Objective. Human urate transporter 1 (hURAT1) is a member of the organic anion transporter family (SLC22A12) that mainly regulates tubular urate reabsorption. Loss-of-function mutations result in idiopathic hypouricemia. The present case-control study was designed to analyze whether hURAT1 might also be a candidate gene for hyperuricemia with primary reduced renal urate excretion.Methods. DNA samples from 389 individuals with reduced fractional excretion of uric acid (FEUA) (<6.5%) and from 263 controls (FEUA >6.5%) were sequenced. Genotype frequencies between groups were compared by Cochran-Armitage trend test.Results. Significantly different genotype distributions could be demonstrated for the ؊788 T>A (promoter; P ‫؍‬ 0.014), the C258T (exon 1; P ‫؍‬ 0.006), and the C426T (exon 2; P ‫؍‬ 0.0002) polymorphisms, but not for the T1309C (exon 8) and the ؉18 C>T (intron 9) polymorphisms. The strongest association with reduced FEUA was observed for the C426T polymorphism, with odds ratios (ORs) of 1.59 and 2.54 (P ‫؍‬ 0.0002) for the CT and TT genotypes, respectively. Adjusted values for FEUA in the C426T genotype, were significantly reduced decreasing to 7.3%, 6.7%, and 6.3% in individuals with the CC, CT, and TT genotypes, respectively (P ‫؍‬ 0.004). Haplotypes were constructed from the ؊788 T>A, C258T, and C426T polymorphisms. Individuals carrying at least 1 ACT haplotype (n ‫؍‬ 349) had a significantly higher risk for reduced FEUA than individuals without any ACT haplotype (n ‫؍‬ 303) (OR 1.39, P ‫؍‬ 0.041).Conclusion. These results indicate that polymorphisms in the N-terminus of the hURAT1 gene were significantly associated with reduced renal uric acid excretion. The main regulating factor seems to be located close to the C426T polymorphism or is in strong linkage disequilibrium.In Germany, as in most Western countries, the prevalence of hyperuricemia is ϳ30% in men and 3% in women (1). Of these individuals, ϳ10% develop gout. The familial nature of hyperuricemia and gout has long been recognized. Among family members of patients with gout, the prevalence of asymptomatic hyperuricemia ranges from 25% to 27% (2,3). In a study of twins, Emmerson et al (4) observed that monozygotic twins had more similar values of urate clearance and fractional excretion of uric acid (FEUA) than did dizygotic twins. The heritability of the renal urate clearance was estimated as ϳ60%, whereas the heritability of the fractional urate excretion was found to be 87% (4). In Ͼ90% of patients with primary gout, reduced renal uric acid clearance causes hyperuricemia.Glomerular filtration and bidirectional urate transport, including both tubular secretion and reabsorption, are the essential physiologic processes in renal handling of uric acid (5). Under normal conditions, uric acid is freely filtered at the kidney glomerulus and almost completely reabsorbed from urine in the proximal tubule. According to the "four-component model" of urate excretion (6), net urate excretion is determined by tubular urate secretion and postsecretory urate ...

Background:While the short-term use of bDMARDs up to 180 days has been associated with an increased risk of venous thromboembolism (VTE) compared to csDMARDs in patients with rheumatoid arthritis (RA), the long term use of more than 730 days has been associated with a decreased risk based on claims data [1]. Among patients with inflammatory bowel disease, observational data indicated that TNF inhibitors may have a protective effect regarding the VTE risk [2].Objectives:To assess the effects of TNF inhibitors and newer bDMARDs (including abatacept, rituximab, sarilumab, and tocilizumab) on the VTE risk based on observational data from RA patients.Methods:The German register RABBIT is a prospective longitudinally followed cohort of RA patients enrolled with a new start of a DMARD after at least one csDMARD failure. This analysis comprises patients who were enrolled with start of a bDMARD between 01/2009 and 04/2019 and had at least one follow-up.Cox regression models were used to calculate hazard ratios (HRs) for VTEs, for csDMARDs, TNF inhibitors and other bDMARDs. Propensity score weighting was used to adjust for confounding by indication.Results:Patients receiving TNF inhibitors or other bDMARDs on average had higher CRP levels and a higher prevalence of cardiovascular diseases at baseline than patients receiving csDMARDs. They also received more often glucocorticoids (Table 1).The HR of patients receiving TNF inhibitors for a serious VTE event was 0.53 (95% CI: 0.33 – 0.86) compared to csDMARDs, while the HR for patients receiving other bDMARDs was 0.66 (95% CI: 0.40 – 1.09). A CRP level of more than 5 mg/L (HR 2.09, 95% CI: 1.39 – 3.14) and an age above 65 years (HR 2.96, 95% CI: 1.94 – 4.52) increased the risk for a serious VTE event. Better physical function was associated with a decreased risk for VTEs (Table 2).Table 1.Patient characteristics at baseline for DMARD groupsParameter (at time of event/end of observation unless specified otherwise)Hazard ratio95% confidence intervalTNF inhibitors (reference: csDMARDs)0.530.330.86Other bDMARDs (reference: csDMARDs)0.660.401.09Age ≥ 65 years (baseline)2.961.944.52CRP ≥ 5 ml2.091.393.14> 5 mg and ≤ 10 mg glucocorticoids/day1.040.551.98> 10 mg and ≤ 15 mg glucocorticoids/day2.350.816.79> 15 mg glucocorticoids/day2.030.765.41% of full physical capacity (per 10 percentage points increase, time of event)0.850.780.92Current smoking (baseline)0.980.611.55Former smoking (baseline)0.800.451.43Table 2.Hazard ratios for VTE eventsParametercsDMARDsTNFiOther bDMARDsN350050602534VTE event38 (1.1)55 (1.1)23 (0.9)Age [years]58.8 (12.6)56.5 (12.9)58.1 (12.4)Female sex2575 (73.6)3734 (73.8)1933 (76.3)Disease duration [years]6.2 (7.2)9.4 (8.6)11.9 (9.2)Seropositivity2189 (62.6)3739 (73.9)2048 (80.8)Joint erosions1024 (31.0)2566 (52.4)1523 (63.3)Prior bDMARD therapies0 (0.2)0.3 (0.6)1.2 (1.2)CRP8.8 (8.1)11.6 (10.6)12.4 (11.8)DAS28-ESR4.4 (1.3)4.9 (1.2)5.1 (1.3)% of full physical capacity71.3 (21.8)66.2 (22.6)62.1 (23.5)Current glucocorticoid therapy2564 (73.3)3951 (78.1)2036 (80.4)Heart failure36 (1)113 (2.2)93 (3.7)Coronary artery disease196 (5.6)326 (6.4)183 (7.2)Cerebrovascular disease60 (1.7)86 (1.7)44 (1.7)Osteoporosis400 (11.4)771 (15.2)530 (20.9)Ever smoker1875 (53.6)2738 (54.1)1402 (55.3)Results are presented as mean ± SD or number (percentage).Conclusion:Treatment with TNF inhibitors (compared to csDMARDs) and better physical function significantly reduced the risk of serious VTE events, while age above 65 years and high CRP levels increased this risk.References:[1]Kim S. C. et al. Am. J. Med. 2015; 128(5): 539.e7–539.e17.[2]Desaj R.J. et al. CMAJ 2017; 189:E1438-47.Acknowledgments:RABBIT is supported by a joint, unconditional grant from AbbVie, Amgen, BMS, Fresenius-Kabi, Hexal, Lilly, MSD, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB.Disclosure of Interests:Martin Schaefer: None declared, Matthias Schneider Grant/research support from: GSK, UCB, Abbvie, Consultant of: Abbvie, Alexion, Astra Zeneca, BMS, Boehringer Ingelheim, Gilead, Lilly, Sanofi, UCB, Speakers bureau: Abbvie, Astra Zeneca, BMS, Chugai, GSK, Lilly, Pfizer, Sanofi, Anett Graessler: None declared, Wolfgang Ochs: None declared, Angela Zink Speakers bureau: AbbVie, Amgen, BMS, Gilead, Hexal, Janssen, Lilly, MSD, Pfizer, Roche, Sanofi Aventis, UCB, Anja Strangfeld Speakers bureau: AbbVie, BMS, Pfizer, Roche, Sanofi-Aventis

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