Guidelines on prescribing and monitoring antimalarials in rheumatic diseases: a systematic review.

OBJECTIVES: The purpose of this systematic review was to identify existing guidelines for antimalarial prescribing and monitoring, specifically for hydroxychloroquine, and how these guidelines compare and have evolved over time. METHODS: A literature search was conducted using Embase and Medline to identify guidelines published from 1946-2018. MeSH terms were used and alternative spelling and related words were entered as keywords to broaden results. RESULTS: 243 results were reviewed to obtain 11 recommendations. Ophthalmology sources included the American Academy of Ophthalmology, Royal College of Ophthalmologists and Canadian editorials. The American College of Rheumatology and Canadian Rheumatology Association consensus statements summarised rheumatology recommendations. Recently, American and British guidelines changed from suggesting hydroxychloroquine doses ≤6.5 mg/kg/day to ≤5 mg/kg/day. American guidelines recommended baseline visual field (VF) testing and annual screening after five years. Visual field (VF) testing evolved from the Amsler grid to current recommendations of 10-2 automated VF and spectral-domain optical coherence tomography (SD-OCT). The 2012 Canadian recommendations suggested initial VF testing every two years, with SD-OCT after 10 years. Older British guidelines advocated for baseline and annual assessment with Amsler grids during rheumatology clinic visits. The 2018 British guidelines supported baseline and annual screening after five years with 10-2 VF, SD-OCT and fundus autofluorescence. CONCLUSIONS: The newest recommendations are heterogeneous suggesting lower hydroxychloroquine dosing. Retinal toxicity is irreversible and the risk increases over time. Annual screening after five years with automated VF and SD-OCT may be warranted to detect early changes and discontinue therapy if necessary.

Fine-mapping of 98 obesity loci in Mexican children.

BACKGROUND/OBJECTIVES: Mexico has one of the highest prevalence of childhood obesity in the world. Genome-wide association studies (GWAS) for obesity have identified multiple single-nucleotide polymorphisms (SNPs) in populations of European, East Asian, and African descent. The contribution of these loci to obesity in Mexican children is unclear. We assessed the transferability of 98 obesity loci in Mexican children and fine-mapped the association signals. SUBJECTS/METHODS: The study included 405 and 390 Mexican children with normal weight and obesity. Participants were genotyped with a genome-wide dense SNP array designed for Latino populations, allowing for the analysis of GWAS index SNPs as well as fine-mapping SNPs, totaling 750 SNPs covering 98 loci. Two genetic risk scores (GRS) were constructed: a "discovery GRS" and a "best-associated GRS", representing the number of effect alleles at the GWAS index SNPs and at the best-associated SNPs after fine-mapping for each subject. RESULTS: Seventeen obesity loci were significantly associated with obesity, and five had fine-mapping SNPs significantly better associated with obesity than their corresponding GWAS index SNPs in Mexican children. Six obesity-associated SNPs significantly departed from additive to dominant (N = 5) or recessive (N = 1) models, and a significant interaction was found between rs274609 (TNNI3K) and rs1010553 (ITIH4) on childhood obesity risk. The best-associated GRS was significantly more associated with childhood obesity (OR = 1.21 per additional risk allele [95%CI:1.17-1.25], P = 4.8 × 10-25) than the discovery GRS (OR = 1.05 per additional risk allele [95%CI:1.02-1.08], P = 8.0 × 10-4), and was also associated with waist-to-hip ratio, fasting glucose, fasting insulin and triglyceride levels, the association being mediated by obesity. An overall depletion of obesity risk alleles was observed in Mexican children with normal weight when compared to GWAS discovery populations. CONCLUSIONS: Our study indicates a partial transferability of GWAS obesity loci in Mexican children, and supports the pertinence of post-GWAS fine-mapping experiments in the admixed Mexican population.

Systemic Lupus Erythematosus May Be a Risk Factor for Antimalarial-Induced Retinopathy Compared With Other Rheumatologic Diseases.

OBJECTIVE: To describe the pattern and risk factors for antimalarial (AM)-induced retinopathy in patients with rheumatic diseases. METHODS: A retrospective chart review was conducted at an urban Canadian center for patients with AM use of more than 3 months and documented retinopathy screening. Univariate and multivariate regression analyses were performed to determine risk factors for retinopathy. Sensitivity analyses included stratification of analysis by method of screening and by hydroxychloroquine (HCQ) versus chloroquine (CQ). RESULTS: A total of 613 patients were included in the final analysis, with systemic lupus erythematosus (SLE) (n = 259) as the most common diagnosis. Definite AM-induced retinal toxicity was observed in 12 patients, 11 of whom had SLE. The earliest diagnosis of toxicity occurred after 5.4 years of AM therapy, and the prevalence beyond 5 years was 3.1%. In univariate analysis, a diagnosis of SLE (P = 0.009; odds ratio [OR]: 15.66; 95% confidence interval [CI]: 2.01-122.05), the daily weight-based dose of HCQ (P = 0.044; OR: 1.49; 95% CI: 1.01-2.20), cumulative CQ dose (P = 0.014; OR: 4.80; CI: 1.37-16.84), and daily CQ weight-based dose (P = 0.0001; OR: 5.70; 95% CI: 2.41-13.49) were significantly associated with toxicity. In multivariate analysis, diagnosis of SLE (P = 0.022; OR: 12.14; 95% CI: 1.44-102.44) and daily CQ weight-based dose (P = 0.005; OR: 1.83; 95% CI: 1.83-26.75) were significant after adjusting for standard covariates. CONCLUSION: The risk of AM-induced retinopathy increases after 5 years of therapy. There may be higher rates of toxicity in patients with SLE because of longer duration of treatment, higher weight-based dosages, and more CQ use in this population, and SLE may be an independent risk factor.

Comprehensive identification of pleiotropic loci for body fat distribution using the NHGRI-EBI Catalog of published genome-wide association studies.

We conducted a hypothesis-free cross-trait analysis for waist-to-hip ratio adjusted for body mass index (WHRadjBMI ) loci derived through genome-wide association studies (GWAS). Summary statistics from published GWAS were used to capture all WHRadjBMI single-nucleotide polymorphisms (SNPs), and their proxy SNPs were identified. These SNPs were used to extract cross-trait associations between WHRadjBMI SNPs and other traits through the NHGRI-EBI GWAS Catalog. Pathway analysis was conducted for pleiotropic WHRadjBMI SNPs. We found 160 WHRadjBMI SNPs and 3675 proxy SNPs. Cross-trait analysis identified 239 associations, of which 100 were for obesity traits. The remaining 139 associations were filtered down to 101 unique linkage disequilibrium block associations, which were grouped into 13 categories: lipids, red blood cell traits, white blood cell counts, inflammatory markers and autoimmune diseases, type 2 diabetes-related traits, adiponectin, cancers, blood pressure, height, neuropsychiatric disorders, electrocardiography changes, urea measurement, and others. The highest number of cross-trait associations were found for triglycerides (n = 10), high-density lipoprotein cholesterol (n = 9), and reticulocyte counts (n = 8). Pathway analysis for WHRadjBMI pleiotropic SNPs found immune function pathways as the top canonical pathways. Results from our original methodology indicate a novel genetic association between WHRadjBMI and reticulocyte counts and highlight the pleiotropy between abdominal obesity, immune pathways, and other traits.

Seizure Risk Associated With Antidepressant Treatment Among Patients With Depressive Disorders: A Population-Based Case-Crossover Study.

OBJECTIVE: To assess the risk of seizure associated with antidepressant use among patients with depressive disorders. METHODS: Individuals visiting the emergency department or hospitalized because of new-onset seizure (ICD-9-CM diagnostic code 345 or 780.3; our primary study outcome) after receiving antidepressants for depressive disorders, were identified from a Taiwanese total population health insurance database. Using a case-crossover study design, relative risk of antidepressant-related seizure was estimated by comparing the rates of antidepressant exposure during the case periods vs control periods. The effects of class and dose of antidepressant on seizure risk were explored, using a conditional logistic regression model adjusting for concomitant medications. Several sensitivity analyses were conducted to attest the results of primary analyses. RESULTS: A total of 10,002 patients were included between 2002 and 2012. Overall, antidepressant exposure was positively associated with increased seizure risk (OR = 1.48, 95% CI, 1.33-1.64). Among the antidepressants, the increases in seizure risk of bupropion (OR = 2.23, 95% CI, 1.58-3.16), selective serotonin reuptake inhibitors (OR = 1.76, 95% CI, 1.55-2.00), serotonin and norepinephrine reuptake inhibitors (OR = 1.40, 95% CI, 1.10-1.78), and mirtazapine (OR = 1.38, 95% CI, 1.08-1.77) showed clear dose-response effects. Furthermore, the seizure risk was highest among patients aged between 10 and 24 years and patients with major depression. The results of sensitivity analyses largely confirmed those from the primary analyses. CONCLUSIONS: The seizure-inducing propensity and dose-response relationship pattern, as well as potential risk factors, associated with individual antidepressants should be taken into consideration when choosing antidepressants during clinical practice.