Avaliação da importância da psoriase em placas moderada a grave como factor de risco cardiovascular: estudo numa população portuguesa

1 Tiago da Costa Ferreira Torres Avaliação da importância da psoríase em placas moderada a grave como factor de risco cardiovascular: estudo numa população portuguesa Tese de candidatura ao grau de Doutor em Ciências Médicas submetida ao Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto Orientadora Professora Doutora Berta Silva Professora Associada, Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto Coorientadores Professor Doutor Carlos Vasconcelos Professor Associado Convidado, Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto Professora Dra Manuela Selores Professora Associada Convidada, Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto 2 Instituições onde foi desenvolvido este trabalho: Serviço de Dermatologia Centro Hospitalar do Porto Laboratório de Imunogenética Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto Depart. de Angio-TC da Unidade de Diagnóstico e Intervenção Cardiovascular Serviço de Cardiologia do Centro Hospitalar Gaia/Espinho Apoios financeiros que permitiram a realização deste projecto: Bolsa de Investigação Juvenal Esteves Sociedade Portuguesa de Dermatologia e Venereologia Bolsa de apoio a teses de doutoramento Centro Hospitalar do Porto 3 ÍNDICE Agradecimentos Lista de Artigos Publicados Abreviaturas Prefácio Resumo Summary 1. Introdução 1.4.1 1.4.2 1.4.3 1.4.4 1.4.5 Manifestações clínicas e características histológicas da psoríase Factores genéticos e ambientais Fisiopatologia da psoríase Comorbilidades cardiometabólicas e doença cardiovascular na psoríase 1.1 1.2 1.3 1.4 Obesidade Hipertensão arterial Dislipidemia Insulino-resistência / diabetes Aterosclerose Influência genética na associação entre psoríase, comorbilidades cardiometabólicas e doença cardiovascular Objectivos da tese 1.5 1.6 5 7 9 11 13 17 21 23 24 25 27 28 30 30 31 31 32 34 4 Artigos Originais2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 2.2.7 2.2.8 2.2.9 Actividade física em doentes com psoríase grave Impacto da psoríase no diagnóstico e tratamento dos factores de risco cardiovasculares e na prevenção primária de eventos cardiovasculares Disfunção eréctil como marcador de risco cardiovascular em doentes com psoríase Complemento C3 como marcador risco cardiometabólico em doentes com psoríase Gordura epicárdica e calcificação coronária em doentes com psoríase Comorbilidades cardiovasculares na psoríase em idade pediátrica Influência de polimorfismos genéticos da IL-6 na gordura epicárdica e calcificação arterial coronária em doentes com psoríase Influência de polimorfismos genéticos do TNF-α na calcificação arterial coronária em doentes com psoríase Influência de polimorfismos genéticos da leptina, receptor da leptina e adiponectina na gordura epicárdica, gordura visceral abdominal e calcificação arterial coronária em doentes com psoríase 2. Artigos Publicados Artigos de Revisão2.1 2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 Psoríase, comorbilidades cardiometabólicas e doença cardiovascular Psoríase e obesidade Psoríase e síndrome metabólico Importância da abordagem multidisciplinar dos doentes com psoríase Importância de estudos genéticos na relação psoríase/doença cardiovascular 3. Discussão e Conclusão 4. Perspectivas Futuras 5. Bibliografia 39 39 41 51 71 87 95 101 101 111 117 125 135 145 155 163 173 191 215 219 5 À minha orientadora, Prof. Doutora Berta Silva, Directora do Laboratório de Imunogenética do Instituto de Ciências Biomédicas Abel Salazar, agradeço o reconhecimento de potencial e o desenvolvimento das minhas capacidades de investigação, e especialmente por me ter iniciado na área da Imunogenética. Esteve sempre presente e com uma enorme dedicação na missão de ensino, dando um especial ênfase ao incentivo e motivação para a procura de conhecimento. À minha coorientadora, Prof. Dra Manuela Selores, Directora do Serviço de Dermatologia do Centro Hospitalar do Porto, agradeço o apoio, o estímulo e o empenho demonstrado na formação e ensino, salientando com admiração e amizade a criação das condições essenciais ao desenvolvimento deste projecto. Ao Prof. Doutor Carlos Vasconcelos, Director da Unidade de Imunologia Clínica do Centro Hospitalar do Porto, meu coorientador, que sempre acompanhou este percurso, corrigiu e incentivou, agradeço-lhe com enorme reconhecimento. À Prof. Doutora Denisa Mendonça estou grato pela revisão, cuidado e dedicação no ensino e aprofundamento do conhecimento de estatística e interpretação de dados. Ao Prof. Doutor Nuno Bettencourt, responsável pelo Departamento de Angio-TC da Unidade de Diagnóstico e Intervenção Cardiovascular do Serviço de Cardiologia do Centro Hospitalar Gaia/Espinho, que foi determinante na realização deste projecto, agradeço-lhe toda a disponibilidade demonstrada, receptividade e apoio. À Dra Susana Machado, Dermatologista do Centro Hospitalar do Porto e Dra Ana Ferreira e Dra Joana Cabete, Dermatologistas do Centro Hospitalar Lisboa Central, agradeço terem aceitado participar neste projecto em trabalhos conjuntos. Agradeço igualmente a todos os que, directa ou indirectamente, estiveram envolvidos neste projecto, salientando as Sras Enfermeiras Ana Gouveia e AGRADECIMENTOS 6 Ângela Dias pela sua disponibilidade e ajuda na colheita de sangue aos doentes, a Dra Joana Ferreira, Dra Cláudia Carvalho e restantes elementos do Laboratório de Imunogenética do Instituto de Ciências Biomédicas Abel Salazar pelo apoio fundamental na realização da genotipagem das amostras e aos técnicos do Departamento de Angio-TC da Unidade de Diagnóstico e Intervenção Cardiovascular do Serviço de Cardiologia do Centro Hospitalar Gaia/Espinho pela realização das Tomografias Computadorizadas Multidetectores. Finalmente à Prof. Doutora Laetitia Teixeira pelo apoio na análise estatística efectuada. O entusiasmo e a dedicação demonstrada em participar nos estudos, pelos alunos do Curso de Medicina Rita Sales, José Alexandre e Bernardo Correia permitiu-me ter sempre presente a importância de ensinar mas em especial a alegria de o fazer - muito obrigado. À minha família e aos meus amigos que estiveram sempre presentes. Por último, mas nunca menos importante, agradeço aos doentes e voluntários, aqueles que nos motivam diariamente e por quem todo o trabalho se justifica. 7 LISTA DE ARTIGOS PUBLICADOS Artigos Originais Torres T, Alexandre JM, Mendonça D, Vasconcelos C, Silva BM, Selores M. Levels of Physical Activity in Patients with Severe Psoriasis: A CrossSectional Questionnaire Study. Am J Clin Dermatol. 2014 Apr;15(2):129-35. Factor de Impacto: 1.844 Torres T, Sales R, Vasconcelos C, Martins da Silva M, Selores M. Framingham Risk Score underestimates cardiovascular disease risk in severe psoriatic patients: Implications in cardiovascular risk factors management and primary prevention of cardiovascular disease. J Dermatol. 2013 Nov;40(11): 923-6. Factor de Impacto: 1.765 Cabete J*, Torres T*, Vilarinho T, Ferreira A, Selores M. Erectile dysfunction in psoriasis patients. Eur J Dermatol. 2014. Factor de Impacto: 1.756 Torres T, Bettencourt N, Mendonça D, Vasconcelos C, Silva BM, Selores M. Complement C3 as a marker of cardiometabolic risk in psoriasis. Arch Dermatol Res. 2014 May 22. Factor de Impacto: 2.708 Torres T, Bettencourt N, Mendonça D, Vasconcelos C, Gama V, Silva BM, Selores M. Epicardial adipose tissue and coronary artery calcification in psoriasis patients. J Eur Acad Dermatol Venereol. 2014 Apr 21. Factor de Impacto: 2.694 Torres T, Machado S, Mendonça D, Selores M. Cardiovascular comorbidities in childhood psoriasis. Eur J Dermatol. 2014 Apr 1;24(2):229-35. Factor de Impacto: 1.756 1. 2. 3. 4. 5. 6. 8 Torres T, Sales R, Vasconcelos C, Selores M. Psoriasis and cardiovascular disease. Acta Med Port. 2013 Sep-Oct;26(5):601-7. Factor de Impacto: 0.151 Torres T, Bettencourt N. Psoriasis: The visible killer. Rev Port Cardiol. 2014 Feb;33(2):95-9. Factor de Impacto: 0.592 Torres T, Chiricozzi A, Chimenti S, Saraceno R. Genetic markers for cardiovascular disease in psoriasis: the missing piece. Mol Diagn Ther. 2014 Feb;18(1):93-5. Factor de Impacto: 1.692 Sales R, Torres T. Psoriasis and metabolic syndrome. Acta Dermatovenerol Croat. 2014. Factor de Impacto: 0.481 Correia B, Torres T. Obesity: a key component of psoriasis. (submetido) 1. 2. 3. 4. 5. 7. 8. 9. Torres T, Bettencourt N, Ferreira J, Carvalho C, Mendonça D, Pinho-Costa P, Vasconcelos C, Selores M, Silva B. Influence of IL-6 gene polymorphisms in epicardial adipose tissue and coronary artery calcification in psoriasis patients. Br J Dermatol. 2014. Factor de Impacto: 3.759 Torres T, Bettencourt N, Ferreira J, Carvalho C, Mendonça D, Pinho-Costa P, Vasconcelos C, Selores M, Silva B. Influence of TNF-α gene polymorphisms in coronary artery calcification in psoriasis patients. J Eur Acad Dermatol Venereol. 2014. Factor de Impacto: 2.694 Torres T, Bettencourt N, Ferreira J, Carvalho C, Mendonça D, Pinho-Costa P, Vasconcelos C, Selores M, Silva B. Lack of association between leptin, leptin receptor and adiponectin gene polymorphisms and epicardial adipose tissue, abdominal visceral fat and atherosclerotic burden in psoriasis patients. (submetido) Artigos de Revisão 9 ABREVIATURAS AVC BSA CAC CCL20 CXCL10 CI C3 DLQI EAM FRCV FRS HLA HR HTA IL-1 IL-6 IL-8 IL-10 IL-12 IL-17 IL-22 Acidente vascular cerebral Body Surface Area Calcificação arterial coronária Chemokine ligand 20 Chemokine ligand 10 Confidence interval Componente C3 do sistema de complemento Dermatology Life Quality Index Enfarte agudo do miocárdio Factores de risco cardiovasculares Framingham risk score Human Leukocyte Antigen Hazard-ratio Hipertensão arterial Interleucina 1 Interleucina 6 Interleucina 8 Interleucina 10 Interleucina 12 Interleucina 17 Interleucina 22 16 metabólico, era significativamente superior à da população controlo. Adicionalmente observou-se um perfil lipídico alterado, mais aterogénico, nos doentes com psoríase, comparativamente com a população sem doença. A presença destas alterações numa idade pediátrica e especialmente numa fase inicial da doença sugerem uma influência genética no desenvolvimento de comorbilidades cardiometabólicas. Na população adulta estudada demonstrámos, pela primeira vez, que a presença do alelo G do polimorfismo genético rs2069840 [-1753C/G] da IL-6 estava associada ao aumento do volume de gordura epicárdica em doentes com psoríase. Estes resultados podem constituir o primeiro passo para a identificação de biomarcadores genéticos que identifiquem os doentes em maior risco de desenvolver doença cardiovascular. A investigação desenvolvida no âmbito desta tese contribuiu para uma melhor compreensão dos diversos factores que influenciam o desenvolvimento de doença cardiovascular e de comorbilidades cardiometabólicas nos doentes com psoríase. Permitiu ainda, identificar novos mecanismos nesta associação e encontrar marcadores clínicos e laboratoriais que podem ter um papel na identificação de doentes em maior risco. Salienta-se que estes resultados poderão ter implicações clínicas importantes, o principal objectivo da investigação clínica. 17 Psoriasis is a chronic inflammatory disease, affecting 2 to 3% of the general populations, associated with decreased quality of life and high social and economic impacts. Over the last few years the understanding of psoriasis as a disease evolved. It was primarily viewed as a simple skin disease, however, nowadays it is recognized as a systemic inflammatory disease associated with multiple comorbidities, particularly cardiometabolic. The increased risk of cardiovascular events observed in psoriasis patients versus the general population, with a consequent increase of mortality and a 5 to 6 years decrease of life expectancy was decisive to this classification. Increased cardiovascular risk factors and systemic inflammation, present especially in patients with severe psoriasis, have a crucial role in the early and accelerated atherosclerosis observed in such patients. The precise mechanisms responsible for such association are still not totally understood, although it is believed to be multifactorial, involving genetic, immunologic and environmental factors. Identifying genetic, laboratorial and clinical markers, enabling early recognition of patients at increased risk is essential and may carry significant practical implications as it would allow preventive and therapeutical measures that could ultimately decrease psoriasis associated cardiovascular mortality. The main aim of this thesis was to evaluate potential genetic, laboratorial and clinical markers that could allow identifying psoriasis patient at higher risk of developing cardiometabolic comorbidities and cardiovascular disease. Particular emphasis was given to the study of the influence of genetic polymorphisms in the increased risk of cardiovascular disease in severe psoriasis patients, notably proinflammatory cytokines and adipokines known to have a role in the pathogenesis of psoriasis but also of other comorbidities and atherosclerosis. Additionally, other factors that could influence the increase of cardiovascular risk, as behaviour factors, SUMMARY 18 inflammation factors and recently identified risk markers for cardiovascular disease were also evaluated. We observed that besides the psoriasis’ intrinsic risk of cardiovascular disease, due to increased prevalence of cardiometabolic comorbidities and systemic inflammation, other factors, including behavioural and related to medical management of these patients, contribute to the increase of cardiovascular risk. We showed that physical activity and the proportion of patients who met the recommendations for healthy physical activity were significantly decreased in patients with psoriasis compared with the control group. Furthermore, when studying the current approach of cardiovascular risk factors and primary prevention of cardiovascular events, we verified that it was not ideal, as a high rate of underdiagnosis and undertreatment of cardiovascular risk factors was observed. Moreover, it was noted that current recommendations and therapeutic goals for cardiovascular risk factors management and primary prevention of cardiovascular events are not ideal for the population understudy as the current indications do not take into account the increased risk attributable to this disease (Framingham risk score = 6.2%). Indeed, taking into account this increased risk attributable to severe psoriasis, we observed that a high proportion of patients with hypertension and hypercholesterolemia considered properly treated according to current guidelines, would no longer be considered as such, and no patients with indication for primary prevention of cardiovascular events was being properly treated. Evaluating erectile dysfunction as a possible clinical marker for cardiovascular disease in patients with psoriasis, it was found that psoriasis was associated with an increased prevalence and severity of erectile dysfunction and that psoriasis was an independent risk factor for erectile dysfunction. Currently, in addition to psychological factors, it is recognized that atherosclerosis is a leading cause of erectile dysfunction. In fact, erectile dysfunction usually precedes cardiovascular events and is considered an expression of endothelial dysfunction and a marker of cardiovascular risk. In the psoriatic population the presence of genital lesions or a higher Dermatology Life Quality Index was not associated with higher erectile dysfunction, whereby the inherent psoriasis psychological component did not appear to be decisive in the results. Thus, erectile dysfunction may be a risk marker to be taken into account in patients with psoriasis, and may allow to early identify increased risk of cardiovascular disease. 19 Within this project, several inflammatory biomarkers were evaluated in patients with psoriasis, in particular their influence on cardiometabolic risk. We describe for the first time that levels of C3 are elevated in psoriasis, regardless of waist circumference, indicating that this association is not only due to excess adiposity observed in these patients, but also probably due to immune-mediated mechanisms. Additionally, it was found that C3 may be a better marker of cardiometabolic risk than C-reactive protein because, unlike the latter, it was associated with several cardiometabolic metabolic syndrome. These findings may have important clinical implications, since C3 may be used as a new biomarker in the identification of psoriatic patients with increased risk of cardiovascular disease. Epicardial adipose tissue was also evaluated in psoriasis patients in this research. We have demonstrated for the first time that epicardial adipose tissue, a type of visceral adipose tissue surrounding the heart and coronary vessels, was increased in psoriasis patients, independently from abdominal visceral adiposity. Furthermore, in the psoriasis population, epicardial adipose tissue volume was associated with subclinical arteriosclerosis (evaluated by coronary artery calcification), independently from other arteriosclerosis risk factors. These results showed that epicardial adiposity is probably another important contributor to increased cardiovascular risk in psoriasis and may be used as an independent predictor of coronary arteriosclerosis in such patients. Lastly, the influence of genetic factors in the development of arteriosclerosis and/or cardiometabolic comorbidities in patients with psoriasis was also evaluated. The results suggest that the association between psoriasis, cardiometabolic comorbidities and cardiovascular disease may be, in part, genetically determined rather than exclusively acquired. It was observed that in a pediatric population with psoriasis, the prevalence of excess adiposity as well as some metabolic syndrome components was significantly higher than in the control population. In addition, an altered lipid profile was observed in this population. The presence of these metabolic alterations at a pediatric age and notably at an early stage of the disease suggests a genetic influence in the development of cardiometabolic comorbidities. In the adult population studied, we have demonstrated for the first time that the presence of the G allele of the IL-6 rs2069840 [-1753C/G] polymorphism was associated to an increased epicardial adipose tissue volume in psoriasis patients, a first step toward the identification of genetic biomarkers allowing to identify higher risk patients. 20 This project resulted in a better understanding of the various factors that influence the development of cardiovascular disease and cardiometabolic comorbidities in patients with psoriasis and in the identification of new mechanisms of this association. Moreover, new clinical, laboratory and genetic markers that may have a role in identifying patients at higher risk were found. It is noted that these results may have important clinical implications, which should be the central objective in clinical research. 21 CAPÍTULO 1: INTRODUÇÃO 22 23 1. INTRODUÇÃO 1. INTRODUÇÃO A psoríase é uma doença inflamatória crónica que afecta 2-3% da população (1). Apesar de ter uma baixa mortalidade, tem um grande impacto na qualidade de vida dos doentes, estimando-se que seja igual ou superior ao observado noutras patologias como doenças oncológicas, artrite, doença cardíaca, diabetes e depressão (2). Adicionalmente este impacto na qualidade de vida parece ser cumulativo, uma vez que, muitas das decisões dos doentes são negativamente influenciadas pela doença ao longo da sua vida (3). A psoríase tem, também, um importante impacto na sociedade e nos sistemas de saúde. A produtividade laboral destes doentes é habitualmente menor, o absentismo maior, e os tratamentos actuais, embora cada vez mais eficazes, não são curativos e estão associados a custos cada vez mais elevados (4-6). Nos últimos anos, a psoríase tem sido alvo de extensa investigação, com naturais implicações clínicas e terapêuticas. Devido à elevada prevalência e consequências na qualidade de vida dos doentes, a psoríase sempre foi uma importante patologia para os clínicos. No entanto, ao ser recentemente considerada uma doença sistémica, associada a múltiplas comorbilidades cardiometabólicas e a eventual aumento do risco cardiovascular, a sua abordagem sofreu alterações significativas. No campo da investigação, passou a constituir o principal modelo para estudo de mecanismos fisiopatológicos de inflamação crónica e a primeira escolha para avaliação de novas terapêuticas. 1.1. Manifestações clínicas e características histológicas da psoríase A psoríase caracteriza-se pela presença de placas eritematosas, bem delimitadas, com descamação prateada, aderente e muitas vezes pruriginosas. Atinge habitualmente as superfícies extensoras (cotovelos e joelhos), couro cabeludo, 24 1. INTRODUÇÃO região lombo-sagrada e umbigo. Tem evolução crónica, com períodos de exacerbação, frequentemente modificada pelo início e/ou suspensão de tratamentos, sendo a remissão espontânea muito rara (7). Estão descritos vários fenótipos de psoríase sendo a psoríase em placas a forma mais comum, afectando 80-90% dos doentes, caracterizando-se histologicamente por hiperplasia epidérmica, paraqueratose, hipogranulose, dilatação e proliferação vascular (angiogénese) e acumulação na derme de células inflamatórias, particularmente neutrófilos, células dendríticas e linfócitos T (8). Outras formas de psoríase menos comuns incluem: a psoríase inversa, que envolve as pregas cutâneas como as axilas ou as virilhas; a psoríase gutata, caracterizada por pequenas pápulas redondas dispersas, que ocorre mais frequentemente em crianças e geralmente após uma infecção respiratória por estreptococos β-hemolíticos do grupo A; a psoríase eritrodérmica, uma forma grave de psoríase caracterizada por eritrodermia; e a psoríase pustulosa que se manifesta por uma erupção pustulosa generalizada também esta grave e associada a febre e sintomas sistémicos. Por fim, também as unhas são frequentemente envolvidas (em cerca de 50% dos doentes), apresentado essencialmente picotado ungueal, hiperqueratose subungueal, mancha de óleo e onicólise (7). 1.2. Factores genéticos e ambientais Actualmente, reconhece-se que a psoríase resulta da combinação de predisposição genética e de factores ambientais desencadeantes. A importância do componente genético foi demonstrada em múltiplos estudos em famílias e em gémeos com psoríase. Esses estudos, mostraram que 71% das crianças com psoríase têm história familiar da doença(9) e que os familiares directos de doentes com psoríase têm um risco 4 vezes superior de desenvolver a doença, enquanto gémeos homozigóticos apresentam um risco 3 vezes superior de ambos terem psoríase comparativamente com gémeos dizigóticos (10). Foram identificados, até ao momento, 36 regiões cromossómicas de susceptibilidade para psoríase (11). Contudo, apenas uma, localizada na região do Complexo de Histocompatibilidade Major (MHC) e denominada de PSOR1, tem sido consistentemente identificada em estudos genéticos (11). Esta região é responsável por 50% da susceptibilidade à psoríase. Incluído na região do PSORS1, o gene que parece ser mais relevante é o HLA-C, sendo o alelo HLA-Cw6*0602 o 25 1. INTRODUÇÃO principal alelo de risco (11). Este alelo é observado em 60% dos doentes com psoríase comparativamente com 15% na população geral e parece aumentar o risco de desenvolver psoríase em 10 a 20 vezes (12), especialmente em idade jovem (<40 anos) (13). Outros genes têm sido descritos (8) como estando associados a aumento de susceptibilidade de desenvolver psoríase, em particular genes envolvidos na regulação da resposta imune, embora a evidência científica seja ainda limitada. Em indivíduos geneticamente predispostos, os factores ambientais são essenciais para o desenvolvimento da psoríase. Os mais comummente reconhecidos são as infecções bacterianas (especialmente nas formas gutata e pustulosa) mas também os traumatismos, a infecção por VIH, a hipocalcemia, o stress e a exposição a fármacos, como o lítio, β-bloqueadores, anti-maláricos, interferon ou a suspensão abrupta de corticoesteróides (14). 1.3. Fisiopatologia da psoríase A psoríase foi considerada, até ao início dos anos 80, uma doença fundamentalmente dos queratinócitos na qual o infiltrado inflamatório cutâneo era um evento secundário. No entanto, desde a demonstração da eficácia da ciclosporina que a psoríase é considerada uma doença imunomediada. Apesar da evidência actual não permitir considerá-la uma doença auto-imune, a psoríase pertence provavelmente ao espectro das doenças relacionada com auto-imunidade, caracterizadas por inflamação crónica na ausência de um antigénio ou agente infeccioso conhecido (15). A fisiopatogenia da psoríase é complexa, não estando ainda totalmente esclarecida; contudo, é reconhecido que tanto o sistema imune inato, como o adaptativo, são essenciais para o início e manutenção das lesões psoriáticas (8). Na psoríase existe uma desregulação do sistema imune inato (16). As células apresentadoras de antigénios, particularmente as células dendríticas plasmocitóides e as células dendríticas mielóides, têm um papel fundamental no início da inflamação psoriática. As células dendríticas plasmocitóides são essenciais na produção de INF-α, um importante indutor das lesões psoriáticas, sendo activadas através da ligação dos seus receptores de superfície toll-like a complexos constituídos pelo peptídeo antimicrobiano catelecidina LL-37 e DNA, produzidos e libertados por queratinócitos, em resposta a factores ambientais 32 1. INTRODUÇÃO Th1 e Th17, células dendríticas, macrófagos, neutrófilos) e citocinas envolvidas (IL-2, IL-8, IL-17, IL-23, TNF-α, VEGF) (23, 37, 65). A inflamação da psoríase caracteriza-se por elevados níveis de TNF-α, INF-α, INF-γ, IL-1, IL-6 e IL-17, que são produzidos pelos queratinócitos e diferentes células inflamatórias que infiltram a pele, e que, especialmente nos casos mais graves, também se encontrem elevados a nível sistémico (26, 27). Estas citocinas promovem múltiplos efeitos pró-aterogénicos como resistência à insulina, dislipidemia, stress oxidativo e disfunção endotelial (66). Em particular o TNF-α promove disfunção endotelial através da diminuição da expressão da síntase de óxido nítrico e da cicloxigenase-1 (67). Além destes efeitos, estas citocinas têm ainda a capacidade de promover múltiplas funções pró-aterogénicas hepáticas e do tecido adiposo, incluído a produção de proteína C-reactiva, IL-6, fibrinogénio e múltiplas adipocinas, como a leptina e resistina (68). O termo “marcha psoriática” tem sido utilizado para descrever um processo progressivo que explica a ligação entre psoríase e doença cardiovascular. Assim, a inflamação crónica existente na psoríase seria responsável não só pelas manifestações cutâneas mas também pelo desenvolvimento de diferentes comorbilidades e em particular da doença cardiovascular (69). Este modelo postula que a inflamação sistémica associada à psoríase induz insulino-resistência, causando disfunção endotelial, aterosclerose e eventualmente eventos cardiovasculares. Finalmente, a demonstração da redução do risco de eventos cardiovasculares com a utilização de agentes inibidores do TNF-α é outra importante evidência que confirma o papel da inflamação psoriática no desenvolvimento de aterosclerose e doença cardiovascular (70). 1.5. Influência genética na associação entre psoríase, comorbilidades cardiometabólicas e doença cardiovascular É provável que factores genéticos contribuam para a associação entre psoríase e as comorbilidades cardiometabólicas e doença cardiovascular. Reconhece-se, actualmente, que a susceptibilidade genética tem um papel no desenvolvimento da psoríase (71, 72), assim como, das diferentes comorbilidades cardiometabólicas e mesmo da doença cardiovascular (73-75). No entanto a evidência da influência e importância de factores genéticos no desenvolvimento de comorbilidades e doença cardiovascular nos doentes com psoríase é ainda 33 1. INTRODUÇÃO limitada. Um estudo de associação genética de 2009 identificou pelo menos 21 loci genéticos distintos que contribuiriam para o desenvolvimento de doença cardiovascular (76). No entanto, nenhum dos genes identificados correspondia ou fazia parte de loci de susceptibilidade da psoríase. Contudo, outros estudos identificaram marcadores genéticos comuns à psoríase e algumas destas doenças metabólicas, como o CDKALI na diabetes tipo 2, APOE4 na dislipidemia e TNFAIP3 na doença coronária (59, 77-80). Mais recentemente, Lu, et al, seleccionou 363 single-nucleotide polymorphisms (SNPs) que mostraram uma associação significativa com doença arterial coronária, hipertensão, obesidade, hiperlipidemia e diabetes tipo 2 em estudos de associação genética anteriores, e avaliou a sua associação com psoríase em 4 coortes envolvendo um total de 4476 doentes com psoríase e 7463 controlos (81). Neste trabalho, os autores mostraram que os doentes com psoríase apresentavam algumas variantes genéticas que predispunham a um aumento do risco de dislipidemia, hipertensão e doença arterial coronária, como FUT2, UBE2L3 ou SH2B3 (81). Apesar destes estudos de associação serem importantes para identificar genes e vias patogénicas para investigação futura é essencial analisar a sua associação com aterosclerose e comorbilidades cardiometabólicas em doentes com psoríase. Entre os genes que também poderão ser factores de risco comuns à psoríase e doenças metabólicas estão os genes de um alargado conjunto de citocinas (TNF-α, IL-6, VEGF, endotelina-1), adipocinas (leptina, adiponectina) e seus receptores, que têm um papel reconhecido na fisiopatogenia das diferentes patologias. A IL-6 é uma citocina envolvida em vários processos fisiológicos e patológicos, particularmente na reposta inflamatória, sendo produzida por diferentes células incluindo os linfócitos, monócitos, fibroblastos, células endoteliais e adipócitos (82, 83). A IL-6 tem sido implicada na fisiopatogenia de diversas doenças inflamatórias crónicas, incluindo a psoríase, participando na diferenciação das células Th17 e na inflamação cutânea induzida pela IL-23, que não ocorre sem a participação da IL-6 (27, 84-86), mas também da obesidade (87, 88), aterosclerose (89, 90) e doença cardiovascular (91). O TNF-α é uma citocina pró-inflamatória produzida por inúmeras células incluindo monócitos e macrófagos activados, linfócitos, mastócitos e células NK, que tem sido implicado na patogénese de inúmeras doenças imunomediadas, incluído a psoríase (8). O TNF-α tem sido igualmente envolvido na patogénese das 34 1. INTRODUÇÃO comorbilidades cardiometabólicas associadas à psoríase (HTA, insulino-resistência, dislipidemia e obesidade) (48) e também na inflamação que acompanha a aterosclerose (92). Vários estudos demonstraram a associação entre as concentrações séricas de TNF-α e o risco de doença cardiovascular (93). A leptina é sintetizada predominantemente pelos adipócitos, estando implicada na regulação do peso corporal, gasto energético e apetite (42, 94). Participa igualmente na modulação da imunidade inata e adaptativa, actuando em processos de inflamação aguda e crónica (95). A leptina actua na modulação da actividade das células T, promovendo as respostas Th1, induzindo a produção de IL-2 e INF-γ, e inibindo as células Treg. Na imunidade inata, promove a actividade dos macrófagos, resultando na produção de IL-1β, IL-6, IL-12 e TNF-α. Desta forma, a leptina poderá estar envolvida na patogénese da psoríase, pela síntese de citocinas da via Th1 e diminuição da actividade de linfócitos Treg (42, 96), e igualmente na aterosclerose (97) e obesidade (43). De facto, níveis elevados de leptina têm sido associados a psoríase (42) e doença cardiovascular (98). A adiponectina é produzida essencialmente pelos adipócitos, exercendo efeitos insulino-sensibilizantes, anti-inflamatórios e ateroprotectores, através da redução da expressão de moléculas de adesão vascular (VCAM-1), citocinas pró-inflamatórias (TNF-α, IL-6 e IL-8), espécies reactivas de oxigénio nas células endoteliais (42, 99) e pela indução de citocinas anti-inflamatórias como IL-10 e o antagonista do receptor da IL-1. A sua secreção encontra-se diminuída na obesidade (100), diabetes tipo 2 (101) e doença arterial coronária (102) e, nos últimos anos, vários estudos têm demonstrado que também na psoríase, os níveis de adiponectina estão diminuídos (42). A expressão dos genes responsáveis por estas moléculas é fortemente influenciada por variações genéticas (103-105) pelo que, a presença de certos polimorfismos genéticos poderá ser responsável pelo desenvolvimento de psoríase e também das diferentes comorbilidades. Contudo, estudos avaliando a influência de variantes genéticas destas citocinas e adipocinas no risco de comorbilidades cardiometabólicas, aterosclerose, ou doença cardiovascular em doentes com psoríase, usando marcadores específicos, estão ainda por desenvolver. 1.6. Objectivos da tese A associação entre psoríase, comorbilidades cardiometabólicas e doença cardiovascular está bem definida existindo extensa literatura comprovando esta 35 associação. No entanto, os mecanismos fisiopatológicos não estão ainda totalmente esclarecidos, em particular a influência de factores genéticos. A identificação de doentes com psoríase em maior risco de desenvolver comorbilidades ou doença cardiovascular é de extrema importância, uma vez que permitiria uma abordagem e tratamento mais precoce e mais agressiva dos diferentes factores de risco cardiovasculares, assim como a adopção de estilos de vida saudáveis, como a cessação tabágica e a prática de exercício físico regular. O principal objectivo desta tese foi avaliar possíveis marcadores clínicos e laboratoriais (genéticos e analíticos) que permitissem a identificação de doentes em maior risco de desenvolver comorbilidades cardiometabólicas e doença cardiovascular. Foi dado especial destaque à influência de polimorfismos genéticos de citocinas pró-inflamatórias e adipocinas, conhecidas por terem um papel na fisiopatologia da psoríase assim como das diversas comorbilidades e aterosclerose, no aumento do risco de doença cardiovascular em doentes com psoríase grave. Avaliaram-se ainda outros factores que podem ter influência no aumento do risco de doença cardiovascular nestes doentes, como factores comportamentais, inflamatórios e marcadores de risco de doença cardiovascular recentemente identificados. Objectivos específicos • • • • • • • Avaliar a presença de factores de risco de doença cardiovascular relacionados com o estilo de vida (exercício físico) nos doentes com psoríase grave; Avaliar o impacto da psoríase no diagnóstico e tratamento dos factores de risco cardiovasculares; Avaliar a presença e gravidade de disfunção eréctil em doentes com psoríase grave, como marcador precoce de doença cardiovascular; Avaliar a influência do factor de complemento C3 no perfil cardiometabólico em doentes com psoríase grave; Avaliar a gordura epicárdica e a calcificação arterial coronária em doentes com psoríase grave; Avaliar a presença de factores de risco de doença cardiovascular em doentes com psoríase em idade pediátrica; Identificar marcadores genéticos associados a maior risco de doença cardiovascular nos doentes com psoríase grave (polimorfismos genéticos da IL-6, TNF-α, leptina, receptor da leptina, adiponectina). 36 Esta tese foi estruturada de forma a apresentar todos os artigos publicados no decorrer deste projecto de investigação (artigos de revisão e artigos originais), seguindo-se a discussão e conclusão. Os artigos estão incluídos no próximo capítulo. Artigos de revisão Psoríase, comorbilidades cardiometabólicas e doença cardiovascular: · Psoriasis and cardiovascular disease. Acta Med Port. 2013;26:601-7. Psoríase e obesidade: · Obesity: a key component of psoriasis. (submetido) Psoríase e síndrome metabólico: · Psoriasis and metabolic syndrome. Acta Dermatovenerol Croat. 2014. Importância da abordagem multidisciplinar dos doentes com psoríase: · Psoriasis: The visible killer. Rev Port Cardiol. 2014;33:95-9. Importância da avaliação da influência genética na associação psoríase/doença cardiovascular: · Genetic markers for cardiovascular disease in psoriasis: the missing piece. Mol Diagn Ther. 2014;18:93-5. • • • • • Actividade física em doentes com psoríase: Artigos originais • • • • · Levels of Physical Activity in Patients with Severe Psoriasis: A CrossSectional Questionnaire Study. Am J Clin Dermatol. 2014;15:129-35. Impacto da psoríase no diagnóstico e tratamento dos factores de risco cardiovasculares e na prevenção primária de eventos cardiovasculares: · Framingham Risk Score underestimates cardiovascular disease risk insevere psoriatic patients: Implications in cardiovascular risk factors management and primary prevention of cardiovascular disease. J Dermatol. 2013;40:923-6. Disfunção eréctil como marcador de risco cardiovascular em doentes com psoríase: · Erectile dysfunction in psoriasis patients. Eur J Dermatol. 2014 Complemento C3 como marcador de risco cardiometabólico em doentes com psoríase: · Complement C3 as a marker of cardiometabolic risk in psoriasis. Arch Dermatol Res. 2014 May 22. 37 Gordura epicárdica e calcificação arterial coronária em doentes com psoríase:• • • • • · Epicardial adipose tissue and coronary artery calcification in psoriasis patients. J Eur Acad Dermatol Venereol. 2014 Apr 21. Comorbilidades cardiovasculares na psoríase em idade pediátrica: · Cardiovascular comorbidities in childhood psoriasis. Eur J Dermatol. 2014;24:229-35. Influência de polimorfismos genéticos da IL-6 na gordura epicárdica e calcificação arterial coronária em doentes com psoríase: · Influence of IL-6 gene polymorphisms in epicardial adipose tissue and coronary artery calcification in psoriasis patients. Br J Dermatol. 2014. Influência de polimorfismos genéticos do TNF-α na calcificação arterial coronária em doentes com psoríase: · Influence of TNF-α gene polymorphisms in coronary artery calcification in psoriasis patients. J Eur Acad Dermatol Venereol. 2014 Influência de polimorfismos genéticos da leptina, receptor da leptina e adiponectina na gordura epicárdica, gordura visceral abdominal e calcificação arterial coronária em doentes com psoríase: · Lack of association between leptin, leptin receptor and adiponectin gene polymorphisms and epicardial adipose tissue, abdominal visceral fat and atherosclerotic burden in psoriasis patients (submetido). 38 39 CAPÍTULO 2: ARTIGOS PUBLICADOS 40 41 Psoríase, Comorbilidades Cardiometabólicas e Doença Cardiovascular Torres T, Sales R, Vasconcelos C, Selores M. Psoriasis and cardiovascular disease. Acta Med Port. 2013 Sep-Oct;26(5):601-7. 48 606 Revista Científica da Ordem dos Médicos www.actamedicaportuguesa.com ARTIGO DE REVISÃO alguns marcadores de risco de doença cardiovascular (por exemplo disfunção endotelial) e que a longo prazo parecem reduzir efectivamente a incidência de diabetes e de eventos cardiovasculares.63,64 Por outro lado, o tratamento dos factores de risco cardiovasculares, especialmente a obesidade, parece ter efeito na gravidade da psoríase, provavelmente por diminuição da inflamação associada à obesidade.65 CONCLUSÃO Na última década, observou-se uma mudança drástica no conceito de doença na psoríase, deixando esta de ser vista como uma doença exclusivamente cutânea mas sim como uma doença inflamatória crónica, multissistémica, com um envolvimento muito para além da pele. Os doentes com psoríase têm um risco aumentado de desenvolver várias comorbilidades cardiometabólicas, como hipertensão arterial, dislipidemia, resistência à insulina e obesidade, que conjuntamente com a inflamação sistémica crónica que promove uma aterosclerose precoce, é responsável pelo aumento do risco de doença cardiovascular observado nestes doentes. Esta associação a factores de risco cardiovasculares e risco aumentado de doença cardiovascular observa-se em todo o espectro de gravidade da psoríase, contudo parece ser mais importante nos doentes com psoríase grave provavelmente decorrente de um estado inflamatório mais elevado. Embora esta associação esteja ainda por esclarecer completamente, a partilha genética e certas citoquinas pró- -inflamatórias e adipocitoquinas parecem contribuir para o desenvolvimento destas comorbilidades e de doença cardiovascular. O papel dos dermatologistas é da maior importância, não só pela possibilidade de identificar precocemente as diversas comorbilidades ou doença cardiovascular, mas também pela possibilidade de ao tratar correcta e eficazmente a psoríase e inflamação sistémica subjacente, poderem prevenir as possíveis complicações. A abordagem destes doentes deve ser multidisciplinar, com os dermatologistas, cardiologistas, endocrinologistas e médicos de medicina geral e familiar a trabalhar conjuntamente de forma a optimizar o diagnóstico, monitorização e tratamento das diversas comorbilidades, prevenindo os eventos cardiovasculares. Os doentes deverão ser encorajados a corrigir os factores de risco cardiovasculares modificáveis, como a obesidade, tabaco e sedentarismo e adoptarem um estilo de vida saudável, uma vez que para além de melhorarem o seu perfil cardiovascular, há hoje evidencia que tal pode resultar numa melhor resposta ao tratamento. 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Smoking and the risk of psoriasis in women: Nurses’ Health Study II. Am J Med. 2007;120:953-9. 60. Naldi L. Cigarette smoking and psoriasis. Clin Dermatol. 1998;16:571-4. 61. Favato G. High incidence of smoking habit in psoriatic patients. Am J Med. 2008;121:e17. 62. Orosz Z, Csiszar A, Labinskyy N, Smith K, Kaminski PM, Ferdinandy P, et al. Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation. Am J Physiol Heart Circ Physiol. 2007;292:H130-9. 63. Wu JJ, Poon KY, Channual JC, Shen AY. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148:1244-50. 64. Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA. 2011;305:2525-31. 65. Torres T, Selores M. Does treatment of metabolic syndrome components improve psoriasis? Report of three cases. Eur J Dermatol. 2012;22:2702. Torres T, et al. Psoríase e doença cardiovascular, Acta Med Port 2013 Sep-Oct;26(5):601-607 2. ARTIGOS PUBLICADOS 50 51 Psoríase e Obesidade Correia B, Torres T. Obesity: a key component of psoriasis. (submetido) 52 53 Obesity: a key component of psoriasis Bernardo Correia - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal Tiago Torres - Department of Dermatology, Centro Hospitalar do Porto, Porto, Portugal - Unit for Multidisciplinary Investigation in Biomedicine - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal Corresponding author: Tiago Torres Serviço de Dermatologia Centro Hospitalar do Porto, Rua D. Manuel II s/n, Ex-CICAP, 4099-001 Porto, Portugal [email protected] Fax: 226097429 Telephone number: 226097429 Short title: Obesity and psoriasis Total text word count: 2766 (excluding abstract) Abstract word count: 197 2. ARTIGOS PUBLICADOS 54 Obesity: a key component psoriasis Abstract Psoriasis has been associated with several cardiometabolic comorbidities and with clinically significant increased risk of cardiovascular disease and cardiovascular mortality. Obesity seems to have a key role linking psoriasis and cardiovascular disease as there is a growing number of epidemiological studies associating psoriasis and obesity.The mechanism responsible for the association between these two conditions is not certain, but it is probably multifactorial, with genetic, environmental and immune-mediated factors having a role. The chronic inflammatory state associated with obesity seems to be a key component of this relationship. For this reason, obesity is a major factor in the management of psoriatic patients, with implications in treatment efficacy and safety. Moreover, weight loss has been shown to improve psoriasis severity and response to treatment. The aim of this review is to synthesize the current literature on the association between psoriasis and obesity, to explore the physiopathological mechanisms that link both diseases and to highlight the importance of obesity control in the efficacy and safety of systemic treatment of psoriasis. It is essential that all clinicians are aware of this association, so they can recognize it and provide the patients a proper follow-up and multidisciplinary approach when needed. Key-words Psoriasis, obesity, systemic inflammation, cardiometabolic comorbidities, cardiovascular disease, adipokines, adipocytes 2. ARTIGOS PUBLICADOS 55 Introduction Psoriasis is a chronic, immune-mediated inflammatory skin disease affecting 1.5 to 3% of the world’s population1. Disease onset can occur at any age, however generally there are two peaks of onset, the first at 20-30 years and the second at 50-60 years. Men and women are equally affected, and there is higher prevalence in Caucasians compared with African Americans2,3. Patients with psoriasis present a range of clinical manifestations, that go from limited disease to very extensive disease. It is characterized by erythematous, scaling plaques and concurrent symptoms such as burning or itching of the skin, affecting the nails in 35 to 50% of cases4,5. Furthermore, quality of life impairment and increased social and economic costs to both patients and health care systems are still concerning issues around the management of the disease6,7. In the past years, several epidemiological studies have shown that psoriasis is associated with multiple comorbidities, particularly cardiovascular/metabolic diseases, such as hypertension, diabetes mellitus type II, dyslipidemia and obesity8. Moreover, it has also been suggested that it is linked to a higher risk of cardiovascular mortality, specially within patients with greater disease severity, possibly due to the concomitant systemic inflammation9-11. Obesity seems to have a central role, as it is often strongly associated with these cardiovascular risk factors. The precise mechanism linking these two conditions is not certain, but it is probably multifactorial, with genetic, environmental and immune-mediated factors playing a role, and the chronic inflammatory state of obesity being a key component of this association12. Thus, obesity is nowadays considered to be a major factor on the management of psoriatic patients13,14. The objective of this review is to synthesize the current literature on the association between psoriasis and obesity, to explore the physiopathological mechanisms that link both diseases and to highlight the importance of obesity control in the efficacy of systemic treatment of psoriasis, as it is essential that all medical doctors recognize the presence of these comorbidities in psoriatic patients, in order to improve their screening and management. 2. ARTIGOS PUBLICADOS 56 Obesity and psoriasis: current evidence The association between psoriasis and obesity has been the focus of several epidemiologic studies and review articles over the last years15. Lindegård first described this association in 1986, as the result of a study of 159,200 Swedish citizens over a 10-year period, reporting a higher prevalence of obesity in women with psoriasis than in the female general population16. Also, in 1995 Henseler and Christophers concluded that obesity was one of the systemic disorders that often affected psoriatic patients, analyzing data from 40,000 patients17. More recently, a growing number of studies confirmed this association, demonstrating that patients with psoriasis are more frequently overweight (Body Mass Index (BMI) 26 – 29 kg/m2) or obese (BMI ≥ 30 kg/m2) when compared with patients without psoriasis18-20. Some cross-sectional studies even noted that the increase in BMI is related to a greater degree of psoriasis disease severity20,21. In an Italian case-control study with 560 psoriatic patients, obesity was found to be an independent risk factor for the development of psoriasis, as the odds ratio (OR) of having psoriasis were 1.6 (95% CI, 1.1-2.1) and 1.9 (95% CI, 1.2-2.8) for overweighted and obese patients, respectively, compared to non-obese control individuals18. A population-based study from the UK consisting of 127,706 patients with mild psoriasis and 3,854 patients with severe psoriasis demonstrated higher adjusted odds of obesity in patients with severe disease (OR 1.84; 95% CI, 1.60-2.11) than in patients with mild disease (OR 1.3; 95% CI, 1.26-1.32) compared with patients without psoriasis21. In another study, with a sample of 16,851 patients with psoriasis and 48,681 controls, obesity was present in 8.4% of the psoriatic patients as opposed to 3.6% of controls (p<0.001). Moreover, after multivariate adjusting for age and other confounders, patients younger than 35 years old were more likely to be obese (OR 2.2; 95% CI, 1.72.7) than patients older than 65 years old (OR 1.6; 95% CI, 1.4-1.8), compared with normal controls19. In 2012, a systematic review and meta-analysis of observational studies concerning the association between psoriasis and obesity was published. 16 observational studies were selected and a total of 2.1 million study participants (201 831 psoriatic patients) fulfilled the inclusion criteria. The pooled OR for obesity among psoriatic patients was 1.66 (95% CI, 1.46-1.89) compared with those without psoriasis. Regarding psoriasis 2. ARTIGOS PUBLICADOS 57 severity, the pooled OR for obesity among patients with mild psoriasis was 1.46 (95% CI, 1.17-1.82) and the pooled OR for patients with severe psoriasis was 2.23 (1.633.05). Reporting one incidence study, it was found that psoriatic patients have a hazard ratio of 1.18 (95% CI, 1.14-1.23) for new-onset obesity. It was concluded that psoriatic patients have higher prevalence and incidence of obesity as well as patients with severe disease have greater odds of obesity than those with mild disease15. Interestingly, this association appears to be present already at young age. In an international cross-sectional study, developed by Paller et al to investigate the relationship between excess and central obesity and psoriasis in 409 psoriatic children and 205 controls from 9 different countries, the OR of obesity (BMI above the 95th percentile) in psoriatic children versus controls was 4.29 (95% CI, 1.96-9.39), being higher in severe psoriasis (4.92; 95% CI, 2.20-10.99) than in mild psoriasis (3.60; 95% CI, 1.56-8.30). Moreover, an increased central adiposity in the psoriasis group was also found, as waist circumference and waist-to-height ratio, two non-invasive surrogates for central adiposity and more sensitive indicators for metabolic disease than BMI percentile, were significantly higher in psoriatic children than in controls22. This data suggests that the association between obesity and psoriasis may be in part genetically determined rather than uniquely acquired. Inflammation: the main link between obesity and psoriasis Once described as a skin disease derived primarily of epidermal keratinocyte proliferation, psoriasis is now seen as a dysregulation of both innate and adaptive immune system, mediated by cytokines, decisive to the initiation and maintenance of the psoriatic plaques23. Lymphocytes T-helper (Th)-1 and Th-17 are highly concentrated within the skin lesions and are fundamental to disease expression, producing several inflammatory cytokines such as interferon (IFN)-, tumor necrosis factor (TNF)- α, IL-2, IL-6, , IL-17 and IL-22, essential to keratinocyte activation and proliferation24-26. Keratinocytes produce autocrin growth factors and cytokines (TNF-α, IL-1, IL-6, IL-8, IL-15, IL-20) that lead to further epidermal hyperplasia and recruitment of T-cells, thus sustaining and amplifying the inflammatory responses and the psoriatic lesions27,28 (Fig. 1). (Insert Figure 1 here) 2. ARTIGOS PUBLICADOS 64 14. 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Herron MD, Hinckley M, Hoffman MS, et al. Impact of obesity and smoking on psoriasis presentation and management. Arch Dermatol. 2005;141(12):1527-34. 21. Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol. 2006;55(5):829-35. Epub 2006 Sep 25. 22. Paller AS, Mercy K, Girolomoni G, et al. Association of pediatric psoriasis severity with excess and central adiposity: an international cross-sectional study. JAMA Dermatol. 2013;149(2):166-76. 23. Bachelez H. Immunopathogenesis of psoriasis: recent insights on the role of adaptive and innate immunity. J Autoimmun. 2005;25 Suppl:69-73. 24. Lowes MA, Kikuchi T, Fuentes-Duculan J, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128(5):1207-11. 25. Nograles KE, Zaba LC, Guttman-Yassky E, et al. 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Obesity and psoriasis: inflammatory nature of obesity, relationship between psoriasis and obesity, and therapeutic implications. Actas Dermosifiliogr. 2014;105(1):31-44. 65. Simons RD. Additional studies on psoriasis in the tropics and in starvation camps. J Invest Dermatol. 1949;12(5):285-94. 66. Rucević I, Perl A, Barisić-Drusko V, Adam-Perl M. The role of the low energy diet in psoriasis vulgaris treatment. Coll Antropol. 2003;27 Suppl 1:41-8. 2. ARTIGOS PUBLICADOS 68 67. Gisondi P, Del Giglio M, Di Francesco V, Zamboni M, Girolomoni G. Weight loss improves the response of obese patients with moderate-to-severe chronic plaque psoriasis to low-dose cyclosporine therapy: a randomized, controlled, investigatorblinded clinical trial. Am J Clin Nutr. 2008;88(5):1242-7. 68. Porres JM. Jejunoileal bypass and psoriasis. Arch Dermatol. 1977;113(7):983. 69. de Menezes Ettinger JE, Azaro E, de Souza CA, et al. Remission of psoriasis after open gastric bypass. Obes Surg. 2006;16(1):94-7. 70. Higa-Sansone G, Szomstein S, Soto F, Brasecsco O, Cohen C, Rosenthal RJ. Psoriasis remission after laparoscopic Roux-en-Y gastric bypass for morbid obesity. Obes Surg. 2004;14(8):1132-4. 71. Sako EY, Famenini S, Wu JJ. Bariatric surgery and psoriasis. J Am Acad Dermatol. 2014;70(4):774-9. 2. ARTIGOS PUBLICADOS 69 Figure 1 – Inflammatory mediators associating obesity, psoriasis and cardiovascular disease. 2. ARTIGOS PUBLICADOS 70 71 Psoríase e Síndrome Metabólico Sales R, Torres T. Psoriasis and metabolic syndrome. Acta Dermatovenerol Croat. 2014. 72 73 Psoriasis and metabolic syndrome Short title: Psoriasis and metabolic syndrome Rita Sales 1 ; Tiago Torres 1,2 1Instituto de Ciências Biomédicas Abel Salazar, University of Porto 2Department of Dermatology, Centro Hospitalar do Porto, Portugal Corresponding Author: Tiago Torres Address: Serviço de Dermatologia, Centro Hospitalar do Porto, Rua D. Manuel II, s/n, Ex. CICAP, 4099-001 Porto, Portugal E-mail: [email protected] Telephone number: +351226097429 Fax number: +351226097429 Words: 1666 Tables: 2 Figures: 0 Conflicts of interest: none declared. 2. ARTIGOS PUBLICADOS 80 REFERENCES 1. Schon MP, Boehncke WH. Psoriasis. N Engl J Med 2005;352:1899-912. 2. Gudjonsson JE, Elder JT. Psoriasis: epidemiology. Clin Dermatol 2007;25:535-46. 3. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 1985;13:450-6. 4. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet 2007;370:263-71. 5. Mak RK, Hundhausen C, Nestle FO. Progress in understanding the immunopathogenesis of psoriasis. Actas Dermosifiliogr 2009;100 Suppl 2:2-13. 6. Kastelan M, Massari LP, Pasic A, Gruber F. New trends in the immunopathogenesis of psoriasis. Acta Dermatovenerol Croat 2004;12:26-9. 7. Pasic A, Lipozencic J, Ceovic R, Kostovic K. 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Prevalence of metabolic syndrome in patients with psoriasis: a hospital-based case-control study. Br J Dermatol 2007;157:68-73. 33. Sommer DM, Jenisch S, Suchan M, Christophers E, Weichenthal M. Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis. Arch Dermatol Res 2006;298:321-8. 34. Cohen AD, Gilutz H, Henkin Y, Zahger D, Shapiro J, Bonneh DY, et al. Psoriasis and the metabolic syndrome. Acta Derm Venereol 2007;87:506-9. 35. Lang-Jensen T. Monitoring of cardiac output and cardiac work during anaesthesia by means of pulsed ultrasound Doppler. Acta Anaesthesiol Scand 1988;32:36-40. 36. Zindanci I, Albayrak O, Kavala M, Kocaturk E, Can B, Sudogan S, et al. Prevalence of metabolic syndrome in patients with psoriasis. ScientificWorldJournal 2012;2012:312463. 37. Davidovici BB, Sattar N, Prinz J, Puig L, Emery P, Barker JN, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol 2010;130:1785-96. 38. Azfar RS, Gelfand JM. Psoriasis and metabolic disease: epidemiology and pathophysiology. Curr Opin Rheumatol 2008;20:416-22. 39. Quaranta M, Burden AD, Griffiths CE, Worthington J, Barker JN, Trembath RC, et al. Differential contribution of CDKAL1 variants to psoriasis, Crohn's disease and type II diabetes. Genes Immun 2009;10:654-8. 40. Wolf N, Quaranta M, Prescott NJ, Allen M, Smith R, Burden AD, et al. Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease. J Med Genet 2008;45:114-6. 41. Zhao YF, Feng DD, Chen C. Contribution of adipocyte-derived factors to beta-cell dysfunction in diabetes. Int J Biochem Cell Biol 2006;38:804-19. 2. ARTIGOS PUBLICADOS 83 42. Wang Y, Chen J, Zhao Y, Geng L, Song F, Chen HD. Psoriasis is associated with increased levels of serum leptin. Br J Dermatol 2008;158:1134-5. 43. Boehncke S, Thaci D, Beschmann H, Ludwig RJ, Ackermann H, Badenhoop K, et al. Psoriasis patients show signs of insulin resistance. Br J Dermatol 2007;157:1249-51. 44. Love TJ, Qureshi AA, Karlson EW, Gelfand JM, Choi HK. Prevalence of the metabolic syndrome in psoriasis: results from the National Health and Nutrition Examination Survey, 2003-2006. Arch Dermatol 2011;147:419-24. 45. Langan SM, Seminara NM, Shin DB, Troxel AB, Kimmel SE, Mehta NN, et al. Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom. J Invest Dermatol 2012;132:556-62. 46. Armstrong AW, Harskamp CT, Armstrong EJ. Psoriasis and metabolic syndrome: a systematic review and meta-analysis of observational studies. J Am Acad Dermatol 2013;68:654-62. 47. Kimball AB, Szapary P, Mrowietz U, Reich K, Langley RG, You Y, et al. Underdiagnosis and undertreatment of cardiovascular risk factors in patients with moderate to severe psoriasis. J Am Acad Dermatol 2012;67:76-85. 48. Parsi KK, Brezinski EA, Lin TC, Li CS, Armstrong AW. Are patients with psoriasis being screened for cardiovascular risk factors? A study of screening practices and awareness among primary care physicians and cardiologists. J Am Acad Dermatol 2012;67:357-62. 49. Kimball AB, Gladman D, Gelfand JM, Gordon K, Horn EJ, Korman NJ, et al. National Psoriasis Foundation clinical consensus on psoriasis comorbidities and recommendations for screening. J Am Acad Dermatol 2008;58:1031-42. 50. Chen YJ, Wu CY, Shen JL, Chu SY, Chen CK, Chang YT, et al. Psoriasis independently associated with hyperleptinemia contributing to metabolic syndrome. Arch Dermatol 2008;144:1571-5. 51. Chen YJ, Shen JL, Wu CY, Chang YT, Chen CM, Lee FY. Elevated plasma osteopontin level is associated with occurrence of psoriasis and is an unfavorable cardiovascular risk factor in patients with psoriasis. . J Am Acad Dermatol 2009;60:225-30. 52. Augustin M, Reich K, Glaeske G, Schaefer I, Radtke M. Co-morbidity and age-related prevalence of psoriasis: Analysis of health insurance data in Germany. Acta Derm Venereol 2010;90:147-51. 53. Bongiorno MR, Doukaki S, Rizzo D, Arico M. The prevalence of the obesity in patients with moderate to severe psoriasis in Sicily populations. J Eur Acad Dermatol Venereol 2010;24:92-3. 2. ARTIGOS PUBLICADOS 84 54. Nisa N, Qazi MA. Prevalence of metabolic syndrome in patients with psoriasis. Indian J Dermatol Venereol Leprol 2010;76:662-5. 55. Takahashi H, Takahashi I, Honma M, Ishida-Yamamoto A, Iizuka H. Prevalence of metabolic syndrome in Japanese psoriasis patients. J Dermatol Sci 2010;57:143-4. 2. ARTIGOS PUBLICADOS 85 Table I. Study population characteristics and outcomes: Psoriasis and metabolic syndrome Study Study setting Study design Total no. of patients Measure of association (95% CI) Control Psoriasis Sommer et al (33) (2006) Germany; inpatient (hospital charts) Crosssectional 1044 581 (hospitalized psoriasis pts) OR 4.22 (2.06-8.65) Gisondi et al (32)(2007) Italy; outpatient (outpatient clinics) Crosssectional 334 338 OR 1.65 (1.16-2.35) Cohen et al (34) (2007) Israel Crosssectional 48,681 16,851 OR 1.3 (1.1–1.4) Chen et al (50) (2008) Taiwan; outpatient (dermatology clinics) Case-control 81 77 OR 0.84 (0.31-2.26) Chen et al (51) (2009) Taiwan; outpatient (dermatology clinics) Case-control 37 40 OR 2.40 (0.67-8.58) Al-Mutairi et al (30) (2010) Kuwait; outpatient (medical records) Case-control 1835 1835 Mild psoriasis: OR 2.62 (2.093.28) Severe psoriasis: OR 4.93 (3.217.60) Augustin et al (52) (2010) Germany; outpatient (health insurance database) Crosssectional 1,310,090 33,981 OR 2.86 (2.21-3.71) Bongiorno et al (53) (2010) Italy; outpatient (dermatology department) Crosssectional 348 400 OR 3.4 (2.23-5.24) Nisa and Qazi (54) (2010) India; outpatient (dermatology department) Case-control 150 150 OR 6.09 (NR) Takahashi et al (55) (2010) Japan; outpatient (dermatology clinic) Case-control 154 151 OR 1.74 (0.99-3.05) Love et al (44) (2011) United States; outpatient (NHANES) Crosssectional 2385 71 OR 2.16 (1.16-4.03) AOR 1.96 (1.02-3.77) Mebazaa et al (31) (2011) Tunisia; outpatient (dermatology clinic) Case-control 216 164 OR 1.39 (0.88-2.18) AOR 1.73 (1.06-2.82) Langan et al (45) (2012) United Kingdom; outpatient (THIN database) Case-control 40,650 4065 OR 1.50 (1.40-1.61) Overall AOR 1.41 (1.31-1.51) Mild psoriasis: AOR 1.22 (1.111.35) NHANES, National Health and Nutrition Examination Survey; pts, patients; THIN, The Health Improvement Network; AOR, Adjusted odds ratio; OR, odds ratio; CI, confidence interval; NR, not reported. 2. ARTIGOS PUBLICADOS 86 Table II. AHA recommendations for risk factor screening Measurement Recommendation Target Pulse Evaluated at least every 2 years Blood pressure Evaluated at least every 2 years <120/80 mmHg Body mass index Evaluated at least every 2 years <25 Kg/m2 Waist circumference Evaluated at least every 2 years <88 cm for women; <102 cm for men Fasting blood glucose Evaluated at least every 5 years or every 2 years if risk factors are present <100 mg/dL Fasting serum lipoprotein or total and HDL cholesterol Evaluated at least every 5 years or every 2 years if risk factors are present (a positive family history, presence of diabetes or smoking habits) Total Cholesterol < 200 mg/dL HDL ≥ 50 mg/dL LDL: Optimal < 100 mg/dL; Near Optimal/Above Optimal 100 to 129 mg/dL; Borderline High 130 to 159 mg/dL; High 160 to 189 mg/dL; Very High 190 mg/dL and above 2. ARTIGOS PUBLICADOS 87 Importância da Abordagem Multidisciplinar dos Doentes com Psoríase Torres T, Bettencourt N. Psoriasis: The visible killer. Rev Port Cardiol. 2014 Feb;33(2):95-9. 88 89 Rev Port Cardiol. 2014;33(2):95---99 Revista Portuguesa de Cardiologia Portuguese Journal of Cardiology www.revportcardiol.org REVIEW ARTICLE Psoriasis: The visible killer Tiago Torresa,b,∗,Nuno Bettencourtc aDepartment of Dermatology, Centro Hospitalar do Porto, Porto, Portugal bUnit for Multidisciplinary Investigation in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar --- Universidade do Porto, Porto, Portugal cDepartment of Cardiology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal Received 27 June 2013; accepted 28 June 2013 Available online 10 February 2014 KEYWORDS Psoriasis; Cardiovascular disease; Atherosclerosis; Inflammation; Cardiovascular risk factors; Multidisciplinary approach Abstract Psoriasis is a common chronic inflammatory disease associated with serious comorbidities. In recent years, increased mortality due to cardiovascular disease (myocardial infarction and stroke) has been documented in patients with severe psoriasis. Patients with psoriasis have a higher prevalence of traditional cardiovascular risk factors such as diabetes, hypertension, dyslipidemia and obesity, but it has been suggested that the chronic inflammatory nature of psoriasis is also a contributing and potentially an independent risk factor for the development of cardiovascular disease. The authors highlight the need for early identification and treatment of psoriasis-related comorbidities and cardiovascular disease, as well as effective treatment of psoriasis, in order to reduce the underlying systemic inflammation, and also the importance of a multidisciplinary approach of severe psoriasis patients to optimize the diagnosis, monitoring and treatment of various comorbidities, so as to prevent cardiovascular events. © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L. All rights reserved. PALAVRAS-CHAVE Psoríase; Doenc¸a cardiovascular; Aterosclerose; Inflamac¸ão; Fatores de risco cardiovasculares; Abordagem multidisciplinar Psoríase: o «assassino visível» Resumo A psoríase é uma doenc¸a inflamatória crónica, comum, associada a comorbilidades importantes. Nos últimos anos tem sido demonstrado que os doentes com psoríase grave têm um risco aumentado de mortalidade por doenc¸as cardiovasculares, como enfarte agudo do miocárdio ou acidente vascular cerebral. Por um lado os doentes com psoríase têm uma prevalência aumentada de fatores de risco cardiovasculares como diabetes, hipertensão, dislipidemia e obesidade, e por outro, a natureza inflamatória da doenc¸a parece contribuir e ser um fator de risco independente para o desenvolvimento de doenc¸a cardiovascular. Os autores pretendem alertar para a necessidade da identificac¸ão precoce e tratamento das diversas comorbilidades associadas à psoríase e doenc¸a cardiovascular, assim como o tratamento ∗Corresponding author. E-mail address: [email protected] (T. Torres). 0870-2551/$ – see front matter © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L. All rights reserved. http://dx.doi.org/10.1016/j.repc.2013.06.017 Document downloaded from http://www.elsevier.pt, day 23/04/2014. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. 2. ARTIGOS PUBLICADOS 96 97 SHORT COMMUNICATION Genetic Markers for Cardiovascular Disease in Psoriasis: The Missing Piece Tiago Torres •Andrea Chiricozzi • Sergio Chimenti •Rosita Saraceno Published online: 28 September 2013 Springer International Publishing Switzerland 2013 Abstract Psoriasis is a common, chronic inflammatory disease associated with serious comorbidities. Severe psoriasis has been associated with increase cardiovascular mortality, due to a higher prevalence of traditional cardiovascular risk factors such as diabetes, hypertension, dyslipidemia and obesity, and premature atherosclerosis, as a consequence of its systemic inflammation. It is likely that there are genetic links between psoriasis, its comorbidities and cardiovascular disease. Although there are some studies performed in rheumatoid arthritis reporting some gene polymorphisms that may be associated with cardiovascular diseases and comorbidities these studies are lacking in psoriasis. Recognizing genetic markers that could predict which patients are at risk of developing psoriasis-linked cardiovascular comorbidities would facilitate screening strategies and permit an earlier management of cardiovascular risk factors, with important clinical implications. Psoriasis is a chronic, immune-mediated inflammatory disease affecting 2 % of the global population [1]. In the majority of cases skin manifestations negatively impact on patient’s quality of life, however there is mounting evidence that psoriasis is more than a skin disease and it is now widely believed that psoriasis is a systemic inflammatory process, associated with several cardiovascular comorbidities [2]. Diseases that occur concurrently (namely comorbidities) are often thought to be related to common pathogenic mechanisms, shared genetic risk variants, shared environmental triggers or a combination of these factors. Thus, it is likely that there are genetic links between psoriasis and its comorbidities. Psoriasis has been associated with an increased risk of cardiovascular disease, such as myocardial infarction and stroke [3,4]. Due to this higher incidence of cardiovascular disease, life expectancy in severe psoriasis is reduced up to 5 years [5]. Moreover, it appears that the age of mortality is linked to age of psoriasis onset, with a longevity decrease as much as 20 years in patients whose psoriasis begins before 25 years [6]. This higher cardiovascular risk may be explained in part by an increased prevalence of classical coronary risk factors, including hypertension, hypercholesterolemia, diabetes mellitus and obesity [7]. On the other hand, some studies have suggested that psoriasis could be an independent risk for cardiovascular disease, as this risk remained after adjustment for the traditional risk factors [8]. Atherosclerosis is driven by inflammation in all pathogenic phases, from initiation of fatty streak to final culmination in acute coronary syndromes, and the inflammatory pathways characterizing psoriasis seem to be involved in the pathogenesis of atherosclerosis, as suggested by the accelerated atherosclerosis observed in psoriasis patients, mainly in the more severe and long-lasting cases [9,10]. T. Torres (&) Servic¸o de Dermatologia, Centro Hospitalar do Porto, Edifı ´cio das Consultas Externas, Ex-CICAP, Rua D. Manuel II, s/n, 4100 Porto, Portugal e-mail: [email protected] T. Torres Instituto Cie ˆncias Abel Salazar, University of Porto, Porto, Portugal A. Chiricozzi S. Chimenti R. Saraceno Department of Dermatology, University of Rome Tor Vergata, Rome, Italy Mol Diagn Ther (2014) 18:93–95 DOI 10.1007/s40291-013-0056-1 Author's personal copy 2. ARTIGOS PUBLICADOS 98 Psoriasis, atherosclerosis and cardiovascular comorbidities share some pathological features including endothelial dysfunction, alteration in angiogenesis, and some inflammatory pathways including macrophages, dendritic cells, T cellsmediated inflammation and their key-cytokines (TNF-a, INFc, IL-1, IL-6, IL-8, IL-12, IL-17, IL-20, IL-23) [10,11]. Moreover, psoriasis and its associated cardiovascular comorbidities not only affect morbidity and mortality but also healthcare costs [12]. For this reason, identifying patients who present a higher risk of developing these cardiovascular comorbidities is of upmost importance. Genetic biomarkers are being more commonly used in laboratory medicine to predict the onset of disease or disease recurrence, to individualize treatment, and to assess response to treatment. Recognizing genetic markers that could predict which patients are at risk of developing psoriasis-linked cardiovascular comorbidities would permit an earlier management, with important clinical implications. Genes encoding pro-inflammatory cytokines, for instance, are candidates for predisposing to cardiovascular disease in psoriasis. Many pro-inflammatory cytokines, adipokines or proangiogenic factors, have been implicated in the pathogenesis of psoriasis and atherosclerosis such as, TNF-a, IL-6, or vascular endothelial growth factor A, while other mediators including endothelin-1, leptin, and resistin have been implicated in the pathogenesis of psoriasis and psoriasis-linked comorbidities, as hypertension, dyslipidemia and obesity [11,13–16]. The synthesis of these cytokines is tightly regulated at the gene transcription level and partly due by cytokine induction. For instance, approximately 60 % of TNF-a expression may be genetically determined because of specific single-nucleotide polymorphisms (SNP), which are able to increase TNF-agene expression as shown by its spontaneously enhanced or stimulated production, both in vitro and in vivo [17,18]. In studies performed in rheumatoid arthritis, it has been reported that some gene polymorphisms, for example, on TNF-a, IL-6, endothelin-1, and ApoE genes may be associated with cardiovascular disease, subclinical atherosclerosis, hypertension or dyslipidemia, reinforcing the potential implication of a genetic component in the development of cardiovascular disease in patients with rheumatoid arthritis [19–22]. However, this kind of studies are lacking in psoriasis. Evaluation of SNPs of cytokine genes, implicated in the pathogeneses of psoriasis, atherosclerosis and cardiovascular comorbidities may be important to elucidate whether particular subsets of psoriasis patients carry a higher risk for the development of cardiovascular and metabolic comorbidities. Abdel Hay et al. [23] showed that LEP G-2548A polymorphism could be a predictor for higher plasma leptin (as a marker for cardiovascular comorbidity) and for psoriasis, but the authors did not analyse its association with an increased risk of cardiovascular disease or with subclinical atherosclerosis, using surrogate markers of atherosclerosis as endothelial dysfunction or increased carotid artery intima-media wall thickness. A meta-analysis, conducted by Tian et al. [24], using microarray data from 5 studies consisting in 386 pairedsamples from 193 patients, produced a list of differentially expressed genes (DEGs) between lesional and non-lesional skin of psoriasis patients, that are candidate genes for further investigation of psoriasis pathology and biomarker selection, representing a robust reference psoriasis transcriptone, that was termed MAD-5 transcriptone (MetaAnalysis Derived transcriptone). In this study it was included patients with ‘‘mild to severe’’ diseases, while in MAD3 transcriptione, samples were obtained only from patients with ‘‘moderate to severe psoriasis’’. Analysis of the list of DEGs in Ingenuity Pathway Analysis (software used to examine data in the context of known biological response and regulatory networks, supported by a published reference) indicated that pathways of great importance such as Atherosclerosis Signalling and Fatty Acid Metabolism were significantly over-represented in the DEGs list, along with several genes involved in Cardiovascular Development and Function network and Lipid Metabolism, highlighting the genetic relationship between psoriasis and cardiovascular disease. Moreover it appears that some factors that influence cardiovascular risk may be produced locally in psoriasis skin lesions and become systemically available to increase risk of cardiovascular pathology. Recently, Lu et al. [25] using the genome-wide association studies (GWAS) catalogue, selected 363 SNPs that showed significant association with coronary artery disease (CAD), hypertension, body mass index, hyperlipidemia and type 2 diabetes and evaluated them for association with psoriasis in four psoriasis GWAS cohorts including 1368, 725, 211 and 2178 psoriasis cases and 1348, 438, 502 and 5175 controls [26,27]. The authors showed that patients with psoriasis were enriched for certain common genetic variants that predispose to an increased risk for dyslipidemia, hypertension, and increased CAD risk itself. They found SNPs with evidence of shared genetic risk between psoriasis, cardiovascular, and metabolic diseases, as some alleles associated with increased risk for dyslipidemia, increased blood pressure levels, and increased risk for CAD were associated with increased risk for psoriasis. Some SNPs were located in the HLA gene region, which is a known psoriasis susceptibility locus and others were nonHLA SNPs, in FUT2 (encodes an alpha-1,2) fucosyltransferase that determines the secretor status of blood group antigens on epithelial cells), in UBE2L3 (encodes an ubiquitin-conjugating enzyme involved in cell proliferation and 94 T. Torres et al. Author's personal copy 2. ARTIGOS PUBLICADOS 99 immune function) and near or in SH2B3 (encodes a protein with pleiotropic signaling roles in regulating lymphocyte differentiation, induction of VCAM-1 and E-selectin on endothelial cells by TNF-aand thrombus formation). Although, these genetic association studies are very important to identify genes and pathways for further investigation, it is also imperative to analyse its association with a higher risk of cardiovascular disease or subclinical atherosclerosis in psoriasis cohorts of patients. Identifying this kind of genetic markers in psoriasis could be a useful prognostic indicator and facilitate screening strategies that would help clinicians in finding predictors of cardiovascular disease, leading to early, aggressive risk factors management including patient education to adopt healthy life-style behaviours, such as, smoking cessation, weight control and exercise. Well conducted studies, with a robust number of severe psoriasis patients, analysing whether certain polymorphisms are associated with increased cardiovascular disease, cardiovascular risk factors (hypertension or dyslipidemia) or increased risk of subclinical atherosclerosis manifested by the presence of endothelial dysfunction, increased carotid artery intima-media wall thickness or even coronary artery calcification are needed. Acknowledgments No sources of funding were used to prepare this manuscript. Conflict of interest The authors have no conflicts of interest that are directly relevant to the content of this manuscript. References 1. Scho ¨n MP, Boehncke WH. Psoriasis. N Engl J Med. 2005;352:1899–912. 2. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361:496–509. 3. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296:1735–41. 4. Gelfand JM, Dommasch ED, Shin DB, et al. The risk of stroke in patients with psoriasis. J Invest Dermatol. 2009;129:2411–8. 5. Abuabara K, Azfar RS, Shin DB, et al. Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the UK. Br J Dermatol. 2010;163:586–92. 6. Gulliver WP, Macdonald D, Gladney N, et al. Long-term prognosis and comorbidities associated with psoriasis in the Newfoundland and Labrador founder population. J Cutan Med Surg. 2011;15:37–47. 7. Gisondi P, Girolomoni G. Psoriasis and atherothrombotic diseases: disease-specific and non-disease-specific risk factors. Semin Thromb Hemost. 2009;35:313–24. 8. Mehta NN, Azfar RS, Shin DB, et al. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. Eur Heart J. 2010;31:1000–6. 9. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006;6:508–19. 10. Chiricozzi A, Zhang S, Dattola A, et al. New insights in the pathogenesis of cutaneous autoimmune disorders. J Biol Regul Homeost Agents. 2012;26:165–70. 11. Davidovici BB, Sattar N, Prinz J, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130: 1785–96. 12. Kimball AB, Gue ´rin A, Tsaneva M, et al. Economic burden of comorbidities in patients with psoriasis is substantial. J Eur Acad Dermatol Venereol. 2011;25:157–63. 13. 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ARTIGOS PUBLICADOS 100 101 Actividade Física em Doentes com Psoríase Grave Torres T, Alexandre JM, Mendonça D, Vasconcelos C, Silva BM, Selores M. Levels of Physical Activity in Patients with Severe Psoriasis: A Cross-Sectional Questionnaire Study. Am J Clin Dermatol. 2014 Apr;15(2):129-35. 102 103 ORIGINAL RESEARCH ARTICLE Levels of Physical Activity in Patients with Severe Psoriasis: A Cross-Sectional Questionnaire Study Tiago Torres •Jose ´Manuel Alexandre • Denisa Mendonc¸a •Carlos Vasconcelos • Berta Martins Silva •Manuela Selores Published online: 24 January 2014 Springer International Publishing Switzerland 2014 Abstract Background Psoriasis is a chronic inflammatory disease associated with increased cardiovascular mortality, secondary to the increased prevalence of cardiovascular risk factors and premature atherosclerosis. Physical activity is a vital component in prevention and management of cardiovascular disease. Few studies have examined the level of physical activity in psoriasis patients, using validated questionnaires or other objective assessment tools. Objective The aim of this study was to analyze and compare physical activity undertaken by patients with severe psoriasis and healthy controls, using the International Physical Activity Questionnaire—Short Form (IPAQ-S), a validated instrument for assessing physical activity. Methods Ninety patients with severe plaque-type psoriasis and 160 healthy subjects were enrolled in the present study. Physical activity was evaluated using IPAQ-S. Results Psoriasis patients had reduced levels of physical activity compared with non-psoriasis patients, regardless of sex or whether the variable was continuous or categorical. The odds ratio for low-level physical activity for psoriasis patients, compared with controls, was 3.42 (95 % CI 1.47–7.91), indicating that this severe psoriasis population did not undertake recommended levels of physical activity. Conclusions Psoriasis patients exhibit decreased levels of physical activity, possibly for both psychological and physiological reasons. The lack of physical activity may contribute to the increased risk of cardiovascular disease in psoriasis patients, in addition to the intrinsic risks related to systemic inflammation and psoriasis-linked comorbidities. Regular physical activity should be encouraged in all psoriasis patients because of its beneficial effects on systemic inflammation and cardiometabolic comorbidities associated with psoriasis. 1 Introduction Psoriasis is a chronic, systemic, inflammatory skin disease, which affects 1–3 % of the general population [1]. Psoriasis has been associated with increased cardiovascular mortality, because of a higher prevalence of traditional cardiovascular risk factors (such as hypertension, dyslipidemia, diabetes, obesity, and tobacco use) and premature atherosclerosis, probably as a consequence of systemic inflammation [2–7]. Currently, it is well accepted that all T. Torres (&)M. Selores Servic¸o de Dermatologia, Centro Hospitalar do Porto, Edifı ´cio das Consultas ExternasEx-CICAP, Rua D. Manuel II, s/n, 4100 Porto, Portugal e-mail: [email protected] T. Torres J. M. Alexandre C. Vasconcelos M. Selores Instituto de Cie ˆncias Biome ´dicas Abel Salazar, University of Porto, Porto, Portugal T. Torres B. M. Silva Unit for Multidisciplinary Investigation in Biomedicine, Instituto de Cie ˆncias Biome ´dicas Abel Salazar, University of Porto, Porto, Portugal D. Mendonc¸a Department of Population Studies, Instituto de Cie ˆncias Biome ´dicas Abel Salazar, University of Porto, Porto, Portugal C. Vasconcelos Department of Clinical Immunology, Centro Hospitalar do Porto, Porto, Portugal B. M. Silva Immunogenetics Laboratory, Instituto Cie ˆncias Biome ´dicas Abel Salazar, University of Porto, Porto, Portugal Am J Clin Dermatol (2014) 15:129–135 DOI 10.1007/s40257-014-0061-0 Author's personal copy 2. ARTIGOS PUBLICADOS 104 psoriasis patients should be encouraged to correct their modifiable cardiovascular risk factors, particularly obesity and smoking, and to adopt healthy lifestyle behaviors such as regular physical activity [8]. It is well known that physical activity is vital for the prevention and management of cardiovascular disease, and it has beneficial effects on obesity, diabetes, metabolic syndrome, and other cardiovascular risk factors [9,10]. Few studies have examined the physical activity of psoriasis patients, and even fewer have used validated questionnaires or objective tools such as accelerometers in their analyses. Instead, in most studies on the physical activity of psoriasis patients, physical activity was analyzed as a secondary objective rather than as a primary study objective, and control groups were lacking, assessment of physical activity was based on a limited number of questions, and study definitions were inconsistent [11]. Despite these shortcomings, previous studies have suggested that physical activity was decreased in psoriasis patients and could be related to the incidence, prevalence, and severity of psoriasis. By contrast, other studies have shown no significant difference in mean physical activity between psoriasis and non-psoriasis patients [12,13]. A recent study of 30 patients with mild to moderate psoriasis showed that daily physical activity, measured with an accelerometer, was greater in the psoriasis group than in the control group [14]. The aim of this study was to analyze and compare physical activity in patients with severe psoriasis and healthy controls, using a validated instrument to assess physical activity. 2 Methods Consecutive adult patients with severe plaque-type psoriasis (defined as [10 % of the body surface area [BSA] covered by lesions and/or disease requiring systemic therapy or phototherapy) managed at our Psoriasis Center were enrolled in this cross-sectional study. The control group consisted of relatively healthy patients referred to the dermatology outpatient clinic for management of benign conditions such as nevi, benign skin tumors, or skin infections such as tinea or warts. All recruited patients were more than 18 years old. Patients were excluded if any of the following were present: psoriatic arthritis (previous/current signs/symptoms indicative of joint involvement); cardiovascular disease, including coronary heart disease (a history of myocardial infarction, angina, angioplasty, or coronary artery bypass grafting), cerebrovascular disease (a history of stroke or transient ischemic attack), or peripheral vascular disease; systemic inflammatory disease (such as lupus erythematous, rheumatoid arthritis, or spondyloarthropathies); or conditions that could impair normal physical activity, such as neurological disease or amputations. The following patient data were recorded: age, sex, height, weight, presence of cardiovascular risk factors (a previous medical diagnosis or current treatment for hypertension, diabetes, dyslipidemia, tobacco use, and a family history of cardiovascular disease), and current medications. Psoriasis characteristics, including family history, disease duration, current and previous treatments, and severity (as assessed by the Dermatology Life Quality Index [DLQI] questionnaire and BSA covered by lesions, assessed by the same dermatologist, T.T.) were also recorded. Physical activity was evaluated using a validated, selfreport questionnaire known as the International Physical Activity Questionnaire (IPAQ). IPAQ is an instrument designed to assess levels of physical activity, and short and long forms of the questionnaire have been developed on the basis of self-report population surveys. In the present study, the IPAQ Short Form (IPAQ-S) was selected to reduce the burden on participants. IPAQ-S has been developed for adults (15–69 years of age) and tested in this population, and the instrument has been validated in different languages, including Portuguese [15]. IPAQ-S asks participants to report activities that have been performed for at least 10 min in the past 7 days. The amount of physical activity is indicated by the time spent in physical activity during leisure-, work-, domesticand transport-related activities at three different levels of intensity, which are categorized as ‘‘walking’’, ‘‘moderate’’, and ‘‘vigorous’’ activities. Examples of activities that represent each intensity are provided. Using the instrument’s scoring protocol, total weekly physical activity is estimated by weighting time spent in each activity intensity, with its estimated metabolic equivalent (MET) energy expenditure. METminutes (MET-min) are calculated by multiplying the MET score of an activity by the minutes for which it is performed, and are equivalent to kilocalories for a 60 kg person. IPAQS was found to have fair to moderate agreement with accelerometer-measured physical activity (pooled r=0.30) [15]. IPAQ-S also allows physical activity to be measured as a categorical variable, with the categories defined as ‘‘low’’, ‘‘moderate’’, or ‘‘high’’ levels of physical activity [16]. The definitions for low, moderate, and high levels of physical activity are described in Table 1. Finally, physical activity was separated into either ‘‘low-level’’ or ‘‘non-low-level’’ physical activity, to understand the influence of non-compliance with the recommended physical activity, considering the recent update of the 1995 recommendations on the physical activity needed to improve and maintain health, by the Committee on Exercise and Cardiac Rehabilitation of the American Heart Association: healthy 130 T. Torres et al. Author's personal copy 2. ARTIGOS PUBLICADOS 105 adults aged between 18 and 65 years should have moderateintensity aerobic physical activity for a minimum of 30 min on 5 days each week or vigorous-intensity aerobic physical activity for a minimum of 20 min on 3 days each week— grade of evidence IA [17]. 2.1 Statistical Analysis Continuous variables were expressed as either means ±SDs or medians and interquartile ranges. Categorical variables were expressed as percentages. Variable distribution was tested for normality, using the Kolmogorov–Smirnov test. Patients and controls were compared using the Student’s ttest and the Mann–Whitney Utest for normally and non-normally distributed continuous variables, respectively. The v 2 test was used for categorical variables. The odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were calculated. The association between disease status (psoriasis patients and controls) and outcome variables was assessed using multivariable logistic and linear regression models, for categorical and continuous variables, respectively, with adjustment for confounders of age and sex. Pearson’s or Spearman’s rank correlation coefficients were used to assess the bivariate relationships between continuous and categorical variables and total MET-min among psoriasis patients. The independent association was examined by multivariate linear regression with adjustment covariates of age. The level of statistical significance was set at a=0.05. Statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS) Version 21 (SPSS, Chicago, IL, USA). 3 Results A total of 90 patients with severe psoriasis and 160 healthy subjects were studied. The two groups were similar in terms of sex and age (Table 2). Psoriasis patients had a mean disease duration of 22.1 ±11.5 years; 39 % had a family history of psoriasis; and their mean BSA covered by lesions and DLQI score were 11.1 ±7.4 % (54.8 % with BSA [10 % coverage) and 7.5 ±6.5 (43.8 % with a DLQI score [10), respectively. Most patients (83.3 %) were receiving or had previously received systemic therapy or phototherapy. With respect to cardiovascular risk factors, patients with psoriasis were more likely than controls to have hypertension, diabetes, dyslipidemia, obesity, and an increased body mass index (BMI). No significant statistical differences were observed for a family history of cardiovascular disease and tobacco use. Patients with psoriasis had an increased likelihood (adjusted for age and sex) of having hypertension (OR 2.50, 95 % CI 1.29–4.88), diabetes (OR 4.19, 95 % CI 1.53–11.44), dyslipidemia (OR 1.91, 95 % CI 1.04–3.53), and obesity (OR 2.42, 95 % CI 1.30–4.51) (Table 2). Analysis of physical activity revealed that the mean total MET-min of psoriasis patients was significantly decreased compared with that of controls (p=0.001). Levels of physical activity of psoriasis patients in each category of intensity (walking, moderate, and vigorous) was less than that of controls, with statistical significance for walking (p=0.024) and moderate intensity (p=0.008), and an underlying trend toward decreased physical activity of vigorous intensity in psoriasis patients (p=0.059). Adjusting for age and sex, the total MET-min and the MET-min in moderate intensity remained statistically significant (p=0.002 and 0.011, respectively), while trends Table 1 Definitions of low, moderate, and high levels of physical activity [14] Definition Low level The lowest level of physical activity; it includes the individuals who do not meet criteria for moderate or high physical activity level Moderate level Half an hour of at least moderate-intensity physical activity on most days; it includes individuals who meet at least one of the following criteria: (a) 3 or more days of vigorous-intensity activity of at least 20 min per day; (b) 5 or more days of moderate-intensity activity and/or walking of at least 30 min per day; (c) 5 or more days of any combination of walking, moderate-intensity, or vigorous-intensity activities achieving a minimum total physical activity of at least 600 MET-minutes/week High level At least 1 hour per day, or more, of at least moderate-intensity activity above the basal level of physical activity—basal activity may be considered to be equivalent to approximately 5,000 steps per day, i.e. those who move at least 12,500 steps per day or the equivalent in moderate and vigorous activities; it includes individuals who meet one of the following criteria: (a) vigorous-intensity activity on at least 3 days, achieving a minimum total physical activity of at least 1,500 MET-minutes/ week; (b) 7 days of any combination of walking, moderate-intensity, or vigorous-intensity activities achieving a minimum total physical activity of at least 3,000 MET-minutes/week MET metabolic equivalent Physical Activity in Psoriasis Patients 131 Author's personal copy 2. ARTIGOS PUBLICADOS 112 113 CONCISE COMMUNICATION Framingham Risk Score underestimates cardiovascular disease risk in severe psoriatic patients: Implications in cardiovascular risk factors management and primary prevention of cardiovascular disease Tiago TORRES, 1,2,3 Rita SALES, 2 Carlos VASCONCELOS, 2,3,4 Berta MARTINS DA SILVA, 3,5 Manuela SELORES 1,2 Departments of 1 Dermatology, 4 Clinical Immunology, Centro Hospitalar do Porto, and 2 Medical School 3 Unit for Multidisciplinary Investigation in Biomedicine, 5 Immunogenetics Laboratory, Instituto de Ci^encias Biom�edicas Abel Salazar, University of Portugal, Porto, Portugal ABSTRACT Severe psoriasis has been associated with increase cardiovascular mortality, due to a higher prevalence of traditional cardiovascular risk factors and premature atherosclerosis, as a consequence of its systemic inflammation. Recently, it has been estimated that severe psoriasis may confer an increased 6.2% on long-term risk of cardiovascular disease based on Framingham Risk Score, which can have practical implications in the treatment of cardiovascular risk factors and primary prevention of cardiovascular disease, as treatment guidelines account for the risk of cardiovascular disease in treatment goals. The aim of this study was to analyze the influence of the attributable risk of severe psoriasis on long-term risk of cardiovascular disease and its implication on the correct treatment of cardiovascular risk factors and primary prevention of cardiovascular disease on a real-world cohort of patients. One hundred severe psoriasis patients without psoriatic arthritis or previous cardiovascular disease were evaluated and it was found that more than half of the patients were reclassified to a higher cardiovascular risk category with important clinical implications on the correct management of their cardiovascular risk factors and primary prevention of cardiovascular disease, as a considerable proportion of patients with hypertension, hypercholesterolemia and coronary heart disease equivalent risk were not being correctly managed. Key words: cardiovascular disease, cardiovascular risk factors, Framingham Risk Score, psoriasis, treatment goals. INTRODUCTION Psoriasis is a chronic inflammatory skin disease that affects approximately 3% of the population. 1 In past years, an increased mortality due to cardiovascular diseases (CVD), such as myocardial infarction and stroke, has been documented in patients with severe psoriasis. 2 For this reason, these patients appear to have a shorter life expectancy, estimated as approximately 5 years. 2 Psoriatic patients have increased prevalence of traditional cardiovascular risk factors (CVRF) such as diabetes, hypertension, dyslipidemia, tobacco use and obesity. 3 Moreover, psoriasis, mainly if severe, appears to be an independent risk factor for atherosclerotic CVD, as the risk persists even after adjusting for the traditional risk factors, probably due to its systemic inflammation, responsible for the premature atherosclerosis seen in these patients. 4 Framingham Risk Score (FRS) estimates the long-term risk of CVD analyzing the traditional CVRF, such as age, sex, smoking status, systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and diabetes mellitus, stratifying patients into three risk categories: low (<10%), intermediate (10–20%) and high (>20%). 5 However, this may underestimate this risk in severely psoriatic patients, not accounting for the excess risk attributable to severe disease. Similarly to rheumatoid arthritis (RA), that risk score models should be adapted for RA patients by introducing a 1.5 multiplication factor, 6 Methta et al. 7 estimated the attributable risk that severe psoriasis confers on 10-year major adverse cardiac events, which was found to be 6.2%. Moreover, they showed that it could have practical implications in the treatment of CVRF in such patients. 8 Cardiovascular risk factors treatment guidelines, for hypertension and hypercholesterolemia, account for the risk of CVD Correspondence: Tiago Torres, M.D., Servic o de Dermatologia, Centro Hospitalar do Porto, Rua D. Manuel II, s/n, 4099-Porto, Portugal. Email: [email protected] Received 18 June 2013; accepted 24 July 2013. ©2013 Japanese Dermatological Association 1 doi: 10.1111/1346-8138.12267 Journal of Dermatology 2013; 40: 1–4 2. ARTIGOS PUBLICADOS 114 in treatment goals. For example, the treatment goal for LDL-C is 160 mg/dL for low-risk patients, and 130 and 100 mg/dL for intermediate and high-risk patients, respectively. 9 Likewise, SBP/diastolic blood pressure (DBP) goal is less than 130/ 80 mmHg for high-risk patients instead of 140/90 mmHg for non-high-risk patients. 10 Moreover, according to National Cholesterol Education Program guidelines, patients with FRS greater than 20% in the absence of atherosclerotic CVD or diabetes are patients with coronary heart disease (CHD) risk equivalent. In such patients, especially in the presence of other CVRF, treatment with aspirin and statins may be considered. 9,11 As a recent high proportion of underdiagnosis and inadequate treatments of these CVRF in patients with severe psoriasis has been documented, 12 correct screening, monitoring and treatment of CVRF has gained higher importance. The authors decided to analyze the influence of the attributable risk of severe psoriasis estimated by Methta et al. 7 (6.2%) on long-term risk of CVD based on FRS and its implication in the correct treatment of CVRF and primary prevention of cardiovascular disease. METHODS One hundred consecutive patients with severe plaque-type psoriasis (Psoriasis Area and Severity Index [PASI] >10 and/or biologic/phototherapy) without psoriatic arthritis (no previous/ current signs/symptoms of joint evolvement) or previous CVD (ischemic heart disease, cerebrovascular disease or peripheral arteriopathy) were observed in a dermatology outpatient clinic of a tertiary hospital. For the purpose of this analysis, patients currently under treatment or treated in the previous 4 months with retinoids or cyclosporin were not included due to possible effects on blood pressure and lipid profile. All patients underwent clinical evaluation, including complete medical history and physical examination and a thorough laboratory evaluation. The following information was systematically recorded: demographic characteristics, psoriatic disease duration, severity and current therapy, medical history of cardiovascular risk factors and therapy. Blood pressure was the mean of three measurements taken at 5-min intervals on the right arm with the patient in a seated position after at least 5 min rest. Blood tests included fasting glucose and insulin, hemoglobin A1c, leptin, high-sensitivity C-reactive protein and fasting serum lipids (total cholesterol, HDL-C, LDL-C, very low-density lipoprotein cholesterol, oxidized LDL-C, triglycerides, lipoprotein[a] and apolipoprotein B). FRS was calculated for each subject using the risk score of Wilson et al. 5 Metabolic syndrome was defined by the definition of the National Cholesterol Education Program Adult Treatment Panel (ATP III) guidelines. 13 RESULTS The mean age was 48.0 10.3 years (range, 30–70) and 64% were men; 82% had undergone previous systemic/phototherapy/biologic treatment, although at the time of the observation only 23% were under systemic therapy, with most patients (79%) having a PASI of more than 10. Considering the prevalence of CVRF, 49% had hypertension (male 51.6%; female 44.4%), 36% were hypercholesterolemic (male 42.3%; female 25%), 37% of the patients were obese (male 31.2%; female 47.2%), 13% were diabetic (male 12.5%; female 13.9%), 20% were current smokers (male 25%; female 11.1%) and 34% had metabolic syndrome (male 34.7%; female 33.3%). Mean body mass index was 28.79 5.19 (male 28.22 4.38; female 29.80 6.34). Mean FRS was 8.39% 7.07 (male 9.64% 6.81; female 6.17% 7.05), with 71%, 22% and 7% classified at low, intermediate and high risk, respectively. After considering the estimated attributable risk for severe psoriasis, the mean FRS increased to 14.59% 7.07 (male 15.84% 6.81; female 12.37% 7.05); 57% of the patients were reclassified as higher risk (68.8% of the men and 36.1% of the women), 63.4% of patients at low risk were reclassified as intermediate risk and 54.5% of those at intermediate risk were reclassified as high risk (26%, 55% and 19% at low, intermediate and high risk, respectively) (Tables 1,2). Interestingly, 65.3% of the patients with hypertension and 63.9% of the patients with hypercholesterolemia were reclassified as higher risk (hypertension, 40.8% to intermediate risk and 24.5% to high risk; hypercholesterolemia, 38.9% to intermediate risk and 25% to high risk). Moreover, this reclassification had important implications in the correct treatment of patients with hypertension and hypercholesterolemia; after the reclassification, 28.6% of the patients considered well treated Table 1. Demographic and clinical data Total, n=100 Men, n=64 Women, n=36 Age, years* 48.0 10.3 48.2 9.8 47.8 11.3 Family history of psoriasis 41% 40.7% 41.7% Psoriasis duration, years* 20.3 11.3 20.3 10.0 25.9 12.7 Psoriasis severity (at the time of evaluation) PASI ≤10 21% 18.8% 25% PASI >10 79% 81.% 75% Previous treatment Topical only 18% 18.8% 16.7% Phototherapy 57% 50% 69.4% Systemic (conventional/ biologic) 70% 68.8% 72.2% Current treatment Topical treatment 78% 81.2% 72.2% Systemic (methotrexate, cyclosporin, acitretin) 0% 0% 0% Phototherapy 2% 1.6% 2.8 Biologic therapy 20% 17.2% 25% *Mean standard deviation. 2©2013 Japanese Dermatological Association T. Torres et al. 2. ARTIGOS PUBLICADOS 115 for hypertension were not following guideline treatment goal recommendations (SBP/DBP <130/80 mmHg for high-risk patients), while 42.9% of patients being treated for hypercholesterolemia were considered undertreated (treatment goals: 160 mg/dL for low-risk, 130 mg/dL for intermediate-risk and 100 mg/dL for high-risk patients). Additionally, none of the patients who were reclassified as high risk (CHD risk equivalent) was receiving aspirin and 40% were not receiving statins. DISCUSSION As recognized by the ATP III, there are emerging risk factors that are not captured in the FRS, contributing to CHD risk to varying degrees. Similar to RA, severe psoriasis is one of them. In fact, it has been reported that assessing cardiovascular disease risk using scores such as FRS in severely psoriatic patients may underestimate the real risk for CVD, as it does not take into account its independent risk, naturally, with important clinical implications in the management of CVRF and CVD prevention in these patients. 7,8 Considering the estimated attributable risk for severe psoriasis on long-term risk of CVD based on the FRS (6.2%) in a real-world cohort of severely psoriatic patients without psoriatic arthritis, it was observed that a considerable proportion of the patients was reclassified to a higher risk category and that 28% and 42% of the patients considered well treated for hypertension and hypercholesterolemia, respectively, were undertreated if considering their new CVD risk category. Moreover, and of more importance, it had implications in the correct primary prevention of CVD, as a significant proportion of severely psoriatic patients may be at CHD equivalent risk and not being managed as such. Although the most suitable system of CVD risk estimation for European populations is SCORE (Systematic Coronary Risk Evaluation), developed in 2004 because of concerns that FRS could overestimate the risk of CVD disease in European populations, there is evidence that risk estimates based on Framingham data generalize well to other populations at similar levels of risk both in the USA and Europe. 14 Moreover, most data evaluating the CVD risk in psoriasis patients, including European populations Table 2. Patients’ cardiovascular risk factors and risk evaluation Total, n=100 Men, n=64 Women, n=36 Diabetes (%) 13% 12.5% 13.9% Hypertension (%) 49% 51.6% 44.4% Hypercholesterolemia (%) 36% 42.3 25% Hypertriglyceridemia (%) 19% 26.6% 5.6% Tobacco use (%) 20% 25% 11.1% Body mass index * 28.79 5.19 28.22 4.38 29.80 6.34 Normal weight 17% 18.8% 13.9% Overweight 46% 50% 38.9% Obese 37% 31.2% 47.2% Waist circumference, cm * 96.37 12.8 96.55 10.91 96.06 15.84 Waist-to-height ratio * 0.580 0.08 0.565 0.068 0.607 0.093 Metabolic syndrome (%) 34% 34.7% 33.3% Systolic blood pressure, mmHg * 134.0 16.0 135.2 15.5 131.8 16.9 Diastolic blood pressure mmHg * 80.9 8.9 82.1 8.8 78.6 8.9 10-year Framingham Risk Score (LDL-C) * Without psoriatic attributable risk 8.39% 7.07 9.64% 6.81 6.17% 7.05 With psoriatic attributable risk 14.59% 7.07 15.84% 6.81 12.37% 7.05 Glucose, mg/dL † 87 (79–100) 93 (81.3–100.8) 81.5 (76.0–93.0) HgA1c% † 5.4 (5.2–5.6) 5.4 (5.2–5.6) 5.4 (5.2–5.7) Total cholesterol, mg/dL * 207.4 40.3 204.2 33.6 213.2 50.4 HDL-C, mg/dL * 51.2 13.1 47.1 10.6 58.5 14.0 LDL-C, mg/dL * 130.1 38.8 47.1 10.6 133.9 45.3 VLDL-C, mg/dL † 22.0 (14.3–33.8) 24.5 (17–42.5) 18.5 (13.0–24.8) Oxidized LDL-C, mg/dL * 184.8 56.8 189.8 53.3 176.0 62.3 Triglycerides, mg/dL † 108.5 (72.5–155.8) 113.5 (84–193.5) 93.5 (65.3–124.8) Apolipoprotein B, mg/dL * 94.6 24.3 96.1 21.6 91.8 28.6 Lipoprotein(a), mg/dL † 22.5 (5.3–45.5) 21.0 (4.3–43.3) 25.5 (6.0–47.8) High-sensitivity CRP, mg/dL † 2.4 (2.3–4.8) 1.82 (0.9–4.1) 3.3 (1.1–5.8) Insulin, lU/mL † 10.4 (10.4–15.5) 11 (7.5–16.3) 9.8 (6.4–14.3) Leptin, ng/mL † 0.70 (0.70–1.6) 0.51 (0.26–0.73) 1.5 (0.8–2.8) HOMA >2.5 (excluding diabetic patients) 34.5% 41.1% 22.6% *Mean standard deviation. † Median (interquartile range). CRP, C-reactive protein; HOMA, Homeostasis Model of Assessment; HDL-C, high-density lipoprotein cholesterol; HgA1c, hemoglobin A1c; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol. ©2013 Japanese Dermatological Association 3 Framingham Risk Score in severe psoriasis 2. ARTIGOS PUBLICADOS 116 used FRS 15 and more importantly the attributable risk of severe psoriasis estimated by Metha et al. was calculated using the FRS. In summary, due to this higher risk attributable to the disease, probably owing to its systemic inflammation, these patients should be more aggressively treated and controlled for their CVRF. Current treatment goals for CVRF, such as hypertension and hypercholesterolemia, may be inappropriate for patients with severe psoriasis and should be reevaluated for such patients, similarly to what has been done for RA patients with the recent European League Against Rheumatism evidence-based recommendations on managing CVD risk in patients with RA and psoriatic arthritis. 6 ACKNOWLEDGMENT: Sponsored by an unrestricted grant from the Portuguese Society of Dermatology and Venereology. CONFLICT OF INTEREST: None. REFERENCES 1 Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009; 30: 496–509. 2 Abuabara K, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the U.K. Br J Dermatol 2010; 163: 586–592. 3 Gisondi P, Girolomoni G. Psoriasis and atherothrombotic diseases: disease-specific and non-disease-specific risk factors. Semin Thromb Hemost 2009; 35: 313–324. 4 Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA 2006; 296: 1735–1741. 5 Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 1837–1847. 6 Peters MJ, Symmons DP, McCarey D et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010; 69: 325–331. 7 Mehta NN, Yu Y, Pinnelas R et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. Am J Med 2011; 124: e1–e6. 8 Mehta NN, Krishnamoorthy P, Yu Y et al. The impact of psoriasis on 10-year Framingham risk. J Am Acad Dermatol 2012; 67: 796–798. 9 Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. Circulation 2004; 110: 227–239. 10 Rosendorff C, Black HR, Cannon CP et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association council for high blood pressure research and the councils on clinical cardiology and epidemiology and prevention. Circulation 2007; 115: 2761–2788. 11 Hennekens CH, Dalen JE. Aspirin in the treatment and prevention of cardiovascular disease: past and current perspectives and future directions. Am J Med 2013; 126: 373–378. 12 Kimball AB, Szapary P, Mrowietz U et al. Underdiagnosis and undertreatment of cardiovascular risk factors in patients with moderate to severe psoriasis. J Am Acad Dermatol 2012; 67: 76–85. 13 Grundy SM, Cleeman JI, Daniels SR et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/ National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112: 2735–2752. 14 D’Agostino RBS, Grundy S, Sullivan LM et al. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA 2001; 286: 180–187. 15 Gisondi P, Farina S, Giordano MV et al. Usefulness of the Framingham risk score in patients with chronic psoriasis. Am J Cardiol 2010; 106: 1754–1757. 4©2013 Japanese Dermatological Association T. Torres et al. 2. ARTIGOS PUBLICADOS 117 Disfunção Eréctil como marcador precoce de Risco Cardiovascular em Doentes com Psoríase Cabete J*, Torres T*, Vilarinho T, Ferreira A, Selores M. Erectile dysfunction in psoriasis patients. Eur J Dermatol. 2014. 118 119 Journal Identification = EJD Article Identification = 2388 Date: May 28, 2014 Time: 10:39 am doi:10.1684/ejd.2014.2388 EJD 2014 (epub ahead of print) 1 To cite this article: Cabete J, Torres T, Vilarinho T, Ferreira A, Selores M. Erectile dysfunction in psoriasis patients. Eur J Dermatol 2014 (epub ahead of print) doi:10.1684/ejd.2014.2388 Clinical report Eur J Dermatol 2014 (epub ahead of print) Joana CABETE1,a Tiago TORRES2,3,a Tiago VILARINHO4 Ana FERREIRA1 Manuela SELORES2,5 1Dermatology Department, Centro Hospitalar de Lisboa Central, Alameda Santo António dos Capuchos, 1169-050, Lisbon, Portugal 2Dermatology Department, Hospital de Santo António, Centro Hospitalar do Porto, Oporto, Portugal 3Unit for Multidisciplinary Investigation in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Oporto, Portugal 4USF S. Félix da Marinha, ACES Espinho/Gaia, Portugal 5Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Oporto, Portugal aJoana Cabete and Tiago Torres equally contributed to this work. Reprints: Joana Cabete <[email protected]> Article accepted on 4/24/2014 Erectile dysfunction in psoriasis patients Background: An association between psoriasis and sexual dysfunction has been explored. However, not much is known about the factors behind erectile dysfunction in these patients. Objectives: To compare the prevalence and the severity of erectile dysfunction in patients with and without psoriasis and to determine potential associations between erectile dysfunction and psoriasis patients’ characteristics. Materials & Methods: An observational cross-sectional study was conducted at two tertiary hospital-based Dermatology departments. Consecutive adult men with psoriasis or other skin conditions were recruited. Data were collected using an anonymous, self-completed, designed questionnaire, which included the Dermatology Life Quality Index and the 5-item version of the International Index of Erectile Function. Results: A total of 135 psoriasis patients and 201 controls were included. Psoriasis patients had a higher prevalence of erectile dysfunction than controls (61.5% vs 43.8%, p = 0.001), and an increased risk of more severe forms of erectile dysfunction. Dermatology Life Quality Index, genital psoriasis and psoriasis duration were not associated with the presence of erectile dysfunction. In multivariate logistic regression, psoriasis and diabetes were found to be independent risk factors for erectile dysfunction with estimated odds ratios of 2.28 (CI 95%, 1.40-3.27) and 3.49 (CI 95%, 1.40-8.66), respectively. Conclusion: This study suggests psoriasis as a risk factor for erectile dysfunction. Atherosclerosis is a plausible connecting link, adding up to the already acknowledged effect of psychological factors in these patients. From a clinical standpoint, because erectile dysfunction may precede overt cardiovascular disease, it can be used as a precocious marker of cardiovascular risk in psoriatic men. Key words: erectile dysfunction, psoriasis Psoriasis is a chronic, systemic, inflammatory skin disease that affects approximately 2-4% of the population [1]. This condition has a significant negative impact on patients’ quality of life, affecting both physical and psychosocial well-being [2]. Psoriasis has been associated with a number of behavioural and systemic comorbidities, including depression, obesity, hypertension, diabetes mellitus, hyperlipidemia, metabolic syndrome and cardiovascular disease [3]. Regarding the latter, proatherogenic systemic inflammation is thought to promote premature and subclinical atherosclerosis, ultimately increasing the risk of cerebrovascular and ischemic heart diseases in psoriasis patients [4, 5]. The National Institutes of Health defines erectile dysfunction (ED) as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance [6]. In addition to psychological factors, ED usually has a physical etiology. Atherosclerosis is a common cause of ED. In fact, penile atherosclerosis/vascular ED has been considered an expression of systemic endothelial dysfunction and is often a neglected marker of cardiovascular risk [7, 8]. An association between psoriasis and sexual dysfunction has been explored. However, other than the psychological dimension of psoriasis [9-14], not much is known about the factors behind ED in these patients. The present study aimed to compare the prevalence and the severity of ED in patients with and without psoriasis, and to determine potential associations between ED and psoriasis patients’ characteristics. Patients and methods An observational cross-sectional study was conducted at two tertiary hospital-based Dermatology departments. Consecutive adult men attending outpatient Dermatology appointments were enrolled. Informed consent was granted beforehand, along with establishing the physical and mental capability to participate in the study. Patients were categorized in two groups according to their clinical diagnosis: the psoriasis and the control groups. The psoriasis group included patients with severe psoriasis (Psoriasis Area Severity Index [PASI]>10 and/or under systemic therapies) without psoriatic arthritis (no previous/current signs/symptoms of joint involvement). The control group consisted of patients with skin conditions other than psoriasis, such as benign skin tumours, superficial skin infections or eczema. Exclusion criteria included, for both groups, the presence of cardiovascular disease, defined as the presence 2. ARTIGOS PUBLICADOS 120 Journal Identification = EJD Article Identification = 2388 Date: May 28, 2014 Time: 10:39 am 2EJD 2014 (epub ahead of print) of coronary heart disease (myocardial infarction, angina, angioplasty or coronary artery bypass grafting), cerebrovascular accident (stroke or transient ischemic attack) or peripheral vascular disease, of autoimmune or inflammatory systemic diseases, as well as the existence of clinical conditions that could be associated with ED (namely hormonal, testis, and prostate or penis conditions, along with column fracture or surgery). Data were collected during clinic attendance, using an anonymous, self-completed, designed questionnaire. The following information was systematically recorded for psoriasis patients and control subjects: age, height, weight, known cardiovascular disease (as previously stated), and presence of cardiovascular risk factors (CVRF) (previous medical diagnosis or current treatment for hypertension, diabetes, dyslipidemia and tobacco use). Participants were asked about the presence of any disease that could determine sexual dysfunction, as formerly stated. The use of medical devices or drugs for the treatment of ED was also registered. For patients with psoriasis, information regarding disease duration, involvement of genital skin, and treatment (phototherapy, topical, systemic agents) were recorded. Both groups answered the Dermatology Life Quality Index (DLQI) and the 5-item version of the International Index of Erectile Function (IIEF-5). The last-mentioned consists of a multidimensional scale for assessment of ED severity that addresses relevant domains of male sexual function, that is, erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction. An IIEF-5 score ≤21 discloses the presence of ED. The Ethics Committee of both centres approved the study protocol. Statistical analysis Descriptive statistics are presented as a percentage for categorical variables and as a mean with standard deviation or median with interquartile range (IQR) for continuous variables. Variable distribution was tested for normality using the Kolmogorov-Smirnov test. Log transformation was performed for non-normal variables. Patients and control subjects were compared using Student’s t-test for continuous variables and the chi-squared test for categorical variables. The association between disease status (psoriasis and controls) and the outcome variables was assessed using multivariable logistic and linear regression models for categorical and continuous variables, respectively, with adjustment for confounders. A multivariate logistic regression model was built with the categorical variable “presence of erectile dysfunction (IIEF-5≤21)” as dependent variable to analyse an independent association between disease psoriasis and ED. A univariate analysis of each variable was first carried out and those that were significant (p<0.10) were included in the logistic regression model. Among psoriasis patients, the relationship between the presence of ED and anthropomorphic measures, cardiovascular risk factors and psoriasis characteristics was examined by multivariate logistic regression with adjustment for age as covariate. The level of statistical significance was set at = 0.05. The statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS) version 21 (SPSS, Chicago, IL). Results A total of 135 psoriasis patients and 201 controls were studied (table 1). Both groups were similar regarding age. Psoriasis patients had a higher body mass index (BMI) compared to controls (p = 0.009), and this difference was statistically significant even after adjustment for age (p = 0.007). Concerning the prevalence of CVRF, no difference was found between the two groups. The mean psoriasis duration was 18.9 ±10.2 years. A total of 26.7% of patients had genital psoriasis. The median DLQI was 3 (IQR 1-7). With reference to psoriasis therapy, 89.6% were receiving systemic or phototherapy, including biological therapy in 35.6%. Association of disease status with ED Psoriasis patients had a higher prevalence of ED (IIEF5≤21) than controls (61.5% vs 43.8%, p = 0.001), with a 2.09-fold higher risk of having ED, independent of age and CVRF (OR 2.09, CI 95%, 1.31-3.35) (table 1). Moreover, psoriasis patients had more severe ED: IIEF5 was significantly lower than in control subjects (19.23 ±5.11 vs 20.92 ±3.72, p = 0.001), even after adjustment for age and CVRF (p<0.001). When compared to controls, psoriasis patients had a 2.69 and 5.3-fold increased risk of having mild-moderate and moderate-severe ED, respectively (table 1). A multiple regression model was performed considering the variables with a p<0.100 in univariate analysis (age, height, BMI, hypertension, diabetes, dyslipidemia and obesity). ED (IIEF-5≤21) was independently associated with psoriasis (p = 0.001), height (p = 0.002) and diabetes (p = 0.007). Psoriasis was found to be an independent risk factor for ED with an estimated OR of 2.28 (CI 95%, 1.40-3.27). The estimated OR for ED in patients with diabetes was 3.49 (CI 95%, 1.40-8.66) (table 2). Association of anthropomorphic measures, cardiovascular risk factors and psoriasis characteristics with ED in patients with psoriasis Within psoriasis patients, age, height, and diabetes were associated with ED (p<0.05). There were no differences regarding DLQI between psoriasis patients with and without ED. Genital involvement was higher in those patients without DE, although this difference was not statistically significant. Similarly, psoriasis duration was not associated with the presence of ED (table 3). Discussion Few studies have addressed sexual dysfunction in patients with psoriasis. Evidence supports an increase of ED in this subset of patients [9, 10, 14]. Up until recently, the emphasis of these studies was on the psychological aspects of psoriasis and its impact in sexual health [9-14]. Feelings such as anxiety, shame, and depression, especially in the presence of genital lesions, have been associated with sex2. ARTIGOS PUBLICADOS 121 Journal Identification = EJD Article Identification = 2388 Date: May 28, 2014 Time: 10:39 am EJD 2014 (epub ahead of print) 3 Table 1. Group characteristics according to responses to the questionnaire. Psoriasis (n = 135) Controls (n = 201) p-value p-value* Age, y 47.27 ±11.36 47.48 ±15.27 0.886 ... Height 1.73 ±0.08 1.72 ±0.07 0.105 0.091 Weight 82.59 ±15.60 77.47 ±12.30 0.002 0.001 BMI 27.33 ±4.15 26.16 ±3.92 0.009 0.007 Psoriasis characteristics Disease duration, y 18.9 ±10.2 ... Genital psoriasis 26.7% ... DLQI 3 (1-7) ... Psoriasis treatment Topical therapy 10.4% ... Phototherapy 28.1% ... Conventional systemic therapy 25.9% ... Biologic therapy 35.6% ... Cardiovascular risk factors p-value OR (95% CI)* Hypertension 33.3% 27.4% 0.241 1.65 (0.97-2.82) Diabetes 12.4% 11.4% 0.750 1.35 (0.66-2.76) Hyperlipidemia 40.0% 33.8% 0.249 1.37 (0.86-2.19) Obesity 17.8% 14.4% 0.409 1.32 (0.73-2.39) Tobacco use 28.9% 26.4% 0.611 1.16 (0.71-1.90) Erectile dysfunction assessment OR (95% CI)# With ED (IIEF-5: ≤21) 61.5% 43.8% 0.001 2.09 (1.31-3.35) ED severity No ED (IIEF-5: 22-25) 38.5% 56.2% 1 Mild (IIEF-5: 17-21) 31.1% 31.8% 0.93 (0.58-1.50) Mild-moderate (IIEF-5: 12-16) 21.5% 10.0% 2.96 (1.51-5.82) Moderate-severe (IIEF-5: 5-11) 8.9% 2.0% <0.001 5.30 (1.62-17.37) p-value# IIEF-5 19.23 ±5.11 20.92 ±3.72 0.001 <0.001 *Adjusted for age. #Ajusted for age and cardiovascular risk factors.BMI, body mass index; DLQI, Dermatology Life Quality Index; ED, erectile dysfunction; IIEF-5, 5-item version of the International Index of Erectile Function; OR, odds ratio; CI, confidence interval. Table 2. Univariate and multivariate logistic regression analysis for erectile dysfunction. Univariate analysis Multivariate analyses Unadjusted OR (95% CI) p-value Adjusted OR (95% CI) p-value Psoriasis 2.05 (1.31-3.20) 0.002 2.28 (1.40-3.72) 0.001 Age . . . <0.001 ... 0.240 Height ... 0.002 ... 0.002 Weight ... 0.488 ... ... BMI ... 0.002 ... 0.302 Hypertension 2.28 (1.40-3.69) 0.001 1.14 (0.63-2.08) 0.669 Diabetes 5.40 (2.31-12.59) <0.001 3.49 (1.40-8.66) 0.007 Hyperlipidemia 1.96 (1.25-3.09) 0.004 1.34 (0.80-2.25) 0.272 Obesity 2.03 (1.09-3.76) 0.025 1.44 (0.55-3.79) 0.458 Tobacco use 0.79 (0.49-1.29) 0.350 ... ... BMI, body mass index; OR, odds ratio; CI, confidence interval. ual distress [9, 11-13]. However, ED in psoriasis is most likely multifactorial. In fact, a previous study has explored the possible link between atherosclerosis and ED in psoriasis. Whilst this association was not clearly statistically established, the increased prevalence of ED in the psoriasis group was not entirely explained by psychosocial factors, raising the possibility of an atherosclerotic etiology [15]. 2. ARTIGOS PUBLICADOS 128 known that inflammatory processes play a key role in atherogenesis [20], and many studies suggest that complement activation is involved in this process. C3 has been shown to be present in the atherosclerotic plaque [50] and the complement system to be activated in the atherosclerotic lesions [35]. Moreover, it appears to be a stronger inflammatory marker of insulin resistance and future coronary events than C-reactive protein (CRP) [9,32]. C3 is mainly produced by the liver, but it is also synthesized by activated macrophages and adipocytes [34], therefore, behaving as an inflammatory cytokine and an adipokine. C3 mRNA expression is increased in adipose tissue of obese compared with lean subjects [24], and systemic C3 concentrations have been associated with several measures of body fat, such as body mass index (BMI), waist circumference (WC) and visceral and subcutaneous adipose tissue on computed tomography [17]. Additionally, C3 levels appear to decrease with weight loss [33]. Psoriasis is currently considered a systemic inflammatory disorder associated with numerous medical comorbidities and with clinically significant increased risk of CVD and cardiovascular mortality [22,30,38,39]. The increased inflammatory load of these patients may play an important role in the accelerated atherosclerosis observed in psoriasis [3,18,26]. Mainly severe psoriasis is associated with a systemic and chronic inflammatory state characterized by an increased production of pro-inflammatory cytokines (TNF-a, INF-c, IL-1b, IL-6, IL-17), adipokines (leptin, resistin) and inflammatory biomarkers, such as CRP, that generate a spectrum of pro-atherogenic changes. Obesity has been associated with and considered detrimental for psoriasis [2]. It is associated with persistent lowgrade inflammation, particularly abdominal obesity, which is caused by excess accumulation of visceral adipose tissue that functions as an endocrine organ, releasing proinflammatory cytokines and adipokines [13]. Psoriasis has been independently associated with increased amount of visceral fat [4]. Data on the role of complement in psoriasis are scarce in the literature, but it is probably involved in psoriasis pathophysiology. Early studies have shown elevated serum C3 levels and complement activation in psoriasis patients and recently that C3 is expressed in psoriatic skin lesions [1,41,42]. Moreover, also in psoriatic arthritis, C3 levels have been shown to be increased, to correlate with disease activity and to decrease with antiTNF-a therapy [10,11]. The aim of this study was to compare serum C3 levels in psoriasis patients and controls and to analyze if eventual differences were independent of excess adiposity, using waist circumference as an indicator of visceral adipose tissue accumulation. Furthermore, to investigate within psoriasis patients, the relationship between C3 levels with several measures of body fat, other markers of cardiometabolic risk and subclinical atherosclerosis is assessed by coronary artery calcification (CAC) quantification. Methods In this cross-sectional study, adult patients with severe plaque-type psoriasis (PASI [ 10) consecutively observed at our psoriasis center were enrolled. The control group consisted in patients consecutively referred to the Dermatology outpatient clinic for conditions, such as nevi, other benign skin tumors or skin infections (tinea/warts). All patients were older than 18 years. Exclusion criteria for the psoriasis group were the presence of psoriatic arthritis (previous/current signs/symptoms of joint evolvement) and systemic therapy/phototherapy for at least 3 months before study enrollment. Patients being treated with topical therapy (corticosteroids or vitamin D analogs) were not excluded. Considered for both groups were the presence of CVD defined as the presence of coronary heart disease (CHD) (myocardial infarction, angina, angioplasty or coronary artery bypass grafting), cerebrovascular accident (stroke or transient ischemic attack) or peripheral vascular disease, the presence of other systemic inflammatory disease (lupus erythematous, rheumatoid arthritis or other spondyloarthropathies), the use of anti-inflammatory drugs and a positive history of any infectious diseases in the 4 weeks prior to study enrollment. All subjects underwent clinical and laboratory evaluation. The following information was systematically recorded: demographic characteristics, medical history of cardiovascular risk factors (CVRF) and concomitant therapy. Patients were considered to have diabetes, hypertension or hyperlipidaemia if they were receiving specific treatment or had previously been diagnosed or if they had fasting plasma glucose C126 mg/dL, blood pressure C140/ C90 mmHg and fasting LDL-cholesterol C160 mg/dL or triglycerides C200 mg/dL, respectively. Overweight and obesity were defined by a BMI C25 or BMI C30, respectively, smoking status as current smokers (current tobacco use or stop smoking within the last year), non-smokers and ex-smokers (smoking cessation for more than a year) and family history of premature CHD (CHD in male first degree relative \55 years and in female first degree relative \65 years). Cardiovascular risk was assessed using Framingham risk score [48] and metabolic syndrome (MetS) was defined using NCEP ATPIII definition [19]. In the psoriasis group, psoriasis characteristics (family history, disease duration and previous treatments) and severity (according to PASI) were also recorded. Blood tests included fasting glucose and insulin, leptin, C3, high-sensitivity CRP (hs-CRP) and fasting serum lipids [total Arch Dermatol Res 123 Author's personal copy 2. ARTIGOS PUBLICADOS 129 cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, oxidized low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, lipoprotein(a)]. Homeostasis model assessment (HOMA) was used to evaluate insulin resistance using the following formula: fasting serum insulin (lU/ml) 9fasting plasma glucose (mmol/ L)/22.5 [8,28]. Psoriasis patients underwent multidetector computed tomography (MDCT) scan for CAC, abdominal fat and epicardial adipose tissue (EAT) quantification. The 64-slice CT scanner (Somaton Sensation 64, Siemens Medical Solutions, Forchheim, Germany) used included 2 different acquisitions: one for abdominal fat quantification [abdominal visceral fat (AVF) and abdominal subcutaneous fat (ASF)], and the other for CAC and EAT assessment. The scan parameters and used methods have been previously described [5]. Mean radiation exposure was estimated as proposed by the European Working Group for Guidelines on Quality Criteria in CT [7]. The study was approved by the Hospital Institutional Review Board and all subjects gave written informed consent for use of their data. Statistical analysis Variables were tested for normality using Kolmogorov– Smirnov test. Descriptive statistics are presented as percentage for categorical variables and mean ±standard deviation or median with interquartile range (IQR) according to the distribution of the continuous variables. Log transformation was performed for non-normal variables. Patients and control subjects were compared using Student’s ttest for continuous variables and Chi-squared test for categorical variables. The independent association between disease status (psoriasis/ control) and C3 levels was assessed using multivariable linear regression models with adjustment for age, sex, and in separate models with additional adjustment for WC or presence of MetS. Among psoriasis patients, the relationship between C3 and hs-CRP levels and clinical, laboratory and imaging variables was evaluated using Pearson’s correlation coefficients (bivariate relationships) and multivariate linear (adjusting for age, sex and WC). The level of statistical significance was set at a=0.05. Statistical analyses were performed with SPSS version 21 (SPSS IBM, New York, USA). Results A total of 80 psoriasis patients and 95 controls were studied, with both groups being similar in terms of age and sex. The mean psoriasis duration was 22.3 ±11.6 years, 42.5 % had family history of the disease, and mean PASI was 15.4 ±7.0. Concerning CVRF and MetS syndrome, psoriasis patients were more likely to be obese (P=0.002), to have hypertension (P=0.045) and MetS (P=0.002) compared to controls. Clinical indicators of excess adiposity, such as BMI and WC, were also significantly higher in psoriasis patients than in the control group (P\0.001) (Table 1). The laboratory features of the subjects are shown in Table 2. C3 and hs-CRP levels were significantly higher in psoriasis patients as compared with controls. Adjusting for age, sex and WC, as a marker of excess adiposity, and particularly abdominal visceral adipose tissue accumulation, C3 Table 1 Demographic and clinical characteristics of the study population Psoriasis Controls P N80 95 Male 66.3 % 62.1 % 0.636 Age (years) 48.06 ±10.70 48.44 ±11.95 0.827 Psoriasis duration (years) 22.3 ±11.6 – – Family history 42.5 % – – PASI 15.4 ±7.0 – – Psoriasis therapy a – – Topical only 23.8 % – – Ever phototherapy 52.5 % – – Ever conventional systemic therapy b 60 % – – Ever biologic therapy 2.5 % – – Weight (kg) 80.59 ±16.55 73.10 ±14.13 0.001 Height (m) 1.67 ±0.10 1.68 ±0.09 0.426 Body mass index (kg/m 2 ) 28.93 ±5.26 25.84 ±4.07 <0.001 Waist circumference (cm) 97.33 ±13.10 89.16 ±11.63 <0.001 Systolic blood pressure (mmHg) c 129.11 ±12.85 127.69 ±13.39 0.547 Diastolic blood pressure (mmHg) c 78.39 ±7.80 78.03 ±9.06 0.813 Hypertension 47.5 % 32.6 % 0.045 Hypertensive therapy 32.5 % 21.1 % 0.087 Diabetes 13.8 % 6.3 % 0.098 Diabetes therapy 12.5 % 6.3 % 0.157 Hyperlipidemia 57.5 % 45.3 % 0.107 Statin therapy 23.8 % 14.7 % 0.129 Fibrate therapy 3.8 % 1.1 % 0.234 Obesity 38.8 % 17.9 % 0.002 Tobacco use 18.8 % 20 % 0.953 Family history CVD 11.3 % 10.5 % 0.878 Metabolic syndrome 35 % 14.7 % 0.002 Framingham risk score 8.76 ±7.16 8.08 ±5.75 0.584 Bold values indicate P\0.05 a Patient could be in more than one group b Includes acitretin, cyclosporine, methotrexate c Excluding patients receiving treatment for hypertension Arch Dermatol Res 123 Author's personal copy 2. ARTIGOS PUBLICADOS 130 levels continued to be significantly higher in psoriasis patients than in controls, being on average 5.76 ±2.83 mg/dL higher (P=0.043), while the difference between groups in hs-CRP levels did not persist after the multivariate adjustment. Similar results were found with adjustment for MetS. Concerning lipid profile, and excluding patients receiving statins/fibrates, no significant difference between psoriasis patients and control subjects was found except for oxidized LDL (oxLDL) levels that were remained significantly higher in psoriasis patients than in controls after adjustment for age, sex and WC (P=0.028) or MetS (P=0.013). No significant differences between groups were found regarding insulin resistance (measured by HOMA or HOMA [2.5) and leptin levels. Table 3shows the relationship, within psoriasis patients, between C3 and hs-CRP levels and the clinical, laboratory and imaging parameters investigated in this study. C3 and hs-CRP levels were significantly and positively correlated with all clinical and imaging measures of body fat (Weight, BMI, WC, AVF and ASF) except for EAT to which only C3 was significantly correlated. Adjusting for age, sex and WC, C3 and hs-CRP remained associated exclusively with AVF (P=0.007 and P=0.027, respectively). Patients with MetS had significantly higher C3 and hs-PCR levels than those without (P=0.001, P=0.043, respectively); however, after adjusting for age, sex and WC, only C3 was associated with MetS (P=0.049). Using HOMA value [2.5 as a marker of insulin resistance, C3 levels were higher in psoriasis patients with insulin resistance than those without, independently of age, sex and WC (P=0.030), and a trend toward increased HOMA was also observed (P=0.056). Increased levels of hs-CRP were not associated with insulin resistance and hs-CRP did not correlate with HOMA adjusting for age, sex and WC. Regarding lipid profile, C3 levels were significantly correlated with oxLDL, independently of age, sex and WC, exclusively with oxLDL (P=0.028), while no association was found for hs-CRP. No association was found between C3 and hs-CRP levels and subclinical atherosclerosis (CAC [0) neither with disease severity and psoriasis duration. Discussion The major finding of this study is that C3 levels were increased in psoriasis patients compared to control subjects, independently of the excess adiposity observed in those patients, indicating that this association is not solely mediated by the adipose tissue. Moreover, within psoriasis patients, C3 levels were independently associated with AVF, insulin resistance, MetS and oxLDL, while CRP did not, showing that C3 may be a better marker of cardiometabolic risk than CRP. Several inflammatory proteins have been evaluated as predictive biomarkers for CVD, and CRP has been the most widely studied and has consistently been shown to predict the development of CVD [36,40]. The elevation of CRP among psoriasis patients has been extensively studied and linked to the excess cardiovascular risk associated with the disease [6]. However, CRP levels are not elevated specifically in CVD as a wide variety of stimuli including acute and chronic infection can be inducers. Recently, C3 has been independently associated with myocardial infarction after accounting for CRP, fibrinogen and CVRF, while CRP was not if accounting for C3 and the remaining variables [9]. In another study, patients undergoing carotid endarterectomy were followed-up for a median of Table 2 Laboratory features of the study population Bold values indicate P\0.05 Log transformation was performed for non-normal variables prior to analysis * Age-, sexand waist circumference-adjusted ? Age-, sex,-metabolic syndrome-adjusted a Excluding patients receiving hyperlipidemia treatment b Excluding diabetic patients Psoriasis Controls P P * P ? C3 (mg/dL) 129.25 ±20.92 118.24 ±17.86 <0.001 0.043 0.006 hs-CRP (mg/dL) 2.56 (0.96–5.49) 1.57 (0.73–3.30) 0.011 0.272 0.053 Total cholesterol (mg/dL) a 206.80 ±37.91 206.60 ±39.23 0.976 0.686 0.566 HDL-cholesterol (mg/dL) a 48.0 (41.25–59.0) 54.0 (44.0–61.0) 0.434 0.724 0.904 LDL-cholesterol (mg/dL) a 129.14 ±36.98 129.41 ±34.11 0.964 0.771 0.489 OxLDL-cholesterol (mg/dL) a 174.20 ±53.53 154.29 ±58.32 0.041 0.08 0.013 VLDL-cholesterol (mg/dL) a 25.88 ±16.51 22.91 ±11.54 0.447 0.845 0.697 Triglycerides (mg/dL) a 107.00 (72.25–161.25) 99.0 (74.0–144.0) 0.745 0.433 0.365 ApoB a 93.12 ±24.30 99.18 ±27.06 0.176 0.251 0.173 Lp(a) a 21.0 (6.0–41.0) 22.0 (9.0–41.0) 0.875 0.948 0.907 Leptin 0.61 (0.40–1.97) 0.53 (0.30–1.10) 0.159 0.528 0.281 Glucose (mg/dL) 88.5 (81.0–100.0) 90.0 (81.0–96.0) 0.611 0.243 0.469 HOMA b 2.34 (1.48–4.03) 1.88 (1.42–2.72) 0.173 0.633 0.458 HOMA [2.5 b 41.4 % 27.0 % 0.071 0.930 0.303 Arch Dermatol Res 123 Author's personal copy 2. ARTIGOS PUBLICADOS 131 14 months and C3 concentrations were found to predict restenosis, whereas CRP did not [43]. Therefore, C3 may be a more specific marker of CVD risk than CRP. Although the association of body fat with C3 is clear, in this study psoriasis was associated with increased levels of C3, independently of WC, an indirect but reliable marker of excess adiposity, particularly visceral adipose tissue accumulation, postulated to have stronger associations with CHD biomarkers and a stronger predictor of CHD risk than BMI [25]. Thus, this association is probably not only mediated by the excess adipose tissue observed in psoriasis patients. Several pro-inflammatory cytokines like TNF-a, IL-1b, IL-6, and INF-chave been shown to increase the production of C3 in many cell types, including the liver [45]. Although this stimulatory effect on adipocyte C3 production has not been clearly demonstrated, mRNA expression of C3 was shown to be increased by those cytokines in cultured mouse adipocytes and human preadipocytes [37,50]. Therefore, these pro-inflammatory cytokines that are systemically and chronically increased in psoriasis may increase C3 production from the liver and probably from adipose tissue in psoriasis patients. Another Table 3 Association between C3 and hs-CRP levels with clinical, laboratory and imaging variables within psoriasis patients Bold values indicate P\0.05 * Age-, sexand waist circumference-adjusted ? Age-, sexand cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, obesity, Tobacco use and family history CVD)-adjusted a Excluding patients receiving hypertensive therapy b Excluding patients receiving with statins/fibrates c Excluding diabetic patients C3 hs-CRP r P P * r P P * Male – 0.612 – – 0.198 – Age (years) 0.106 0.349 – 0.159 0.159 – Weight (kg) 0.319 0.004 0.833 0.251 0.024 0.585 Height (m) -0.083 0.464 0.253 -0.161 0.154 0.271 Body mass index (kg/m 2 ) 0.405 <0.001 0.401 0.383 <0.001 0.607 Waist circumference (cm) 0.409 <0.001 – 0.384 <0.001 – Systolic blood pressure (mmHg) a 0.292 0.032 0.113 0.256 0.061 0.070 Diastolic blood pressure (mmHg) a 0.123 0.374 0.302 -0.051 0.716 0.916 Hypertension – 0.115 0.402 – 0.080 0.350 Diabetes – 0.536 0.160 – 0.099 0.949 Hyperlipidemia – 0.150 0.373 – 0.445 0.852 Obesity – <0.001 0.162 – 0.002 0.567 Tobacco use – 0.041 0.261 – 0.318 0.879 Family history CVD – 0.642 0.847 – 0.971 0.782 Metabolic syndrome – 0.001 0.049 –0.043 0.631 Framingham risk score 0.166 0.146 0.237 0.179 0.117 0.269 Coronary artery calcification [0 – 0.445 0.844 ? – 0.426 0.826 ? Epicardial adipose tissue 0.262 0.021 0.116 0.115 0.319 0.881 Abdominal visceral fat 0.445 <0.001 0.007 0.385 0.001 0.027 Abdominal subcutaneous fat 0.349 0.002 0.470 0.337 0.003 0.371 C3 (mg/dL) – – – 0.572 <0.001 <0.001 hs-CRP, 0.572 <0.001 <0.001 – – – Total cholesterol (mg/dL) b 0.100 0.445 0.261 -0.024 0.856 0.949 HDL-cholesterol (mg/dL) b -0.139 0.284 0.836 -0.114 0.386 0.577 LDL-cholesterol (mg/dL) b 0.009 0.947 0.593 -0.028 0.832 0.836 OxLDL-cholesterol (mg/dL) b 0.205 0.113 0.028 -0.061 0.641 0.913 VLDL-cholesterol (mg/dL) b 0.286 0.025 0.161 0.039 0.766 0.700 Triglycerides (mg/dL) b 0.364 0.004 0.071 0.059 0.651 0.597 ApoB b 0.106 0.416 0.380 0.003 0.984 0.850 Lp(a) b -0.006 0.964 0.885 0.125 0.337 0.249 Leptin 0.283 0.011 0.640 0.303 0.006 0.773 Glucose (mg/dL) 0.157 0.164 0.747 0.149 0.188 0.863 HOMA c 0.441 <0.001 0.056 0.170 0.163 0.808 HOMA [2.5 c –<0.001 0.030 – 0.286 0.601 Psoriasis duration (years) -0.129 0.255 0.088 -0.087 0.443 0.105 PASI 0.106 0.350 0.445 0.145 0.200 0.190 Arch Dermatol Res 123 Author's personal copy 2. ARTIGOS PUBLICADOS 132 possible explanation may be the acylation stimulating protein (ASP) resistance in adipocytes caused by TNF-a. C3 is the precursor protein for ASP and TNF-ahas been shown to cause a downregulation of ASP receptor, interfering with downstream ASP signalling [49]. Finally, also keratinocytes in psoriatic lesions have been shown to produce C3, being another possible source of C3 in psoriasis. Keratinocyte C3 expression may have an important role, along with other proteins, as the heterodimeric complex S100A8–S100A9, also termed calprotectin, in the initial immune activation of psoriasis inflammation in response to several environmental insults, such as barrier breakdown and bacterial invasion, leading infiltrating immune cells to produce additional inflammatory cytokines, like IL-17, MCP-1, and RANTES that will further activate keratinocytes, consequently leading to an autoamplification loop, which subsequently results in a chronic inflammatory state, as observed in psoriasis [42]. Within psoriasis patients, C3 showed to be a stronger marker of insulin resistance and MetS than CRP, independently of excess adiposity. In a study comparing four inflammatory markers (C3 and three other markers proved to be increased in psoriasis, CRP, ESR, leukocyte count), C3 was the inflammatory marker that most strongly correlated with insulin resistance and independently of the main indexes of obesity [32]. In another study, it was found that adjusting for WC the relationship between CRP and HOMA was greatly weakened [47]. Evidently, and differently from CRP, the association of C3 with insulin resistance is not mainly mediated by adipose tissue. A possible explanation is that C3 hepatic production is mainly induced by IL-1band TNF-a, which may interfere with insulin receptor functioning, through its phosphorylation and proteasomal degradation [27], causing insulin resistance, while CRP synthesis is stimulated by IL-6 produced in the adipose tissue and may mainly reflect the important contribution of obesity rather than provide a significant independent contribution to insulin resistance [32]. Another possibility is that C3 levels may parallel insulin resistance but not coinciding with it. The main activation fragment of C3, the ASP, is provided with insulin-like properties. Therefore, similarly to the increase in insulin levels in the presence of insulin resistance, a hypothetical ASP resistance could induce an increase in its precursor C3 [12]. The pathophysiologic role of C3 in metabolic syndrome remains unclear, but it has been stated that C3 concentrations may play an important role in its expression and to be an independent determinant of incident metabolic syndrome [44]. However, more studies, particularly population-based prospective studies, are needed to clarify whether C3 may help to identify psoriasis patients at risk of developing metabolic syndrome. C3 levels were associated with all measurements of body fat, including AVF, ASF and EAT, a type of visceral adipose tissue surrounding the heart and coronary vessels, potentially relevant for the development of CHD due to local inflammation [29]. However, after adjusting to WC, it was associated exclusively with AVF, confirming that the visceral component of abdominal fat has more influence than the subcutaneous in the adipose tissue inflammation, while the association between C3 and EAT was not independent of visceral adiposity. Psoriasis patients also presented significantly higher circulating oxLDL than controls and, within psoriasis patients, C3 was correlated with oxLDL, independently of WC. OxLDL has been found to amplify several CVD risk factors, triggering a chronic inflammatory reaction, resulting in a more vulnerable plaque, prone to rupture and thrombosis. Recently, it has been shown that oxLDL positively regulates C3 gene expression and protein secretion in human macrophages [31]. Finally, although C3 has been suggested to be involved in atherosclerosis, the mechanism of C3 accumulation in atherosclerotic lesions is not well elucidated. At least in this cohort of psoriasis patients, no association between C3 concentration and CAC was shown. Limitations A major limitation of the present study is the cross-sectional study design, which does not allow drawing definitive conclusion on causality. The small sample may be another limitation of the study. The imaging method used to assess AVF, EAT and subclinical atherosclerosis is a strength of the current study, but it was only available for psoriasis patients. Although WC is a good clinical indicator of visceral fat accumulation [23], MDCT assessment of AVF is the most reliable technic to assess it. Conclusion Serum C3, an important inflammatory marker of cardiovascular and cardiometabolic disorders, was increased in psoriasis. The excess adiposity, particularly visceral adiposity observed in these patients, surely plays a role, but the systemic inflammatory load of psoriasis probably increases the expression of C3 enhancing the risk of CVD. Moreover, C3 levels showed to have a stronger association with insulin resistance, metabolic syndrome and oxidized LDL-cholesterol than CRP. Although more studies are needed, C3 could be applied as a useful marker of cardiometabolic risk in psoriasis. Arch Dermatol Res 123 Author's personal copy 2. ARTIGOS PUBLICADOS 133 References 1. Acevedo F, Hammar H (1989) Complement C3 proteins in psoriasis. Br J Dermatol 12:329–335 2. Armstrong AW, Harskamp CT, Armstrong EJ (2012) The association between psoriasis and obesity: a systematic review and meta-analysis of observational studies. Nutr Diabetes 2:e54 3. 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Yasojima K, Schwab C, McGeer EG, McGeer PL (2001) Complement components, but not complement inhibitors, are upregulated in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 21:1214–1219 Arch Dermatol Res 123 Author's personal copy 2. ARTIGOS PUBLICADOS 135 Gordura Epicárdica e Calcificação Arterial Coronária em Doentes com Psoríase Torres T, Bettencourt N, Mendonça D, Vasconcelos C, Gama V, Silva BM, Selores M. Epicardial adipose tissue and coronary artery calcification in psoriasis patients. J Eur Acad Dermatol Venereol. 2014 Apr 21. 136 137 ORIGINAL ARTICLE Epicardial adipose tissue and coronary artery calcification in psoriasis patients T. Torres, 1,2, * N. Bettencourt, 3 D. Mendonc a, 4 C. Vasconcelos, 2,5 V. Gama, 3 B.M. Silva, 2,6 , M. Selores 1 1 Department of Dermatology, Centro Hospitalar do Porto, Porto, Portugal 2 Unit for Multidisciplinary Investigation in Biomedicine, Instituto de Ci^ encias Biom� edicas Abel Salazar, University of Porto, Porto, Portugal 3 Department of Cardiology, Centro Hospitalar Gaia/Espinho, Porto, Portugal 4 Department of Population Studies, Instituto Ci^ encias Biom� edicas Abel Salazar, University of Porto, Porto, Portugal 5 Department of Clinical Immunology, Centro Hospitalar of Porto, Porto, Portugal 6 Immunogenetics Laboratory, Instituto Ci^ encias Biom� edicas Abel Salazar, University of Porto, Porto, Portugal *Correspondence: T. Torres. E-mail: [email protected] Abstract Background Psoriasis is a chronic, immune-mediated disease associated with several cardio-metabolic comorbidities, accelerated atherosclerosis and cardiovascular disease (CVD). Other causes beyond systemic inflammation and traditional cardiovascular risk factors (CVRF) may be implicated in the increased risk of CVD observed in these patients. Epicardial adipose tissue (EAT), a type of visceral adipose tissue surrounding the heart and coronary vessels has been implicated in the development of coronary artery disease, by endocrine mechanisms, but particularly by local inflammation. Objective To compare EAT volumes in psoriasis patients and controls using multidetector computed tomography (MDCT) and to analyse if eventual differences were independent from abdominal visceral adiposity; to determine, within psoriasis patients, its relation with subclinical atherosclerosis and other markers of cardiometabolic risk. Methods One hundred patients with severe psoriasis, without CVD underwent MDCT, with EAT and abdominal visceral fat (AVF) assessment and coronary artery calcification (CAC) quantification and were compared with 202 control patients. Results EAT volume was increased in psoriasis patients compared to control subjects, independently from age, sex and AVF, being, on average, 15.2 4.41 mL higher (95% CI: 6.5–26.0, P=0.001) than in controls. Moreover, psoriasis patients had a statistically significant higher risk of having subclinical atherosclerosis (OR 2.52, 95% CI: 1.23–5.16) than controls, after adjusting for traditional CVRF. Within psoriasis patients EAT volume was associated with subclinical atherosclerosis, independently of age, sex, psoriasis duration, classical CVRF and AVF. Conclusion This study showed that psoriasis was associated with increased EAT volume independently of visceral abdominal fat and with subclinical atherosclerosis. Within psoriasis patients EAT volume was independently associated with CAC. EAT may be another important contributor to the higher cardiovascular risk observed in psoriasis. Received: 20 December 2013; Accepted: 17 March 2014 Conflicts of interest None declared. Fundings This study was supported in part by an unrestricted grant from the Portuguese Society of Dermatology and Venereology. Introduction Psoriasis is a chronic inflammatory disease affecting 1–3% of the population. 1 Nowadays, it is considered as a systemic inflammatory disorder 2 associated with numerous medical comorbidities and with clinically significant increased risk of cardiovascular disease (CVD) and cardiovascular mortality. 3–6 Psoriasis appears to be an independent risk factor for subclinical atherosclerosis, probably due to disease’s inflammatory burden, as an increased prevalence of subclinical atherosclerosis has been reported in several studies using various surrogate markers of atherosclerosis. 7–9 However, other causes beyond systemic inflammation and traditional cardiovascular risk factors (CVRF) may be implicated ©2014 European Academy of Dermatology and VenereologyJEADV 2014 DOI: 10.1111/jdv.12516 JEADV 2. 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Patients with psoriasis have an increased amount of epicardial fat tissue. Clin Exp Dermatol 2014; 39: 123–128. 37 Carter AM, Prasad UK, Grant PJ. Complement C3 and C-reactive protein in male survivors of myocardial infarction. Atherosclerosis 2009; 203: 538–543. 38 Onat A, Hergenc G, Can G et al. Serum complement C3: a determinant of cardiometabolic risk, additive to the metabolic syndrome, in middleaged population. Metabolism 2010; 59: 628–634. 39 Ormseth MJ, Lipson A, Alexopoulos N et al. Association of epicardial adipose tissue with cardiometabolic risk and metabolic syndrome in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2013; 65: 1410–1415. 40 Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and obesity: a systematic review and meta-analysis of observational studies. Nutr Diabetes 2012; 2: e54. 41 Iacobellis G, Singh N, Wharton S et al. Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. Obesity (Silver Spring) 2008; 16: 1693–1697. 42 Kim MK, Tomita T, Kim MJ et al. Aerobic exercise training reduces epicardial fat in obese men. J Appl Physiol 2009; 106: 5–11. ©2014 European Academy of Dermatology and Venereology JEADV 2014 8Torres et al. 2. ARTIGOS PUBLICADOS 145 Comorbilidades Cardiovasculares na Psoríase em Idade Pediátrica Torres T, Machado S, Mendonça D, Selores M. Cardiovascular comorbidities in childhood psoriasis. Eur J Dermatol. 2014 Apr 22. 146 147 © John Libbey Eurotext, 2014 Journal Identification = EJD Article Identification = 2291 Date: May 8, 2014 Time: 3:31 pm doi:10.1684/ejd.2014.2291 EJD, vol. 24, n◦2, March-April 2014 229 To cite this article: Torres T, Machado S, Mendonc¸a D, Selores M. Cardiovascular comorbidities in childhood psoriasis. Eur J Dermatol 2014; 24(2): 229-35 doi:10.1684/ejd.2014.2291 Clinical report Eur J Dermatol 2014; 24(2): 229-35 Tiago TORRES1,2 Susana MACHADO1,3 Denisa MENDONC¸ A4 Manuela SELORES1,3 1Department of Dermatology, Centro Hospitalar do Porto, Ex. CICAP, Rua D. Manuel II, s/n, 4100 Porto, Portugal 2Unit for Multidisciplinary Investigation in Biomedicine, 3Instituto de Ciências Biomédicas, 4Population Studies Department, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Portugal Reprints: T. Torres <[email protected]> Article accepted on 12/06/2013 Cardiovascular comorbidities in childhood psoriasis Background: Psoriasis is a common, chronic, systemic inflammatory skin disease associated with numerous cardiovascular comorbidities. Much evidence of this association exists in the adult population, data available in childhood psoriasis is more limited. Objectives: To analyze the prevalence of excess adiposity, cardiovascular risk factors, metabolic syndrome and lipid profile in children with psoriasis comparing to control group with similar age and sex distribution. Materials & methods: A case-control study was conducted with children, 5-15 yearsold, with moderate-to-severe plaque-type psoriasis and a control group comprising children with other skin diseases without systemic inflammatory diseases. Results: Psoriatic children had a significantly higher prevalence and greater odds of excess adiposity compared to controls: BMI (≥85th percentile; OR 4.4; 95%CI 1.2-15.6), waist circumference (>75th percentile; OR 7.4; 95%CI 2.0-27.7) and waist-to-height ratio (>0.490; OR 4.6; 95%CI 1.3-17.0). A higher prevalence of metabolic syndrome was observed in children with psoriasis compared to controls (25% vs 3.7%; P=0.07), and two components of the metabolic syndrome were significantly higher in the psoriasis group: waist circumference (75% vs 29.6%; P=0.002) and the high blood pressure component (30% vs 3.7% P=0.032). Finally, an altered and more atherogenic lipid profile was observed among psoriatic patients without excess adiposity. Conclusion: This study demonstrates that comorbidities known to be associated with adult psoriasis are also observed in childhood psoriasis, reinforcing the need for screening cardiovascular comorbidities in children with psoriasis and promoting healthy lifestyle choices in these patients. Moreover, it also suggests that its association with psoriasis may be in part genetically determined rather than uniquely acquired. Key words: cardiovascular comorbidities, childhood psoriasis, excess adiposity, lipid profile, metabolic syndrome, visceral adiposity Psoriasis is a common chronic inflammatory skin disease that affects 1% to 3% of the general population [1]. While most patients report its negative impact on their quality of life, psoriasis appears to be more than skin deep. In fact, psoriasis is now considered a systemic inflammatory disorder associated with numerous medical comorbidities [2]. Large epidemiological studies have found that adult patients with psoriasis have increased prevalence of traditional cardiovascular (CV) risk factors such as diabetes, hypertension, dyslipidemia, obesity and metabolic syndrome compared with the general population [3, 4] and more importantly a clinically significantly increased risk of CV disease and CV mortality [5]. The connection between psoriasis, atherosclerosis and cardiovascular disease may be related to a common genetic basis, shared inflammatory pathways, including Th-1 and Th17 mediated inflammation, alterations in angiogenesis and endothelial dysfunction [6, 7]. Data available on cardiovascular risk in childhood psoriasis is more limited, although there is increasing evidence that childhood psoriasis is also associated with an increased prevalence of cardiovascular comorbidities, especially obesity but also hypertension, diabetes, hyperlipidemia and metabolic syndrome [8-12]. The prevalence of childhood plaque-type psoriasis appears to be between 0.37% and 0.55% within the first decade of life and 1.01% to 1.37% within the second decade, showing that psoriasis is also a common disease in childhood [9, 13]. Children with psoriasis appear to be at increased risk of being overweight or obese and thus are at increased risk of complications related to excess adiposity, as it has been found that obesity may be 1.7 to 2.6-fold more frequent in psoriatic children than in controls [9, 14, 15]. Interestingly, it has also been shown that psoriasis severity may be associated with obesity [8]. On the other hand, overweight or obese children appear to be at increased risk of having psoriasis [16]. Concerning other cardiovascular risk factors, data is more limited. Augustin et al assessed the prevalence rate of comorbidities of juvenile psoriasis in Germany, based on Author offprint 2. ARTIGOS PUBLICADOS 148 © John Libbey Eurotext, 2014 Journal Identification = EJD Article Identification = 2291 Date: May 8, 2014 Time: 3:31 pm 230 EJD, vol. 24, n◦2, March-April 2014 health insurance data, and hyperlipidemia, diabetes and hypertension were twice as common in patients with psoriasis [8] while Au et al found a higher prevalence of metabolic syndrome in 20 children with psoriasis, although no statistically significant difference was found in body mass index or for any of the individual components of metabolic syndrome [10]. The aim of the present study was to analyse the prevalence of excess adiposity, particularly central/visceral adiposity, cardiovascular risk factors, metabolic syndrome and its components and lipid profile in a group of children with psoriasis, compared to a control group with a similar age and sex distribution. Materials and methods In this case control study, children aged between 5-15 years old, with moderate-to-severe plaque type psoriasis (BSA >5% and/or previous/current systemic therapy), without psoriatic arthritis, consecutively observed at our Psoriasis Centre, were enrolled. The control group was recruited from the same setting, during the same period and comprised children who attended the Dermatology Department for other skin diseases, such as eczema, acne or skin infections and required blood collection for their clinical condition workup. They had no psoriasis or family history of psoriasis/psoriatic arthritis or other systemic inflammatory diseases, such as rheumatoid arthritis, lupus erythematous or inflammatory bowel disease. All psoriatic patients and controls underwent a thorough clinical and laboratory evaluation including complete medical history and physical examination. The following information was systematically recorded: demographic characteristics (age, sex), psoriasis age of onset, severity and treatment, height, weight, abdominal circumference and blood pressure were recorded, as well as determination of fasting plasma concentration of glucose, insulin, glycosylated hemoglobin and lipid profile (total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, oxidized LDL-cholesterol (ox-LDL), triglycerides, lipoprotein(a), apolipoprotein B (apoB)). Body mass index (BMI) was calculated as weight in kilograms divided by height squared in meters. Children were classified as normal-weight (<85th percentile), overweight (≥85th and <95th percentile) and obese (≥95th percentile) [17]. Evaluation of central adiposity was performed using 2 sensitive, non-invasive surrogate markers of central adiposity: waist circumference (WC) and waistto-height ratio. WC was determined using a measuring tape, positioned horizontally, parallel to the floor, between the top of the iliac crest and the lowest rib. Patients were classified into 6 percentile groups, according to sex, age and ethnicity cutoffs (Overweight and obesity were defined as WC >75th percentile and WC >90th percentile respectively) [18]. Waist-to-height ratio was used to estimate cardiovascular risk, classifying patients at high risk (≥0.539) and intermediate risk (≥0.490), using the cutoffs established by Kahn [19]. Hypertension was defined as systolic and/or diastolic BP ≥the 95th age-, sexand height-specific percentile [20] and dyslipidemia as LDL-C and/or triglycerides ≥the 95th age-, sex-specific percentile and/or HDL-C ≤the 5th age-, sex-specific percentile [21]. Diabetes diagnosis was based on a fasting plasma glucose ≥126 mg/dL or HbA1c ≥ 6.5% [22] and insulin resistance was based on the homeostatic model assessment (HOMA), calculated as the product of the fasting plasma insulin level (in micro units per millilitre) and the fasting plasma glucose level (in millimoles per litre) divided by 22.5. HOMA>3.16 was considered insulin resistance and <3.16 as insulin sensitive [23]. For the definition of metabolic syndrome, the modified criteria of ATPIII proposed by de Ferranti was used, defined as the presence of 3 or more of the following criteria: waist circumference ≥75th percentile for age and sex, triglycerides ≥100mg/dL, HDL-C <50mg/dL, fasting glucose ≥110 mg/dL and systolic or diastolic blood pressure greater than the 90th percentile for age, gender and height [24]. The study protocol was approved by the Hospital Ethical Committee and all patients and controls agreed to participate. Statistical analysis Descriptive statistics are presented as counts and percentages for categorical variables and means (±SDs) or medians (IQR) for continuous data. Distribution of continuous variables was tested for normality using the Kolmogorov-Smirnov test. The 2test and Fisher exact test were used to compare categorical variables and the t-test or Mann-Whitney U test to compare continuous variables between groups. Odds ratios (OR) and the corresponding 95% confidence intervals (CI), were estimated. The independent associations between disease status (psoriasis and controls) and the clinical and analytical variables were assessed using multivariable logistic or linear regression models adjusting for age and sex as confounders. The level of statistical significance was set at α= 0.05. Statistical analyses were performed with SPSS version 21 (SPSS IBM, New York, U.S.A). Results This study included 20 psoriatic children and 27 controls. There was no difference between cases and controls for age (10.40 ±3.15 years vs 10.4 ±2.87 years, p = 0.993) and sex (female: 65% vs 66.7%, p = 0.905). Mean psoriasis duration time was 3.0 years (±1.11; 2-6 years); mean BSA was 7.2% (±3.66; 5-17%). Most psoriatic children were receiving topical therapy (90%), while 10% were on UVBnb phototherapy; 30% had already received previously systemic therapy (UVBnb phototherapy, cyclosporine, methotrexate and acitretin). Descriptive characteristics of the study population are reported in table 1. The mean BMI percentile was significantly higher among psoriatic patients (80.89 ±18.42 vs 65.97 ±23.36, p = 0.018). Compared to the control group, a significantly higher percentage of children with psoriasis were overweight or obese (35% vs 22.2% and 25% vs 3.7%; P = 0.03). The ageand sex-adjusted odds ratio (OR) for excess adiposity (overweight/obese) was 4.4 (95% CI 1.2-15.6). Although a higher proportion of children with psoriasis Author offprint 2. ARTIGOS PUBLICADOS 149 © John Libbey Eurotext, 2014 Journal Identification = EJD Article Identification = 2291 Date: May 8, 2014 Time: 3:31 pm EJD, vol. 24, n◦2, March-April 2014 231 Table 1. Characteristics of the study population Psoriasis Controls Pvalue Pvalue* Participants, No. 20 27 Age, mean (SD), y 10.40 (3.15) 10.4 (2.87) 0.993 Female sex (%) 65% 66.7% 0.905 Psoriasis characteristics Psoriasis duration, mean (SD); min-max, y 3.0 (1.11); 2-6 ...... ...... BSA, mean (SD); min-max, % 7.2% (3.66); 5-17 ...... ...... Family history - 1st degree relative (%) 35% ...... ...... Current treatment (%) Topical 90% ...... ...... Systemic 10% ...... ...... Previous systemic treatment 30% ...... ...... Metabolic characteristics SBP, mm/Hg 107.1 (12.1) 105.1 (11.7) 0.579 0.507 DBP, mm/Hg 62.0 (9.2) 63.1 (8.3) 0.647 0.630 SBP percentile 59.2 (26.3) 49.3 (27.5) 0.224 0.212 DBP percentile 51.0 (25.5) 55.2 (24.1) 0.569 0.580 Weight 46.2 (16.3) 41.6 (13.9) 0.310 0.065 Height 145 (165) 146 (158) 0.919 0.818 BMI 21.1 (4.0) 19.0 (2.9) 0.038 0.011 BMI percentile 80.89 (18.42 65.97 (23.36) 0.018 0.025 BMI categories (%) Normal weight 40 74.1 0.03 Overweight 35 22.2 Obese 25 3.7 Waist circumference 73.5 (11.7) 67.9 (10.1) 0.088 0.028 Waist circumference percentile (%) <25th percentile 5 11.1 0.015 25th to 75th percentile 20 59.3 75th to 90th percentile 50 14.8 >90th percentile 25 14.8 Waist-to-height ratio, median (IQR) 0.510 (0.40;0.64) 0.460 (0.40;0.58) 0.019 0.014 WC/height ratio categories (%) Normal 45 77.8 0.05 Intermediate 25 14.8 High 30 7.4 Metabolic syndrome (%) 25 3.7 0.07 WC ≥75th percentile (%) 75 29.6 0.002 SBP/DBP>90th percentile (%) 30 3.7 0.032 Triglycerides ≥100 mg/dL (%) 10 7.4 1 HDL-C <50 mg/dL (%) 40 37 1 Fasting glucose ≥110 mg/dL (%) 0 0 - Cardiovascular risk factors (%) Hypertension 10 3.7 0.567 Dyslipidemia 15 7.4 0.68 Diabetes 0 0 - Insulin Resistance 5 11.1 0.6 Author offprint 2. ARTIGOS PUBLICADOS 150 © John Libbey Eurotext, 2014 Journal Identification = EJD Article Identification = 2291 Date: May 8, 2014 Time: 3:31 pm 232 EJD, vol. 24, n◦2, March-April 2014 Table 1. (Continued) Psoriasis Controls Pvalue Pvalue* Excess adiposity 1) BMI (%) Normal weight 40 74.1 0.011 Overweight and obese 60 25.9 2) WC percentile (%) <75th percentile 25 70.4 0.003 >75th percentile 75 29.6 3) Waist-to-height ratio (%) <0.490 45 77.8 0.021 ≥0.490 55 22.2 Glucose, mean (SD), mg/dL 82.1 (4.4) 79.9 (6.8) 0.191 0.230 HbA1c, mean (SD), mg/dL 5.18 (0.18) 5.19 (0.23) 0.903 0.915 Triglycerides, median (IQR), mg/dL 48 (32; 229) 53 (27; 151) 0.796 0.750 Total cholesterol, mean (SD), mg/dL 160.6 (31.7) 157.7 (31.7) 0.759 0.763 LDL-C, mean (SD), mg/dL 94.1 (23.7) 90.8 (30.9) 0.690 0.690 HDL-C, mean (SD), mg/dL 53.8 (9.9) 54.9 (17.0) 0.786 0.796 VLDL-C, median (IQR), mg/dL 10.0 (8.0; 8.7) 11.0 (8.0; 15.0) 0.681 0.769 Ox-LDL, mean (SD), mg/dL 128.5 (45.2) 110.3 (31.8) 0.113 0.121 ApoB, mean (SD), mg/dL 65.6 (17.1) 60.5 (12.8) 0.247 0.260 Lp(a), mean (SD), mg/dL 34.7 (35.8) 26.6 (22.5) 0.344 0.359 hs-CRP, median (IQR), mg/L 0.54 (0.15; 2.97) 0.49 (0.15; 13.6) 0.561 0.363 HOMA, mean (SD) 1.99 (1.20) 1.84 (1.10) 0.641 0.610 Lipid profile All patients Ox-LDL, mean (SD), mg/dL 128.5 (45.2) 110.3 (31.8) 0.113 0.120 ApoB, mean (SD), mg/dL 65.6 (17.3) 60.4 (12.8) 0.247 0.255 BMI <85th percentile Ox-LDL, mean (SD), mg/dL 136.6 (47.3) 104.8 (28.4) 0.037 0.035 ApoB, mean (SD), mg/dL 70.6 (14.4) 59.1 (12.9) 0.049 0.037 BMI <85th percentile + WC <75th percentile + waist-to-height ratio ≤0.490 Ox-LDL, mean (SD), mg/dL 147.8 (41.8) 107.0 (26.2) 0.010 0.011 ApoB, mean (SD), mg/dL 74.0 (12.7) 59.7 (11.74) 0.019 0.018 * Sex and age adjusted were obese compared to controls, this difference was not statistically significant, however there was an underlying trend toward obesity in psoriatic children, with an ageand sex-adjusted OR of 9.4 (95% CI 1.0-90.4). Concerning central/visceral adiposity evaluation, using WC percentile and waist-to-height ratio, the ageand sexadjusted odds of a WC percentile greater than 75 were significantly higher for children with psoriasis vs controls (OR 7.4; 95% CI 2.0-27.7), as the percentage of children with a WC percentile greater than 75 was significantly higher in psoriatic children than in controls (75% vs 29.6%, P=0.002). However for a WC percentile greater than 90 (vs <90th percentile), there was no statistically significant difference (25% vs 14.8, P=0.380; OR 2.1; 95% CI 0.5-9.4). Waist-to-height ratio was significantly higher in children with psoriasis than controls (median (IQR): 0.510 (0.40; 0.64) vs 0.460 (0.40; 0.58), P = 0.019). A significantly higher percentage of children with psoriasis had a waistto-height ratio above the normal range (>0.490) (55% vs 22.2%, P=0.021) with a 4.3-fold higher risk for excess central adiposity comparing to controls (OR 4.6; 95% CI 1.3-17.0). Finally, the OR of a waist-to-weight ratio ≥0.539 (vs <0.539) was 5.5 (95% CI 1.0-31.1), as 30% of psoriatic children vs 7.4% of controls (P = 0.05) had a waist-toweight ≥0.539, table 2. There was no difference in the other cardiovascular risk factors (hypertension, hypercholesterolemia, hypertriglyceridemia and diabetes) or insulin resistance. Concerning the lipid profile, no statistically significant difference was noted between the two groups. However, ox-LDL and apoB levels were higher in the psoriasis group (ox-LDL: 125.5 ±45.2 mg/dL vs 110.3 ±31.8mg/dL, P=0.113 and apoB: 65.6 ±17.3 mg/dL vs 60.4 ±12.8 mg/dL, P=0.247). Analysing exclusively patients without excess adiposity, considering only BMI <85th percentile or all three surrogate measures of excess adiposity (BMI <85th percentile Author offprint 2. ARTIGOS PUBLICADOS 151 © John Libbey Eurotext, 2014 Journal Identification = EJD Article Identification = 2291 Date: May 8, 2014 Time: 3:31 pm EJD, vol. 24, n◦2, March-April 2014 233 Table 2. Ageand sex-adjusted ORs OR (95% CI) Predicting Referent Control BMI WC Waist-to-Height ratio Excess adiposity (overweight + obesity) Normal weight 4.4 (1.2-15.6) 7.4 (2.0-27.7) 4.6 (1.3-17.0) Obesity Normal weight 13.4 (1.3-137.1) 5.0 (0.9-27.3) 7.5 (1.2-45.9) Obesity Overweight 4.6 (0.4-52.6) 0.5 (0.1-3.2) 2.4 (0.3-19.0) Obesity Overweight + normal weight) 9.4 (1.0-90.4) 2.1 (0.5-9.4) 5.5 (1.0-31.3) + WC <75th percentile + waist-to-height ratio ≤0.490), a statistically significant difference between psoriatic children and controls was found for ox-LDL (136.6 ±47.3 vs 104.8 ±28.4, p = 0.037; 147.8 ±41.8 vs 107.0 ±26.2, P=0.010) and apoB (70.6 ±14.4 vs 59.1 ±12.9, P=0.049; 74.0 ±12.7 vs 59.7 ±11.74, P = 0.019), with both groups maintaining no differences for age and sex. The prevalence of metabolic syndrome was higher in the psoriatic group (25% vs 3.7%; P = 0.07), and although this difference was not statistically significant, there was an underlying trend toward an increased prevalence of metabolic syndrome in psoriatic children, with 2 components of the metabolic syndrome being significantly higher in the psoriasis group: waist circumference (75% vs 29.6%; P=0.002) and SBP/DBP>90th percentile for age, gender and height (30% vs 3.7% P=0.032). Discussion In this study, it was observed that children with psoriasis had a significantly greater prevalence and greater odds of excess adiposity and central adiposity than controls using several surrogate markers, such as BMI (≥85th percentile – OR 4.4; 1.2-15.6), WC (>75th percentile – OR 7.4; 2.0-27.7) and waist-to-height ratio (>0.490 – OR 4.6; 1.3-17.0). Moreover, a greater prevalence of metabolic syndrome was observed in children with psoriasis and although this difference was not statistically significant, there was an underlying trend toward an increased prevalence of metabolic syndrome in these patients comparing to controls (25% vs 3.7%; P = 0.07). Additionally, two components of the metabolic syndrome were significantly higher in the psoriasis group: waist circumference (75% vs 29.6%; P = 0.002) and the high blood pressure component (30% vs 3.7% P = 0.032). Finally, an altered and more atherogenic lipid profile was observed among psoriatic patients without excess adiposity. It is well known that obesity and mainly central adiposity during childhood is associated with an increased risk of cardiovascular risk factors and cardiovascular disease and mortality in adulthood [25]. Current literature supports an association between psoriasis and obesity. A recent metaanalysis of cross-sectional and case-control studies showed that adult psoriasis patients have >50% increased odds of being obese, and that these odds are significantly higher for those with moderate-to-severe psoriasis than for patients with mild disease [26]. Although there is less data considering childhood psoriasis, some studies have addressed the association between excess adiposity and psoriasis in children and it has been observed that psoriatic children have a significantly greater risk of being overweight or obese and having increased central adiposity [8, 9, 14, 15]. Moreover, childhood psoriasis severity has been shown to be associated and/or influenced by excess adiposity, as, in a multi-centre, cross-sectional study of 409 psoriatic children, the odds ratio (95% CI) of obesity in psoriatic children vs controls was higher with severe psoriasis than mild psoriasis (4.92; 2.20-10.99 vs 3.60; 1.56-8.30) [8]. Interestingly, it has also been shown that overweight or obese children have increased odds of having psoriasis, as in an US cross-sectional study, overweight, moderately obese and extremely obese children had 1.31-, 1.39-, and 1.78-fold greater odds, respectively, of having psoriasis [16]. The precise mechanism underlying this association is unknown but it is probably multifactorial. Genetic and immune mediated mechanisms and behavioural factors such as diminished physical activity probably have an important role in explaining the association between psoriasis and obesity. The recent understanding of obesity as a pro-inflammatory state and adipose tissue, especially visceral adipose tissue, as an immune and endocrine organ, help explain the association between these two conditions [27]. In fact, overproduction of types 1 and 17 helper T-cell inflammatory cytokines has been associated with both obesity and psoriasis, which suggests that chronic inflammation may drive both conditions [28]. Adipocytes and inflammatory-type macrophages are key cell types that perpetuate inflammation within adipose tissue. Activated macrophages stimulate adipocytes to secrete inflammatory mediators, known as adipokines, such as leptin and resistin, that have been shown to be increased in psoriasis patients, which may promote activation of T cells and monocytes, driving both Th1 and Th17 immune responses and at the same time impairing the function of regulatory T cells [29]. Interestingly, low levels of regulatory adipokines have also been observed in psoriasis [30]. It is unclear if obesity precedes psoriasis or vice-versa. On the one hand, a prospective cohort study including 892 psoriatic women showed that increased adiposity preceded the onset of psoriasis [31], however, the pro-inflammatory state associated with psoriasis could be responsible and act as a driving force for the development of obesity and other cardiovascular comorbidities. However, obesity-related inflammatory processes are probably more important, contributing to the severity of psoriasis rather than to the development the disease, since remission/amelioration of psoriasis has been reported after the treatment of obesity or bariatric surgery [32]. Thus, obesity and psoriasis are related and influence each other, probably deriving from a common underlying Author offprint 2. ARTIGOS PUBLICADOS 152 © John Libbey Eurotext, 2014 Journal Identification = EJD Article Identification = 2291 Date: May 8, 2014 Time: 3:31 pm 234 EJD, vol. 24, n◦2, March-April 2014 pathophysiology. Common genetics may be in part responsible for the association between these two conditions, as this association is observed even at a young age. Interestingly, higher levels of ox-LDL and apoB in psoriatic patients compared to controls were observed in this study, although without statistical significance. However, analysing exclusively patients without excess adiposity, a significant difference was found in the levels of ox-LDL and apoB in psoriatic children, two important players in the atherosclerotic process. Over the past decade, several studies have established that the oxidatively-modified form of LDL is more important than native LDL in atherogenesis, as it enhances endothelial activation and/or dysfunction, processes widely accepted to be the earliest events in atherosclerosis [33]. Additionally, ox-LDL is considered a useful marker for cardiovascular diseases, as the measurement of ox-LDL correlates with the presence of CV disease, indicating that ox-LDL is a potential prognostic marker for future CV events [34]. Likewise, subendothelial retention of apoB-containing lipoproteins is an essential initiating event in atherogenesis and high plasma levels of apoB is a risk factor for atherosclerosis, while low levels may provide protection [35]. Moreover, apoB predicts ischemic cardiovascular events in both genders, being better than LDL in this respect [36]. Naturally, the interpretation of these results is limited by the small number of patients, although the observation of a more atherogenic lipid prolife among psoriatic children, independent of excess adiposity, should not be unnoticed. Moreover, Mallbris et al evaluated the plasma lipid, lipoprotein and apolipoprotein profiles in adult patients with onset of psoriasis within the past 12 months, comparing it with a closely matched control group and found that psoriatic patients had an aberrant lipoprotein composition, showing that patients with psoriasis are predisposed to lipid abnormalities. These results support the idea that an abnormal lipid profile and possibly other psoriasis linked co-morbidities may be genetically determined rather than acquired [37]. Recognizing genetic markers that could predict which patients are at risk of developing psoriasis-linked cardiovascular comorbidities would facilitate screening strategies and earlier management, with important clinical implications [38]. Concerning metabolic syndrome, a combination of cardiovascular risk factors, including central obesity, hypertension, glucose intolerance and dyslipidemia, is widely accepted as an important predictor of cardiovascular disease and type 2 diabetes; several studies in adult populations have shown its association with psoriasis [39]. A recent study evaluated the potential relationship between age at the onset of psoriasis on the frequencies of cardiovascular and metabolic comorbidities in adulthood and it was showed that childhood onset of psoriasis had no effect on the frequencies of metabolic and cardiovascular comorbidities, indicating that psoriasis duration does not appear to influence the development of cardiovascular/metabolic comorbidities [40]. Data on children, however, are scant. Au et al compared 20 children with psoriasis with a control group of 1563 aged matched from the NHANES database and showed a higher prevalence of metabolic syndrome in the psoriasis group (30% vs 7.4%: P = 0.045), although there was no statistically significant difference in body mass index or for any of the individual components of metabolic syndrome. Only the levels of HDL-C were found to be decreased in psoriasis patients (44.3 mg/dL vs 51.6 mg/dL, P=0.017) [10]. Some limitations of this study should be addressed, particularly its sample size, therefore results must be interpreted with caution. Even so, in accordance with other previous studies, statistically significant differences were found between the two groups in several surrogate markers of obesity, mainly indicators for central obesity and metabolic risks (BMI, waist circumference and waist to height ratio). Moreover, although no statistically significant difference was found between psoriasis children and controls for the prevalence of metabolic syndrome, there was a trend towards an increased prevalence in the psoriasis group, with statistically significant differences in two metabolic syndrome components. Another limitation is the potential risk for selection bias, as in any hospital-based study design. Amongst the strengths of this study are the validity of the diagnosis of cases and controls, made by the same dermatologist, the recruitment of children with similar psoriasis severity, the uniform data collection ensuring comparability of data collection in cases and controls and the use of several surrogate measures of excess adiposity, like BMI percentile, WC percentile and waist-to-height ratio. These last two, sensitive, non-invasive markers of central adiposity are superior indicators to BMI for metabolic risk, correlating better with a higher risk of cardiovascular risk factors, such as hypertension, hypercholesterolemia, hypertriglyceridemia and insulin resistance. Moreover, an extensive laboratory workup was performed, analysing the lipid profile and insulin resistance. In conclusion, this study demonstrates that comorbidities known to be associated with adult psoriasis are also observed in childhood psoriasis. Moreover, an altered and more atherogenic lipid profile was observed among psoriatic patients without excess adiposity. The increased rate of cardiovascular comorbidities, particularly obesity and metabolic syndrome, observed in childhood psoriasis, along with the observation of lipid abnormalities at the onset of skin disease, suggests that its association with psoriasis may be in part genetically determined rather than uniquely acquired. These results reinforce the need for screening for cardiovascular comorbidities in children with psoriasis, mainly obesity and central adiposity, and to promote healthy lifestyle choices in these young patients.  Disclosure. Financial support: Sponsored by an unrestricted grant from the Portuguese Society of Dermatology and Venereology. Conflict of interest: none. References 1. Gudjonsson JE, Elder JT. Psoriasis: epidemiology. Clin Dermatol 2007;25:535-46. 2. Reich K. The concept of psoriasis as a systemic inflammation: implications for disease management. J Eur Acad Dermatol Venereol 2012;26:3-11. Author offprint 2. ARTIGOS PUBLICADOS 153 © John Libbey Eurotext, 2014 Journal Identification = EJD Article Identification = 2291 Date: May 8, 2014 Time: 3:31 pm EJD, vol. 24, n◦2, March-April 2014 235 3. Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol 2006;55:829-35. 4. 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