Person:

Choi, Hyon

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Objectives: For most gout patients, excruciatingly painful gout attacks are the major clinical burden of the disease. The goal of this study was to assess the association of frequent gout flares with healthcare burden, and to quantify how much lower gout-related costs and resource use are for those with infrequent flares compared to frequent gout flares. Design: Retrospective cohort study. Setting: Administrative claims data from a large US health plan. Participants: Patients aged 18 years or above, and with evidence of gout based on medical and pharmacy claims between January 2009 and April 2012 were eligible for inclusion. Patient characteristics were assessed during a 12-month baseline period. Outcome measures Frequency of gout flares, healthcare costs and resource utilisation were assessed in the 12 months following the first qualifying gout claim. Generalised linear models were employed to assess the impact of flare frequency on cost outcomes after adjusting for covariates. Results: 102 703 patients with gout met study inclusion criteria; 89 201 had 0–1 gout flares, 9714 had 2 flares, and 3788 had 3+ flares. Average counts of gout-related inpatient stays, emergency room visits and ambulatory visits were higher among patients with 2 or 3+ flares, compared to those with 0–1 flares (all p<0.001). Adjusted annual gout-related costs were $1804, $3014 and $4363 in those with 0–1, 2 and 3+ gout flares, respectively (p<0.001 comparing 0–1 flares to 2 or 3+ flares). Conclusions: Gout-related costs and resource use were lower for those with infrequent flares, suggesting significant cost benefit to a gout management plan that has a goal of reducing flare frequency.

Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. However other factors must exist that control the progression from hyperuricaemia to gout. A previous genetic association study has implicated the toll-like receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway upon stimulation by MSU crystals. The T-allele of single nucleotide polymorphism rs2149356 in TLR4 is a risk factor associated with gout in a Chinese study. Our aim was to replicate this observation in participants of European and New Zealand Polynesian (Māori and Pacific) ancestry. A total of 2250 clinically-ascertained prevalent gout cases and 13925 controls were used. Non-clinically-ascertained incident gout cases and controls from the Health Professional Follow-up (HPFS) and Nurses Health Studies (NHS) were also used. Genotypes were derived from genome-wide genotype data or directly obtained using Taqman. Logistic regression analysis was done including age, sex, diuretic exposure and ancestry as covariates as appropriate. The T-allele increased the risk of gout in the clinically-ascertained European samples (OR = 1.12, P = 0.012) and decreased the risk of gout in Polynesians (OR = 0.80, P = 0.011). There was no evidence for association in the HPFS or NHS sample sets. In conclusion TLR4 SNP rs2143956 associates with gout risk in prevalent clinically-ascertained gout in Europeans, in a direction consistent with previously published results in Han Chinese. However, with an opposite direction of association in Polynesians and no evidence for association in a non-clinically-ascertained incident gout cohort this variant should be analysed in other international gout genetic data sets to determine if there is genuine evidence for association.

Background: Prior qualitative research on gout has focused primarily on barriers to disease management. Our objective was to use patients’ perspectives to construct an explanatory framework to understand how patients become engaged in the management of their gout. Methods: We recruited a sample of individuals with gout who were participating in a proof-of-concept study of an eHealth-supported collaborative care model for gout involving rheumatology, pharmacy, and dietetics. Semistructured interviews were used. We analyzed transcripts using principles of constructivist grounded theory involving initial coding, focused coding and categorizing, and theoretical coding. Results: Twelve participants with gout (ten males, two females; mean age, 66.5 ± 13.3 years) were interviewed. The analysis resulted in the construction of three themes as well as a framework describing the dynamically linked themes on (1) processing the diagnosis and management of gout, (2) supporting management of gout, and (3) interfering with management of gout. In this framework, patients with gout transition between each theme in the process of becoming engaged in the management of their gout and may represent potential opportunities for healthcare intervention. Conclusions: Findings derived from this study show that becoming engaged in gout management is a dynamic process whereby patients with gout experience factors that interfere with gout management, process their disease and its management, and develop the practical and perceptual skills necessary to manage their gout. By understanding this process, healthcare providers can identify points to adapt care delivery and thereby improve health outcomes.

Objective: Dual-energy CT (DECT) detects and quantifies monosodium urate (MSU) crystal deposition with high precision. This DECT study assessed crystal deposition in patients with gout treated with stable-dose allopurinol, and investigated potential clinical determinants for crystal deposition. Methods: Patients with gout treated with allopurinol ≥300 mg daily for at least 3 months were prospectively recruited from the USA and New Zealand, using monitored enrolment to include approximately 25% patients with palpable tophi and approximately 50% with serum urate (sUA) levels <6.0 mg/dL (<357µmol/L). MSU crystal deposition was measured in the hands/wrists, feet/ankles/Achilles and knees bilaterally. The presence and total volume of crystals were assessed by DECT and analysed according to sUA levels and gout characteristics. Results: Among 152 patients receiving allopurinol ≥300 mg/day for 5.1 years on average, 69.1% had crystal deposition on DECT, with a median total crystal volume of 0.16 cm3 (range: 0.01–19.53 cm3). The prevalence of crystal deposition ranged from 46.9% among patients with sUA <6.0 mg/dL and no palpable tophi to 90.0% among those with sUA ≥6.0 mg/dL and tophi. Total volume of crystal deposition was positively associated with sUA ≥6.0 mg/dL, gout flares within the past 3 months and tophi. Total volume of crystal deposition correlated positively with Patient Global Impression of Disease Activity scores. Conclusion: A substantial proportion of patients without palpable tophi have MSU crystal deposition, despite receiving allopurinol doses ≥300 mg/day for a considerable duration. Patients with higher sUA and clinical features of severe disease have a higher frequency and greater volume of MSU crystal deposition.

Objective: To assess the effect of treatment with febuxostat versus placebo on joint damage in hyperuricemic subjects with early gout (1 or 2 gout flares). Methods: In this double‐blind, placebo‐controlled study, 314 subjects with hyperuricemia (serum uric acid [UA] level of ≥7.0 mg/dl) and early gout were randomized 1:1 to receive once‐daily febuxostat 40 mg (increased to 80 mg if the serum UA level was ≥6.0 mg/dl on day 14) or placebo. The primary efficacy end point was the mean change from baseline to month 24 in the modified Sharp/van der Heijde erosion score for the single affected joint. Additional efficacy end points included change from baseline to month 24 in the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) scores for synovitis, erosion, and edema in the single affected joint, the incidence of gout flares, and serum UA levels. Safety was assessed throughout the study. Results: Treatment with febuxostat did not lead to any notable changes in joint erosion over 2 years. In both treatment groups, the mean change from baseline to month 24 in the modified Sharp/van der Heijde erosion score for the single affected joint was minimal, with no between‐group differences. However, treatment with febuxostat significantly improved the RAMRIS synovitis score at month 24 compared with placebo treatment (change from baseline −0.43 versus −0.07; P <0.001), decreased the overall incidence of gout flares (29.3% versus 41.4%; P < 0.05), and improved serum UA control (62.8% versus 5.7%; P < 0.001). No major safety concerns were reported. Conclusion: Urate‐lowering therapy with febuxostat improved magnetic resonance imaging–determined synovitis and reduced the incidence of gout flares in subjects with early gout.