Le métabolisme des lipides joue un rôle primordial au cœur de l'homéostasie cutanée. Précisément, les acides gras polyinsaturés (PUFAs) n-3 et n-6 sont impliqués dans des fonctions à la fois structurales et métaboliques, essentielles au développement et au maintien de la fonction barrière de la peau. Ces fonctions variables et complexes sont toujours partiellement incomprises à ce jour, et les conséquences qui en découlent sont évidentes et parfois néfastes. En effet, cette incompréhension limite notre capacité à reconstruire des modèles cutanés plus représentatifs de la peau normale humaine, qui sont nécessaires aux études pharmaceutiques. De plus, cette dernière fait partie intégrante de notre incapacité à déterminer les causes de certaines pathologies multifactorielles complexes telles que le psoriasis et, conséquemment, à développer des traitements efficaces pour les soigner. Les modèles de peau humaine sains et psoriasiques produits par génie tissulaire ont été exploités afin de mettre en lumière le rôle des acides gras polyinsaturés dans la fonction barrière de la peau. Au cours de cette thèse, plusieurs objectifs spécifiques ont été étudiés. Les deux premiers objectifs visaient l'optimisation du modèle de peau saine grâce à la supplémentation des milieux de culture avec, dans un premier temps, soit une supplémentation individuelle en acide alpha-linolénique (n-3 PUFAs) ou en acide linoléique (n-6 PUFAs). Dans un deuxième temps, une double supplémentation a été réalisée où l'acide alpha-linolénique et l'acide linoléique ont été ajoutés simultanément. Les résultats issus de ces deux études ont montré que la supplémentation des milieux de culture avec l'acide alpha-linolénique et celle avec les deux acides simultanément permettaient d'améliorer la fonctionnalité des substituts cutanés en diminuant l'absorption percutanée de la testostérone, alors que la supplémentation en acide linoléique seul n'avait pas d'effet. Ces résultats surprenants ont mis en évidence l'importance du ratio de n-3 et de n-6 PUFAs lors de la formation de la barrière cutanée in vitro. Le troisième objectif de cette thèse a été de caractériser l'endocannabinoïdome de la peau normale humaine et des substituts sains reconstruits par génie tissulaire. Cette étude a permis de mieux comprendre les différents acteurs du métabolisme des endocannabinoïdes au sein de la peau. Nos résultats ont aussi montré que les différents endocannabinoïdes présents dans la peau humaine étaient également retrouvés dans les substituts cutanés. De plus, une double supplémentation en acide alpha-linolénique et en acide linoléique a permis de moduler le profil d'endocannabinoïdes, confirmant que les peaux représentent un modèle adéquat pour l'étude du métabolisme des endocannabinoïdes cutanés. Finalement, le dernier objectif spécifique de cette thèse consistait à étudier le potentiel de l'acide alpha-linolénique (n-3 PUFAs) comme traitement pour soigner le psoriasis. Cette étude a permis de confirmer que les n-3 PUFAs pouvaient réguler la prolifération et la différenciation des kératinocytes psoriasiques in vitro afin qu'ils retrouvent un phénotype se rapprochant davantage de celui des cellules saines. Nos résultats montrent que cette régulation est induite par la modulation de la production des médiateurs lipidiques issus des acides gras polyinsaturés n-3 et n-6 ainsi que par l'activation et l'inhibition subséquentes des cascades de transduction du signal des kinases. En conclusion, le travail présenté dans cette thèse a permis de faire avancer de manière importante l'état des connaissances en ce qui a trait au métabolisme des acides gras polyinsaturés n-3 et n-6 au sein des peaux saines et psoriasiques. Ce dernier a également permis l'optimisation de la reconstruction tissulaire d'un modèle de peau dans le but d'obtenir un tissu affichant une barrière cutanée similaire à celle d'une peau normale humaine et, par conséquent, de mener à un modèle répondant davantage aux besoins de l'industrie pharmaceutique. Finalement, cette thèse a contribué à supporter et à promouvoir l'utilisation des n-3 PUFAs en tant que traitement possible pour les patients atteints de psoriasis, ainsi qu'à démontrer la pertinence de poursuivre les recherches dans ce domaine puisqu'elles offrent un potentiel important quant à l'amélioration de la qualité de vie des patients. / Lipid metabolism plays a central role in the skin homeostasis. More specifically, omega-3 and omega-6 polyunsaturated fatty acids (n-3 and n-6 PUFAs) are involved in both structural and metabolic functions, which are essential for the development and maintenance of the skin barrier function. These highly variable and complex functions are still partially misunderstood to this day, and the resulting consequences are obvious. Indeed, these gaps in knowledge limit our ability to produce reconstructed skin models that are representative of normal human skin, which are necessary for pharmaceutical studies. In addition, improving our knowledge of skin lipids would help understand the causes of certain complex multifactorial pathologies such as psoriasis and would consequently lead to the development of more effective therapies. Tissue-engineered healthy and psoriatic human skin substitutes have been exploited to shed light on the role of polyunsaturated fatty acids regarding the barrier function of the skin. This thesis evaluated several specific objectives. The first two objectives aimed at the optimization of the healthy skin substitutes using first, individual supplementation of culture media with alpha-linolenic acid (n-3 PUFA) or linoleic acid (n-6 PUFA), as well as in a second step, a dual supplementation with both alpha-linolenic and linoleic acids. The results of these two studies showed that supplementation of culture media with alpha-linolenic acid and with the dual supplementation improved the functionality of skin substitutes by reducing the percutaneous absorption of testosterone, whereas the linoleic acid supplementation alone had no effect. These surprising results demonstrated the importance of the ratio of n-3 to n-6 PUFAs in the formation of the skin barrier in vitro. The third objective of this thesis was to characterize the endocannabinoidome of human skin compared to that of healthy tissue-engineered skin substitutes. This study provides a better understanding of the different actors in the metabolism of endocannabinoids within the skin. Our results show that the different endocannabinoids present in human skin were also found in the skin substitutes, and that they were modulated following a double supplementation with alpha-linolenic acid and linoleic acid, confirming that reconstructed skin equivalents are an adequate model for the study of the metabolism of cutaneous endocannabinoids. Finally, the last specific objective of this thesis was to study the potential of alpha-linolenic acid (n-3 PUFA) as a treatment for psoriasis. This study confirmed that n-3 polyunsaturated fatty acids can regulate the proliferation and differentiation of psoriatic keratinocytes so that they adopt a healthier behavior. This regulation is mediated by the modulation of the lipid mediators produced from n-3 and n-6 polyunsaturated fatty acids, as well as by the activation and inhibition of subsequent signal transduction cascades involving kinases. In conclusion, the results reported in this thesis significantly contribute to advancing the state of knowledge regarding the metabolism of n-3 and n-6 polyunsaturated fatty acids in healthy and psoriatic skin. This thesis also allowed the optimization of a skin model to be more representative of the functionality of normal human skin, and thus the generation of a more efficient model for the pharmaceutical industry. Ultimately, our work will help to support and promote the use of n-3 polyunsaturated fatty acids as a treatment for patients with psoriasis, which could greatly improve their quality of life.

Background: Financial constraints challenge evidence of the effectiveness of dermatological inpatient management. Objective: To evaluate the effectiveness of hospitalization in atopic dermatitis and psoriasis regarding initial and sustained benefits. Methods: Prospective study on adults with psoriasis vulgaris (n = 22) and atopic dermatitis (n = 14). At admission, discharge, and 3 months after discharge, validated outcomes of objective and subjective disease severity were assessed by trained investigators. Results: Hospitalization resulted in substantial benefit in quality of life and clinical disease severity. Looking at mean scores, the observed benefit appeared stable until 3-month follow-up. The analysis of individual patient data revealed significant changes in disease severity between discharge and 3-month follow-up with some patients relapsing, others further improving. Reasons for hospitalization and treatment performed were not related to sustained benefit. Conclusions: In psoriasis vulgaris and atopic dermatitis, hospitalization effectively improved quality of life and clinical disease severity. Further research should focus on prognostic factors for sustained improvement. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

In order to convince, one must know which arguments are most suitable for the specific situation. But even if you think you know how others will react to your arguments, you may be wrong. Therefore, the purpose of this paper is to find out a way of examining to what extent informative text take account to the subjective views of their addressees. The theoretical framework is Blitzer's theory of the rhetorical situation, pragmatic theory of speech acts and their presuppositions, Burk´s theory of consubstantiality and phenomenographic theory of subjective perceptions. Methodologically, phenomenography has also been used as a guideline for selecting informants, collecting data and processing the interviews. The material analyzed consists interviews with four persons suffering from psoriasis, a brochure addressed to an unspecified audience with the same problem plus an interview with a spokesperson for the Swedish Psoriasis Association. The analysis reveals a clear difference in certain important respects between the subjective views of the intended reader and the implied addressees of the text, i.e. a lack of consubstantiality between sender and receiver. This points to a rhetorical problem when addressing an unknown audience without exploring their specific perceptions of concepts related to the transmitted information, a problem which may be grasped and perhaps to some extent even solved by applying a method similar to the one used in this study.

We present a system for data-driven therapy decision support based on techniques from the field of recommender systems. Two methods for therapy recommendation, namely, Collaborative Recommender and Demographic-based Recommender, are proposed. Both algorithms aim to predict the individual response to different therapy options using diverse patient data and recommend the therapy which is assumed to provide the best outcome for a specific patient and time, that is, consultation. The proposed methods are evaluated using a clinical database incorporating patients suffering from the autoimmune skin disease psoriasis. The Collaborative Recommender proves to generate both better outcome predictions and recommendation quality. However, due to sparsity in the data, this approach cannot provide recommendations for the entire database. In contrast, the Demographic-based Recommender performs worse on average but covers more consultations. Consequently, both methods profit from a combination into an overall recommender system.

We present a system for data-driven therapy decision support based on techniques from the field of recommender systems. Two methods for therapy recommendation, namely, Collaborative Recommender and Demographic-based Recommender, are proposed. Both algorithms aim to predict the individual response to different therapy options using diverse patient data and recommend the therapy which is assumed to provide the best outcome for a specific patient and time, that is, consultation. The proposed methods are evaluated using a clinical database incorporating patients suffering from the autoimmune skin disease psoriasis. The Collaborative Recommender proves to generate both better outcome predictions and recommendation quality. However, due to sparsity in the data, this approach cannot provide recommendations for the entire database. In contrast, the Demographic-based Recommender performs worse on average but covers more consultations. Consequently, both methods profit from a combination into an overall recommender system.

Background: Financial constraints challenge evidence of the effectiveness of dermatological inpatient management. Objective: To evaluate the effectiveness of hospitalization in atopic dermatitis and psoriasis regarding initial and sustained benefits. Methods: Prospective study on adults with psoriasis vulgaris (n = 22) and atopic dermatitis (n = 14). At admission, discharge, and 3 months after discharge, validated outcomes of objective and subjective disease severity were assessed by trained investigators. Results: Hospitalization resulted in substantial benefit in quality of life and clinical disease severity. Looking at mean scores, the observed benefit appeared stable until 3-month follow-up. The analysis of individual patient data revealed significant changes in disease severity between discharge and 3-month follow-up with some patients relapsing, others further improving. Reasons for hospitalization and treatment performed were not related to sustained benefit. Conclusions: In psoriasis vulgaris and atopic dermatitis, hospitalization effectively improved quality of life and clinical disease severity. Further research should focus on prognostic factors for sustained improvement. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Abstract Hidradenitis suppurativa (HS) is a chronic inflammatory disease of hair follicles, characterized by subcutaneous inflammatory nodules and abscesses, typically on the axillary, genitofemoral, and perianal skin. Symptoms of HS, such as foul-smelling discharge from the inflamed lesions, pain, and disease location in sensitive areas, markedly diminish patients’ quality of life. Smoking and obesity are associated with HS, which also has several common comorbidities. While there is a growing body of evidence of somatic comorbidities in HS, psychiatric comorbidities have received less attention. Furthermore, literature on comorbidities in young patients with HS is scarce, and no systematic evaluation of mortality in HS has yet been undertaken. This study aimed to clarify the associations between HS and mental disorders, to explore both somatic and psychiatric comorbidities of HS in children and adolescents, and to determine the life expectancy and cause-specific risks of death in patients with HS. The study population comprised over 4300 cases with HS diagnosed in Finnish hospitals between 1987 and 2014. Age- and sex-matched patients with psoriasis and melanocytic nevi served as controls. Patient data were obtained from the statutory Finnish Care Register for Health Care. Information on dates and causes of death of the cases and controls were acquired from Statistics Finland. This study showed a heavy psychiatric disease burden in patients with HS. The prevalence rates and risks of all studied psychiatric comorbidities were higher in the HS than in the control groups. This was also evident in children and adolescents with HS, not only in adults. Furthermore, younger patients also had elevated risks for many somatic disorders including inflammatory bowel and joint diseases. Remarkably, the mean age at death in the HS group was only 60.5 years. The most common causes for death in the order of likelihood were: cardiovascular diseases, neoplasms, ‘accidents, suicides or violence’ and alcohol-related diseases. Suicide risk was elevated in women with HS. HS patients should be cautiously monitored for possible somatic and psychiatric comorbidities. It is clear that these patients require effective, comprehensive and multidisciplinary care to improve their quality of life and prevent premature death. / Tiivistelmä Hidradenitis suppurativa (HS) on krooninen tulehduksellinen karvatuppien sairaus, joka heikentää elämänlaatua merkittävästi. Kivuliaat kyhmyt ja paiseet sekä vuotavat käytävät, jotka sijaitsevat useimmiten kainaloissa, nivusissa, genitaalialueella ja pakaravaossa, ovat sen tyypillisimpiä ilmenemismuotoja. HS-potilailla on moninaisia terveysongelmia, joita ovat mm. tupakointi, lihavuus ja suurentunut riski useisiin somaattisiin sairauksiin. Tutkimustieto HS-potilaiden psykiatrisista sairauksista on kuitenkin vähäistä eikä liitännäissairauksista lapsilla ole juuri lainkaan tietoa. Tämän lisäksi HS-potilaiden kuolemansyitä tai eliniänodotetta ei ole perusteellisesti selvitetty. Tällä tutkimuksella haluttiin määrittää psykiatristen sairauksien riski HS-potilailla ja selvittää sekä somaattisten että psykiatristen liitännäissairauksien todennäköisyyttä lapsuudessa ja nuoruudessa. Tarkoituksena oli myös tutkia, mihin sairauksiin HS-potilailla on suurentunut riski kuolla ja minkä ikäisinä he menehtyvät. Terveyden ja hyvinvoinnin laitoksen hoitoilmoitusjärjestelmästä etsittiin tiedot kaikista Suomen sairaaloissa vuosina 1987–2014 diagnosoiduista HS-tapauksisista (N=4381). Liitännäissairauksien tutkimista varten verrokeiksi valittiin psoriaasi- tai luomidiagnoosin saaneet henkilöt, jotka kaltaistettiin iän ja sukupuolen mukaan. Kuolintiedot menehtyneistä tutkimuspotilaista saatiin Tilastokeskukselta. HS-potilailla havaittiin selkeästi suurentunut psykiatristen sairauksien riski niin aikuisena kuin myös jo alle 18 vuoden iässä. Lisäksi monien somaattisten sairauksien, esim. tulehduksellisten suoli- ja nivelsairauksien, riski oli suurentunut lapsuudessa. HS-potilaiden todettiin menehtyvän huomattavan nuorella iällä, sillä heidän keskimääräinen elinikänsä oli vain 60,5 vuotta. Yleisimmät kuolinsyyt olivat sydän- ja verisuonitaudit, kasvaimet, ’onnettomuudet, itsemurhat ja väkivalta’ sekä alkoholiin liittyvät kuolemat. Itsemurhariski havaittiin suurentuneeksi naisilla. Tämän tutkimuksen perusteella HS-potilailla on runsaasti psykiatrisia liitännäissairauksia. Sekä somaattisten että psykiatristen sairauksien riski onkin pidettävä mielessä aina HS-potilaita hoidettaessa. Tehokas, kokonaisvaltainen ja moniammatillinen hoito on tärkeää potilaiden elämänlaadun parantamiseksi ja ennenaikaisen kuoleman ehkäisemiseksi.

In der vorliegenden Arbeit wurde die Expression von Angiotensinogen, Renin, Angiotensin-Converting-Enzym (ACE) und von den Agiotensin-Rezeptoren AT1 und AT2 in humaner Haut untersucht, um zu sehen, ob humane Haut ein lokales Gewebe Renin-Angiotensin-System (RAS) besitzt und fähig ist, Angiotensin II (Ang II) zu synthetisieren sowie welche physiologische Rolle Ang II in humaner Haut haben könnte. Außerdem wurde das Expressionsmuster von Angiotensinogen, Renin und ACE in gesunder humaner Haut mit dem in Psoriasis, Basaliom und Spinaliom (SCC) verglichen, um einen Einblick in pathophysiologische Funktionen des RAS zu gewinnen. Mit Hilfe von RT-PCR konnten alle Komponenten des RAS in vitro auf mRNA Ebene in kultivierten primären Keratinozyten, Melanozyten, dermalen Fibroblasten und dermalen mikrovaskulären Endothelzellen (MVEC´s) nachgewiesen werden, mit einer Ausnahme: Melanozyten scheinen keine AT2-Rezeptoren zu exprimieren. Immunhistochemische Untersuchungen zeigten die Expression aller Komponenten auf Proteinebene in Epidermis und dermalen Gefäßwänden in Gewebeschnitten humaner Haut. Zusätzlich erfolgte der Nachweis von Ang II in kultivierten Keratinozyten mittels enzymatischen immunometrischen Assays. Während Angiotensinogen, Renin und ACE bei immunhistochemischen Untersuchungen an Gewebeschnitten gesunder menschlicher Haut in allen Epidermalschichten gleichmäßig verteilt waren, zeigte sich bei der Psoriasis eine deutliche Betonung der unteren Epidermalschichten. Immunhistochemische Untersuchungen von Basaliomen erbrachten eine verminderte Expression von Angiotensinogen und Renin innerhalb der Tumornester. ACE wurde in den Tumorzellen noch weniger exprimiert. In immunhistochemischen Untersuchungen von Spinaliomen färbten sich die Tumorzellen deutlich homogen an. Die Experimente haben gezeigt, dass alle Komponenten des RAS in enger Lokalisation in menschlicher Haut vorkommen und dass folglich ein lokales Gewebe RAS in humaner Haut existiert sowie dass humane Haut fähig ist, Ang II ohne Zufuhr weiterer Komponenten und ohne regulatorische Einflüsse aus der Zirkulation zu synthetisieren. Eine mögliche physiologische Rolle von Ang II könnte die Regulation von Keratinozyten-Proliferation und –Differenzierung über seine Rezeptoren sein. Bezüglich der pathophysiologischen Rolle haben die Untersuchungen eine Fehlregulation des kutanen RAS in Epidermis psoriatisch veränderter Haut gezeigt, welches ein Hinweis auf eine pathogenetische Rolle des RAS bei der gestörten Keratinozyten-Proliferation und –Differenzierung sein könnte. Das Expressionsmuster in den untersuchten Tumoren war uneinheitlich, weshalb eine Interpretation der Rolle des RAS in kutanen Tumoren ohne weitere Untersuchungen kaum möglich erscheint. 1 / The present study was designed to elucidate whether a local tissue renin-angiotensin system (RAS) is expressed in human skin, whether cutaneous cells are able to autonomously synthesise angiotensin II (Ang II), and to get a first insight into a putative physiological role of Ang II in this location. For this purpose, the expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE) and of the angiotensin receptors AT1 and AT2 was examined in human skin samples and in diverse cutaneous cells in primary culture on mRNA- and protein-level. Furthermore, the study compared the expression pattern of angiotensinogen, renin and ACE in healthy human skin with that in psoriasis, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) to look for possible differences between healthy and diseased skin. Using mRNA derived from cultured primary keratinocytes, melanocytes, dermal fibroblasts and dermal microvascular endothelial cells (MVECs), all components of the RAS could be demonstrated by RT-PCR except for AT2 receptors in melanocytes. Immunohistochemical stainings of cryostat sections of human skin revealed the expression of all components at protein level within the epidermis and in dermal vessel walls. In addition, the presence of Ang II in cultured keratinocytes and their supernatants could be proven by enzyme immunometric assay giving strong evidence for the ability of keratinocytes to autonomously synthesise Ang II. Regarding the comparison of RAS expression in healthy versus diseased skin, expression of angiotensinogen, renin and ACE was altered in all dermatoses examined. While in normal skin, RAS components were distributed equally and homogenously throughout all layers of the epidermis, in psoriatic skin their expression was more intense in the basal epidermal layers and less intense in the upper layers. In BCC sections, expression of angiotensinogen and renin was down-regulated, and tumour cells stained negatively for ACE. In SCC cryostat sections, tumour cells stained positively for all RAS components with an intensity comparable to normal skin. Taken together, the experiments revealed that a local tissue RAS exists in human skin, and that human skin is able to autonomously synthesise Ang II without any supply of components from the circulation. The physiological role of Ang II in normal skin may comprise the regulation of keratinocyte proliferation and differentiation. Concerning a putative pathophysiological role of Ang II in skin, this study provides evidence for a deregulation of the RAS in psoriatic skin and in BCC pointing to an involvement of the RAS in the pathomechanisms of these dermatoses. 1

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No. of bitstreams: 1 ALEXANDRA APARECIDA DOS REIS.pdf: 2254046 bytes, checksum: bf0291b84101fecae5af414bf1032ff7 (MD5) Previous issue date: 2017-02-21 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / INTRODUCTION: Psoriasis, chronic inflammatory skin disease, Characterized by pink or reddish lesions, covered by whitish and dry scales,Its plaque format is the most common type.In all forms of psoriasis, nail involvement may be present in about 50% of cases.Individuals with psoriasis have nail deformities and a tendency to develop psoriatic arthritis.Psoriatic arthritis inflammatory disease of the joints in a divergent way involves the spine and peripheral joints, can affect up to 30% of people with psoriasis between 5 to 12 years after their development as dactylitis, enthesitis and peripheral joints.This complicates the diagnosis because the involvement of the skin can affect before the joint involvement. There is an immunological development in the pathogenesis of this disease immunized by Th1 and Th17 cells.Recently there is evidence that plays a crucial role in the pathology of psoriatic arthritis.The prevalence of 06% to 42% of patients with psoriasis develop a joint disease. Some studies have been analyzing these items in detail, thus giving rise to methods for measuring quality of life, since to obtain a quality life it is necessary to evaluate the individual as a whole in psychological, social and physical aspects. The questionnaires are instruments, in which they collect information and characterize a composite research technique, in the objective form of questions presented in writing in the research, in application of the knowledge of the researcher.PASE-P: developed as a screening tool for PAs more effectively in individuals with Ps and validated by Husni, et al.2007. Its sensitivity is 76% and specificity is 82%. NAPSI instrument that evaluates each nail by dividing them into four quadrants, to be evaluated for the presence of any alteration coming from both the nail matrix and nail bed. PASI: An instrument developed in 1978 to quantify the severity of Ps in order to evaluate the body surface and was segmented into 04 regions of the head, trunk, lower limbs and upper limbs evaluated on a scale of 0 to 72.DLQI: Questionnaire aiming to obtain detailed data on the quality of life of patients with psoriasis.And it consists of 10 questions about symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment. CASPAR: Investigates the presence of joint manifestations, dermatological diseases or family history, typical nail changes, the existence of joint swelling and radiological changes. OBJECTIVES: To evaluate the presence of arthritis in male and female patients with Ps, aged between 18 and 80 years using a specific questionnaire to evaluate the severity of psoriasis, using PASE-P, NAPSI, PASI, DLQI AND CASPAR. And determine by means of laboratory variables the PCR and FR. OBJECTIVE: To compare and correlate the severity parameters of psoriasis PASE-P, NAPSI, PASI, DLQI and CASPAR in a screening with patients from the dermatology outpatient clinic to identify psoriatic arthritis, seeking correlations with literature content.METHOD: The study used a cross-sectional, longitudinal and prospective study, approved by the Research Ethics Committee (CEP) of the Celso Pierro Hospital and Maternity Hospital (HMCP) in Campinas-SP. RESULTS: During the study, 63 patients did not present withdrawal, 57.1% were men and 42.9% were women. We obtained a statistically significant correlation between PASE-B, which depicts the functionality and the CRP that characterizes the inflammatory activity.Patients with a PASE-P score greater than 44, defined as suspected APs, 15.9% of arthritis. Correlations for PASE-P greater than 44 obtained the following statistically significant correlations PASE-B with PASI r = 0.736, p = 0.037, DLQI with PCR r = 0.900, p = 0.037, PASE-B with PCR; R = 0.360, p-0.021, PASI with NAPSI ML, r = 0.353. There was a statistically significant correlation between PASE-B which depicts functionality and the CRP that characterizes inflammatory activity. DISCUSSION: The choice of PASE-P, NAPSI, DLQI, PASI and CASPAR instruments in psoriasis was to evaluate their applicability in clinical practice. PASE-P has proved to be relevant, since it is a simple and quick and practical resource, and so far there are few studies with the publication in the Portuguese language version. The questionnaire PASS a recent tool to evaluate psoriatic arthritis, developed by Husni, et al, 2007. CONCLUSION: PASE-P as a specific instrument has been shown to be effective in the detection of some PA patients in a group of patients with psoriasis, as seen in the literature. Each case should be individualized and treated according to the association of disease severity parameters. It can be emphasized, therefore, that the association of PASE, CASPAR, NAPSI and DLQI can be of great assistance in clinical practice for both evolutionary follow-up and therapeutic decision-making. Taking into account that according to what was shown in this study the PASE-P is a specific instrument and that in a dynamic and effective way when detecting PAs in patients. / INTRODU??O: Psor?ase doen?a inflamat?ria cr?nica da pele, caracterizada por les?es r?seas ou avermelhadas, recobertas por escamas esbranqui?adas e secas, seu formato em placas ? o tipo mais comum. Em todas as formas de psor?ase o envolvimento ungueal pode estar presente em cerca de 50% dos casos. Os indiv?duos com psor?ase apresentam deformidades nas unhas e tend?ncia a desenvolver artrite psori?sica. A artrite psori?sica doen?a inflamat?ria das articula??es de maneira divergente envolve a coluna vertebral e articula??es perif?ricas, pode afetar at? 30% das pessoas portadoras da psor?ase entre 5 a 12 anos ap?s seu desenvolvimento como dactilite,entesite e articula??es perif?ricas. O que dificulta o diagn?stico pois os envolvimento cut?neo pode acometer antes do comprometimento articular. Existem um desenvolvimento imunol?gico na patog?nese desta doen?a imunodiada por c?lulas Th1 e Th17. Recentemente h? evidencias que desempenham um papel crucial na patologia da artrite psori?sica. A preval?ncia de 06% a 42% dos pacientes com psor?ase desenvolvem uma doen?a articular. Alguns estudos vem analisando minuciosamente estes itens, surgindo assim m?todos para mensurar a qualidade de vida, pois para obter uma vida com qualidade ? necess?rio avaliar o indiv?duo como um todo em aspectos psicol?gicos, social e f?sico. Os question?rios s?o instrumentos, nos quais coletam informa??es e caracterizam uma t?cnica de investiga??o composta, na forma objetiva de quest?es apresentadas por escrito na pesquisa, em aplica??o do conhecimento do pesquisador. PASE-P: desenvolvidos como uma ferramenta de triagem para APs de forma mais eficaz em indiv?duos com Ps e validados por Husni, et al.2007.Sua sensibilidade e de 76% e especificidade de 82%. NAPSI instrumento que avalia cada unha dividindo as em quatro quadrantes, para ser avaliada quanto a presen?a de qualquer altera??o provenientes tanto da matriz da unha quanto leito ungueal. PASI: Instrumento desenvolvido em 1978, para quantificar a gravidade da Ps, com o objetivo de avaliar a superf?cie corporal e para isto foi segmentado em 04 regi?es cabe?a, tronco, membros inferiores e membros superiores, avaliado em uma escala de 0 a 72.DLQI: Question?rio com intuito em obter dados de forma detalhada sobre a qualidade de vida dos portadores da psor?ase. E composto por 10 quest?es sobre sintomas e sentimentos, atividades di?rias, lazer, trabalho e escola, rela??es pessoais e tratamento. CASPAR: Investiga a presen?a de manifesta??es articulares, doen?as dermatol?gicas ou hist?rico familiar, mudan?as ungueais de forma t?pica, exist?ncia de incha?o articular e altera??es radiol?gicas. OBJETIVOS: Avaliar a presen?a da artrite em pacientes do g?nero masculino e feminino com Ps, com idade entre 18 a 80 anos atrav?s de question?rio espec?fico para avalia??o da gravidade da psor?ase, atrav?s de instrumentos de avalia??o e classifica??o PASE-P, NAPSI, PASI, DLQI E CASPAR. E determinar por meio de vari?veis laboratoriais o PCR e FR. OBJETIVO ESPECIFICO: Comparar e correlacionar os par?metros de gravidade da psor?ase PASE-P, NAPSI, PASI, DLQI E CASPAR em uma triagem com pacientes do ambulat?rio de dermatologia afim de identificar a artrite psori?sica, buscando correla??es com conte?do da literatura. M?TODO: A pesquisa utilizou um estudo transversal, longitudinal e prospectivo, aprovado pelo Comit? de ?tica em Pesquisa (CEP) do Hospital e Maternidade Celso Pierro (HMCP) em Campinas-SP. RESULTADOS: Durante a pesquisa fizeram parte da popula??o 63 pacientes n?o havendo desist?ncia, sendo 57,1% eram homens e 42,9% eram mulheres. Obtivemos correla??o estatisticamente significativa entre o PASE-B, que retrata a funcionalidade e o PCR que caracteriza a atividade inflamat?ria. Pacientes com escore de PASE-P maior que 44, definiram se como suspeita de APs, 15,9% de artrite. Correla??es para o PASE-P maior que 44 obtivemos as seguintes correla??es estatisticamente significativas PASE-B com PASI r= 0,736, p=0,037, DLQI com PCR r=0,900, p=0,037, PASE-B com PCR; r=0,360, p- 0,021, PASI com NAPSI ML, r=0, 353.Houve correla??o estatisticamente significativa entre PASE-B que retrata funcionalidade e o PCR que caracteriza atividade inflamat?ria. DISCUSSAO: A escolha dos instrumentos PASE-P, NAPSI, DLQI, PASI E CASPAR, na psor?ase foram para avaliar suas aplicabilidades na pratica cl?nica. O PASE-P mostrou se relevante, pois e um recurso simples r?pido e pr?tico, e at? o momento h? poucos estudos com a publica??o na vers?o da l?ngua portuguesa. O question?rio PASE uma ferramenta recente em avaliar a artrite psori?sica, desenvolvido por Husni, et al,2007. CONCLUS?O: O PASE-P como instrumento especifico se mostrou eficaz na detec??o de alguns pacientes com APs em um grupo de pacientes com psor?ase, como visto na literatura. Cada caso deve ser individualizado e tratado de acordo com a associa??o dos par?metros de gravidade da doen?a. Pode-se ressaltar, portanto, que a associa??o do PASE, CASPAR, NAPSI e DLQI pode servir de grande aux?lio na pr?tica cl?nica tanto para o acompanhamento evolutivo, quanto para a tomada de decis?es terap?uticas. Levando em considera??o que de acordo com o que foi mostrado neste estudo o PASE-P ? um instrumento espec?fico e que de forma din?mica e eficaz ao detectar a APs em pacientes.

A psoríase é uma doença inflamatória crônica com uma elevada incidência, que afeta a pele. A patogênese da psoríase caracteriza-se pela participação de inúmeras células, incluindo os queratinócitos que são as principais células efetoras da citocina IL-17, críticas para a doença, que produzidas pelas células T. Evidências crescentes sugerem o importante papel da piruvato quinase M2 (PKM2) na regulação da resposta inflamatória, mas o mecanismo subjacente permanece obscuro. Nesse sentido, no presente estudo investigamos o papel da PKM2 no desenvolvimento da psoríase. Observamos o aumento de PKM2 em biópsia humana, em modelo de psoríase induzida por imiquimode e em modelos espontâneos K14-IL-17Aind e DC-IL-17Aind. Em adição, esse aumento observado na enzima foi predominante nos queratinócitos e isso foi associado a marcadores de ativação de queratinócitos. Utilizando o inibidor de PKM2, Shikonin (SKN), como abordagem farmacológica, observamos que o tratamento com esse composto foi capaz de reverter a psoríase experimental e a reduzir marcadores associados a doença como: K17, LCN2, TNF-?, KC, S100A8, S100A9, IL-6 e IL-17A. Associado a isso, observamos a redução na frequência de células T (?? e ??) produtoras de IL-17 e do número de neutrófilos na pele em modelo de imiquimode após inibição da PKM2. O SKN, também, reduziu o número de neutrófilos no modelo DC-IL-17Aind. Em nosso próximo passo, observamos que queratinócitos HACAT estimulados com IL-17A apresentou um aumento da expressão de PKM2 e que a sua inibição foi associada a redução da ativação de queratinócitos e de mediadores inflamatórios como a IL-8. Além disso, a deleção da PKM2, utilizando a tecnologia CRISPR/Cas9, reduziu a expressão do receptor de IL-17. Por fim, o desenvolvimento da psoríase por imiquimode foi atenuada em animais deficientes para PKM2 em queratinócitos (K14-PKM2fl/+), no qual foi observado a redução de neutrófilos na pele e, além disso, evidenciamos a redução da expressão de IL-17A nesses animais. O conjunto de resultados apresentados nesse trabalho demonstram que a PKM2 apresenta um papel crítico no desenvolvimento da psoríase e que a ativação do receptor de IL-17 promove um aumento da PKM2 em queratinócitos e esta contribui para ativação de mediadores que é responsável diretamente para o desenvolvimento da psoríase. Esses resultados, ainda, sugerem a PKM2 como um biomarcador para diagnóstico da psoríase e consequentemente, um potencial alvo terapêutico para tratamento dessa doença e outras doenças inflamatórias. / Psoriasis is a chronic inflammatory skin disease with high incidence in the global population. The pathogenesis of psoriasis is characterized by involvement of many cells, including keratinocytes that are targets for IL-17-producing T cells. Evidences suggests a critical role of pyruvate kinase M2 (PKM2) in inflammatory response, but the underlying mechanism remains unclear. In this context, here we investigated the role of PKM2 in the development of psoriasis. We observed overexpression of PKM2 in psoriatic human skin, imiquimod-induced psoriasis and spontaneous K14-IL-17Aind and DC-IL-17Aind models. In addition, the overexpression of this enzyme was observed in keratinocytes associated with keratinocytes activation markers. Using the PKM2 inhibitor, Shikonin (SKN), as a pharmacological approach, we observed that the treatment with this compound was able to reduce experimental psoriasis and disease-associated markers such as K17, LCN2, TNF-?, KC, S100A8, S100A9, IL-6 and IL-17A. Moreover, we observed reduction of frequency of IL-17-producing T cells (?? and ??) and the number of neutrophils in the skin after imiquimod application plus inhibition of PKM2. SKN, also, reduced the number of neutrophils in the DC-IL-17Aind model. In our next step, we observed overexpression of PKM2 in human keratinocytes HACAT stimulated with IL-17A and that its inhibition was associated with less keratinocytes activation and inflammatory mediators such as IL-8. In addition, deletion of PKM2, using CRISPR/Cas9 technology, reduced IL-17 receptor expression. Finally, the development of imiquimod-induced psoriasis was attenuated in PKM2-deficient mice in keratinocytes (K14-PKM2f/+), with reduction in the number of neutrophils in the skin. In addition, we evidenced the reduction of IL-17A expression these animals. Taken together, these results demonstrate that PKM2 plays a critical role in the development of psoriasis and that IL-17 receptor activation promotes an increase of PKM2 in keratinocytes and this contributes to the release of mediators that is directly responsible for development of psoriasis. These results, suggest PKM2 as a biomarker for the diagnosis of psoriasis and consequently a potential therapeutic target for the treatment of this disease and other inflammatory diseases.