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Title: An investigation of late onset psoriasis
Author: Theodorakopoulou, Eleni
ISNI:       0000 0004 5356 1573
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2014
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Psoriasis is a chronic, clinically heterogeneous, skin condition that affects approximately 2% of the general population. In 1985, Henseler and Christophers, classified psoriasis into early onset (EOP; age at onset ≤40 years-y) and late onset disease (LOP; age at onset >40 y). Previous research suggests that there are genetic and immunological differences between EOP and LOP. In particular, the major genetic determinant for psoriasis, the human leukocyte antigen (HLA)-Cw6 allele, occurs more frequently in EOP (55-80%) compared to LOP (15-20%) patients. Epidermal Langerhans’ cells (LC) migration is also different in these 2 subtypes of psoriasis. The primary aim of this thesis was to further explore the clinical, histological and immunohistochemical (IHC) differences between EOP and LOP. We compared clinical characteristics in a total of 497 subjects, including 340 psoriasis patients (108 recruited prospectively; 76 EOP and 32 LOP, mean age of onset 20.3±9.9 and 55.6±7y respectively, and 232 retrospectively; 202 EOP and 30 LOP, mean age of onset 20.7±9.9 and 55.2±7.2y respectively) and 157 controls (mean age 66±11.2y). Information on demographics, family history of psoriasis, clinical features, treatment and co-morbidities were recorded. Patients were also assessed for health-related quality of life and psychological distress. A total of 31 psoriasis patients, ≥ 50y of age, participated in the histological and IHC evaluation; 17 EOP and 14 LOP, mean age of onset 21.1±8.5 and 55.4±7.7y respectively. Skin biopsies were taken from involved (PP) and uninvolved (PN) skin and stained with haematoxylin and eosin (H&E) and IHC antibodies against various T-cell (CD3, CD4, and CD8) and LC (CD1α) markers. The H&E parameters (morphological and inflammatory) were graded with the use of a study specific histological score, whilst IHC positive epidermal cells were counted per microscopic field at 200X magnification. The dermal IHC infiltrate was assessed with a semi-quantitative (0-3) scale. Gender, body mass index, disease duration and severity, diagnosed hypertension and dyslipidemia were treated as covariates. The clinical data showed that LOP patients had a lower likelihood of having a positive family history of psoriasis (62% of EOP versus 35.6% of LOP patients; chi square-x2, P=0.001). In addition, patients with EOP parent(s) were 91% less likely to develop LOP than EOP (odds ratio-OR=0.093, P=0.025, 95% confidence interval-CI 0.012-0.74). Moreover, compared to LOP, EOP patients had a more severe disease (x2, P=0.021), usually requiring 3rd line treatments (x2; P=0.010). They also experienced frequent flares, following upper respiratory tract infections (x2, P=0.049). When data were segregated by age (≥50years) and after accounting for covariates, we observed that, compared to the non-psoriasis population, LOP patients were approximately 3 times more likely to develop type 2 Diabetes Mellitus (OR=2.56, P=0.05, 95% CI 1.01-6.54), whilst, EOP subjects were 98% less likely to develop autoimmune thyroiditis (OR=0.025, P=0.02, 95% CI 0.001-0.55). Psychologically, LOP patients were found to be a clinically more anxious group compared to EOP (t-test, P=0.006). Microscopically, the results from the H&E study showed an increased total inflammatory infiltrate in LOP, PP sections compared to EOP, PP ones (t-test, P=0.028). With IHC stains, we observed that in the epidermis of LOP PP, there was a significantly higher count of CD4+ cells; mean CD4+ in LOP of 15.1 ± 6.2 versus 6.7±4.6 in EOP (Analysis of variance-ANOVA, P<0.001). This subsequently led to a higher epidermal CD4+/CD8+ ratio of 1.3 in the LOP versus 0.5 for the EOP sections (ANOVA, P=0.002). In the PP dermis, CD4+ were also more abundant in the LOP tissue (x2, P=0.049). To assess whether these CD4+ cells were either T-lymphocytes or LC, we examined for differences in the CD3+ and CD1α+ cells. The mean epidermal CD3+ tended to be higher in LOP PP sections; mean epidermal CD3+ in the LOP 42.8 ± 13.3 versus 31.7 ± 17.5 in the EOP group (ANOVA, P= 0.061), while the dermal infiltrate showed a similar pattern (x2,P=0.067). Finally, there was no difference in epidermal and dermal CD1α+ and CD8+ cells in PP between EOP and LOP sections. These data indicate differences in clinical phenotype, heritability, comorbidities and immunopathomechanism between EOP and LOP. Taken together they provide further evidence that EOP and LOP may be different diseases.
Supervisor: Griffiths, Christopher; Warren, Richard Sponsor: University of Manchester
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: psoriasis ; early onset ; late onset ; histological differences ; clinical differences ; immunological differences