrier Formation.

Increased presence of IL-22+ cells in the skin is a characteristic finding in skin barrier defects, such as psoriasis and atopic dermatitis. However, mechanistic insight into effects of IL-22 on epidermal functioning is yet to be elucidated. One crucial step during epidermal differentiation is deimination or citrullination. Here, we show reduced levels of peptidylarginine deiminase 1, an enzyme that converts peptidylarginine into citrulline in lesional psoriatic skin. IL-22 signaling through the IL-22 receptor complex was found to suppress expression of peptidylarginine deiminase 1 in epidermal keratinocytes. Subsequently, total peptidylarginine deiminase activity and extent of protein deimination in keratinocytes treated with IL-22 were reduced together with a significant decrease in deimination of keratin 1 and FLG, both important for epidermal differentiation. Vitamin D and acitretin partly restored the peptidylarginine deiminase 1 defect caused by IL-22. Collectively, we show that IL-22 downregulates deimination, thus identifying a potential target for treatment of skin barrier defects.

Antiviral therapy in children with hydroa vacciniforme.

Hydroa vacciniforme is a rare, usually quite severe, photo-dermatosis. Association with Epstein-Barr virus infection and a possibly increased risk of lymphoproliferative malignancy have been demonstrated. We describe here four patients with Epstein-Barr virus-associated hydroa vacciniforme treated with acyclovir/valacyclovir therapy with a good clinical response. The children were reported to have less fatigue, fewer eruptions, less scarring, and increased ability to spend time outdoors without provoking new eruptions. This was also in agreement with clinical observations. However, one patient progressed into an anaplastic lymphoma kinase-1-negative anaplastic large-cell lymphoma in the upper jaw. This was preceded by an increase in EBV viral load. Acyclovir/valacyclovir therapy is a safe treatment. Further studies are required to confirm these results.

[Psoriasis in childhood and adolescence]. / Psoriasis med debut i barndom och ungdom - Risken för samsjuklighet och påverkan på livskvaliteten måste uppmärksammas.

Psoriasis in childhood and adolescence Psoriasis is a common inflammatory disease affecting 2-3% of the worldwide population. Onset in childhood and adolescence is not uncommon and around 30% of patients report onset before 20 years of age. Childhood psoriasis has been shown to differ in clinical presentation and in underlying genetics compared to adult psoriasis patients. To diagnose psoriasis in children with mild skin involvement may be difficult and the correct diagnosis is often delayed in children compared to adult psoriasis patients. Differential diagnoses include eczema, tinea and pityriasis rubra pilaris (PRP). Topical therapy is often effective but UV-therapy and systemic therapy is sometimes indicated.

Association with Genetic Variants in the IL-23 and NF-κB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease.

Psoriasis is clinically heterogeneous, and symptoms can vary from mild almost cosmetic symptoms to severe disease requiring systemic therapy. Biomarkers predicting disease development are lacking. Herein we explored the genetic background in two polarized cohorts of carefully phenotyped patients with long-term follow-up: consistent mild phenotype (n=696) and severe disease course requiring systemic therapy (n=715). All patients were treated at the same dermatology department ensuring homogenous assessment. Genotyping included known psoriasis-associated variants, with special focus on the IL-23 and NF-κB pathways. A case-case study comparing severe and mild psoriasis phenotypes, controlling for age at disease onset and gender, revealed significant differences between the two groups for SNPs in IL23R, NFKB1, IL21, IL12B, NFKBIL1 and IL23A. HLA-C*06 associated equally in the mild and severe disease cohorts. Strong additive effects when combining HLA-C*06 with IL23A, IL23R, IL12B, NFKB1 or TNIP1 were restricted to the severe cohort, indicating that activation of these pathways may influence disease severity in psoriasis. No protective gene was identified in the mild cohort, suggesting that current screens have primarily identified psoriasis variants associated with a more severe phenotype. These results demonstrate the importance of careful phenotyping and long-term clinical follow-up in genetic studies.

Genetic variants of the IL22 promoter associate to onset of psoriasis before puberty and increased IL-22 production in T cells.

Most psoriasis susceptibility genes were identified in cohorts of mixed clinical phenotypes and the exploration of genes in clinical subtypes is scarce. IL-22 has an established role in host defense and in psoriasis skin pathology, reflecting the delicate balance between control of infection and immunopathology. In a case-control study, we compared the genetic association to IL22 in psoriasis onset in patients between 0-9 (n=207), 10-20 (n=394), and 21-40 (n=468) years with healthy controls (n=1,529). Logistic regression analysis revealed association to regulatory elements in the IL22 promoter confined to onset of psoriasis before puberty (odds ratio=1.45, P<0.0007). The associated variants contain putative binding sites for AhR, a potent inducer of IL-22 expression. In a luciferase assay, transcriptional activity of a high-risk gene variant resulted in 80% higher promoter activity (P=0.012) compared with a low-risk variant. Ex vivo stimulated T cells from peripheral blood were analyzed with flow cytometry. Children with psoriasis carrying a high-risk variant produced 1.7 times more IL-22 compared with low-risk variants (P=0.042). Our combined genetic and functional data support the notion that a genetic IL22 variant that promotes epithelial barrier defense is preferentially enriched in and may precipitate the onset of psoriasis at an early age.

Genetic association with ERAP1 in psoriasis is confined to disease onset after puberty and not dependent on HLA-C*06.

HLA-C remains the strongest susceptibility candidate gene in psoriasis. Evidence for interaction between HLA-C and endoplasmic reticulum aminopeptidase 1 (ERAP1) confined to individuals carrying the HLA-C risk allele was recently reported. Psoriasis displays wide variation, and genetic heterogeneity is likely to contribute to clinical diversity. Age at disease onset is a putative discriminator, and separating psoriasis into early- (<40 years) and late-onset disease has been useful. To sharpen the age-dependent phenotype, we compared genotypes for ERAP1 (rs26653, rs30187, and rs27524) and HLA-C*06:02 in healthy controls and cases stratified for onset of psoriasis at <10, 10-20, 20-40, and >40 years of age. This approach revealed that association with ERAP1 was confined to cases with onset between 10 and 20 years (odds ratio 1.59, 95% confidence interval: 1.28-1.98, P=0.00008) and no association was detected in cases with onset below 10 years, reflecting genetic heterogeneity within the childhood psoriasis population. In contrast to earlier findings, association with ERAP1 was neither dependent on nor interacting with HLA-C*06:02. ERAP1 single-nucleotide polymorphism rs26653, which, to our knowledge, has not previously been reported in psoriasis, is nonsynonymous, has suggestive functional consequences, and herein displays strong association with disease.