Background: Psoriasis is a complex disease with a genetic component contributing to disease pathogenesis. Chronic plaque psoriasis can be dichotomised into two subtypes according to age of onset; type 1 (early-onset; <40 years) and type 2 (late-onset; ≥40 years). Despite clinical and biological differences between the two subtypes, the genetics underpinning late-onset psoriasis remains poorly characterised compared to early-onset psoriasis. Aims: The aim of this project was to identify genetic loci associated with late-onset psoriasis, to assess the overlap of loci with early-onset psoriasis and to elucidate the functional role of the identified variants. Methods: The study had three parts; the first was a candidate-gene association study of the IL1B gene. A total of 16 SNPs from the region were genotyped in 595 late-onset and 1,137 early-onset psoriasis samples and compared to 4,770 controls from the European population. The second was a large-scale study conducted in 543 late-onset psoriasis and 4,373 controls using the Immunochip array. The third was a functional study using bioinformatics data mining, chromatin immunoprecipitation and electrophoretic mobility shift assay techniques to analyse the role of a disease-associated variant at the biological level. Results: The candidate-gene study replicated a previously reported association at a promoter polymorphism, rs16944 (P<0.05), within the IL1B gene and discovered a novel association at a second variant, rs11687624 (P<3.12x10-3), in late-onset psoriasis. None of the variants analysed were significantly associated with early-onset psoriasis. Bioinformatic eQTL data suggests the two variants and their proxies are associated with the expression of IL1A, IL1B, IL38 and PAX8. The Immunochip study identified 6 non-HLA loci (P<2.3x10-5) previously associated with early-onset psoriasis to also be associated with late-onset psoriasis (IFIH1, IL12B, IL23A, IL23R, TRAF3IP2 and ZNF313). Conditional analysis of the MHC region also identified two loci (HLA-C and HLA-A). A novel locus, IL1R1, was associated with late-onset psoriasis, but not early-onset psoriasis. Bioinformatic data mining found no role for the IL1R1 variants as eQTLs and prioritised the IL1B variant rs2708914 for functional analysis. The transcription factor STAT3 was found to be enriched at rs2708914 in keratinocyte and CD8+ T-lymphocyte cell lines. Allele-specific binding could not be established. Conclusions: This project is the largest genetic study of late-onset psoriasis to date and provides evidence that it shares susceptibility loci with early-onset psoriasis as well as having specific susceptibility loci. These findings provide further evidence for the dichotomisation of chronic plaque psoriasis, firstly to facilitate better understanding of the pathogenesis of the two subtypes and secondly to enable tailored therapy to be developed. Both have potential benefits for patients in the future. The genetic and functional studies conducted have provided a platform from which further studies can be carried out.

People with psoriasis are known to engage in high levels of unhealthy lifestyle behaviours which may lead to poorer psoriasis outcomes and increase the risk of cardiovascular disease (CVD). Thus, helping individuals with psoriasis understand the link between behaviours and health risks, that is health risk communication, and direct support for lifestyle behaviour change (LBC) are important aspects in optimal management of psoriasis, a long-term inflammatory skin condition. There are two aspects of the literature that remain unclear. First, whether adequate support is given to patients to enable them to understand the links between lifestyle behaviours and health outcomes is part of psoriasis patient management strategies. Second, whether there is agreement around effective health risk communication techniques. This programme of research aimed to examine these gaps in the literature using four related studies. The first study used content analysis to examine general and dermatology-specific healthcare professionals’ core training competencies for evidence of skills relating to LBC. An important finding was the lack of explicit skills relating to LBC and changing understanding of health risks. There was little or no reference to recognised LBC techniques that could be used to support and facilitate LBC with patients. The second study used observational techniques to examine messages about the links between behaviour and health outcomes and LBC signposting (such as leaflets or posters about healthy living) for patients with psoriasis in primary and secondary care patient waiting areas. There was little evidence of psoriasis-specific information about healthy living. Generic information (not specifically about psoriasis) was often of poor quality and was poorly displayed, and did not conform to evidence-based recommendations for effective LBC signposting. The third study combined observational and qualitative techniques to examine how healthcare professionals communicate information about CVD risk to patients and the role of LBC in reducing risk in the context of primary care risk assessments with people with psoriasis. A key finding was that interpretation of risk information was not always linked to specific advice about how to modify each risk factor. Discussion was mostly instructional rather than a shared collaborative discussion about behaviour change and risk reductionThe fourth study used experimental methods to examine the effects of message framing theory as a health risk communication strategy on reported behavioural intentions (BIs) in people with psoriasis. An important finding was that for messages about psoriasis symptom reduction, gain-framed (positively-framed) messages were more effective in increasing BIs for alcohol reduction. Conversely, for messages about CVD risk reduction, loss-framed (negatively-framed) messages were more effective for increasing BIs to reduce alcohol consumption. The body of work presented in this thesis demonstrated that much needs to be done to increase the skill sets of healthcare professionals in order to help people with psoriasis recognise the specific links between their own health behaviours and health outcomes. In addition specific recommendations have been suggested as a way of improving risk communication strategies, such as using theory-based personally-relevant health information for people with psoriasis.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22150号 / 医博第4541号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 稲垣 暢也, 教授 杉田 昌彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Psoriasis is a chronic recurrent inflammatory disease. Genetic and immunological factors are involved in development of psoriasis. Psoriasis is associated with numerous comorbidities including metabolic syndrome (MetS). Adipocytokines produced by white adipose tissue may be involved in the pathogenesis of psoriasis. Adipocytokines could serve as a missing link in the association between psoriasis and obesity/MetS. The most important adipokines include adiponectin, leptin and resistin. Adiponectin is expressed by adipocytes and has a high anti- inflammatory potential. Leptin is a protein produced in adipose tissue and is an important part in regulating energy metabolism. It has a pro-inflammatory effect. Polypeptide resistin is produced by macrophages and monocytes of the visceral adipose tissue. It was named for its ability to induce insulin resistence. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is also product of macrophages, that can be served as a marker for cardiovascular risk. Increased smoking rates in patients with psoriasis is associated with their reduced quality of life. In addition, smoking of tobacco cigarettes is closely associated with MetS: smokers have an increased risk of MetS. Between psoriasis and smoking has also been demonstrated a direct link. Smoking is a well-recognized cause...

Background: Metronidazole (MTZ) is an anti-oxidant and anti-inflammatory agent with beneficial therapeutic properties. The hydrophilic nature of the molecule limits its penetration across the skin. Existing commercial formulations have limitations of inadequate drug concentration present at the target site, which requires frequent administration and poor patient compliance. Objective: The aim of the current study was to develop and evaluate water in oil microemulsion of Metronidazole with higher skin retention for the treatment of inflammatory skin disorders. Methods: Pseudo ternary phase diagrams were used in order to select the appropriate ratio of sur-factant and co-surfactant and identify the microemulsion area. The selected formulation consisted of Capmul MCM as oil, Tween 20 and Span 20 as surfactant and co-surfactant, respectively, and water. The formulation was characterized and evaluated for stability, Ex vivo permeation studies and in vivo anti-inflammatory effect (carrageenan induced rat paw edema, air pouch model), anti-p-soriatic activity (mouse-tail test). Results: The particle size analyses revealed the average diameter and polydispersity index of the selected formulation to be 16 nm and 0.373, respectively. The results of ex vivo permeation studies showed statistically higher mean cumulative amount of MTZ retained in rat skin from microemul-sion, i.e., 21.90 ± 1.92 µg/cm2, which was 6.65 times higher as compared to Marketed gel (Metro-gyl gel®) with 3.29 ± 0.11 µg/cm2 (p<0.05). The results of in vivo studies suggested the microemul-sion based formulation of MTZ to be similar in efficacy to Metrogyl gel®. Conclusion: Research suggests the efficacy of the developed MTZ loaded microemulsion in the treatment of chronic skin inflammatory disorders.

Publicación a texto completo no autorizada por el autor / Determina la frecuencia, y las características epidemiológicas y clínicas de la enfermedad cardiovascular (hipertensión arterial, enfermedad coronaria y enfermedad cerebrovascular) en pacientes con psoriasis del Hospital PNP Central Luis N. Sáenz durante el período 2006-2011. El estudio es descriptivo de tipo serie de casos retrospectivo. La población estuvo constituida por los pacientes que presentaron simultáneamente enfermedad cardiovascular y psoriasis atendidos en el Hospital Luis N. Sáenz en el período 2006-2011. No se realizó muestreo, se trabajó con la totalidad de la población por ser pequeña y accesible. Se incluyó en las enfermedades cardiovasculares a la hipertensión arterial, enfermedad coronaria isquémica y enfermedad cerebrovascular. Se obtuvo datos relacionados a la presencia de enfermedad cardiovascular así como la frecuencia, características clínicas y epidemiológicas. Se elaboró un instrumento de recolección de datos (Anexo 1) que incluyó datos de filiación, datos epidemiológicos, clínicos, de laboratorio. El instrumento fue validado mediante una prueba piloto. De un total de 8766 pacientes con psoriasis atendidos en el período 2006-2011, se documentó enfermedad cardiovascular en 69 (0.8%) los cuales fueron incluidos en el estudio; de ellos, el 81.2% correspondió al sexo masculino y el 18.8% al sexo femenino. La edad promedio de los pacientes con psoriasis y enfermedad cardiovascular fue de 65.2 ± 12.4 años (mediana 64 años), el grupo de edad más afectado se situó entre los 50 y 79 años que agrupó al 79.7%. La ocupación más frecuente fue la de policía en retiro (50.7%). El tiempo de enfermedad promedio para psoriasis fue de 13.9 ± 10.7 años (mediana 12 años). Las lesiones se presentaron con mayor frecuencia en el cuero cabelludo (37.7%), extremidades superiores (34.8%), extremidades inferiores (30.4%) y el 8.7% de los pacientes presentó artritis psoriática. El PASI promedio fue de 6.0 ± 5.5 (mediana 4.8). Al correlacionarse el PASI con otras variables se encontró que existió leve correlación con el tiempo de enfermedad de la psoriasis (r=0.339; p=0.008) y con el tiempo de enfermedad cardiovascular (r=0.298; p=0.026). / Trabajo académico

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21634号 / 医博第4440号 / 新制||医||1034(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 三森 経世, 教授 濵﨑 洋子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This study explores processes of identity construction among women who have skin conditions and body modifications. Analyzing seven semi-structured qualitative interviews, the author examines how individuals affected by skin conditions employ body modification practices to organize their identities and promote feelings of agency across both personal and social domains. Engaging a Bakhtinian dialogic lens, the author argues that body modification may operate as a de-stigmatization strategy that supports individuals with skin conditions in cultivating a sense of self-determination and bodily sovereignty. Shaped by grounded theory, this study’s findings trace relationships between body modification and the development of agentic identities among women with skin conditions. Confronted by medical, physical, and social disenfranchisement, women affected by skin conditions may implement body modification practices to navigate treatment, incorporate their conditions, and negotiate their relationships. The author additionally suggests implications for the application of body modification practices as somatic therapeutic modalities.

Psoriasis is an immune mediated inflammatory disease which affects 2-3% of the world’s population. Over the last decade, psoriasis has been acknowledged as an independent risk factor for atherosclerosis. The precise mechanism or mechanisms of the heightened risk is widely speculated. Endothelial cells and macrophages are central players in the immunopathological development of both diseases. Interleukin-36 cytokines (IL-36) have been heavily implicated in psoriasis immunopathology. Significant upregulation of epidermal IL-36 is a recognised characteristic of psoriatic skin inflammation. IL-36 induces inflammatory responses in dendritic cells, fibroblasts and epithelial cells. While vascular alterations are a hallmark of psoriatic lesions and dermal endothelial cells are well known to play a critical role in dermal inflammation, the effects of IL-36 on endothelial cells have not been defined. We report that endothelial cells including dermal microvascular cells express a functionally active IL-36 receptor. Adhesion molecules VCAM-1 and ICAM-1 are upregulated following IL-36γ stimulation, and this is reversed in the presence of the endogenous IL-36 receptor antagonist. IL-36γ-stimulated endothelial cells secrete the proinflammatory chemokines IL-8, CCL2 and CCL20. Chemotaxis assays showed increased migration of T-cells following IL-36γ stimulation of endothelial cells. Both resident and infiltrating inflammatory myeloid cells contribute to the immunopathology of psoriasis by promoting the IL-23/IL-17 axis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23, TNFα) and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. Furthermore, IL-36γ stimulated macrophages potently activated endothelial cells as illustrated by ICAM-1(CD54) upregulation, and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, monocytes isolated from psoriasis patients showed increased adherence to both the stimulated and unstimulated endothelium when compared to monocytes from healthy individuals. Collectively, these findings add to the growing evidence for IL-36γ having roles in psoriatic responses, by enhancing endothelium directed leukocyte infiltration into the skin and strengthening the IL-23/IL-17 pathway. Our findings also point to a cellular response which could potentially support cardiovascular comorbidities in psoriasis.

No description available.