Increased frequency of hepatic steatosis and fibrosis in patients with gout detected by transient elastography.

OBJECTIVES: It has been suggested that gout is associated with non-alcoholic fatty liver disease (NAFLD). Our aim was to assess NAFLD in gout patients using the validated non-invasive imaging technique, transient elastography (FibroScan). METHODS: FibroScans in consecutive gout patients in a single centre from 11/1/2016 to 11/1/2021 and reviewed retrospectively. FibroScan results include the E- score (kPA), measuring liver stiffness, and controlled attenuation parameter (CAP) score (dB/m), assessing steatosis. In addition, a FIB-4 fibrosis score was calculated. RESULTS: 47 gout patients (7 females, 14.9%; 40 males, 85.1%) underwent FibroScans. The mean age was 59.8 years, the mean body mass index (BMI) was 30.95 kg/m2, and gout duration 0-49 years. Tophi were present in 11 (26.2%). Comorbidities included dyslipidaemia (86.7%), diabetes mellitus (31.1%), known liver disease (33.3%), current alcohol consumption (46.8%), ALT or AST elevations (54.4%), and hyperuricaemia (53.7%). FibroScan results revealed hepatic steatosis (CAP >238 dB/m) in 40 (85.1%) and were significantly associated with BMI (r=0.53, p=0.0001) but not age, serum urate (SU), glucose, triglycerides, ALT, AST. FibroScan also revealed fibrosis (E score >7) in 9 (19.1%); severe fibrosis (cirrhosis) in 8. Fibrosis was significantly associated with age (p=0.03) and known liver disease (p=0.003) but not BMI, SU, or comorbidities. The FIB-4 score was significantly associated with the fibrosis score (r2=0.24, p=0.0009) but not with CAP, ALT, or AST. CONCLUSIONS: Despite not being associated with common gout comorbidities, fatty liver and liver fibrosis were common in this gout cohort, suggesting FibroScan screening in gout patients to assess NAFLD, irrespective of serum transaminase levels.

Improvement in hepatic fibrosis estimated by Fibrosis-4 index in pegloticase treated chronic refractory gout patients.

OBJECTIVES: To determine whether lowering serum urate (SU) affects the course of non-alcoholic fatty liver disease (NAFLD). METHODS: Retrospective data analysis from chronic refractory gout patients who participated in two 6-month pegloticase randomised clinical trials compared patients who received pegloticase biweekly to those who received placebo. Patients with persistent urate-lowering to <1 mg/dL in response to biweekly pegloticase (responders, n=36) were compared to those who received placebo (n=43). NAFLD was assessed using the Fibrosis-4 (Fib-4) index. Comparisons between groups were carried out using 2 sample Wilcoxon tests or regression analysis. RESULTS: At baseline the mean (standard deviation [SD]) Fib-4 values were 1.40 (0.86) in pegloticase responders, and 1.04 (0.53) in patients receiving placebo. Patients receiving placebo exhibited a change of 0.26 (0.41) in Fib-4 score over 6 months vs 0.13 (0.62) for pegloticase responders (p=0.048). When only patients with a Fib-4 value >1.3 were considered (n=27), a significant difference in the change in the Fib-4 values between pegloticase responders vs. placebo was observed (-0.15 [0.67] vs. 0.7 [0.42], p=0.04). The correlation between the SU area under the curve (AUC) over the 6-month trial period and the change in Fib-4 value was R=0.33 (p=0.0004). Multivariable analysis indicated SU AUC was the only significant contributor to the change in Fib-4 values (p=0.018). CONCLUSIONS: Persistent lowering of SU significantly reduced Fib-4 scores, implying a possible effect on NAFLD progression. These results support the consideration of a complete analysis of the impact of profound urate-lowering on NAFLD as measured by the Fib-4 index.

Pegloticase causes prolonged improvement in multiple disease parameters in patients with chronic refractory gout who maintain low serum urate levels.

OBJECTIVES: To assess the benefit of long-term urate-lowering with pegloticase. METHODS: The results from two, 6-month, randomised controlled trials (RCTs) and their 30-month open-label extension (OLE) were analysed. Efficacy was assessed in urate responders (patients with plasma urate <6.0 mg/dL for ≥80% of assessments around the 3- and 6-month time periods) to the approved regimen (8 mg every 2 weeks [q2w]) and responders to q4w treatment. Assessments included serum urate (sU), Patient Global Assessment (PtGA), tender and swollen joints (TJC and SJC), pain, Health Assessment Questionnaire Disability Index, bodily pain, the Arthritis-Specific Health Index, and reduction of target tophi. RESULTS: 34 responders to pegloticase in the RCTs were followed throughout the 2.5 years of the OLE. Of these, 20 received 8 mg pegloticase q2w and 14 q4w. The results for patients who received pegloticase q2w indicated significant improvements between RCT baseline and the final OLE evaluation for sU (p<0.0001), PtGA (p<0.0001), TJC (p=0.0001), and SJC (p=0.0014); 61.5%, had complete target tophus resolution. The results for patients treated monthly indicated significant improvements between RCT baseline and the final OLE evaluation for sU (p<0.001), PGA (p=0.0003), TJC (p=0.008), and SJC (p<0.0001);100% had complete target tophus resolution. CONCLUSIONS: There were significant sustained clinical benefits with long-term pegloticase treatment in patients with chronic refractory gout achieving a urate-lowering effect during the first 6 months of therapy and followed for up to 30 additional months.

Post-hoc analysis of pegloticase pivotal trials in chronic refractory gout: relationship between fluctuations in plasma urate levels and acute flares.

OBJECTIVES: To determine factors associated with gout flares in subjects treated with pegloticase. METHODS: Gout flares from two randomised controlled trials comparing pegloticase (8 mg every 2 weeks [q2] or monthly [q4]) versus placebo were analysed. Responders had persistent urate lowering (<6mg/dL) whereas, non-responders had transient urate lowering during the 6-month RCTs. Gout flares (self-reported) were defined as acute joint pain and swelling requiring treatment. Gout flare prophylaxis (colchicine, 0.6 mg once or twice daily, or a non-steroidal anti-inflammatory drug) was initiated 1 week before the first infusion and continued throughout the study. Plasma urate at the time of flare and the change in urate preceding a flare were analysed. RESULTS: Mean flare rates increased with pegloticase versus placebo during the first 3 months followed by marked reductions during months 4-6. The increase in flares with pegloticase during the first 3 months was most evident (p=0.0006) and the decrease during the second 3 months was least marked (p=0.0006) in subjects receiving monthly pegloticase. Fluctuation in urate levels was highest in monthly responders (p=0.002) and was associated with flare occurrence. Multivariate linear regression analysis indicated the only variables significantly associated with flares were treatment group and absolute change in plasma urate before flares. CONCLUSIONS: Pegloticase treatment increased flares during the first 3 months of treatment in all groups when plasma urate was significantly lowered and was followed by a decline in months 4-6 in patients maintaining a low plasma urate. Flares associated with pegloticase treatment were associated with decreases and fluctuations in plasma urate levels.

Characterization of patients with chronic refractory gout who do and do not have clinically apparent tophi and their response to pegloticase.

OBJECTIVES: To determine the characteristics and response to pegloticase of patients with chronic refractory gout with and without clinically apparent tophi. METHODS: Results from two randomized controlled trials of pegloticase in patients with chronic refractory gout with clinically apparent tophi or without tophi were used to assess baseline and on-treatment between-group differences. RESULTS: Patients with tophi were significantly older than those without tophi, had a significantly longer duration of disease, higher numbers of tender and swollen joints, higher Patient Global Assessment scores and Health Assessment Questionnaire-Disability Index scores, and lower Arthritis-Specific Health Index scores. Patients with tophaceous gout also had significantly lower scores for physical functioning, role physical, social functioning, and the physical component summary scores of the Short Form 36 vs patients without tophi. In addition, subjects with clinically apparent tophi had a significantly lower mean estimated glomerular filtration rate. Pegloticase treatment of tophaceous patients caused significant reductions in serum urate, flares, Patient Global Assessment, tender joints, swollen joints, Health Assessment Questionnaire-Disability Index, visual analogue scale pain and Short Form 36 Bodily Pain, whereas patients without tophi had significant improvement in serum urate, flares, Patient Global Assessment, tender joints, and Short Form 36 Bodily Pain, but not swollen joints, Health Assessment Questionnaire-Disability Index functional score or pain visual analogue scale. Treatment with pegloticase had no effect on estimated glomerular filtration rate despite significant lowering of the urinary uric acid: creatinine ratio. CONCLUSION: Patients with chronic refractory gout and clinically apparent tophi have more severe disease as well as reduced renal function. Both groups experienced significant clinical benefit with pegloticase treatment, although no change in renal function was noted.

The Burden of Hepatitis C Infection-Related Liver Fibrosis in the United States.

BACKGROUND: Knowledge of the estimated proportion of hepatitis C virus (HCV)-infected persons with advanced fibrosis or cirrhosis is critical to estimating healthcare needs. METHODS: We analyzed HCV-related testing conducted by Quest Diagnostics from January 2010 through December 2013. Tests included hepatitis C antibody, HCV RNA, HCV genotype (nucleic acid tests [NAT]), liver function tests, and platelet counts; patient age was also determined. Aspartate aminotransferase (AST)-to-platelet ratio (APRI) was calculated as = 100*(aspartate aminotransferase [AST]/upper limit of AST)/platelet. Fibrosis-4 (FIB-4) was calculated as (age × AST)/(platelet ×√ alanine aminotransferase [ALT]). Persons were "currently infected" if they had ≥1 positive HCV NAT; "in care" if a positive RNA test was followed <6 months by ≥1 additional NAT(s), or ALT, AST, and platelets <90 days, or any test ordered by an infectious diseases or gastroenterology specialist; and "evaluated for treatment" if they had a genotype test. RESULTS: Approximately 10 million HCV test results were analyzed, representing 5.6 million unique patients. Of the 2.6 million patients with data to estimate liver disease, 5% were currently infected. Among those currently infected, APRI and FIB-4 scores indicated that 23% overall-and 27% among the cohort born during 1945-1965-had advanced fibrosis or cirrhosis at first diagnosis. A total of 54% of infected were in care and 51% of infected with advanced fibrosis or cirrhosis were evaluated for treatment. CONCLUSIONS: Testing from a large US commercial laboratory indicates that about 1 in 4 HCV-infected persons have levels of liver disease put them at highest risk for complications and could benefit from immediate antiviral therapy.

The six-minute walk test is an excellent predictor of functional ambulation after total knee arthroplasty.

BACKGROUND: The Six-minute walk (6 MW) and Timed-Up-and-Go (TUG) are short walk tests commonly used to evaluate functional recovery after total knee arthroplasty (TKA). However, little is known about walking capacity of TKA recipients over extended periods typical of everyday living and whether these short walk tests actually predict longer, more functional distances. Further, short walk tests only correlate moderately with patient-reported outcomes. The overarching aims of this study were to compare the performance of TKA recipients in an extended walk test to healthy age-matched controls and to determine the utility of this extended walk test as a research tool to evaluate longer term functional mobility in TKA recipients. METHODS: The mobility of 32 TKA recipients one year post-surgery and 43 healthy age-matched controls were assessed using the TUG, 6 MW and 30-minute walk (30 MW) tests. The latter test was repeated one week later. Self-reported function was measured using the WOMAC Index and a physical activity questionnaire. RESULTS: 30 MW distance was significantly shorter amongst TKA recipients (mean 2108 m [95% CI 1837 to 2381 m]; Controls 3086 m [2981 to 3191 m], P < 0.001). Test-retest repeatability was high (ICC = 0.97, TKA; 0.96, Controls). Amongst TKA recipients, the 30 MW distance correlated strongly with the shorter tests (6 MW, r = 0.97, P < 0.001; TUG, r = -0.82, P < 0.001). Multiple regression modeling found 6 MW distance to be the only significant predictor (P < 0.001) of 30 MW distance, explaining 96% of the variability. The TUG test models were moderate predictors of WOMAC function (55%) and physical activity (36%) and were stronger predictors than 6 MW and 30 MW tests. CONCLUSIONS: Though TKA recipients are able to walk for 30 minutes one year post-surgery, their performance falls significantly short of age-matched norms. The 30 MW test is strongly predicted by 6 MW test performance, thus providing strong construct validity for the use of the 6 MW test in the TKA population. Neither a short nor long walk test is a strong predictor of patient-reported function after TKA.

The effects of TLR activation on T-cell development and differentiation.

Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

How do dental and prenatal care practitioners perceive dental care during pregnancy? Current evidence and implications.

BACKGROUND: Poor maternal oral health may be associated with adverse pregnancy and infant outcomes. However, women seldom seek dental care during pregnancy, and misconceptions by prenatal care practitioners about oral health care during pregnancy may contribute to the problem. The aim of this study was to review current knowledge, attitudes, and behavior of dental and prenatal care practitioners about oral health care during pregnancy. METHODS: This review examined all studies published in English that explored the knowledge, attitude, behavior, and barriers faced by dentists, general practitioners, midwives, and obstetricians/gynecologists with respect to oral health care during pregnancy. RESULTS: Despite acknowledging the importance of maternal oral health, many dentists are uncertain about the safety of dental procedures and are hesitant in treating pregnant women. General practitioners and midwives are poorly informed about the impact of poor maternal oral health and rarely initiate this topic during prenatal care. Many general practitioners also believe that dental procedures are unsafe during pregnancy. Obstetricians/gynecologists are well informed about perinatal oral health and are supportive of dental procedures, but because of lack of training in this area and competing health demands they seldom focus on oral health care during their prenatal care. CONCLUSION: No real consensus exists among dentists and prenatal care practitioners with respect to oral health care during pregnancy. This issue poses a significant deterrent for pregnant women seeking dental care. Practice guidelines in perinatal oral health are needed for health professionals to emphasize this important aspect of prenatal care.

Improvements in knee range and symptomatic and functional behavior after knee arthroplasty based on preoperative restriction in range.

Recovery of knee range and Oxford Knee Score post knee arthroplasty based on preoperative knee range is described. A total of 191 patients recruited across 5 hospitals were assessed preoperatively, at 8 weeks postoperatively and 1 year. Preoperative knee range was categorized into "low" (≤ 109), "moderate" (> 109 to ≤ 120), and "high" (> 120°) flexion and "normal" (± -5) and "restricted" (> +5°) terminal extension. Recovery was analyzed using MIXED modeling procedures. The low-flexion group gained flexion across time. The moderate-flexion and high-flexion groups lost flexion initially then recovered, but 1-year flexion remained lower than preoperative values. The restricted terminal extension group gained extension across time. The normal terminal extension group lost extension initially then recovered to preoperative values at 1 year. Recovery in Oxford score was independent of preoperative knee range limitation. Improvement in knee range postoperatively, but not self-reported behavior, is highly dependent on the initial restriction in range.

Role of heat-shock protein 90 in hepatitis E virus capsid trafficking.

p239 is a virus-like particle constituted from hepatitis E virus (HEV) recombinant proteins. It can be used as a surrogate for HEV and as an investigative tool to study cellular interactions because of its ability to adsorb to and penetrate HepG2 cellular membranes. Our objective was to use p239 to define the role of HEV capsid proteins during the early stages of infection. Pull-down and MALDI-TOF MS experiments identified three host-cell proteins, Grp 78/Bip, alpha-tubulin and heat-shock protein 90 (HSP90), and the latter was investigated further. Antibodies to p239 alone or HSP90 alone could detect p239 or HSP90, suggesting the formation of a complex between p239 and HSP90. In the HepG2 cell, geldanamycin (GA), an HSP90-specific inhibitor, blocked intracellular transportation of p239, but had no effect on the binding and cellular entry of p239, suggesting that HSP90 was important for HEV capsid intracellular transportation. RT-PCR results showed that the efficiency of wild-type HEV infection was inhibited significantly by GA treatment, suggesting the importance of HSP90 in virus infectivity. It was concluded that HSP90 plays a crucial role in the intracellular transportation of viral capsids in the early stage of HEV infection.

Low incidence of complications from endoscopic gastric variceal obturation with butyl cyanoacrylate.

BACKGROUND & AIMS: Endoscopic variceal obturation with tissue adhesive is used to control gastric variceal bleeding. We investigated the prevalence of serious complications from this therapy. METHODS: We performed a retrospective analysis of complications that occurred in 753 patients with gastric variceal hemorrhages who were hospitalized in 2 tertiary referral hospitals. All patients received N-butyl-2-cyanoacrylate as therapy for endoscopic variceal obturation. RESULTS: Complications occurred in 51 patients. Thirty-three patients experienced rebleeding because of early-onset (within 3 months) extrusion of the N-butyl-2-cyanoacrylate glue cast (4.4%), 10 patients developed sepsis (1.3%), and 5 patients developed distant embolisms (0.7%; 1 pulmonary, 1 brain, and 3 splenic). One patient had major gastric variceal bleeding after endoscopic variceal obturation (0.1%), 1 developed a large gastric ulcer (0.1%), and 1 had mesentery hematoma, hemoperitoneum, and infection in the abdominal cavity (0.1%). The complication-related mortality was 0.53% (3 deaths from sepsis and 1 death from rebleeding after early-onset glue cast extrusion). CONCLUSIONS: The occurrence of complications after endoscopic variceal obturation with N-butyl-2-cyanoacrylate in gastric varices treatment is rare.

Molecular characteristics of occult hepatitis B virus from blood donors in southeast China.

The characteristics of 30 carriers with occult hepatitis B virus (HBV) infection (OBI) were compared with those of 30 individuals diagnosed as being HBV carriers at the time of blood donation, 60 asymptomatic carriers, and 60 chronic hepatitis patients. The prevalence of genotype C was significantly higher in carriers with OBIs than in any other HBsAg-positive (HBsAg(+)) group (P < 0.001). Specific amino acid substitutions in the regions from amino acids 117 to 121 and amino acids 144 to 147 located in the major hydrophilic region of the S gene were associated with carriers with OBIs (P < 0.01 for carriers with OBIs versus HBsAg(+) donors, carriers with OBIs versus HBsAg(+) asymptomatic carriers, and carriers with OBIs versus HBsAg(+) chronic hepatitis patients). G145R was the major variation in the HBV isolates responsible for local occult HBV infections.

RNA Interference inhibits hepatitis B virus of different genotypes in vitro and in vivo.

BACKGROUND: Hepatitis B virus (HBV) infection increases the risk of liver disease and hepatocellular carcinoma. Small interfering RNA (siRNA) can be a potential new tool for HBV therapy. Given the high heterogeneity of HBV strains and the sensitivity towards sequences changes of siRNA, finding a potent siRNA inhibitor against the conservative site on the HBV genome is essential to ensure a therapeutic application. RESULTS: Forty short hairpin RNA (shRNA) expression plasmids were constructed to target conserved regions among nine HBV genotypes. HBV 1.3-fold genome plasmids carrying various genotypes were co-transfected with shRNA plasmids into either Huh7 cells or mice. The levels of various viral markers were examined to assess the anti-HBV efficacy of siRNA. Four (B245, B376, B1581 and B1789) were found with the ability to potently inhibit HBV RNA, DNA, surface antigen (HBsAg), e antigen (HBeAg) and core antigen (HBcAg) expression in HBV genotypes A, B, C, D and I (a newly identified genotype) in Huh7 cells and in mice. No unusual cytotoxicity or off-target effects were noted. CONCLUSIONS: Such siRNA suggests an alternate way of inhibiting various HBV genotypes in vitro and in vivo, promising advances in the treatment of HBV.

Long-term increases in lymphocytes and platelets in human T-lymphotropic virus type II infection.

Human T-lymphotropic viruses types I and II (HTLV-I and HTLV-II) cause chronic infections of T lymphocytes that may lead to leukemia and myelopathy. However, their long-term effects on blood counts and hematopoiesis are poorly understood. We followed 151 HTLV-I-seropositive, 387 HTLV-II-seropositive, and 799 HTLV-seronegative former blood donors from 5 U.S. blood centers for a median of 14.0 years. Complete blood counts were performed every 2 years. Multivariable repeated measures analyses were conducted to evaluate the independent effect of HTLV infection and potential confounders on 9 hematologic measurements. Participants with HTLV-II had significant (P < .05) increases in their adjusted lymphocyte counts (+126 cells/mm(3); approximately +7%), hemoglobin (+2 g/L [+0.2 g/dL]) and mean corpuscular volume (MCV; 1.0 fL) compared with seronegative participants. Participants with HTLV-I and HTLV-II had higher adjusted platelet counts (+16 544 and +21 657 cells/mm(3); P < .05) than seronegatives. Among all participants, time led to decreases in platelet count and lymphocyte counts, and to increases in MCV and monocytes. Sex, race, smoking, and alcohol consumption all had significant effects on blood counts. The HTLV-II effect on lymphocytes is novel and may be related to viral transactivation or immune response. HTLV-I and HTLV-II associations with higher platelet counts suggest viral effects on hematopoietic growth factors or cytokines.

Immunomodulatory effects of dsRNA and its potential as vaccine adjuvant.

dsRNA can be detected by pattern recognition receptors, for example, TLR3, MDA-5, NLRP3 to induce proinflammatory cytokines responsible for innate/adaptive immunity. Recognized by endosomal TLR3 in myeloid DCs (mDCs), dsRNA can activate mDCs into mature antigen presenting cells (mAPCs) which in turn present antigen epitopes with MHC-I molecules to naïve T cells. Coadministration of protein and synthetic dsRNA analogues can elicit an antigen-specific Th1-polarized immune response which stimulates the CD8+ CTL response and possibly dampen Th17 response. Synthetic dsRNA analogues have been tested as vaccine adjuvant against viral infections in animal models. However, a dsRNA receptor, TLR3 can be expressed in tumor cells while other members of TLR family, for example, TLR4 and TLR2 have been shown to promote tumor progression, metastasis, and chemoresistance. Thus, the promising potential of dsRNA analogues as a tumor therapeutic vaccine adjuvant should be evaluated cautiously.

Dissociation Between Clinical Benefit and Persistent Urate Lowering in Patients with Chronic Refractory Gout Treated with Pegloticase.

OBJECTIVE: To assess clinical benefit in patients with chronic refractory gout who did not meet the protocol-defined criteria of responders to pegloticase. METHODS: This analysis used results from 2 randomized controlled trials (ClinicalTrials.gov: NCT00325195, NCT01356498) to assess the clinical efficacy in responders and nonresponders to treatment (8 mg of pegloticase every 2 weeks). Serum urate was measured before each infusion and the following were recorded: assessment of gout flares, tophus reduction, patient's global assessment (PtGA), tender and swollen joints (TJC and SJC), pain using a 100-mm visual analog scale, and a variety of patient-reported outcomes [Medical Outcomes Study Short Form-36 questionnaire physical component summary score and arthritis-specific health index (ASHI) score]. RESULTS: The analysis included 36 persistent urate responders, 49 nonresponders, and 43 patients who received placebo. Results for both responders and nonresponders indicated significant reduction in tophi and improvements from baseline in PtGA, TJC, SJC, pain, and ASHI. No significant improvements were observed in the patients who received placebo. CONCLUSION: Chronic refractory gout patients not achieving protocol-defined persistent urate lowering still achieve significant clinical benefits with pegloticase treatment, suggesting that transient reduction in serum urate may result in sustained clinical benefit.

Development of a multivariable improvement measure for gout.

BACKGROUND: Gout is a heterogeneous inflammatory disease with numerous clinical manifestations. A composite means to assess the impact of therapy on numerous aspects of gout could be useful. METHODS: Results from patients treated with pegloticase or placebo in two randomized clinical trials and their open-label extension were assessed using a novel evidence-based Gout Multivariable Improvement Measure (GMIM) derived from previously reported criteria for remission and complete response. Improvement was defined as serum urate (sU) < 6 mg/dL and absence of flares during the preceding 3 months plus 20, 50, and 70% improvement in tophus size, patient global assessment, pain, and swollen and tender joints. RESULTS: Patients treated with pegloticase manifested a significantly greater GMIM20, 50, and 70 response vs those treated with placebo (GMIM20 at 6 months 37.1% vs 0%, respectively). Higher response rates were significantly more frequent in subjects with persistent urate lowering (GMIM 58.1% at 6 months) in response to pegloticase versus those with only transient urate lowering (GMIM 7.1% at 6 months). However, when the requirement for a decrease in sU to < 6 mg/dL was omitted, a substantial percentage of subjects with transient urate lowering met the GMIM clinical criteria. A sensitivity analysis indicated that gout flares contributed minimally to the model. The response measured by GMIM persisted into the open-level extension for as long as 2 years. Finally, subjects who received placebo in the randomized control trials, but pegloticase in the open-label extension, manifested GMIM responses comparable to that noted with pegloticase-treated subjects in the randomized controlled trials. CONCLUSIONS: GMIM captures changes in disease activity in response to treatment with pegloticase and may serve as an evidence-based tool for assessment of responses to other urate-lowering therapies in gout patients.

Patient ancestry significantly contributes to molecular heterogeneity of systemic lupus erythematosus.

Gene expression signatures can stratify patients with heterogeneous diseases, such as systemic lupus erythematosus (SLE), yet understanding the contributions of ancestral background to this heterogeneity is not well understood. We hypothesized that ancestry would significantly influence gene expression signatures and measured 34 gene modules in 1566 SLE patients of African ancestry (AA), European ancestry (EA), or Native American ancestry (NAA). Healthy subject ancestry-specific gene expression provided the transcriptomic background upon which the SLE patient signatures were built. Although standard therapy affected every gene signature and significantly increased myeloid cell signatures, logistic regression analysis determined that ancestral background significantly changed 23 of 34 gene signatures. Additionally, the strongest association to gene expression changes was found with autoantibodies, and this also had etiology in ancestry: the AA predisposition to have both RNP and dsDNA autoantibodies compared with EA predisposition to have only anti-dsDNA. A machine learning approach was used to determine a gene signature characteristic to distinguish AA SLE and was most influenced by genes characteristic of the perturbed B cell axis in AA SLE patients.

Pegloticase Treatment Significantly Decreases Blood Pressure in Patients With Chronic Gout.

Serum urate is correlated with blood pressure (BP), and lowering urate may decrease BP, but a consistent effect has not been observed. Here, we evaluated whether pegloticase, a recombinant uricase conjugated to polyethylene glycol, which can lead to persistently low serum urate levels (<1 mg/dL), can modulate BP in subjects with chronic refractory gout. This post hoc analysis used results from two 6-month randomized clinical trials in which subjects were treated with 8 mg pegloticase every 2 or 4 weeks (q2w or q4w) or placebo. Responders in this study were defined as those individuals in whom a persistently low urate level (<6 mg/dL and usually <1 mg/dL) was maintained. Serial sitting BP was measured in 173 subjects, and estimated glomerular filtration rate was determined at baseline and after 3 and 6 months. Significant reductions in mean arterial pressure (MAP) from baseline to 6 months were noted in q2w responders ( P=0.0028), whereas reductions in MAP in other groups were not significant. Significant decreases in both systolic and diastolic BP paralleled the change in MAP. Of the 62% of q2w responders exhibiting persistent decreases in MAP, there were no significant differences in baseline age, sex, race, weight, body mass index, history of hypertension, hyperlipidemia, history of coronary artery disease, gout duration, MAP, serum urate, estimated glomerular filtration rate or urinary uric acid/creatinine ratio compared with those who did not lower MAP. No significant changes in estimated glomerular filtration rate occurred in any of the groups during the study. Responders to biweekly pegloticase who maintained a persistently lower serum urate level throughout the trial experienced significant reductions in both systolic and diastolic BP that were independent of changes in renal function. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00325195.