Faculty Bibliography

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: 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: 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)

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

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.

BACKGROUND:Gout patients do not routinely achieve optimal outcomes related in part to suboptimal administration of urate lowering therapy (ULT) including first-line xanthine oxidase inhibitors allopurinol or febuxostat. Studies leading to the approval of febuxostat compared this agent to allopurinol in inappropriately low, fixed doses. We will compare allopurinol with febuxostat in gout using appropriately titrated doses of both agents and a "treat-to-target" strategy congruent with specialty guidelines. METHODS:We have planned and initiated the Veterans Affairs (VA) Cooperative Study Program (CSP) 594, Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study. This large double-blind, non-inferiority trial will enroll 950 gout patients randomized to receive allopurinol or febuxostat. Patients will be followed for a total of 72 weeks encompassing 3 distinct 24-week study phases. During Phase I (0-24 weeks), participants will undergo gradual dose titration of ULT until achievement of serum uric acid (sUA) <6.0 mg/dL or <5.0 mg/dL if tophi are present. Dose escalation will not be allowed during final three study visits of Phase 2 (24-48 weeks) and during Phase 3 (48-72 weeks). The primary study outcome is the proportion of participants experiencing at least one gout flare during Phase 3. Subsequent to the 72-week study, participants will be followed passively for up to 10 years after the study to assess long-term health outcomes. CONCLUSION/CONCLUSIONS:With its completion, the VA Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study will demonstrate the central role of gradual ULT dose escalation and a treat-to-target strategy in gout management.

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.

Colchicine is an ancient medication that is currently approved for the treatment of gout and FMF. However, colchicine has a wide range of anti-inflammatory activities, and studies indicate that it may be beneficial in a variety of other conditions. This paper reviews the evidence for the well-established use of colchicine in gout, as well as several other rheumatic diseases. In addition, we highlight the potential benefit of colchicine in cardiac disease, including coronary artery disease in patients both with and without gout.

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.