Psoriasis patients with obesity and type 2 biabetes: the effect of glucagon-like peptide 1 (GLP-1) receptor agonists

2014/2015 Paula C is ina Ca doso Teixei a Pso iasis pa ien s wi h obesi y and ype 2 diabe es: he e ec o glucagon-like pep ide-1 (GLP-1) ecep o agonis s ma ço, 2015 Mes ado In eg ado em Medicina Á ea: De ma ologia T abalho e e uado sob a O ien ação de: Dou o a So ia Magina T abalho o ganizado de aco do com as no mas da e is a: Jou nal o he Eu opean Academy o De ma ology and Vene eology Paula C is ina Ca doso Teixei a Pso iasis pa ien s wi h obesi y and ype 2 diabe es: he e ec o glucagon-like pep ide-1 (GLP-1) ecep o agonis s ma ço, 2015 P oje o de Opção do 6º ano - DECLARAÇÃO DE INTEGRIDADE Eu, Paula C is ina Ca doso Teixei a, abaixo assinado, nº mecanog á ico 200907067, es udan e do 6º ano do Ciclo de Es udos In eg ado em Medicina, na Faculdade de Medicina da Uni e sidade do Po o, decla o e a uado com absolu a in eg idade na elabo ação des e p oje o de opção. Nes e sen ido, con i mo que NÃO inco i em plágio (a o pelo qual um indi íduo, mesmo po omissão, assume a au o ia de um de e minado abalho in elec ual, ou pa es dele). Mais decla o que odas as ases que e i ei de abalhos an e io es pe encen es a ou os au o es, o am e e enciadas, ou edigidas com no as pala as, endo colocado, nes e caso, a ci ação da on e bibliog á ica. Faculdade de Medicina da Uni e sidade do Po o, 15 /_03 /_2015_ Assina u a con o me ca ão de iden i icação: P ojec o de Opção do 6º ano – DECLARAÇÃO DE REPRODUÇÃO NOME Paula C is ina Ca doso Teixei a CARTÃO DE CIDADÃO OU PASSAPORTE (se es angei o) E-MAIL TELEFONE OU TELEMÓVEL 13942107 paula.ca doso. eixei [email protected] 919249651 NÚMERO DE ESTUDANTE DATA DE CONCLUSÃO 200907067 23 de Ma ço de 2015 DESIGNAÇÃO DA ÁREA DO PROJECTO De ma ologia TÍTULO DISSERTAÇÃO/MONOGRAFIA ( isca o que não in e essa) Pso iasis pa ien s wi h obesi y and ype 2 diabe es: he e ec o glucagon-like pep ide-1 (GLP-1) ecep o agonis s ORIENTADOR P o . D a. So ia Magina COORIENTADOR (se aplicá el) É au o izada a ep odução in eg al des a Disse ação/Monog a ia ( isca o que não in e essa) pa a e ei os de in es igação e de di ulgação pedagógica, em p og amas e p ojec os coo denados pela FMUP. Faculdade de Medicina da Uni e sidade do Po o, _03 /_03_/_2015_ Assina u a con o me ca ão de iden i icação: DEDICATÓRIA “I you ocus on he p oblem, you can' see he solu ion. Ne e ocus on he p oblem! See wha no one else sees. See wha e e yone chooses no o see... ou o ea , con o mi y o laziness. See he whole wo ld as new each day “ Pa ch Adams MONOGRAFIA Pso iasis pa ien s wi h obesi y and ype 2 diabe es: he e ec o glucagon-like pep ide-1 (glp-1) ecep o agonis s Redigida de aco do com as no mas da e is a Jou nal o he Eu opean Academy o De ma ology and Vene eology Re iew A icle 1 PSORIASIS PATIENTS WITH OBESITY AND TYPE 2 DIABETES: THE EFFECT OF GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS 2800 wo ds 2 ables 2 igu es Au ho in o ma ion P. Teixei a1,3, S. Magina1,2,3 1Faculdade de Medicina da Uni e sidade do Po o, Po o, Po ugal; 2Depa men o De ma ology; 3Depa men o Pha macology and The apeu ics, Hospi al de São João, Po o, Po ugal Co espondence P. Teixei a Faculdade de Medicina da Uni e sidade do Po o, Alameda P o . He nâni Mon ei o, 4200 - 319 Po o, Po ugal Tel 220426700 Fax 225513643 Email: paula.ca doso. e[email p o ec ed] Funding Sou ces None Con lic o in e es All au ho s decla e no con lic s o in e es 2 ABSTRACT Pa ien s wi h pso iasis ha e a high p e alence o diabe es melli us (DM), obesi y and ca dio ascula diseases. Glucagon-like pep ide-1 ecep o (GLP-1R) agonis s is a ecen he apy used in obese pa ien s wi h ype 2 diabe es. This new d ugs imp o e glycaemic con ol and educe weigh . Besides, GLP-1R is p esen on some cells o he immune sys em. Recen s udies sugges ed ha GLP-1R agonis s may imp o e pso iasis. We e iewed he li e a u e o examine he e icacy o GLP-1R agonis s on clinical se e i y o pso iasis pa ien s wi h obesi y and ype 2 diabe es and o e alua e he mechanism by which GLP-1R agonis s exe hei e ec s. Pso iasis pa ien s, wi h ype 2 diabe es and obesi y, seem o ha e a signi ican imp o emen in pso iasis se e i y and quali y o li e, a e GLP-1R agonis he apy. They also showed a dec eased in weigh and choles e ol le els and an imp o emen in glycaemic con ol. The e ec s on pso ia ic lesions occu a e a ew weeks o ea men , e en be o e he me abolic imp o emen occu s. GLP-1R agonis s appea o ha e an added bene icial e ec on pso iasis pa ien s, possibly due o i s immunomodula o y e ec s. Fu he mo e, his ea men can also imp o e o he como bidi ies ha may be associa ed, such as diabe es and obesi y. In conclusion, GLP-1R agonis s may be a use ul adjunc i e he apy o he ea men o pso iasis in diabe ics and obese pa ien s. 3 INTRODUCTION Pso iasis is a ch onic in lamma o y disease ha a ec s 2-3% o wo ld’s popula ion. His opa hologically is cha ac e ized by hipe p oli e a ion o epide mal ke a inocy es and hype ke a osis, de mal in lamma o y in il a e and angiogenesis. The in lamma o y in il a e consis s mainly o dend i ic cells, mac ophages, and T cells in he de mis and neu ophils, wi h some T cells in he epide mis (1, 2). Pso iasis is conside ed an immune-media ed in lamma o y skin diso de (3), in which Th17 pa hway plays an impo an ole (1), suppo ed by he good esul s wi h IL-17 based he apies (4). Pso iasis was conside ed a disease con ined o he skin (5), bu ecen indings ha e shown ha pa ien s wi h pso iasis also ha e an inc eased isk o ca dio ascula disease and mo ali y, as well as me abolic synd ome and i s componen s (6-8). Se e al s udies ha e shown ha pa ien s wi h pso iasis ha e a high p e alence o DM, hype ension, obesi y, hype lipidaemia and smoking (9-11). So, i is impo an o app oach pso iasis as a sys emic diso de . Pso iasis pa ien s ha e a highe isk o de eloping impai ed glucose ole ance and ype 2 diabe es (12-14). Obesi y seems o be mo e common in pso iasis pa ien s when compa ed wi h he gene al popula ion (15) and is conside ed a isk ac o o he de elopmen o pso iasis (6). The eason behind his associa ion emains unknown, bu di e en s udies sugges ha obesi y, as a ch onic in lamma o y s a e, may con ibu e o he de elopmen and agg a a ion o pso ia ic lesions (16, 17). Two new d ug classes based on he ac ions o he inc e in ho mones ha e been app o ed o he apy o ype 2 diabe es - inc e in enhance s and inc e in mime ics (18). Inhibi o s o dipep idyl pep idase 4 (DPP4 - he enzyme esponsible o he apid deg ada ion o GLP-1), inc ease inc e ins le els and enhance GLP-1 ac ion. I is known ha DPP4 is also exp essed on T cells su ace, ha ing an impo an ole in ac i a ing T cells (19). Howe e , only wo cases epo s showed ha DPP4 inhibi o s ha e posi i e e ec s in he ea men o pso iasis pa ien s wi h diabe es (19, 20). Glucagon-like pep ide-1 ecep o (GLP-1R) agonis s (inc e in mime ics – li aglu ide and exena ide) ha e been used in obese pa ien s wi h ype 2 diabe es. This he apy imp o es glycaemic con ol and educes weigh . Se e al s udies sugges ha pso iasis pa ien s wi h obesi y and DM2, ea ed wi h GLP-1R agonis s, exhibi ed a signi ican imp o emen o pso iasis lesions, possibly due o i s an i-in lamma o y e ec (21). 10 skin om pso iasis pa ien s (31). Came on e al demons a ed ha cells exp essing NK ma ke s and NK-T cell ma ke s a e p esen in pso iasis lesions (32). Recen da a, epo ed by T. Ahe n e al and Hogan e al, show ha ci cula ing iNKT cells inc eased and plaque iNKT cells dec eased a e li aglu ide ea men in pso iasis pa ien s wi h ype 2 diabe es and obesi y(22, 25). These esul s sugges ha GLP-1R agonis s may ha e a ole in pso iasis ea men , since hey seem o ha e di ec and indi ec e ec s on immune cells in ol ed in pso iasis pa hogenesis. O he s udies ha e shown ha GLP-1 le els also inc eased a e gas ic bypass su ge y. Some case epo s ha e desc ibed ha pso iasis imp o es immedia ely a e his p ocedu e in obese pa ien s (33). Changes on pso iasis mani es a ions occu be o e any weigh loss and coincide wi h a signi ican inc ease in GLP-1 le els (34-36). Fau schou e al sugges ed ha GLP-1 is esponsible o his e ec . The changes on GLP-1 le els a e p esumed o be caused by he su gically-in oduced e ou ing o inges ed nu ien s di ec ly o he dis al pa o jejunum, whe e GLP-1 eleasing L cells a e abundan ( igu e 2). GLP-1 is sec e ed o he blood s eam upon ood inges ion when luminal nu i ional componen s con ac wi h he apical pa o he L cells. These da a suppo he hypo hesis ha GLP-1 is esponsible o he posi i e e ec obse ed in pso iasis and obese pa ien s wi h ype 2 diabe es (37). Mos o he s udies we e limi ed by small sample size, sho du a ion, lack o compa a i e g oups and placebo e ec . Fu he s udies a e ob iously needed, including andomised clinical ials. GLP-1R agonis s appea o ha e an added bene icial e ec on pso iasis pa ien s, possibly due o i s immunomodula o y e ec s. Besides, his ea men can also imp o e o he como bidi ies ha may be associa ed, such as diabe es and obesi y. In conclusion, GLP-1R agonis s seem o ha e a posi i e e ec on pso iasis se e i y and quali y o li e. I appea s o ac by an immune mechanism, h ough a educ ion o IL-17 exp ession and de mal γδ T-cells. These esul s sugges ha GLP-1R agonis s may be a use ul adjunc i e he apy o he ea men o pso iasis in diabe ics and obese pa ien s. 11 ACKNOWLEDGMENTS I would like o exp ess my g a i ude o my supe iso , P o . Doc o So ia Magina, o he help h ough he cou se o his wo k. REFERENCES 1. Nes le FO, Kaplan DH, Ba ke J. Pso iasis. The New England jou nal o medicine. 2009;361(5):496-509. 2. Schon MP, Boehncke WH. Pso iasis. The New England jou nal o medicine. 2005;352(18):1899-912. 3. Jadali Z, Eslami MB. T cell immune esponses in pso iasis. I anian jou nal o alle gy, as hma, and immunology. 2014;13(4):220-30. 4. Lonnbe g AS, Zacha iae C, Sko L. Ta ge ing o in e leukin-17 in he ea men o pso iasis. Clinical, cosme ic and in es iga ional de ma ology. 2014;7:251-9. 5. Somme DM, Jenisch S, Suchan M, Ch is ophe s E, Weichen hal M. Inc eased p e alence o he me abolic synd ome in pa ien s wi h mode a e o se e e pso iasis. A chi es o de ma ological esea ch. 2006;298(7):321-8. 6. Go lieb AB, Dann F. Como bidi ies in pa ien s wi h pso iasis. The Ame ican jou nal o medicine. 2009;122(12):1150.e1-9. 7. G ozde I, Ko man N, Tsanko N. Pso iasis as a sys emic disease. Clinics in de ma ology. 2014;32(3):343-50. 8. Gisondi P, Tessa i G, Con i A, Piase ico S, Schianchi S, Pese ico A, e al. P e alence o me abolic synd ome in pa ien s wi h pso iasis: a hospi al-based case-con ol s udy. The B i ish jou nal o de ma ology. 2007;157(1):68-73. 9. Ahleho O, Gislason GH, Cha lo M, Jo gensen CH, Lindha dsen J, Olesen JB, e al. Pso iasis is associa ed wi h clinically signi ican ca dio ascula isk: a Danish na ionwide coho s udy. Jou nal o in e nal medicine. 2011;270(2):147-57. 10. Da ido ici BB, Sa a N, P inz J, Puig L, Eme y P, Ba ke JN, e al. Pso iasis and sys emic in lamma o y diseases: po en ial mechanis ic links be ween skin disease and co-mo bid condi ions. The Jou nal o in es iga i e de ma ology. 2010;130(7):1785- 96. 12 11. Neimann AL, Shin DB, Wang X, Ma golis DJ, T oxel AB, Gel and JM. P e alence o ca dio ascula isk ac o s in pa ien s wi h pso iasis. Jou nal o he Ame ican Academy o De ma ology. 2006;55(5):829-35. 12. Az a RS, Semina a NM, Shin DB, T oxel AB, Ma golis DJ, Gel and JM. Inc eased isk o diabe es melli us and likelihood o ecei ing diabe es melli us ea men in pa ien s wi h pso iasis. A chi es o de ma ology. 2012;148(9):995-1000. 13. Khalid U, Hansen PR, Gislason GH, Lindha dsen J, K is ensen SL, Win he SA, e al. Pso iasis and new-onse diabe es: a Danish na ionwide coho s udy. Diabe es ca e. 2013;36(8):2402-7. 14. Li W, Han J, Hu FB, Cu han GC, Qu eshi AA. Pso iasis and isk o ype 2 diabe es among women and men in he Uni ed S a es: a popula ion-based coho s udy. The Jou nal o in es iga i e de ma ology. 2012;132(2):291-8. 15. A ms ong AW, Ha skamp CT, A ms ong EJ. The associa ion be ween pso iasis and obesi y: a sys ema ic e iew and me a-analysis o obse a ional s udies. Nu i ion & diabe es. 2012;2:e54. 16. B emme S, Van Voo hees AS, Hsu S, Ko man NJ, Lebwohl MG, Young M, e al. Obesi y and pso iasis: om he Medical Boa d o he Na ional Pso iasis Founda ion. Jou nal o he Ame ican Academy o De ma ology. 2010;63(6):1058-69. 17. Hamminga EA, an de Lely AJ, Neumann HA, Thio HB. Ch onic in lamma ion in and obesi y: implica ions o he apy. Medical hypo heses. 2006;67(4):768-73. 18. Ha e KJ, Knop FK. Inc e in-based he apy and ype 2 diabe es. Vi amins and ho mones. 2010;84:389-413. 19. Nishioka T, Shinoha a M, Tanimo o N, Kumagai C, Hashimo o K. Si aglip in, a dipep idyl pep idase-IV inhibi o , imp o es pso iasis. De ma ology (Basel, Swi ze land). 2012;224(1):20-1. 20. Lynch M, Tobin AM, Ahe n T, O'Shea D, Ki by B. Si aglip in o se e e pso iasis. Clinical and expe imen al de ma ology. 2014;39(7):841-2. 21. D ucke DJ, Rosen CF. Glucagon-like pep ide-1 (GLP-1) ecep o agonis s, obesi y and pso iasis: diabe es mee s de ma ology. Diabe ologia. 2011;54(11):2741-4. 22. Ahe n T, Tobin AM, Co igan M, Hogan A, Sweeney C, Ki by B, e al. Glucagon-like pep ide-1 analogue he apy o pso iasis pa ien s wi h obesi y and ype 2 diabe es: a p ospec i e coho s udy. Jou nal o he Eu opean Academy o De ma ology and Vene eology : JEADV. 2013;27(11):1440-3. 13 23. Fau schou A, Gyldenlo e M, Rohde U, Thyssen JP, Zacha iae C, Sko L, e al. Lack o e ec o he glucagon-like pep ide-1 ecep o agonis li aglu ide on pso iasis in glucose- ole an pa ien s - a andomized placebo-con olled ial. Jou nal o he Eu opean Academy o De ma ology and Vene eology : JEADV. 2014. 24. Buysschae M, Baeck M, P eumon V, Ma o L, Hend ickx E, Van Belle A, e al. Imp o emen o pso iasis du ing glucagon-like pep ide-1 analogue he apy in ype 2 diabe es is associa ed wi h dec easing de mal gammadel a T-cell numbe : a p ospec i e case-se ies s udy. The B i ish jou nal o de ma ology. 2014;171(1):155- 61. 25. Hogan AE, Tobin AM, Ahe n T, Co igan MA, Gaoa swe G, Jackson R, e al. Glucagon-like pep ide-1 (GLP-1) and he egula ion o human in a ian na u al kille T cells: lessons om obesi y, diabe es and pso iasis. Diabe ologia. 2011;54(11):2745- 54. 26. Fau schou A, Pede sen J, Gyldenlo e M, Poulsen SS, Hols JJ, Thyssen JP, e al. Inc eased exp ession o glucagon-like pep ide-1 ecep o s in pso iasis plaques. Expe imen al de ma ology. 2013;22(2):150-2. 27. Fau schou A, Knop FK, Thyssen JP, Zacha iae C, Sko L, Vilsboll T. Imp o emen in pso iasis a e ea men wi h he glucagon-like pep ide-1 ecep o agonis li aglu ide. Ac a diabe ologica. 2014;51(1):147-50. 28. Buysschae M, Tenns ed D, P eumon V. Imp o emen o pso iasis du ing exena ide ea men in a pa ien wi h diabe es. Diabe es & me abolism. 2012;38(1):86-8. 29. Reid CT, Tobin AM, Ahe n T, O'Shea D, Ki by B. Li aglu ide in combina ion wi h aci e in o se e e ecalci an pso iasis. The B i ish jou nal o de ma ology. 2013;169(1):230-1. 30. Cai Y, Fleming C, Yan J. De mal gammadel a T cells--a new playe in he pa hogenesis o pso iasis. In e na ional immunopha macology. 2013;16(3):388-91. 31. Pe e nel S, Kas elan M. Immunopa hogenesis o pso iasis: ocus on na u al kille T cells. Jou nal o he Eu opean Academy o De ma ology and Vene eology : JEADV. 2009;23(10):1123-7. 32. Came on AL, Ki by B, Fei W, G i i hs CE. Na u al kille and na u al kille -T cells in pso iasis. A chi es o de ma ological esea ch. 2002;294(8):363-9. 33. Hossle EW, Ma oon MS, Mowad CM. Gas ic bypass su ge y imp o es pso iasis. Jou nal o he Ame ican Academy o De ma ology. 2011;65(1):198-200. 14 34. Hossle EW, Wood GC, S ill CD, Mowad CM, Ma oon MS. The e ec o weigh loss su ge y on he se e i y o pso iasis. The B i ish jou nal o de ma ology. 2013;168(3):660-1. 35. La e e e B. E ec o gas ic bypass su ge y on he inc e ins. Diabe es & me abolism. 2009;35(6 P 2):513-7. 36. Ming one G. Role o he inc e in sys em in he emission o ype 2 diabe es ollowing ba ia ic su ge y. Nu i ion, me abolism, and ca dio ascula diseases : NMCD. 2008;18(8):574-9. 37. Fau schou A, Zacha iae C, Sko L, Vilsboll T, Knop FK. Gas ic bypass su ge y: imp o ing pso iasis h ough a GLP-1-dependen mechanism? Medical hypo heses. 2011;77(6):1098-101. 15 FIGURES AND TABLES Li e a u e sea ch To al numbe o abs ac s iden i ied om da abase sea ch (MEDLINE, SCOPUS, Web o SCIENCE) n = 84 Duplica ed a icles (excluded n = 17) To al numbe o a icles n = 67 A icles sc eened on basis o i le and abs ac s (excluded 55) Included n = 12 Manusc ip e iew and applica ion o inclusion c i e ia Included n = 8 Excluded n = 4 3 e iews 1 ench a icle 16 Diabe es and Obesi y Pso iasis GLP-1 GLP-1 ecep o agonis s Li aglu ide and Exena ide - p olongs and enhances he e ec o GLP-1 - hey a e esis an o inac i a ion by DPP4 Gas ic Bypass Su ge y - Roux-en-Y gas ic bypass p ocedu e: a small pa o he s omach is used o c ea e a new s omach pouch; he smalle s omach is connec ed di ec ly o he middle po ion o he small in es ine (jejunum), bypassing he es o he s omach and he uppe po ion o he small in es ine (duodenum). - educes body weigh - imp o es glycaemic con ol - imp o es PASI and DLQI - dec eases numbe o de mal γδ T- cells and IL-17 mRNA exp ession in pso ia ic lesions - inc eases ci cula ing iNKT cells dec eases and plaque iNKT cells - Inc eases GLP-1 le els - Immedia ely imp o emen o pso iasis be o e any weigh loss Figu e 2. E ec s o GLP-1 ecep o agonis s and gas ic bypass su ge y in pso ia ic pa ien s wi h diabe es and obesi y 17 Table 1 S udy ou comes S udy S udy design In e en ion Pa icipan s Va iables Resul s T. Ahe n e al, 2013 P ospec i e coho s udy 10 weeks o li aglu ide he apy: sel -adminis e ed by subcu aneous injec ion; 0.6mg daily o 2 weeks and 1.2mg daily o 8 weeks Pso iasis pa ien s wi h diabe es and obesi y (median age 48 yea s, median BMI 48.2 Kg/m2) n = 7 - PASI - DLQI - Ci cula ing iNKT numbe - Monocy e cy okine p oduc ion A week 10 - median PASI d opped om 4.8 (2.6–11.4) o 3.0 (1.9–7.9, P = 0.03) - median DLQI d opped om 6 (3.5–8.9) o 2 (1– 6.1, P = 0.03) - median ci cula ing iNKT cell pe cen age inc eased 37.9% (18.5–234.6, P = 0.03) - PBMC TNFα p oduc ion dec eased by a median o 53% A.Fau schou e al, 2014 Randomized placebo- con olled ial Once-daily subcu aneous injec ions wi h li aglu ide o placebo, o 8 weeks; 0.6mg o 1 week, 1.2mg he ollowing week and hen 1.8mg Glucose- ole an and obese pa ien s (BMI > 25 Kg/m2) wi h plaque pso iasis Placebo n = 9 Li aglu ide n = 11 - PASI - DLQI - Weigh - hsCRP - Ad e se e en s A week 8 - mean PASI dec ease 2.6 ± 2.1 (mean ± SD, P=0.026) in he li aglu ide g oup; non-signi ican change in PASI in he placebo g oup (-1.3 ± 2.4, P=0.141) - no signi ican di e ences we e obse ed in he DLQI - he li aglu ide g oup had a significan loss in bodyweigh compa ed wi h he placebo g oup - no signi ican changes in hsCRP occu ed in bo h g oups - no majo ad e se e en s we e obse ed M.Buysschae e al, 2014 P ospec i e case-se ies Pa ien s sel -adminis e ed subcu aneous injec ions wi h exena ide (5µg wice daily) o li aglu ide (0.6mg once a day o 1 week and hen 1.2mg once a day). The a iables we e measu ed a baseline (T0) and 7±1 (T1) and 18±2 (T2) weeks a e ea men wi h li aglu ide/exena ide. Pa ien s wi h ype 2 diabe es and ch onic pso iasis plaques (mean age 56 ± 8 yea s, mean BMI 32.0 ± 10.1 Kg/m2) n = 7 - PASI - BMI - HbA1c - de mal γδ T-cell pe cen age - IL-17 exp ession - Pso iasis se e i y imp o ed wi h li aglu ide/exena ide ea men (12.0±5.9 (T0), 9.2±6.2 (T1) and 9.2±6.4 (T2)) - BMI dec eased a e 4-5 mon hs o ea men ( om 32.0±10.1(T0) o 30.6±9.1 (T2) Kg/m2, P=0.05) - Glycaemic con ol imp o ed a T2 (HbA1c dec eased om 7.5±1.2 (T0) o 6.5±0.8 (T2), P=0.014) - De mal γδ T-cell pe cen age was highe in pso ia ic lesions compa ed wi h una ec ed skin and a dec eased o 4.0±0.7% (P=0.05) occu ed in he pa ien s wi h imp o ed (n=5) o unchanged (n=1) PASI sco es du ing he ea men . 18 - No signi icance di e ence was seen du ing he ea men in IL-17 exp ession. Hogan e al, 2011 P ospec i e s udy Index pa ien : unde wen ea men wi h exena ide o 2 mon hs and hen wi h li aglu ide. O he pa ien s: wo addi ional pa ien s s a ed li aglu ide o 6 weeks, a e he imp o emen o pso ia ic lesions in he index pa ien Pa ien s wi h ype 2 diabe es and pso iasis (n=2) - PASI - ci cula o y and plaques le els o iNKT cell - GLP-1 ecep o exp ession on iNKT cells - PASI imp o ed om 13.2 o 10.8 (pa ien 1) and om 4.8 o 3.8 (pa ien 2) - ci cula o y iNKT cell numbe inc eased a e he ea men and plaque iNKT cell dec eased - iNKT cells exp ess GLP-1R, which espond o GLP-1 ac i a ing a signalling pa hway Fau schou e al, 2013 C oss- sec ional s udy A skin biopsy was made e e y heal hy olun ee and wo skin biopsies e e y pso iasis pa ien s ( om a ec ed and una ec ed skin). They collec ed a blood sample om all pa icipan s and cul u ed human ke a inocy es we e s imula ed o uns imula ed. Heal h olun ee s (n=6) s Pso iasis pa ien s (n=6) - Exp ession o GLP-1 ecep o s in skin biopsies, blood samples and cul u ed human ke a inocy es - GLP-1 ecep o s we e exp essed in fi e o six skin biopsies om pso iasis plaques, in one o six biopsies om una ec ed pso ia ic skin and in one o six biopsies om heal hy skin. - GLP-1 ecep o s we e exp essed in he blood o all pa icipan s. - GLP-1 ecep o s exp ession we e no ound in s imula ed o uns imula ed cul u ed human ke a inocy es. 19 Table 2. Case epo s S udy Pa ien Medical His o y Physical examina ion T ea men Resul s A.Fau schou e al, 2014 59 yea s Man - Type 2 diabe es (inadequa e glycaemic con ol) - Hype ension - Hype choles e olemia - Acu e myoca dial in a c ion - Plaque pso iasis (diagnosed 15 yea s ago) - BMI 29.3 kg/m2 - HbA1c 8.9% (74mmol/mol) - Pso iasis was loca ed on he elbows, knees, scalp, bu ocks and do sal pa s o he hands - Physician’s global assessmen (PGA) sco e 3 - Li aglu ide: 0.6mg once daily o 1 week and hen 1.2 mg once daily he ollowing 5 weeks and hen 1.8mg. - Me o min: 1g wice a day - Insulin?? A e 3 mon hs o ea men : - HbA1c educed (5.9%) - BMI 26.81 kg/m2 - Ad e se e en s - nausea and headache, in e mi en cons ipa ion and dia hoea. No episodes o hypoglycaemia we e epo ed - Pso iasis symp oms imp o ed - PGA educed (sco e 1) M.Buysschae e al, 2012 61 yea s Man - Type 2 diabe es o 14 yea s - Hype ension - Dyslipidaemia - Pso iasis (since 1980) - BMI 25.5 kg/m2 - HbA1c 8.1% (65mmol/mol) - CRP 0.22 mg/dL - PASI sco e 11 - Exena ide 2x5µg/day (ini ia ed on Sep embe 2008) - Me o min and sulphonylu eas - Pe indop il (5mg/day) - Moxonidine (0.4mg/day) - Sim as a in (20mg/day) A e 12 mon hs o ea men : - BMI 24.07 kg/m2 - HbA1c 7.3% (56mmol/mol) - CRP 0.03 md/dL - PASI sco e 3-4 (he s opped all opical ea men s) Exena ide ea men in e up ed in Sep embe 2009: - PASI sco e (a e 6 mon hs) >10 - weigh gain and wo sening o glycaemic con ol (HbA1c 9.2%) Ap il 2010, s a ed exena ide ea men again: - weigh loss - HbA1c 8.1% (65mmol/mol) - PASI sco e 3.1 Reid e al, 2013 54 yea s Man - Ex ensi e plaque pso iasis - Malignan melanoma (wi hou me as a ic disease) - No diabe es - BMI 42.1 kg/m2 - PASI 14.2 - DLQI 25 - Aci e in 50mg daily - Li aglu ide (0.6mg daily o one week and hen 3mg daily) A e one yea : - PASI 7.6 - DLQI 12 - Weigh dec eased 10kg o he s udies being epo ed should be included in all manusc ip s in he Ma e ials and Me hods sec ion. E hics commi ee o ins i u ional e iew boa d app o al should be s a ed. Pa ien s ha e a igh o p i acy ha should no be in inged wi hou in o med consen . Iden i ying in o ma ion should no be published in w i en desc ip ions, pho og aphs and pedig ees unless he in o ma ion is essen ial o scien i ic pu poses and he pa ien (o pa en o gua dian) gi es w i en in o med consen o publica ion. Iden i ying de ails should be omi ed i hey a e no essen ial bu pa ien da a should ne e be al e ed o alsi ied in an a emp o a ain anonymi y. Comple e anonymi y is di icul o achie e and in o med consen should be ob ained i he e is any doub . Fo example, masking he eye egion in pho og aphs o pa ien s is inadequa e p o ec ion o anonymi y. Au ho ship. All pe sons designa ed as au ho s should quali y o au ho ship and all hose who quali y should be lis ed. Each au ho should ha e pa icipa ed su icien ly in he wo k o ake public esponsibili y o app op ia e po ions o he con en . One o mo e au ho s should ake esponsibili y o he in eg i y o he wo k as a whole, om incep ion o published a icle. Au ho ship c edi should be based only on (i) subs an ial con ibu ions o concep ion and design, o acquisi ion o da a, o analysis and in e p e a ion o da a; (ii) d a ing he a icle o e ising i c i ically o impo an in ellec ual con en ; (iii) inal app o al o he e sion o be published. Condi ions (i), (ii) and (iii) mus all be me . Acquisi ion o unding, he collec ion o da a o gene al supe ision o he esea ch g oup, by hemsel es, do no jus i y au ho ship. All o he s who con ibu ed o he wo k who a e no au ho s should be named in he Acknowledgmen s sec ion. Commi ee on Publica ion E hics (COPE). As a membe o he Commi ee on Publica ion E hics (COPE), adhe ence o hese submission c i e ia is conside ed essen ial o publica ion in heJEADV; manda o y ields a e included in he online submission p ocess o ensu e his. I , a a la e s age in he submission p ocess o e en a e publica ion, a manusc ip o au ho s a e ound o ha e dis ega ded hese c i e ia, i is he du y o he Edi o o epo his o COPE. COPE may ecommend ha ac ion be aken, including bu no exclusi e o, in o ming he au ho s' p o essional egula o y body and/o ins i u ion o such a de elic ion. The websi e o COPE may be accessed a : h p://www.publica ione hics.o g.uk 7 ADDITIONAL INFORMATION ON ACCEPTANCE Copy igh . I you pape is accep ed, he au ho iden i ied as he o mal co esponding au ho o he pape will ecei e an email p omp ing hem o login in o Au ho Se ices; whe e ia he Wiley Au ho Licensing Se ice (WALS) hey will be able o comple e he license ag eemen on behal o all au ho s on he pape . Fo au ho s signing he copy igh ans e ag eemen I he OnlineOpen op ion is no selec ed he co esponding au ho will be p esen ed wi h he copy igh ans e ag eemen (CTA) o sign. The e ms and condi ions o he CTA can be p e iewed in he samples associa ed wi h he Copy igh FAQs below: CTA Te ms and Condi ions h p://au ho se ices.wiley.com/bau ho / aqs_copy igh .asp Fo au ho s choosing OnlineOpen I he OnlineOpen op ion is selec ed he co esponding au ho will ha e a choice o he ollowing C ea i e Commons License Open Access Ag eemen s (OAA): C ea i e Commons A ibu ion Non-Comme cial License OAA C ea i e Commons A ibu ion Non-Comme cial -NoDe i s License OAA To p e iew he e ms and condi ions o hese open access ag eemen s please isi he Copy igh FAQs hos ed on Wiley Au ho Se ices h p://au ho se ices.wiley.com/bau ho / aqs_copy igh .asp and isi h p://www.wileyopenaccess.com/de ails/con en /12 25db4c87/Copy igh - License.h ml. I you selec he OnlineOpen op ion and you esea ch is unded by The Wellcome T us and membe s o he Resea ch Councils UK (RCUK) you will be gi en he oppo uni y o publish you a icle unde a CC-BY license suppo ing you in complying wi h Wellcome T us and Resea ch Councils UK equi emen s. Fo mo e in o ma ion on his policy and he Jou nal’s complian sel -a chi ing policy please isi : h p://www.wiley.com/go/ unde s a emen . Fo RCUK and Wellcome T us au ho s click on he link below o p e iew he e ms and condi ions o his license: C ea i e Commons A ibu ion License OAA To p e iew he e ms and condi ions o hese open access ag eemen s please isi he Copy igh FAQs hos ed on Wiley Au ho Se ices h p://au ho se ices.wiley.com/bau ho / aqs_copy igh .asp and isi h p://www.wileyopenaccess.com/de ails/con en /12 25db4c87/Copy igh --License.h ml. P oo s. Page p oo s will be sen o he co esponding au ho and should be e u ned wi hin 3 days o eceip o he P oduc ion Edi o . Signi ican ex ual al e a ions a e unaccep able a p oo s age wi hou he w i en app o al o he Edi o , and hey a e likely o esul in he delay o publica ion. The co esponding au ho will ecei e an e-mail ale con aining a link o a secu e web si e. A wo king e-mail add ess mus he e o e be p o ided o he co esponding au ho . In he absence o he co esponding au ho , please a ange o a colleague o access he e-mail o e ie e he p oo s. Please no e ha you ha e inal esponsibili y o wha is s a ed in he p oo s o you manusc ip . Howe e , he p oo s a e checked ho oughly by he JEADV edi o ial eam and i we do no ecei e co ec ions a e se e al au oma ed eminde s o he email add ess supplied o he co esponding au ho hen we will assume ha we ha e you app o al o publica ion. Au ho se ices. Au ho Se ices enables au ho s o ack hei a icle - once i has been accep ed - h ough he p oduc ion p ocess o publica ion online and in p in . Au ho s can check he s a us o hei a icles online and choose o ecei e au oma ed e-mails a key s ages o p oduc ion. The au ho will ecei e an e-mail wi h a unique link ha enables hem o egis e and ha e hei a icle au oma ically added o he sys em. Please ensu e ha a comple e e-mail add ess is p o ided when submi ing he manusc ip . Visi h p://au ho se ices.wiley.com/bau ho o mo e de ails on online p oduc ion acking and o a weal h o esou ces including FAQs and ips on a icle p epa a ion, submission and mo e. Ea lyView. JEADV is co e ed by he Publishe ’s Ea ly View se ice. Ea ly View a icles a e comple e ull- ex a icles published online in ad ance o hei publica ion in a p in ed issue. A icles a e he e o e a ailable as soon as hey a e eady, a he han ha ing o wai o he nex scheduled p in issue. Ea ly View a icles a e comple e and inal. They ha e been ully e iewed, e ised and edi ed o publica ion, and he au ho s’ inal co ec ions ha e been inco po a ed. Because hey a e in inal o m, no changes can be made a e online publica ion. The na u e o Ea ly View a icles means ha hey do no ye ha e olume, issue o page numbe s, so Ea ly View a icles canno be ci ed in he adi ional way. They a e he e o e gi en a Digi al Objec Iden i ie (DOI), which allows he a icle o be ci ed and acked be o e i is alloca ed o an issue. A e p in publica ion, he DOI emains alid and can con inue o be used o ci e and access he a icle. Mo e in o ma ion abou DOIs can be ound online a h p://www.doi.o g/ aq.h ml. O p in s. F ee access o he inal PDF o p in o you a icle will be a ailable ia au ho se ices only. Please he e o e sign up o au ho se ices i you would like o access you a icle PDF o p in and enjoy he many o he bene i s he se ice o e s. Addi ional o p in s can be o de ed on he o p in o de o m, which accompanies he p oo s. Disclaime . The Publishe , he Eu opean Academy o De ma ology and Vene eology (EADV) and Edi o s canno be held esponsible o e o s o any consequences a ising om he use o in o ma ion con ained in his jou nal; he iews and opinions exp essed do no necessa ily e lec hose o he Publishe , he EADV and Edi o s o he p oduc s ad e ised.