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Title: Examining multimorbidity in patients with psoriasis and the impact of biologic therapies on the risk of major cardiovascular events
Author: Rungapiromnan, Watcharee
ISNI:       0000 0004 8504 1265
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2018
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Aims: The aims of this thesis were to examine the prevalence of physical and mental health comorbidities in patients with psoriasis and then subsequently examine the impact of biologic therapies on the risk of major cardiovascular events (CVEs) in patients with psoriasis. Methods: The first aim was achieved by conducting a cross-sectional study of participants enrolled in the UK Biobank. Participants with and without psoriasis were compared in terms of sociodemographic, lifestyle characteristics and the presence of both physical and mental health comorbidities. The prevalence ratios (PRs) with 95% confidence intervals (CIs) were estimated using log-binomial regression models. A multinomial logistic regression model was used to examine differences in the numbers of comorbidities overall, and then separately for both physical and mental health comorbidities for participants with psoriasis compared to those without and findings presented as odds ratios (ORs). The association between biologic therapies and major CVEs in patients with psoriasis was assessed firstly via a systematic review and meta-analysis of randomised controlled trials (RCTs) and subsequently via a cohort study in the British Association of Dermatologists Biologic Interventions Register (BADBIR). The systematic review and meta-analysis examined the risk of major adverse cardiovascular events [MACEs; myocardial infarction (MI), cerebrovascular accident or cardiovascular death] in adult patients with plaque psoriasis exposed to biologic therapies. Data were obtained from systematic searches in the Cochrane Library, MEDLINE and Embase, the US Food and Drug Administration, the European Medicines Agency, individual pharmaceutical companies online search platforms and five trials registers. RCTs reporting adverse events in adults with plaque psoriasis receiving at least one licensed dose of biologic therapy, conventional systematic therapy or placebo were included. Peto ORs with 95% CIs and I2 statistics to assess heterogeneity were calculated. The cohort study using data from the BADBIR, compared the risk of major CVEs (acute coronary syndrome, unstable angina, MI or stroke) occurring on therapy or within 90 days after the last dose between different therapies in participants recruited between 09/2007-10/2016. Anti-interleukin-12/23 agent (ustekinumab) was compared with tumour necrosis factor-alpha inhibitors (TNFi; etanercept, and adalimumab) in a main analysis and ustekinumab, etanercept or methotrexate were compared with adalimumab in sensitivity analyses. Overlap weighting by propensity score was used to balance baseline confounders among comparison groups. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) with 95% CIs. Results: Of the 502,543 participants in the UK Biobank, 6,105 (1.21%) had psoriasis. Patients with psoriasis were associated with an increased prevalence of both physical and mental comorbidities compared with participants without psoriasis. Participants with psoriasis were significantly more likely to report cardiovascular risk factors, including hypertension [PR adjusted for age, sex and socioeconomic deprivation: 1.13 (95% CI 1.09 - 1.17)], high cholesterol [adjusted PR: 1.10 (95% CI 1.03 - 1.17)] and diabetes [adjusted PR: 1.26 (95% CI 1.15 - 1.38)]. The prevalence rates of inflammatory arthritis (psoriatic arthritis or rheumatoid arthritis) showed the largest difference between the psoriasis group and the no psoriasis group (16.9% vs 1.1%). Patients with psoriasis were also more likely to smoke and not engage in regular physical activity. The overall numbers of comorbidities, and also when considered separately for physical and mental disorders, were higher for patients with psoriasis. Overall, 38 RCTs involving 18,024 patients with plaque psoriasis were included in the systematic review and meta-analysis. No MACEs were observed in 29 studies, while nine RCTs reported 10 patients experiencing MACEs. There was no statistically significant difference in the risk of MACEs associated with the use of biologic therapies overall [OR 1.45 (95% CI 0.34 - 6.24); TNFi (adalimumab, etanercept and infliximab) [OR 0.67 (95% CI 0.10 - 4.63)]; anti-IL-17A agents (secukinumab and ixekizumab) [OR 1.00 (95% CI 0.09 - 11.09)] or ustekinumab [OR 4.48 (95% CI 0.24 - 84.77)]. No heterogeneity was observed in these comparisons. 5,468 biologic-naive patients with plaque psoriasis subsequently exposed (951 ustekinumab; 1,313 etanercept; and 3,204 adalimumab) from the BADBIR were included in the main analysis of the cohort study. Secondary analyses also included 2,189 patients receiving methotrexate. No differences in the risk of major CVEs were observed between biologic therapies [adjusted HR for ustekinumab vs TNFi (etanercept or adalimumab): 0.98 (95% CI 0.43 - 2.25); ustekinumab vs adalimumab: 0.87 (95% CI 0.33 - 2.30); etanercept vs adalimumab: 0.82 (95% CI 0.28 - 2.36); methotrexate vs adalimumab: 1.06 (95% CI 0.34 - 3.28)]. Overall, there were no significant differences in the risk of major CVEs between three different biologic therapies and methotrexate. Conclusions: Psoriasis is associated with a number of mental health and physical comorbidities including cardiovascular risk factors. Patients with psoriasis were more likely to have deleterious lifestyle habits such as smoking and not undertaking regular physical activity. The findings presented in the meta-analysis suggest that there was no significant difference in the risk of MACEs in psoriasis patients treated with biologic therapies compared with placebo or the different doses of the same biologic therapies. Moreover, no significant difference in the risk of major CVEs was observed in patients treated with biologic therapies compared with different biologic therapies or methotrexate in the cohort study using the BADBIR. The findings suggest that the risk of major CVEs should not be a key discriminator for selecting specific biologic therapies for psoriasis patients. Future larger, well-designed cohort studies with longer follow-up are needed to examine the longer-term impact of biologic therapies on the risk of major CVEs.
Supervisor: Griffiths, Christopher ; Ashcroft, Darren ; Warren, Richard Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Methotrexate ; Cardiovascular events ; Biologic therapy ; Psoriasis ; Comorbidity