Le PAF (Platelet-Activating Factor) est un médiateur reconnu pour son implication dans plusieurs effets physiologiques et pathologiques, particulièrement les états inflammatoires. À l'instar du PAF, les lymphocytes T Th17 sont aussi reconnus comme exerçant un rôle majeur dans la physiopathologie des maladies auto-immunes. L'objectif de ce projet est de déterminer s'il existe un lien entre ces deux composants. En fait, nous avons émis l'hypothèse que le PAF pourrait provoquer une production de cytokines spécifiques par les cellules présentatrices d'antigène qui elles, interagissant avec les lymphocytes T, pourraient mener ultimement à une différentiation en Th17. En effet, les cellules T ne peuvent interagir directement avec le PAF puisqu'elles n'expriment pas de récepteur pour celui-ci à leur surface. Les cellules T Th17 expriment un facteur de transcription spécifique RORr, nécessitent absolument la sous-unité IL-23p19 pour leur expansion et produisent IL-17. Nous avons donc, dans un premier temps, regardé la capacité d'un type de cellules présentatrices d'antigène, les cellules de Langerhans à produire IL-23p19 en réponse au PAF. Ensuite, nous avons mis en contact ces cellules de Langerhans pré-stimulées au PAF avec des lymphocytes T activés pendant 5 jours pour vérifier l'expression de RORII et la production d'IL-17 dans ces lymphocytes T, plus précisément les lymphocytes T CD4 + . Cette étude nous a permis de mettre en évidence que certains éléments impliqués dans les processus inflammatoires sont possiblement inséparables et interagissent probablement les uns avec les autres pour mener aux séquelles multiples de l'inflammation.

Introduktion: Psoriasis är en hudsjukdom som drabbar en till fyra procent av världens befolkning. Symptomen av psoriasis visar sig på huden vilket är ett stort och synligt organ hos människan. En frisk och välmående hud är viktigt för människans fysiska- och psykiska välmående. Syfte: Att beskriva människors upplevelser av att leva med psoriasis. Metod: Litteraturstudien genomfördes enligt Graneheim och Lundmans metod för kvalitativ innehållsanalys med manifest ansats. Resultat: Litteraturstudien visade att människor med psoriasis kan ha upplevelser av att bli sedd och behandlad som annorlunda och upplevelser av att känna sig hindrad av en förändrad kropp. Resultatet visade även att det fanns känslor av att inte få den hjälp och det stöd som behövs samt att en personlig livssyn kan användas för att finna kraft i vardagen. Slutsats: Ökad kunskap om vad det finns för upplevelser hos personer som lever med psoriasis kan ge vårdpersonal större förståelse för de behov som individerna uttrycker. Att lyssna till dessa individers uttryckta behov och vara uppmärksam på behov av stöttning både fysiskt och psykiskt skulle bidra till en bättre omvårdnad här hela människan tas i beaktande. Att ta vara på varje individs egna resurser och förmågor skulle kunna användas som medel för stöttning till att finna kraft i vardagen.

Background: The p63 gene is a member of the p53 transcription factor family and can produce six different proteins using two promoters and differential splicing. Expression of p63 is required for proper formation of epithelial tissues. Studies on the transcriptional control of specific genes involved in cell survival, proliferation, differentiation and adhesion have revealed the contributions of p63 to the continuously renewing stratified epithelium. In this thesis, the aim was to improve our understanding of the roles of p63 in epithelial homeostasis by investigating expression of p63 in normal and benign hyper-proliferative epithelia and exploring the influence of p63 deregulation on cancer progression. Materials and methods: Using quantitative real time RT-PCR and immunohistochemistry, we first examined the expression of different p63 isoforms in patients diagnosed with psoriasis - a benign hyper-proliferative and inflammatory skin disease. Afterwards, we investigated responses of p63 in psoriatic epidermis upon Narrowband-UVB (NB-UVB) phototherapy. At the same time, we studied the potential impact of p63 in carcinogenesis by searching for p63 transcriptional targets in a cell line derived from squamous cell carcinoma of the head and neck (SCCHN) - the sixth most common cancer worldwide with over-expression of the ∆Np63α protein as a common feature. p63 gene silencing and microarray were used to identify p63 regulated genes. Real time RT-PCR, western blot, immunohistochemistry, chromatin immunoprecipitation, transient transfection and reporter assays were performed to confirm specific genes as direct p63 targets. Results: Significant down-regulation of p63 mRNA levels was found in psoriatic lesions compared to patients’ own clinically normal skin. Moreover, a trend of decreased TAp63 mRNA levels was seen in patients’ normal skin compared to age- and sex-matched healthy controls. Following NB-UVB phototherapy, an effective first line therapy for psoriasis, expression of p63 was not significantly affected. However, significant changes in p53, FABP5, miR-21 and miR-125b were found. Surprisingly, location and expression levels of p63 proteins detected by immunohistochemistry were similar under all skin conditions. A direct transcriptional regulation of TRAF4 by p63 was seen in the SCCHN cell line and we further found that the localization of the TRAF4 protein was associated with histological differentiation of SCCHN cells. However, unlike its over-expression in SCCHN, similar TRAF4 mRNA expression levels were seen in psoriatic lesions as compared to healthy controls. Besides TRAF4, a total of 127 genes were identified as potentially p63 regulated in the SCCHN cell line and strikingly, about 20% of these genes are involved in cell adhesion or migration. Conclusions: Dysregulation of p63 isoforms in psoriatic epidermis, especially decreased TAp63 expression, and their resistance to NB-UVB phototherapy implicated a contribution of p63 to the psoriasis phenotype. Transcriptional regulation of genes involved in multiple biological pathways indicated that over-expression of p63 in SCCHN might account for altered cell differentiation, adhesion and migration, thus contributing to SCCHN. In conclusion, our studies have found additional mechanisms through which p63 guarded homeostasis of the established epithelium. Deregulation of p63 might play a role in distinct pathological conditions by participating in diverse cellular pathways under different microenvironments.

La psoriasis es una enfermedad cutánea crónica que ha sido relacionada con el síndrome metabólico. El objetivo de este trabajo fue evaluar en pacientes con psoriasis la presencia de alteraciones en parámetros antropométricos y marcadores séricos relacionados con el síndrome metabólico, y su modificación tras un tratamiento con ultravioleta B de banda estrecha. Comparamos a 50 pacientes con psoriasis con 50 controles emparejados por sus características antropométricas (edad, sexo e índice de masa corporal) en un estudio transversal. Posteriormente, evaluamos los parámetros en estudio en los pacientes antes y después de una pauta de UVB de banda estrecha (UVB-BE). Los pacientes fueron reclutados en el Servicio de Dermatología del Hospital Parc Taulí de forma prospectiva excluyendo los meses de mayor irradiancia solar. Los controles fueron emparejados con cada paciente según sus características. Se excluyeron los pacientes con artritis psoriásica y los pacientes y controles con una lista de enfermedades inflamatorias crónicas. La evaluación consistió en un panel de determinaciones antropométricas y analíticas que se obtuvo al inicio de la inclusión y en los pacientes una vez completado el tratamiento. Estas determinaciones incluyeron un perfil glucémico, lipídico, inflamatorio, del metabolismo fosfocálcico, y de un conjunto de adipocitoquinas. La población mostró una media de sobrepeso. En igualdad de índice de masa corporal, los pacientes con psoriasis presentaron una mayor contenido de grasa corporal medido mediante bioimpedancia, que se correlacionó con la circunferencia de la cintura, y concentraciones séricas más elevadas de colesterol LDL, leptina, lipocalina-2, proteína ligadora de retinoides-4, receptor soluble del TNF, y apo-B. La vitamina D fue baja (<20 ng/ml) tanto en los pacientes como en los controles, y en los pacientes aumentó al final del tratamiento, sin que hubiera correlación entre dicho aumento y la mejoría del PASI. El PASI al inicio mostró una correlación con las concentraciones basales de las lipocalinas RBP-4 y lipocalina-2, así como con la PCR de alta sensibilidad. Al final del tratamiento con fototerapia, los pacientes experimentaron un descenso de la IL-6 y la ferritina en correlación con la dosis total acumulada de UVB-BE. El análisis de componentes principales permitió evidenciar un componente protector del desarrollo de síndrome metabólico en los controles sin psoriasis, que no estaba presente en los pacientes. Los pacientes presentaron frente a los controles un posicionamiento diferente en el mapa de componentes principales de la omentina, la lipocalina-2, la resistina y la RBP-4. En conclusión, identificamos en los pacientes con psoriasis sin artropatía un perfil metabólico y antropométrico distinto al de los controles. La insuficiencia de vitamina D fue habitual en ambos, y el aumento de síntesis de la misma con la fototerapia no mostró correlación con la mejoría del PASI. Nuestros resultados contribuyen a clarificar la función de ciertas adipocitoquinas en la génesis de las alteraciones inflamatorias y metabólicas presentes en la psoriasis. / Psoriasis is a chronic cutaneous disease that has been linked with metabolic syndrome. The present study aimed to evaluate the presence of alterations in anthropometric and serum parameters related to metabolic syndrome in psoriatic patients, along with their changes after treatment with narrow-band UVB. Fifty psoriatic patients were compared with 50 gender, age and body mass index-matched controls in a cross-sectional study. Additionally we evaluated the study parameters in the patients before and after a course of narrow-band UVB phototherapy. Patients were prospectively recruited in the Department of Dermatology of Hospital Parc Taulí excluding the months of high solar irradiance. Controls were matched with patients according to their characteristics. Patients with psoriatic arthritis and patients and controls with a list of inflammatory diseases were excluded. The evaluation consisted of a panel of anthropometric and laboratory determinations, that were obtained at the moment of inclusion, and in the patients after completion of phototherapy. These determinations included a glycaemic, inflammatory and lipid profile, vitamins and adipocytokines. The study population showed overweight. With a comparable body mass index, psoriatic patients had a higher fat content as determined by electric bioimpedance, which was correlated with waist circumference. They also had higher serum concentrations of LDL-cholesterol, apo-B, leptin, lipocalin-2, retinoid binding protein-4 (RBP-4), and soluble receptor of TNF. Vitamin D levels were low (<20 ng/ml) in patients and controls, and it markedly increased after phototherapy in patients, without correlation with PASI (Psoriasis Area and Severity Index) improvement. Initial PASI correlated with basal high sensitivity C-reactive protein, lipocalin-2 and RBP-4. At the completion of phototherapy, the patients showed a decrease in their IL-6 and ferritin levels, in correlation with total cumulative UVB dose. In healthy controls, principal components analysis yielded a protective component against metabolic syndrome, which was not present in the patients. Patients showed a different positioning of omentin, lipocalin-2, resistin and RBP-4 in principal components’ map when compared to healthy controls. In conclusion, we identified in psoriatic patients without arthrtitis a different metabolic and anthropometric profile when compared to healthy gender, age and body mass index-matched controls. Vitamin D insufficiency was common in both study groups, and increase in its synthesis after phototherapy did not correlate with psoriasis improvement. Our results add new data that clarify the role of certain adipocytokines in the genesis of inflammatory and metabolic disturbances in psoriatic disease.

Psoriasis is a chronic, inflammatory skin disorder and approximately 1% to 3% of the world’s populations are suffering from it. As numerous studies have shown that psoriasis is highly correlated with psychological distresses, one of the critical issues in the psoriasis patient care is the psychological problem. However, in the existing care for psoriasis, no guideline has been developed for patients’ psychological issue. Therefore, the aim of this translational research is to develop an evidence-based psychological care guideline with an implementation and evaluation plan for psoriasis patients in a dermatology setting. In this dissertation, 11 studies were selected after assessing the relevance of the obtained full texts. Data of these studies were extracted, and the quality of data was assessed by the Critical Appraisal Skills Programme and the Scottish Intercollegiate Guidelines Network. Evidences obtained from the literature review were aggregated and also critically reviewed. After these processes, an Evidence Based Protocol was developed. In the guideline, information related to the psychological assessment and interventions for psoriasis are included. Then the implementation potential of the guideline produced was examined in terms of the transferability, feasibility and the cost-benefit ratio. A pilot test was also conducted to identify any problems of the actual implementation of the mentioned guideline. Both process and outcome evaluation would be as used to assess the feasibility and the effectiveness of the guideline. In the end, this guideline isexpected to manage psychological aspects of psoriasis patients so as to improve their quality of life. / published_or_final_version / Nursing Studies / Master / Master of Nursing

Η απόπτωση ή προγραμματισμένος κυτταρικός θάνατος είναι ένα φαινόμενο στρατηγικής σημασίας για την ανάπτυξη, διαφοροποίηση και διατήρηση της ακεραιότητος ενός ιστού. Είναι πλέον γνωστό όμως ότι τόσο η υπέρμετρη όσο και η ανεπαρκής ενεργοποίηση των αποπτωτικών μηχανισμών μπορούν να οδηγήσουν στην εκδήλωση διαφόρων παθήσεων. Η απόπτωση χαρακτηρίζεται από συγκεκριμένες μορφολογικές και βιοχημικές μεταβολές ενώ η ρύθμισή της ελέγχεται γενετικά μέσω της εκφράσεως ή καταστολής διαφόρων ογκογονιδίων. Ιδιαίτερη σημασία για την ρύθμιση της αποπτώσεως έχουν τα γονίδια της οικογένειας του bcl-2. Συγκεκριμένα το bcl-2 και το bcl-xL καταστέλλουν την απόπτωση ενώ το bax την προάγει. Η ψωρίαση είναι μία χρόνια υποτροπιάζουσα φλεγμονώδης δερματοπάθεια η οποία προσβάλλει ποσοστό 1%-3% του γενικού πληθυσμού. Η ψωρίαση κατά πλάκας αποτελεί την συχνότερη μορφή της νόσου, η οποία χαρακτηρίζεται από την εμφάνιση σε γενετικώς προδιατεθειμένα άτομα, ερυθηματολεπιδωδών πλακών με σαφή αφορισμό από το πέριξ υγιές δέρμα. Χαρακτηρίζεται από έντονη υπερπλασία της επιδερμίδος, μειωμένη ωρίμανση των κερατινοκυττάρων, φλεγμονώδη διήθηση στην επιδερμίδα (CD8+) και το χόριο (CD4+) και νεοαγγειογένεση. Πρωταρχικό ρόλο στην έναρξη και διατήρηση των ψωριασικών αλλοιώσεων παίζουν τα Τ- λεμφοκύτταρα, τα οποία εκκρίνουν πληθώρα κυτταροκινών Τh1 τύπου. Παρά τα σημαντικά βήματα προόδου που έχουν γίνει τα τελευταία χρόνια στην έρευνα της ψωριάσεως, η παθογένεια της νόσου αυτής παραμένει ακόμα αδιευκρίνιστη. Τα κύτταρα της ψωριασικής επιδερμίδας αποτελούν έναν από τους ταχύτερα αναπτυσσόμενους και πολλαπλασιαζόμενους κυτταρικούς πληθυσμούς του ανθρώπινου οργανισμού. Θεωρητικά τουλάχιστον, η ακάνθωση της ψωριασικής επιδερμίδος θα μπορούσε να προκύπτει όχι μόνο από την αυξημένη μιτωτική δραστηριότητα των κερατινοκυττάρων αλλά επίσης και από έναν μειωμένο κυτταρικό θάνατο στις ζώσες στιβάδες της επιδερμίδος. Συμπερασματικά, στην παρούσα εργασία διαπιστώθηκε ότι υπό αγωγή και με τα δύο θεραπευτικά σχήματα επέρχεται ομαλοποίηση της εκφράσεως της bcl-2 στην ψωριασική διατυπωθεί η υπόθεση ότι τα ευρήματα της παρούσης εργασίας σε σχέση με αυτές τις δύο πρωτεΐνες συνδέονται με την υποστροφή των ψωριασικών αλλοιώσεων και όχι με τους μηχανισμούς θεραπευτικής δράσεως των χορηγηθέντων φαρμάκων. Τόσο υπό ασιτρετίνη όσο και υπό ανθραλίνη + καλσιποτριόλη παρατηρήθηκε μια σημαντική μείωση της εκφράσεως της πρωτεΐνης bcl-x στα κύτταρα της ακανθωτής στιβάδος της ψωριασικής επιδερμίδος. Το εύρημα αυτό σε συνδυασμό με την αντιαποπτωτική δράση της πρωτεΐνης bcl-x στην ψωριασική επιδερμίδα έχει ιδιαίτερη σημασία, αφού η μείωση της εκφράσεως της πρωτεΐνης αυτής υπό θεραπεία ίσως να συμμετέχει στους μηχανισμούς αντιψωριασικής δράσεως των χορηγηθέντων φαρμάκων αφού συνεπάγεται την είσοδο των ψωριασικών κερατινοκυττάρων στην απόπτωση. / Apoptosis or programmed cell death is a phenomenon of crucial importance for the growth, differentiation and maintenance of the integrity of tissues. However, it is well known that excessive or insufficient activation of apoptotic mechanisms can lead to the clinical manifestation of various diseases. Apoptosis is characterized by specific morphological and biochemical alterations, whereas its regulation is genetically determined by the induction or suppression of various oncogenes. Regulatory control of apoptosis is achieved through mechanisms in which proteins encoded by the bcl-2 gene family are involved. Thus, bcl-2 and bcl-xL inhibit the apoptotic process, whereas bax is a proapoptotic protein. Psoriasis is a chronic relapsing inflammatory genodermatosis affecting 1%-3% of general population. Plaque-type psoriasis, the most common form of the disease, is clinically characterized by the appearance of well-circumscribed erythematosquamous lesions in genetically predisposed individuals. On light microscopy, psoriatic lesions reveal marked acanthosis, incomplete maturation of keratinocytes, inflammatory infiltration of the dermis (CD4+) and the epidermis (CD8+) and enhanced angiogenesis. The role of T-cell-mediated immune mechanisms in the triggering of the disease is of particular importance. Despite the considerable progress in the research on various aspects of psoriasis, the pathogenesis of this disorder still remains unclear. Psoriatic keratinocytes represent one of the most rapidly developing and proliferating cellular populations of human body. Theoretically, acanthosis of psoriatic epidermis may have been caused from both, keratinocyte hyperproliferation and decreased cell death in the living epidermal layers. In the present study a normalization of bcl-2 protein expression was observed in psoriatic epidermis under both types of treatment. After 3 and 6 weeks of treatment, the reduction in the expression of bax in the spinous layer of psoriatic epidermis was higher under acitretin, as compared to that seen under topical application of anthralin + calcipotriol, as compared to the pretreatment status. Taking into account the limited differences in the expression of bcl-2 and bax proteins between the two groups (with the intensity of staining inside the normal limits), as well as the apparent absense of contributory role of bcl-2 and bax proteins in the regulation of the apoptosis of psoriatic keratinocytes, we can suppose that the findings of the present study are related to the regression of psoriatic lesions and not to the therapeutic action of the drugs used. Under both therapeutic regimens bcl-x immunoreactivity was reduced in the spinous layer of psoriatic epidermis. This finding, in combination with the antiapoptotic action of bcl-x protein in psoriatic epidermis, is of particular importance since the reduction in the expression of this protein under treatment is possibly implicated in the mechanisms of therapeutic action of these drugs.

Psoriatic Arthritis (PsA) is an inflammatory arthritis associated with psoriasis that leads to progressive joint damage. Genetic variants in the Major Histocompatibility Complex (MHC) region on human chromosome 6p, especially Human Leucocyte Antigen (HLA), are the most important genetic risk variants associated with susceptibility to PsA. I aimed to investigate the heritability of PsA and to determine the association between HLA polymorphisms with susceptibility and severity of PsA. I first validated the new CASPAR classification criteria for PsA in patients in with both early and established disease. Subsequently, I demonstrated that PsA as defined by the CASPAR criteria has a high recurrence risk ratio. In a large case-control and family-based association study, I demonstrated that the class I HLA alleles, HLA-C*12/B*38, -B*27 and -C*06/B*57 are associated with increased susceptibility to PsA. HLA class I molecules biologically interact with Killer-cell Immunoglobulin-like Receptors (KIR) on Natural Killer (NK) to influence immune response. I demonstrated that KIR2DS2 and HLA C group 2 and HLA-B Bw4 were associated with PsA susceptibility. Further analyses of PsA cases with Type II psoriasis and with dactylitis suggested that HLA-C*02, -B*27, -B*38 and KIR2DS2 may be markers of musculoskeletal manifestations of PsA. Furthermore, using longitudinal data, I demonstrated that HLA-B*39, -B*27, -A*02 and KIR3DS1 are associated with peripheral joint damage progression whereas the alleles –DQB1*0604, -C*04 and –B*60 are associated with less damage progression. HLA-C*02, -C*12, -DQB1*0609 and KIR2DS1 are associated with higher risk of sacroiliitis, and HLA-B*27 with syndesmophytes. HLA-A*29 was associated with reduced risk of development of both sacroiliitis and syndesmophytes. These studies indicate that HLA alleles and KIR genes are important in PsA susceptibility and severity and suggest that CD8+ T cells and NK cells that modulate the innate and adaptive immune response play an important role in the susceptibility and severity of PsA.

Kallikrein-8 (KLK8) is a relatively-uncharacterized epidermal protease. Although proposed to regulate wound-healing and barrier repair in KLK8-deficient mouse skin, KLK8-catalytic activity was never demonstrated in human epidermis and its regulators and targets remain largely unknown. KLK8 overexpression was reported in inflammatory skin diseases, but the underlying mechanisms are poorly understood. In this thesis, we elucidated for the first time KLK8-specific activity in normal human non-palmoplantar stratum corneum and sweat, and identified epidermal regulators and targets that augment its involvement in a skin-barrier proteolytic cascade. Given that inflammatory skin diseases have interlinked immune and epidermal roots, we hypothesized that epidermal KLK8 expression is distinctly regulated by the aberrant T-cell immunity implicated in the two common skin diseases, psoriasis and atopic dermatitis, independent of skin-barrier insults. We profiled secretion of KLK8 by normal human keratinocytes post-treatment with T-helper (Th1, Th17 and Th2) cell-derived cytokines, and investigated the effect of KLK8 overexpression on terminal keratinocyte differentiation and innate immunity gene expression. Our results show that TNFα and IL-17A synergistically induce potent KLK8 hyper-secretion, while IL4 and IL13 reduce its expression. TNFα and IL-17A overexpression and KLK8 hyperactivity resulted in hyperkeratosis and upregulation of keratinocyte innate defense genes’ expression mimicking psoriatic lesions. Consistently, KLK8 expression was reduced in lesional skin of atopic dermatitis patients and significantly elevated in lesional skin and sera of psoriatic patients. KLK8 levels correlated with psoriasis skin severity and were significantly reduced by effective treatment with biologic TNFα-blockers, correlating positively with psoriasis clearance. Thus, KLK8 is a new epidermal psoriasis therapeutic target. We performed high throughput screens of small molecule compound libraries to identify KLK8-specific inhibitors and discovered promising KLK8 small molecule inhibitors with IC50s in the nanomolar range. This thesis provides original findings corroborating KLK8 as an active serine protease in normal human skin and a down-stream epidermal respondent to TNFα and IL17A overexpression in psoriatic skin. Our novel KLK8-specific inhibitors may have future potential as topical barrier-enhancing agents in psoriasis.

Psoriasis is a chronic, immunological and systemic disease with an estimated prevalence of about 2-3 percent. Psoriasis is associated with the joint disease psoriasis arthropathy. There are several treatments options available for psoriasis and patients with moderate to severe psoriasis generally need systemic agents. In 2004 biologics were introduced for patients with moderate to severe psoriasis in Sweden. The overall objective of this thesis was to assess the relationship between Health Related Quality of Life (HRQOL) and clinical outcome measures in psoriasis patients, to analyse the effectiveness of biologics in psoriasis in everyday clinical practice and to explore how costs of the psoriasis population changed after the introduction of biologics in Sweden. Methods: Research was based on national administrative registers and PsoReg, the Swedish registry for systemic treatment of psoriasis. In a cross-sectional study (paper I) the three outcome measures: the generic HRQOL measure EQ-5D, the dermatology specific HRQOL measure the Dermatology Life Quality Index (DLQI) and the clinical measure of skin involvement, Psoriasis Area and Severity Index (PASI), were analysed by demographic characteristics. The generic EQ-5D among psoriasis patients was compared to previously published values for the general population in Sweden. Relationships between measures were examined with correlation tests and regression analysis. A longitudinal study included patients registered in PsoReg who switched to a biologic agent for the first time during registration (paper II). The three outcomes EQ-5D, DLQI, and PASI were analysed before and after switch in the overall patient group and in subgroups. The relative effectiveness of continuing with the standard care of conventional treatment compared to switching from standard care to biologics was analysed in patients with moderate to severe psoriasis (paper III). Patients in PsoReg were matched with propensity scores and average treatment effects were estimated. The estimated outcomes were the change of EQ-5D, DLQI, and PASI. Patients were identified in national registers at the National Board of Health and Welfare when analysing costs; either by a registration of a psoriasis diagnosis in the national patients register and/or by a registration in the prescribed drugs register of a topical treatment with calcipotriol, a substance which has the indication psoriasis only (paper IV). Direct costs included patients’ visits in specialist health care and prescribed drugs used for psoriasis treatment, retrieved from the national patients register and the prescribed drugs register, respectively. Indirect costs included productivity loss in terms of sick leave and disability pension, which estimated as excess costs compared to controls. Controls were selected from the normal population and matched on sex, age and municipality. Productivity loss was estimated based on data from the Longitudinal integration database for health insurance and labour market studies at Statistics Sweden. Results: Patients with moderate to severe psoriasis had significantly lower HRQOL in EQ-5D than the general population (paper I). Women rated their HRQOL lower than men, even though men had more severe clinical skin involvement than women. (paper I). The generic measure EQ-5D and the dermatology-specific DLQI had moderate correlations whereas EQ-5D had low correlation with the clinical measure PASI (paper I). Patients who switched to a biologic agent during registration in PsoReg had significant improvements in all outcomes (paper II). Patients who fulfilled the criteria for moderate to severe psoriasis had the highest benefits of the biologic agents (paper II). The matched conventionally and biologically treated patients with moderate to severe psoriasis were essentially equal in important observable variables (paper III). The subgroup of patients not responding to conventional treatment had high potential benefits of biologic agents (paper III). Individuals with psoriasis had sick leave and disability pension to a larger extent than their matched controls (paper IV). Direct costs increased, whereas the indirect costs of productivity loss decreased between 2006 and 2009 (paper IV). Conclusion: Psoriasis is associated both with direct costs and indirect costs, and it has a negative impact on patients’ HRQOL. When evaluating psoriasis treatments and making decisions about treatment guidelines, both generic, dermatology-specific HRQOL measures, and clinical measures are necessary; as they answer to different needs. Although dependent on data quality, generalisability, and current pricing, results suggest that conventional treatments are suitable as first line and biologic agents as second line treatment. Results indicate that the different types of systemic treatments are not allocated optimally among patients with psoriasis in Swedish clinical practice.

Psoriatic Arthritis (PsA) is an inflammatory arthritis associated with psoriasis that leads to progressive joint damage. Genetic variants in the Major Histocompatibility Complex (MHC) region on human chromosome 6p, especially Human Leucocyte Antigen (HLA), are the most important genetic risk variants associated with susceptibility to PsA. I aimed to investigate the heritability of PsA and to determine the association between HLA polymorphisms with susceptibility and severity of PsA. I first validated the new CASPAR classification criteria for PsA in patients in with both early and established disease. Subsequently, I demonstrated that PsA as defined by the CASPAR criteria has a high recurrence risk ratio. In a large case-control and family-based association study, I demonstrated that the class I HLA alleles, HLA-C*12/B*38, -B*27 and -C*06/B*57 are associated with increased susceptibility to PsA. HLA class I molecules biologically interact with Killer-cell Immunoglobulin-like Receptors (KIR) on Natural Killer (NK) to influence immune response. I demonstrated that KIR2DS2 and HLA C group 2 and HLA-B Bw4 were associated with PsA susceptibility. Further analyses of PsA cases with Type II psoriasis and with dactylitis suggested that HLA-C*02, -B*27, -B*38 and KIR2DS2 may be markers of musculoskeletal manifestations of PsA. Furthermore, using longitudinal data, I demonstrated that HLA-B*39, -B*27, -A*02 and KIR3DS1 are associated with peripheral joint damage progression whereas the alleles –DQB1*0604, -C*04 and –B*60 are associated with less damage progression. HLA-C*02, -C*12, -DQB1*0609 and KIR2DS1 are associated with higher risk of sacroiliitis, and HLA-B*27 with syndesmophytes. HLA-A*29 was associated with reduced risk of development of both sacroiliitis and syndesmophytes. These studies indicate that HLA alleles and KIR genes are important in PsA susceptibility and severity and suggest that CD8+ T cells and NK cells that modulate the innate and adaptive immune response play an important role in the susceptibility and severity of PsA.