Faculty Bibliography

Background/UNASSIGNED:Febuxostat is approved in the United States for the management of hyperuricemia in patients with gout. In November 2017 the FDA released a warning alert on a possible link between febuxostat and cardiovascular disease (CVD) reported in a single clinical trial. Objective/UNASSIGNED:To conduct a systematic review and meta-analysis and assess the risk of major adverse cardiovascular events (MACE) in patients receiving febuxostat compared to a control group. Methods/UNASSIGNED:We searched the MEDLINE and EMBASE database for studies published up until March 2018. We included randomized clinical trials (RCTs) that compared febuxostat to control groups including placebo and allopurinol. We calculated the pooled relative risk (RR) of MACE and cardiovascular disease (CVD) mortality with the corresponding 95% confidence intervals (CI). Results/UNASSIGNED:Our search yielded 374 potentially relevant studies. Among the 25 RCTs included in the systematic review, 10 qualified for the meta-analysis. Among the 14,402 subjects included, the median age was 54 years (IQR 52-67) and 90% were male (IQR 82-96); 8602 received febuxostat, 5118 allopurinol, and 643 placebo. The pooled RR of MACE for febuxostat was 0.9; 95% CI 0.6-1.5 (p= 0.96) compared to the control. The RR of CV-related death for febuxostat was 1.29; 95% CI 1.01-1.66 (p=0.03). Conclusions/UNASSIGNED:Compared with other SU-lowering treatments, febuxostat does not increase or decrease the risk of cardiovascular disease but may increase the risk of CVD death. More RCTs measuring cardiovascular safety as a primary outcome are needed to adequately evaluate the risk of CVD with febuxostat.

Background/Purpose: Inflammation plays a pathogenetic role in OA, and catabolic cytokines including IL-1b potentiate joint space narrowing. Elevated serum urate (sUA) levels promote crystal-induced stimulation of inflammasome IL-1b production, potentially contributing to OA incidence and/or progression. Additionally, intraarticular urate concentrations associate with radiographic knee OA (RKOA) severity. However, there is limited research on associations of asymptomatic hyperuricemia (AH) and knee OA outcomes. Therefore, we sought to examine the association of AH with RKOA and symptomatic RKOA (sRKOA) using the National Health and Nutrition Examination Survey III (NHANES III), a large nationally representative survey. We also examined whether body mass index (BMI) modifies the association between AH and RKOA.
Method(s): NHANES III was a cross-sectional health examination survey conducted between 1988 and 1994. It used a multistage, stratified probability cluster design to select a representative sample of noninstitutionalized civilian in the US, and included data on sUA, gout, clinical and radiographic knee OA. We analyzed data (n=2213) for adults over age 60, excluding individuals with self-reported gout. Hyperuricemia was defined as serum urate > 6.8, mg/dL. One non-weight bearing AP knee X-ray was performed with RKOA defined as KL grade >= 2, and sRKOA as RKOA plus pain in the affected joint on most days for the prior 6 weeks. Wald chi-square tests were used to examine differences in proportions between different study characteristics. Multivariate log binomial models were used to examine the association between AH and knee OA outcomes and estimate prevalence ratios (PRs) and 95% confidence intervals (CIs).
Result(s): Among US adults age 60 years and older, prevalence of AH was 17.9% (CI 15.3-20.5). AH prevalence was significantly greater among men vs women (24.5% vs. 13.3%, p=<0.01) and persons with obesity (BMI >=30kg/m2) vs persons without obesity (27.4% vs. 14.8%, p=<0.01). Prevalence of RKOA was 37.7% (CI 35.0-40.3) and was significantly greater in women vs men (42.1% vs. 31.3%, p=0.01). The prevalence of RKOA was highest among subjects with greater age, obesity, non-Hispanic Black race, and less education. RKOA prevalence among adults with AH was 44.0% vs 36.3% for those with normuricemia (p = 0.056). Importantly, sRKOA was significantly higher in the AH group (17.4 vs 10.9%, p=0.04). After adjusting for age, sex, race, and education, adults with AH were more likely to have RKOA (PR = 1.26, 95% CI: 1.06, 1.36) and sRKOA (PR = 1.69, 95% CI: 1.19, 2.42). These associations were observed for persons without obesity, but were severely attenuated among persons with obesity, suggesting that obesity status may modify the association between AH and knee OA.
Conclusion(s): We identified a greater prevalence of RKOA among persons with AH, along with a greater prevalence of sRKOA, suggesting urate may participate in OA pathogenesis. This association appeared to be modified by obesity status with non-obese adults (but not adults with obesity) reporting a greater prevalence of knee OA among participants with AH. Longitudinal studies are needed to verify these findings

Background/Purpose: Precise estimates of the comorbidity burden of gout and hyperuricemia are critical as their presence has important implications for the treatment of both gout and hyperuricemia. We therefore estimated the decadal US prevalence of cardiovascular-renal-metabolic comorbidities according to gout and hyperuricemia status, based on the National Health and Nutritional Examination Survey (NHANES) 2007-2016.
Method(s): Using data from 26,332 participants (12,793 men and 13,539 women) aged >=20 years old from NHANES 2007- 2016, we determined the prevalence (%) of cardiovascular-renal-metabolic comorbidities according to gout and hyperuricemia status. Obesity was defined as body mass index>=30 kg/m². Other comorbidities were defined based on an affirmative answer to a question asking if a physician or a health professional had diagnosed the said comorbidity. Hyperuricemia was defined as a serum urate level >7.0 mg/dL in men and >5.7 mg/dL in women. All statistical analyses were conducted using survey commands of Stata (Version 15.1, Stata Corporation, College Station, Texas) to adjust for clusters and strata of the complex sample design as well as incorporate sample weights. Population estimates (in millions) were calculated as per the NHANES analytic guidelines.
Result(s): Among gout patients, 69.4% (6.0 million) had hypertension, 55.9% (4.8 million) were obese, 26.5% (2.3 million) had type II diabetes mellitus (T2DM), 22.5% (1.9 million) had chronic kidney disease (CKD) stage >=3, 19.9% (1.7 million) had nephrolithiasis, 11.8% (1.0 million) had a myocardial infarction (MI), 11.1% (1.0 million) had heart failure (HF), and 8.7% (0.7 million) had suffered a stroke over 2007-2016. Among the US adults with both gout and hyperuricemia, 73.9% had hypertension, 60.8% were obese, 28.5% had CKD stage >=3, 25.0% had T2DM, 18.2% had nephrolithiasis, 11.9% had HF, 11.6% had a MI, and 9.3% had suffered a stroke (Table). These prevalences were substantially higher compared with individuals without gout or hyperuricemia. Hyperuricemia without gout was also associated with higher prevalences of comorbidities (all P-values < 0.005, Table). Among individuals with gout, the presence of hyperuricemia conferred additional risk for hypertension, CKD and obesity (all P-values<0.05, Table).
Conclusion(s): The findings from this recent, nationally-representative sample of US adults highlight that both gout patients and those with hyperuricemia continue to carry a substantial burden of cardiovascular-renal-metabolic comorbidities. These add to the overall disease burden of gout and hyperuricemia to society, and provide support for the consideration of these comorbidities in optimizing gout and hyperuricemia care in the US. (Table Presented)

Background/Purpose: Previous studies suggest that patients with gout are at increased risk for developing diabetes.1 One possible explanation for this increased risk is the activation of pathologic pathways common to both diabetes and gout, including IL-1b.2 Among its many mechanisms, colchicine has been found to suppress activation of the NLRP3 inflammasome, inhibiting activation of IL-1b. Colchicine may also activate AMPK, a down regulator of inflammation and gluconeogenesis.3 In the present study, we investigated whether chronic colchicine use reduces diabetes incidence among patients with gout.
Method(s): We reviewed the Computerized Patient Record System (CPRS) of the New York Harbor Veterans' Affairs Healthcare System to assess the incidence of diabetes between 2000 and 2015 among 140 randomly selected patients with gout who had taken colchicine daily for some or all of the study period. We compared the diabetes incidence among these patients with 115 randomly selected patients with gout who did not take colchicine during the same time period. At study entry, all subjects met a modified version of 1977 ARA gout classification criteria and had no diabetes diagnosis. Patients were excluded if their duration of colchicine use was <60 contiguous days. Incident diabetes was defined as a new hemoglobin A1c value of >=6.5% during the study period.
Result(s): Among gout patients who had taken colchicine, we observed no difference in diabetes incidence compared to patients not taking colchicine (17.1% versus 17.4%, OR = 0.983, p = 1.0). When patients were analyzed by duration of colchicine use, there was no significant difference in diabetes incidence between patients in the longest (36.5 to 114 months) compared to the shortest tertile (2.3 to 14 months)(27.3% versus 9.1%, p=0.24) of colchicine exposure. Among patients in the colchicine group who experienced incident diabetes during the study period (n=24), 50% (n=12) were actively taking colchicine at the time of their diagnosis and 50% (n=12) had discontinued colchicine use prior to their diabetes diagnosis.
Conclusion(s): We found no significant difference in the 15-year diabetes incidence between patients taking colchicine and those not taking colchicine, suggesting that colchicine is not beneficial to prevent incident diabetes. Larger and prospective studies will be needed to confirm this observation

Background/Purpose: To determine the latest national prevalence of urate-lowering therapy (ULT) use and achievement of a therapeutic target serum urate level (SUL) in gout patients, and their predictors in the US (National Health and Nutrition Examination Survey [NHANES] 2007-2014).
Method(s): Using data from NHANES 2007-2014, we estimated the prevalence of ULT use and achievement of a therapeutic target SUL in patients with gout. During the home interview of NHANES, all participants were asked about a history of health professional- or physician-diagnosed gout and current prescription medications. We defined ULT as taking allopurinol, febuxostat or probenecid, either alone or in combination, and a therapeutic SUL as <6.0 mg/dL. We conducted logistic regression to examine the potential independent associations with purported factors among gout patients.
Result(s): The prevalence of ULT usage among US gout patients was 32.8% [95% CI 28.3% to 37.6%] in 2007-2014 (39.0% [95% CI 33.6% to 44.7%] among men and 19.4% [95% CI 15.3 to 44.7%] among women). Allopurinol comprised 95.3% [95% CI 92.2% to 98.4%] of ULT usage. Among gout patients, the mean SULs were 5.8 mg/dL [95%CI 5.5 mg/dL to 6.0 mg/dL] among ULT users and 6.9 mg/dL [95% CI 6.7 mg/dL to 7.1 mg/dL] among non-ULT users (mean difference -1.1 mg/dL [95% CI -1.4 mg/dL to -0.8 mg/dL]). Among gout patients, male sex and chronic kidney disease (CKD) were associated with increased fully-adjusted odds of ULT use (Table 1). The prevalence of reaching a therapeutic SUL (<6.0 mg/dL) among gout patients was 38.5% [95% CI 35.3% to 41.7%] in 2007-2014 (32.3% [95% CI 28.3% to 36.5%] among men and 52.0% [95% CI 44.8% to 59.1%] among women). Furthermore, among gout patients, ULT use was associated with a fivefold higher odds for reaching a SUL <6.0 mg/dL. By contrast, male sex, obesity, CKD and thiazide diuretic use were associated with a lower fully-adjusted odds for reaching this target SUL (Table 2).
Conclusion(s): These findings from a nationally-representative samples of US adults indicate that 32.8% of US gout patients are receiving ULT. Among gout patients, males, and those with either obesity or CKD are more often receiving ULT. The benefit of ULT among gout patients in achieving this target SUL appears apparent. Male sex, obesity, CKD and thiazide diuretic use were inversely associated with reaching a therapeutic SUL, suggesting a potential need for more aggressive therapy among these groups. (Table Presented)

To determine whether arterial responsiveness is impaired among patients with gout, and whether arterial responsiveness inversely correlates with serum urate and inflammatory measures. This is a cross-sectional study of untreated gout subjects (n = 34) and non-gout healthy controls (n = 64). High-resolution dynamic ultrasound-measured flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent arterial responsiveness respectively. Serum urate (sUA) and high-sensitivity C-reactive protein (hsCRP) were measured in the gout group, and correlated with FMD and NMD responses. Both FMD (2.20 ± 0.53 vs 3.56 ± 0.31, p = 0.021) and NMD (16.69 ± 1.54 vs 24.51 ± 0.90, p = 0.00002) were impaired in the gout versus control group. Stratification for individual comorbidities suggested that no single risk factor accounted for impaired FMD/NMD in the gout subjects. However, the degree of association between gout and FMD, but not NMD impairment, was dampened after multivariable adjustment (FMD unadjusted beta = - 1.36 (SE 0.58), p = 0.02; adjusted beta = - 1.16 (SE 0.78), p = 0.14 and NMD unadjusted beta = - 7.68 (SE 1.78), p < 0.0001; adjusted beta = - 5.33 (SE 2.46), p = 0.03). Within the gout group, there was an inverse correlation between FMD and sUA (R = - 0.5, p = 0.003), and between FMD and hsCRP (R = - 0.42, p = 0.017), but not between NMD and sUA or hsCRP. Compared with healthy controls, subjects with gout have reduced arterial function. Individual comorbidities are insufficient to account for differences between gout and control groups, but multiple comorbidities may collectively contribute to impairment in endothelium-dependent arterial responsiveness. Endothelial impairment is also related to sUA and hsCRP, markers of gout severity and inflammation respectively. Studies to determine whether gout therapy may improve arterial responsiveness are warranted.

Tracheal inflammation, or tracheitis, is a pathologic process that can occur secondary to a number of systemic inflammatory diseases, or it may be idiopathic in nature. Regardless of the underlying etiology, tracheitis can, in its most severe form, be life-threatening, thus making its treatment an area of interest. Our case is one of a 50-year-old man with a remote history of inflammatory bowel disease achieving clinical cure following surgical resection who presented with progressive dyspnea due to tracheal stenosis that was presumed secondary to an autoimmune and inflammatory etiology. His disease was initially refractory to recurrent surgical interventions. He ultimately achieved clinical improvement with a combination of methotrexate and the tumor necrosis factor alpha (TNF-α) inhibitor, adalimumab. While both clinical trials and standardized treatment guidelines are lacking in this domain, this case illustrates a potential role for TNF-α inhibitors in the treatment of inflammatory tracheitis, irrespective of the underlying etiology.

Drug discovery and development (DDD) is an interdisciplinary enterprise that spans the translational continuum. Despite DDD's importance, formal training within medical and biomedical schools is lacking. In this tutorial, we outline the current educational landscape in DDD and the growing educational need in this area. Lastly, we describe the Health Innovations and Therapeutics concentration as an example of how to design and implement an educational program in DDD.