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SAMMANFATTNING PÅ SVENSKA
Psoriasisartrit (PsA) är en inflammatorisk ledsjukdom som är associerad med hudsjukdomen psoriasis. PsA har en mångfacetterad sjukdomsbild med många olika sjukdomsuttryck som t ex mild artrit i enstaka eller fåtal leder eller mycket svår, erosiv och destruktiv ledsjukdom i många leder. Den mätbara sjukdomsaktiviteten uttryckt i SR och andra inflammationsmarkörer är inte alltid särskilt framträdande. Förekomst av PsA i befolkningen är okänd och det finns varierande uppgifter på hur ofta personer med hudpsoriasis drabbas. Sjukdomens etiologi är fortfarande okänd även om genetiska faktorer anses ha stor betydelse. De genetiska studier som hittills genomförts visar på ett sannolikt polygent ärftlighetsmönster med flera gener inblandade. Syftet med avhandlingen har varit att, bland patienter från norra Sverige, undersöka förekomst av led och rygg manifestationer hos patienter med hudpsoriasis och PsA, att karaktärisera PsA i relation till inflammatoriska och genetiska markörer samt att identifiera gener som styr sjukdomsuppkomst eller sjukdomsutveckling. Avhandlingen består av fyra delarbeten.
Delstudie I: Ur ett register över patienter med hudpsoriasis (n=1737), insamlat vid Hudkliniken, Universitetssjukhuset, Umeå, erbjöds alla patienter boende i Umeå (n=276) att delta i en prevalens studie. 202 patienter undersöktes och 97 (48%) hade inflammatoriska manifestationer som perifer artrit, inflammatorisk ryggsjukdom, spondylartropati uns och entesopati. Av de 67 patienterna (33%) med perifer artrit och/eller inflammatorisk rygg- sjukdom hade 30 patienter inte tidigare diagnosticerats med artritsjukdom. Delstudie II: Associationen mellan kliniska sjukdomsmanifestationer och potentiella markörer för aggressiv ledsjukdom samt HLA associationer, analyserades hos 88 patienter med PsA. Aggressiv sjukdom definierades som röntgenologiska tecken på leddestruktion och/eller deformiteter och/eller inskränkt rörlighet i angripna leder. Studien visade ökad förekomst av HLA- B17, B37 och B62 i jämförelse med friska kontroller, men vid multipel
Sammanfattning på svenska
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regressions analys var de starkaste prediktiva faktorerna för aggressiv sjukdom polyartikulär sjukdomsbild och engagemang i DIP-leder.
Forskningsresultat från tidigare studier, där starka associationer med flera HLA-antigener rapporterats, kunde inte verifieras.
Delstudie III: I denna studie analyserades 5 genetiska loci med microsatelliter och SNPs med avsikt att undersöka deras association med PsA hos 120 patienter. Signifikant association kunde ses med TNFB lokus på kromosom 6 men inte med övriga undersökta områden, 1q21 (PSORS4), 3q21 (PSORS5), 8q24 och CTLA4. Vid stratifiering för TNFB allelerna begränsades associationen till allel 123. I en subgrupp av patienter som tidigare HLA- typats (n=83), undersöktes eventuell förekomst av koppling mellan TNFB allel 123 och HLA-antigenerna B17, B27, B27, B62 och Cw*0603. Någon koppling kunde dock inte verifieras.
Deltstudie IV: Förekomsten av njurpåverkan som en manifestation av systemisk inflammation utvärderades hos patienter med PsA. Av de 73 undersökta patienterna hade 23% njurpåverkan definierat som nedsatt kreatinin-clearence med mer än -2SD av medelvärdet hos normalbe- folkningen och/eller ökad albuminuri > 25 mg/24 tim. Den prediktiva faktorn för njurpåverkan var mätbar inflammatorisk aktivitet (SR > 25 mm/tim och/eller CRP > 15 mg/L) vilket indikerar systemisk effekt hos dessa patienter.
Sammanfattningsvis visade studierna i avhandlingen hög prevalens av inflammatoriska led- och rygg-manifestationer hos patienter med psoriasis. Ingen stark association mellan HLA-antigener och PsA kunde verifieras. De prediktiva faktorerna för aggressiv sjukdom var polyartikulär sjukdomsbild och engagemang i DIP-lederna. TNFB lokus var associerad med PsA och ingen koppling mellan TNFB och HLA antigenerna B17, B27, B37, Cw*0602 kunde visas. Njurpåverkan kunde ses hos patienter med PsA och mätbar inflammatorisk aktivitet.
Acknowledgement
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ACKNOWLEDGEMENT
I would like to express my sincere gratitude to everyone who has supported me to complete this project, and in particular:
Solbritt Rantapää Dahlqvist, my supervisor and friend, for never-ending
interest and support, for stimulating discussions and advices and for always being there when needed
Bernd Stegmayr, my co-supervisor, for guiding me through the difficulties of
nephrology
Hans Stenlund and Staffan Nilsson for statistical explanations, in general and
in genetics
Jan Wahlström, Lena Samuelsson and Camilla Friberg for genetic
discussions
All my co-authors, for fruitful collaboration
All my colleagues and co-workers at the Department of Rheumatology, for
support, interest and patience
Gun-Britt Johansson for invaluable help with collection of data and patient
support, and Inger Bucht and Inger Hamberg for excellent technical assistant and laboratory work
Solweig Jonsson and Agneta Uddhammar for friendship and encouragement Mina föräldrar; Inger och Rolf, som stöttat mig och som uppmuntrat mig att
söka kunskap
My family; Bosse, Emelie, Frida and Felicia, for love and patience, for
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