AN INVESTIGATION OF LATE ONSET PSORIASIS A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy (PhD) in the Faculty of Medical and Human Sciences 2013 ELENI THEODORAKOPOULOU SCHOOL OF MEDICINE 1 Table of Contents List of figures __________________________________________________________________ 7 List of tables ___________________________________________________________________ 8 Abstract ______________________________________________________________________ 14 Declaration ___________________________________________________________________ 15 Copyright statement ___________________________________________________________ 15 Acknowledgements ____________________________________________________________ 16 Dedication ____________________________________________________________________ 16 Published abstracts arising from this thesis _______________________________________ 17 1. Introduction ______________________________________________________________ 18 1.1 Historical background of psoriasis ________________________________________ 18 1.2 Epidemiology of psoriasis _______________________________________________ 18 1.3 Clinical phenotypes of psoriasis _________________________________________ 19 1.3.1 Plaque psoriasis ___________________________________________________ 19 1.3.2 Guttate psoriasis ___________________________________________________ 23 1.3.3 Pustular psoriasis __________________________________________________ 24 1.3.3.1 Generalised pustular psoriasis____________________________________ 24 1.3.3.2 Localised pustular psoriasis ______________________________________ 25 1.3.4 Erythrodermic psoriasis _____________________________________________ 26 1.3.5 Eczematous psoriasis _______________________________________________ 26 1.3.6 Photosensitive psoriasis _____________________________________________ 27 1.4 Histology of normal skin ________________________________________________ 27 1.4.1 Histology of psoriasis _______________________________________________ 28 1.4.2 Inflammatory changes of psoriasis _____________________________________ 31 1.5 Pathogenesis of psoriasis _______________________________________________ 32 1.5.1 Genetics of psoriasis ________________________________________________ 32 1.5.2 The role of cellular and humoral immune response in psoriasis _______________ 35 1.5.3 Environmental and psychological influences in psoriasis ____________________ 40 1.6 Psoriasis associated comorbidities _______________________________________ 41 1.7 Management of psoriasis________________________________________________ 42 1.8 Other phenotypic classifications of psoriasis _______________________________ 43 1.9 Early and late onset psoriasis ____________________________________________ 45 1.9.1 Defining the age of onset ____________________________________________ 45 1.9.2 Clinical differences between early and late onset psoriasis __________________ 45 1.9.3 Genetic differences between early and late onset psoriasis _________________ 47 2 1.9.4 Immunological differences ___________________________________________ 48 1.9.5 Identifying the knowledge gap ________________________________________ 49 1.10 Summary _____________________________________________________________ 50 1.11 Hypothesis, aims and objectives _________________________________________ 52 1.12 Study design __________________________________________________________ 53 2. Materials and methods _____________________________________________________ 54 2.1 Clinical and psychological evaluation of early and late onset psoriasis _________ 54 2.1.1 Study design ______________________________________________________ 54 2.1.2 Prospective cohort _________________________________________________ 54 2.1.2.1 Study population ________________________________________________ 54 2.1.2.2 Ethical approval and study specific training ___________________________ 55 2.1.2.3 Inclusion and exclusion criteria ____________________________________ 55 2.1.2.4 Study questionnaire ______________________________________________ 55 2.1.2.4.1 The clinical section of the questionnaire __________________________ 56 2.1.2.4.2 Demographic characteristics ___________________________________ 56 2.1.2.4.3 Social history _______________________________________________ 56 2.1.2.4.4 Medical history ______________________________________________ 56 2.1.2.4.5 Drug history ________________________________________________ 57 2.1.2.4.6 Family history _______________________________________________ 57 2.1.2.4.7 Triggering factors ____________________________________________ 57 2.1.2.4.8 Clinical phenotype and disease severity __________________________ 57 2.1.2.4.9 Psoriasis Area and Severity Index_______________________________ 58 2.1.2.4.10 Patient Global Psoriasis Assessment ____________________________ 60 2.1.2.4.11 Assessing nail changes _______________________________________ 61 2.1.2.5 The psychometric sections of the questionnaire ________________________ 61 2.1.2.5.1 Dermatology Life Quality Index _________________________________ 61 2.1.2.5.2 Hospital Anxiety and Depression Scale __________________________ 62 2.1.2.5.3 Beck Depression Inventory-II __________________________________ 63 2.1.2.5.4 Penn State Worry Questionnaire ________________________________ 64 2.1.3 The retrospective group _____________________________________________ 65 2.1.4 The control group __________________________________________________ 66 2.1.4.1 iSOFT and Salford Integrated Records ______________________________ 66 2.1.5 Statistical analysis _________________________________________________ 67 2.2 Histological and immunohistochemical evaluation of early and late onset psoriasis ___________________________________________________________________________ 68 2.2.1 Study design ______________________________________________________ 68 2.2.2 Study population ___________________________________________________ 68 2.2.2.1 Ethical approval and study specific training ___________________________ 68 2.2.2.2 Study visits ____________________________________________________ 68 2.2.2.3 Screening visit __________________________________________________ 69 3 2.2.2.4 Main study visit _________________________________________________ 69 2.2.2.5 Inclusion and exclusion criteria _____________________________________ 69 2.2.3 Punch biopsy protocol ______________________________________________ 70 2.2.4 Histological assessment ____________________________________________ 71 2.2.4.1 Haematoxylin and eosin and periodic-acid-Schiff protocol ________________ 71 2.2.4.1.1 Haematoxylin & Eosin ________________________________________ 72 2.2.4.1.2 Periodic acid Schiff __________________________________________ 72 2.2.5 Psoriasis Histological Assessment Score ________________________________ 72 2.2.6 Immunohistochemical assessment ____________________________________ 77 2.2.6.1 Immunohistochemical staining _____________________________________ 77 2.2.7 Statistical analysis _________________________________________________ 79 3. A clinical investigation of early and late onset psoriasis _________________________ 81 3.1 Introduction ___________________________________________________________ 81 3.2 Objectives ____________________________________________________________ 82 3.3 Methods ______________________________________________________________ 82 3.3.1 Psoriasis prospective arm of the questionnaire ___________________________ 82 3.3.2 Psoriasis retrospective arm of the questionnaire __________________________ 82 3.3.3 Control group _____________________________________________________ 83 3.3.4 Study cohort and clinical evaluation ____________________________________ 83 3.3.5 Assessing disease severity ___________________________________________ 84 3.3.6 Assessing the clinical phenotype ______________________________________ 84 3.3.7 Assessing family history of psoriasis ___________________________________ 84 3.3.8 Assessing psoriasis-related comorbidities _______________________________ 85 3.3.9 Assessing triggering factors of psoriasis ________________________________ 85 3.3.10 Assessing psychological impairment ___________________________________ 85 3.3.11 Measurement of other covariates ______________________________________ 85 3.3.12 Sample size and study power _________________________________________ 86 3.3.13 Statistical analysis _________________________________________________ 86 3.4 Results _______________________________________________________________ 88 3.4.1 Demographic data of enrolled patients __________________________________ 88 3.4.1.1 General characteristics ___________________________________________ 88 3.4.1.2 Familial predisposition to psoriasis __________________________________ 89 3.4.2 Social characteristics _______________________________________________ 92 3.4.3 Clinical characteristics ______________________________________________ 93 3.4.3.1 Disease severity ________________________________________________ 93 3.4.3.2 Clinical Phenotype ______________________________________________ 94 3.4.3.3 Therapeutic management _________________________________________ 97 3.4.4 Associated comorbidities ____________________________________________ 99 3.4.4.1 Psoriatic Arthritis ________________________________________________ 99 3.4.4.2 Type II Diabetes Mellitus _________________________________________ 100 4 3.4.4.3 Autoimmune Diseases __________________________________________ 101 3.4.4.4 Other comorbidities _____________________________________________ 101 3.4.5 Psychological impact