Mahyoodeen, Nasrin Goolam2020-10-202020-10-202019https://hdl.handle.net/10539/29893A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2019Background: Psoriasis is a chronic, immune-mediated inflammatory disease in which cardiometabolic diseases (CMDs) are increasingly recognised as major comorbidities, often resulting in premature death. The aim of this research was firstly to determine the burden of CMDs and non-alcoholic fatty liver disease (NAFLD) in South Africans with psoriasis and then to investigate the interplay between visceral fat, metabolic biomarkers, adipokines and pro-inflammatory cytokines in psoriasis. Methods and Participants: A cross-sectional study of 103 patients with psoriasis and 98 control participants, matched for body mass index, ethnicity and gender was undertaken. The severity of cutaneous psoriasis was assessed using the Psoriasis Area and Severity Index (PASI) score. Demographic, clinical, anthropometric and biochemical data was obtained. Consenting participants (n=149) also underwent limited non-contrast abdominal CT scans to assess for visceral, subcutaneous and intra-hepatic fat. Patients were defined as having the metabolic syndrome by the Harmonised guidelines. NAFLD was defined radiologically based on a liver-to-spleen attenuation ratio (LAR) of less than one. Results: There was a high prevalence of CMDs, specifically MetS, type 2 diabetes (T2D) and hypertension in psoriasis patients compared to matched controls (52.4% vs. 33.7%, p=0.007; 25.2% vs. 4.1%, p<0.0001; 70.9% vs. 49.0%, p=0.001 respectively). Multiple logistic regression analysis showed that severe psoriasis was an independent risk factor for MetS (odds ratio [95% CIs]: 4.42 [1.72, 11.4]; p=0.002), hypertension (2.48 [0.97, 6.32]; p=0.05) and T2D (11.3 [3.07, 41.3]; p=0.0002). In addition, we demonstrated that psoriasis patients had a higher visceral fat volume than control participants matched for body mass index (BMI); that visceral fat was an independent predictor of psoriasis (odds ratio [95% CI]: 1.56 [1.15, 2.11], p<0.005) and that its effect was mediated by the pro-inflammatory cytokine interleukin 6 (IL-6). Furthermore, psoriasis was an independent risk factor for T2D (7.94 [2.64, 23.9], p<0.01). Although we found no difference in NAFLD overall between patients and controls, participants with NAFLD had a significantly higher prevalence of CMDs compared to those without NAFLD. The NAFLD prevalence was highest in patients with PsA receiving methotrexate (50.0% vs. 16.4% in participants without PsA not using methotrexate, p<0.05). Therapy with methotrexate in PsA, as well as insulin resistance and hypertriglyceridaemia, were independent predictors of NAFLD (odds ratio [95% CI], odds ratio: 2.77 (1.31, 5.87), p<0.05; 1.98 (1.44, 2.72), p<0.0001; 1.63 (2.55, 2.52), p<0.05, respectively) Conclusions: There is a high burden of CMDs, in this population with psoriasis, particularly in patients with severe psoriasis. Visceral fat and its mediators play a role in psoriasis-associated CMD. Patients with PsA receiving methotrexate are vulnerable to NAFLD. The present study highlights the need for CMD prevention and screening programmes in psoriasis patients and the need for further mechanistic studies into the aetiology of CMDs in psoriasis.enThesis