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Title: Response to hydroxychloroquine in discoid lupus erythematosus
Author: Wahie, Shyamal
ISNI:       0000 0004 2742 1956
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2011
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Discoid Lupus Erythematosus (DLE) is the most common form of cutaneous lupus and causes irreversible facial scarring and disfigurement. Hydroxychloroquine is the oral therapy of choice. The factors influencing clinical response to hydroxychloroquine are unclear. Patients with Systemic Lupus Erythematosus (SLE) treated with hydroxychloroquine demonstrate a positive correlation between whole-blood hydroxychloroquine levels and clinical response. Variation in response to hydroxychloroquine might, in part, be due to genetic differences in the CYP450 genes responsible for hepatic metabolism of hydroxychloroquine between individuals, which therein could influence whole-blood hydroxychloroquine levels. The influence of genetic polymorphisms on the therapeutic response to hydroxychloroquine, in comparison with host or disease attributes such as smoking status or disease extent, is unknown. A multicentre retrospective cohort study was conducted in 200 patients with DLE treated with hydroxychloroquine. The outcomes of interest were: (i) the clinical response to hydroxychloroquine by 6 months and (ii) the effects of disease attributes, smoking, and CYP450 polymorphisms on clinical response. Although the majority of patients responded to hydroxychloroquine, a significant proportion (39%) either failed to respond or was intolerant of the drug. Cigarette smoking and CYP 206 and 2CB genotypes did not have any Significant influence on response to hydroxychloroquine. Multivariate analysis indicated that disseminated disease and concomitant SLE at baseline were both Significantly associated with lack of response to hydroxychloroquine. These findings suggest that baseline lupus severity and SLE are important predictors of response to hydroxychloroquine. A prospective study is required to further explore the response of DLE to hydroxychloroquine and to investigate the relationships between disease activity and eventual response. A validated scoring instrument was designed to specifically measure activity and damage attributable to DLE and will be essential for quantifying disease and appraising responsiveness to hydroxychloroquine in future prospective studies. Following peer review, pilot work and two reliability studies, the Score of Activity and Damage in DLE (SADDLE) was developed as a measure of disease severity in DLE. Activity is measured using erythema, induration and scaling and damage is represented by scarring and dyspigmentation. SADDLE demonstrates evidence of inter and intra-rater reliability and construct validity. In summary, these inter-related studies not only indicate that 1 in 3 patients with DLE do not respond to hydroxychloroquine by 6 months, but also show that lack of response may be associated with disease extent and concomitant SLE at baseline. Cigarette smoking did not influence response, casting doubt on the results of previous small single-site retrospective studies, which did not assess confounding variables such as disease extent and SLE and suggested smoking was associated with poor response to therapy. A disease activity score has been developed for future use in prospective trials to help investigate these findings further.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available