الفهرس 
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Abstract
The antimalarial agent hydroxychloroquine (HCQ) have been used widely for the treatment of rheumatoid arthritis and systemic lupus erythematosus. Among rheumatic diseases, the primary role of HCQ is in the management of articular and skin manifestations of systemic lupus erythematosus (SLE) and the treatment of mild to moderately active rheumatoid arthritis (RA). As a cornerstone of SLE management, HCQ leads to reduction in the risk of disease flare as well as providing a valuable adjunct in the therapy of lupus nephritis, and is a relatively safe option for treatment of SLE during pregnancy, It also has been linked to the prevention of thrombosis as well as a reduced risk of permanent organ damage. HCQ’s beneficial effects on lipid levels and reduction in the risk of diabetes. It is a member of the “triple therapy” triad for the treatment of RA, serving as an important component of the therapeutic approach in active disease. Retinal toxicity from HCQ is of serious ophthalmologic concern. Because even after the drug is discontinued, there is little if any visual recovery.It has been shown that the retinal degeneration caused by HCQ can continue to progress. For this reason, regular screening for retinal toxicity is recommended to detect early retinopathy and discontinue the therapy. Cytochrome P450 (CYP) enzymes play major roles in drug metabolism. Certain single-nucleotide polymorphisms (SNPs) in CYP genes may have a great impact on CYP enzyme activity. Polymorphisms in the CYP450 gene might influence blood concentration. HCQ is metabolized to N-desethyl HCQ (DHCQ) in the liver through the Ndesethylation pathway, This reaction is mediated by CYP 2D6, 3A4, 3A5, and 2C8 isoforms. Aim of the work: This cross sectional study aimed to identify CYP, ABCC variants among Egyptian patients received HCQ, correlate these variants with both therapeutic efficacy and toxicity of HCQ and screening and early detection of HCQ ocular toxicity which allows for early preventive intervention. Patients and method: This study was performed on 80 patients received HCQ (72 RA patients who were diagnosed according to the 2010 (ACR/EULAR) classification criteria for RA,and 8 SLE patients diagnosed according to SLICC classification criteria for SLE). All patients subjected to complete history taking including medication history [HCQ dose (daily, cumulative) and duration], clinical examination, disease activity of RA was defined by DAS 28 and disease activity of SLE by SELDAI-2K. Full ophthalmic examination was done: including examination of the anterior segment using slit lamp and fundus examination using both direct and indirect ophthalmoscope. Screening for HCQ ocular toxicity was done via perimetry using Octopus perimeter and utilizing 24-2 test strategy, electroretinography (ERG) under scotopic and photopic conditions and spectral domain optical coherence tomography (SD-OCT) according to 2016 guidelines of the American academy of Ophthalmology. Laboratory assessment was performed including: routine investigation, autoantibodies, Genotyping using real time PCR (Taqman discrimination assay) for study frequency of single nucleotide polymorphisms (SNPs) of CYP2D6, CYP3A4, CYP3A5, ABCC4. Results: HCQ may have role in control DM 79.2% of our diabetic patients were controlled (HA1C less than 6.4 mmol) and also had role in in reducing the risk for atherosclerosis and a significant reduction in the lipid profiles as well as AI has been observed. No retinal abnormality was detected in any patients, although,77.55% of patients received HCQ > 5 years duration,77.5% of patients received daily dose > 5 mg actual body WT,52.5% received daily dose > 6.5 mg ideal body weight,this could be due to small sample size of our study. CYP3A4 rs28371759 was significantly associated with higher WBCs count so no bone marrow suppression, CYP2D6 rs1135840 CC genotype was associated with the least DAS28 score among RA patients compared to CG and GG genotypes. Surprisingly; none of the included patients showed any abnormal ophthalmological findings,although 77.55% of patients received HCQ > 5 years duration,77.5% of patients received daily dose > 5 mg actual body WT,52.5% received daily dose > 6.5 mg ideal body weight. CYP3A4 rs28371759 was associated with higher WBCs count (but within normal range; not leukocytosis) when compared to the wild allele so no bone marrow suppression in CYP3A4 rs 28371759, while the CYP2D6 rs1135840 CC genotype was associated with the least DAS28 score among RA patients compared to CG and GG genotypes.