Dongbao Zhao

An allopurinol‐controlled, multicenter, randomized, double‐blind, parallel between‐group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia

Febuxostat, a novel non‐purine selective inhibitor of xanthine oxidase, has been identified as a potential alternative to allopurinol in patients with hyperuricemia. The purpose of this study was to compare the urate‐lowering (UL) efficacy and safety of daily febuxostat and allopurinol in Chinese gout patients with hyperuricemia.

Total glucosides of paeony can reduce the hepatotoxicity caused by Methotrexate and Leflunomide combination treatment of active rheumatoid arthritis

OBJECTIVE Total glucosides of paeony (TGP) have been confirmed to exert anti-inflammatory and hepatoprotective effects. Methotrexate (MTX) and Leflunomide (LEF) combination has a better efficacy in the treatment of active rheumatoid arthritis (RA), but hepatotoxicity was observed. In this study, we investigated the effect of TGP on hepatic dysfunction caused by MTX and LEF in patients with active RA. METHODS A total of 268 patients with active RA (disease activity score in 28 joints, DAS28>3.2) were enrolled in this study. All patients were randomly assigned to two groups, the therapeutic group in which patients were treated with TGP (1.8 g/day) combined with MTX and LEF (MTX 10mg/week plus LEF 20mg/day) while in the control group, patients were treated without TGP up to 12 weeks. The efficacy and liver abnormalities were observed. RESULTS The incidence of abnormal liver function within 12 weeks in TGP group was significantly lower than that in control group (11.38% vs 23.26%, P=0.013). The proportion of patients with ALT/AST >3 times ULN (upper limits of normal) was significantly lower in TGP group than control group (1.63% vs 7.75%, P=0.022). More patients achieved remission, good and moderate response in TGP group than control group at 4, 8 and 12 weeks, but the difference was not significant (P>0.05). The proportions of all adverse events were comparable in the two groups except for diarrhea. CONCLUSIONS Our study demonstrates that TGP can significantly reduce the incidence and severity of liver damage caused by MTX+LEF in the treatment of active RA patients.

Effects of multiple genetic loci on the pathogenesis from serum urate to gout

Gout is a common arthritis resulting from increased serum urate, and many loci have been identified that are associated with serum urate and gout. However, their influence on the progression from elevated serum urate levels to gout is unclear. This study aims to explore systematically the effects of genetic variants on the pathogenesis in approximately 5,000 Chinese individuals. Six genes (PDZK1, GCKR, TRIM46, HNF4G, SLC17A1, LRRC16A) were determined to be associated with serum urate (PFDR < 0.05) in the Chinese population for the first time. ABCG2 and a novel gene, SLC17A4, contributed to the development of gout from hyperuricemia (OR = 1.56, PFDR = 3.68E-09; OR = 1.27, PFDR = 0.013, respectively). Also, HNF4G is a novel gene associated with susceptibility to gout (OR = 1.28, PFDR = 1.08E-03). In addition, A1CF and TRIM46 were identified as associated with gout in the Chinese population for the first time (PFDR < 0.05). The present study systematically determined genetic effects on the progression from elevated serum urate to gout and suggests that urate-associated genes functioning as urate transporters may play a specific role in the pathogenesis of gout. Furthermore, two novel gout-associated genes (HNF4G and SLC17A4) were identified.

FCGR3B copy number loss rather than gain is a risk factor for systemic lupus erythematous and lupus nephritis: a meta-analysis.

Some studies have been performed to elucidate the association between Fc gamma receptor 3B (FCGR3B) copy number (CN) and the risk of systemic lupus erythematosus (SLE) and/or lupus nephritis (LN), yet the results remain conflicting. Therefore, we have undertaken a systematic review of all the studies published and carried out a meta‐analysis to obtain a better understanding of the role of FCGR3B CN in the susceptibility of SLE and LN.

TNF-α Promoter Polymorphisms Predict the Response to Etanercept More Powerfully than that to Infliximab/Adalimumab in Spondyloarthritis

While previous studies have researched in association analyses between TNFα promoter polymorphisms and responses to TNF blockers in spondyloarthritis patients, their results were conflicting. Therefore, we aimed to determine whether TNFα promoter polymorphisms could predict response to TNF blockers and find the source of heterogeneity. Data were extracted and analyzed from published articles and combined with our unpublished data. We found that the greatest potential sources of heterogeneity in the results were gender ratio, disease type, continents, and TNF blockers. Then Stratification analysis showed that the TNFα −308 G allele and the −238 G allele predicted a good response to TNF blockers (OR = 2.64 [1.48–4.73]; 2.52 [1.46–4.37]). However, G alleles of TNFα −308 and −238 could predict the response to etanercept (OR = 4.02 [2.24–7.23]; 5.17 [2.29–11.67]) much more powerfully than the response to infiliximab/adalimumab (OR = 1.68 [1.02–2.78]; 1.28 [0.57–2.86]). TNFα −857 could not predict the response in either subgroup. Cumulative meta-analysis performed in ankylosing spondylitis patients presented the odds ratio decreased with stricter response criteria. In conclusion, TNFα −308 A/G and −238 A/G are more powerful to predict the response to Etanercept and it is dependent on the criteria of response.

Common Variants in LRP2 and COMT Genes Affect the Susceptibility of Gout in a Chinese Population

Gout is a common inflammation disease resulting from an increase in serum uric acid. Nearly 70% of uric acid is excreted via the kidneys. To date, evidence for an association between genetic loci and gout is absent, equivocal or not replicated. Our study aims to test variants in two genes abundantly expressed in the kidney, LRP2 and COMT, for their association with uric acid and gout. In total, 1318 Chinese individuals were genotyped for rs2544390 in LRP2 and rs4680 in COMT. These LRP2 and COMT gene polymorphisms showed no significant effect on uric acid (P = 0.204 and 0.188, separately); however, rs2544390 in LRP2 did influence uric acid levels in individuals with BMI ≥ 25 (P = 0.009). In addition, the allele frequency distributions of the two loci showed a significant difference between gout patients and healthy controls. A missense variation in rs4680 (G > A) decreased the risk of gout (OR = 0.77, P = 0.015), whereas the T allele of rs2544390 was associated with gout pathogenesis risk (OR = 1.26, P = 0.020). The present study provides the first evidence for an association between COMT and gout. Rs2544390 in LRP2 only influenced uric acid levels in individuals with BMI ≥ 25, which might explain the discrepant results among previous studies. In addition, we are the first to identify the association between LRP2 and gout in a Chinese population and to confirm this association in Asians.

Safety of infliximab therapy in rheumatoid arthritis patients with previous exposure to hepatitis B virus

To evaluate the safety of tumor necrosis factor‐α (TNF‐α) monoclonal antibody (infliximab) therapy in patients with rheumatoid arthritis (RA) and previous exposure to hepatitis B virus (HBV) who had normal liver function.

Copy number variants of ABCF1, IL17REL, and FCGR3A are associated with the risk of gout

Gout is usually characterized by recurrent flares of acute inflammatory arthritis and the crystallization of urate in tissues and joints (Dong et al., 2017). The formation of monosodium urate crystals (MSU) is due to the elevated uric acid levels in the blood (Yang et al., 2016). But only 10% of individuals with hyperuricemia develop gout, suggesting that certain people are at a higher risk of developing MSU crystals (Merriman and Dalbeth, 2011) or initiating of the acute inflammatory response than others. This phenomenon is likely explained by the complex pathogenic process of inflammation and innate immunity in the development of gout since theMSU crystal-mediated inflammatory pathways have been reported to associate with many immunological processes (Behrens et al., 2008). Theabove results suggest that inflammationand immunity-related factors can regulate the development of gout, particularly the progression from hyperuricemia to gout. Recent genome-wide association studies (GWAS) identified some single nucleotide polymorphisms (SNPs) that were associated with the risk of gout (Kottgen et al., 2013). However, the common SNPs only explained part of the heritability of gout, and copy number variants (CNVs), an important source of genetic diversity in humans, have been shown to play a critical role in the genetic susceptibility to multiple rheumatic diseases (Zhang et al., 2009). Therefore, CNVs might be a new source for the genetic variants associated with the pathogenesis of gout. However, CNV studies on gout have not been reported, making it necessary to explore the pathogenesis of gout through the copy number variants in the inflammationand immunity-related genes. In this study, we aimed to identify the gout-associated CNVs in a Chinese population using a three-step approach. The entire analysis strategy, from genome-wide CNV discovery to gout-associated CNV identification to CNV validation, was illustrated in Fig. S1. Using this strategy, we provided the first evidence that CNVs could influence the pathogenesis of gout, and identified three novel genes, ABCF1, IL17REL and FCGR3A, which are associated with the risk of gout. Based on a genome-wide analysis of CNVs, a total of 1,901 CNVs were identified in 22 patients with inflammationand immunity-related rheumatic disorders (inclunding gout, ankylosing spondylitis, systemic lupus erythematosus, and systemic sclerosis) compared to the controls by using Agilent SurePrint G3 Human 1 × 1 M comparative genomic hybridization (CGH) microarray. After they were filtered according to their frequency (>5% and ≤50%), genome location (in gene region), gene function (related with inflammation and immunity), reliability (at least five consecutive probes) and previous studies for these CNVs, 48 gene regions with CNVs were selected (Table S1). To identify candidate gout-associated CNVs, the above pre-selected CNVs were further tested in 46 gout patients and 47 healthy Chinese individuals using the NimbleGen CGH Arrays (12 × 270 K), which is a high-density CGH assay, designed and made by Roche. Five CNVs appeared in more than 5% of the subjects, and located at a chromosome region that contained exons for inflammationand immunity-related genes (ABCF1, IL17REL, FCGR3A, DPCR1, and DEFA10P), and were identified to be candidate CNVs associated with gout. To validate the significance of the CNVs, the above five candidate CNVs (Table S2) were tested in an additional 1,274 Chinese individuals (576 gout patients and 698 control subjects, Tables S3 and S4) using AccuCopy (Du et al., 2012). The distributions of three CNVs in ABCF1, IL17REL, and FCGR3A were significantly different between the gout patients and the controls according to Fisher’s exact test, with P values of 0.018, 0.021 and 0.022, respectively (Tables S5 and S6). After correcting for multiple comparisons, the distributions of these CNVs were still significantly different (all P = 0.037) (Table S5). In addition, to avoid the heterogeneity of gender and age, deviance analysis for the logistic regression model adjusted for gender and age also showed that the CNVs in IL17REL and FCGR3A were significantly different between gout patients and control subjects (P = 0.002 and 0.038, respectively). The other two CNVs in the DPCR1 and DEFA10P genes were not associated with the risk of gout in the Chinese population (P = 0.328 and 0.221, respectively). The ABCF1 gene encodes a superfamily member of the ATP-binding cassette (ABC) transporters. The ABC

Common UCP2 variants contribute to serum urate concentrations and the risk of hyperuricemia

Elevated serum urate, which is regulated at multiple levels including genetic variants, is a risk factor for gout and other metabolic diseases. This study aimed to investigate the association between UCP2 variants and serum urate as well as hyperuricemia in a Chinese population. In total, 4332 individuals were genotyped for two common UCP2 variants, −866G/A and Ala55Val. These loci were not associated either serum urate level or with a risk of hyperuricemia in the total group of subjects. However, in females, −866G/A and Ala55Val were associated with a lower serum urate (P = 0.006 and 0.014, seperately) and played a protective role against hyperuricemia (OR = 0.80, P = 0.018; OR = 0.79, P = 0.016). These associations were not observed in the males. After further stratification, the two loci were associated with serum urate in overweight, but not underweight females. The haplotype A-T (−866G/A-Ala55Val) was a protective factor for hyperuricemia in the female subgroup (OR = 0.80, P = 0.017). This present study identified a novel gene, UCP2, that influences the serum urate concentration and the risk of hyperuricemia, and the degree of association varies with gender and BMI levels.

The Risk Factors for Nosocomial Infection in Chinese Patients with Active Rheumatoid Arthritis in Shanghai

Objective. To analyse the potential risk factors of nosocomial infections in patients with active rheumatoid arthritis (RA). Methods. A total of 2452 active RA patients at Hospitals in Shanghai between January 2009 and February 2011 were analyzed. Their demographic and clinical characteristics were compared with those without infection, and the potential risk factors were determined by logistic regression analysis. Results. Multivariate analysis indicated the gender (OR = 0.70, 95% CI 0.53–0.92), duration in hospital (OR = 1.03 , 95%CI 1.01–1.05), number of organs involved (OR = 0.82, 95%CI 0.72–0.92), number of disease-modifying antirheumatic drugs ((DMARDs) (OR = 1.22, 95%CI 1.061–1.40)), corticosteroid therapy (OR = 1.02, 95%CI 1.01–1.03), peripheral white blood cell counts ((WBC) (OR = 1.04, 95%CI 1.00–1.08)), levels of serum albumin (OR = 0.98, 95%CI 0.97–0.99), and C-reactive protein ((CRP) (OR = 1.03 , 95%CI 1.01–1.04)) that were significantly associated with the risk of infections. Conclusion. The female patients, longer hospital stay, more organs involved, more DMARDs, corticosteroid usage, high counts of WBC, lower serum albumin, and higher serum CRP were independent risk factors of infections in active RA patients.