Faculty Bibliography

Background/Purpose : Several studies implicate gout and/or xanthine oxidase activity as risk factors for type 2 diabetes. However, no studies have directly evaluated the effect of the xanthine oxidase inhibition on type 2 diabetes development. We therefore assessed the impact of allopurinol use on diabetes incidence in a retrospective cohort study of Veterans' Affairs patients with gout. Methods : The New York Harbor VA Computerized Patient Record System was searched to identify patients with an ICD-9 code for gout also meeting at least 4 1977 American Rheumatology Association gout diagnostic criteria. Pharmacy records were reviewed, and subjects divided into subgroups based on >30 continuous days of allopurinol prescription, versus no allopurinol. Incident diagnoses of diabetes, defined as first hemoglobin A1c <= 6.5% or physician documentation, were identified during an observation period from January 1, 2000 through December 31, 2015. Categorical variables, including the primary endpoint, were analyzed utilizing Fisher's exact test. Continuous variables were analyzed using binomial regression and the Student's T test. Results : 1032 subjects were allopurinol users, and 485 subjects were allopurinol never-users. The average duration of allopurinol use was 48.4 months. There were significantly more Black subjects in the allopurinol group, whereas there were significantly more Asian subjects and subjects with chronic kidney disease in the non-allopurinol group. Over a mean 94.3 months of follow-up, there was no significant difference in diabetes incidence between the allopurinol and non-allopurinol groups (8.0/1000 person-years versus 11.3/1000 person-years, p=0.64). There was also no significant difference in diabetes incidence when subjects were analyzed by baseline serum urate level, colchicine use, allopurinol dose, extent of urate lowering with allopurinol or achieving target urate level. When stratified into quartiles by duration of allopurinol use, a significant difference was observed between diabetes incidence in the longest and shortest quartiles among subjects in the allopurinol cohort (7.3 per 1000 person-years versus 21.3 per 1000 person-years, p=0.007). Conclusion : In this study, allopurinol use was overall not associated with reduced diabetes incidence, but longer durations of allopurinol use may have been associated with decreased diabetes. Prospective studies may further elucidate the relationship between hyperuricemia, gout, xanthine oxidase activity and diabetes, and the potential impact of gout treatments on diabetes incidence. (Figure Presented )

Background/Purpose : Gout is a very prevalent condition associated with many metabolic and cardiorenal comorbidities. A few studies have investigated the comorbidity subtypes of gout patients by cluster analyses; however, such analyses have not yet been performed among Blacks nor confirmed in a general population cohort. As such the generalizability of these findings remains unknown. Thus, our objective was to identify gout subtypes based on comorbidities using cluster analysis among Black adults with gout in the US general population. Furthermore, we sought to compare these findings to that of White adults with gout. Methods : We used data from 371 Black and 656 White participants in the 2007-2016 cycle of the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of adults in the US with detailed clinical and physical examination data. Diagnosis of gout was based on survey of physician-or health professionaldiagnosed gout. We employed Ward's minimum variance method of clustering to group patients with gout into clusters (i.e., subtypes) based on distinct comorbidity patterns according to 8 variables: obesity, hypertension, diabetes, dyslipidemia (i.e., hypercholesterolemia and/or hypertriglyceridemia), coronary heart disease (CHD), heart failure (HF), chronic kidney disease (CKD), and non-alcoholic fatty liver disease (NAFLD). Results : Metabolic and cardiorenal comorbidities were prevalent among both Black and White participants with gout ( Table 1 ). Cluster analysis identified 5 comorbidity subgroups among Black patients with gout ( Table 2 ). All patients in Group 1 had dyslipidemia and hypertension. Group 2 had the highest proportion of patients with diabetes (95%), and nearly all patients with NAFLD belonged to this group. Group 3 consisted of patients with gout but few other comorbidities. All patients in Group 4 had CKD. Group 5 had the highest proportion of patients with CHD and HF. Cluster analysis among Whites also identified subgroups with isolated gout (Group 2) and dyslipidemia and hypertension (Group 1) ( Table 3 ). It also identified a subgroup that combined cardiac and renal disease (Group 5). Key differences among Whites was the presence of obese (Group 3) and hypertension only (Group 4) clusters, and the lack of a diabetes group. The higher prevalence of obesity in Blacks and the smaller number of Black participants likely contributed to these differences. Conclusion : These findings from a nationally representative sample of Black US adults identified 5 subgroups of gout based on comorbidities: dyslipidemia/HTN, diabetes, isolated gout, CKD, and heart disease. Notable differences from the European population and American White cohorts included the separation of CKD and cardiac disease and the absence of a group defined by obesity among US Blacks. Overall, these subgroups could be broadly classified as i) isolated gout, ii) dyslipidemia/hypertension, iii) obese or diabetes, and iv) cardiorenal disease (separately or together). These subgroups may shed light on pathophysiologic mechanisms that contribute to gout and have implications for personalized interventions to reduce the burden of gout and its comorbidities

Hyperuricemia is a common condition, and in a subset of patients leads to gout, the most common inflammatory arthritis. Osteoarthritis is the most common form of arthritis overall, and gout and osteoarthritis frequently coexist in the same patient. However, the relationship between the two remains poorly defined. More particularly, the impact of osteoarthritis on the development of gout, and the impact of gout on the development of osteoarthritis, remain to be determined. Additionally, whether hyperuricemia mediates osteoarthritis in the absence of gout is uncertain. Here, we review the evidence linking gout and osteoarthritis, with a special focus on the role of hyperuricemia in the presence or absence of gout. Since disease modifying agents are currently available for hyperuricemia and gout but not for osteoarthritis, a contributory role for urate in the pathogenesis of osteoarthritis could have important clinical implications.

OBJECTIVE:In vitro and clinical studies suggest that urate may contribute to osteoarthritis (OA) risk. We tested the associations between hyperuricemia and knee OA, and examined the role of obesity, using a cross-sectional, nationally representative dataset. METHOD/METHODS:National Health and Nutrition Examination Survey (NHANES) III used a multistage, stratified probability cluster design to select USA civilians from 1988 to 1994. Using NHANES III we studied adults >60 years, with or without hyperuricemia (serum urate > 6.8 mg/dL), excluding individuals with gout (i.e., limiting to asymptomatic hyperuricemia (AH)). Radiographic knee OA (RKOA) was defined as Kellgren-Lawrence grade ≥ 2 in any knee, and symptomatic radiographic knee osteoarthritis (RKOA) (sRKOA) was defined as RKOA plus knee pain (most days for 6 weeks) in the same knee. RESULTS:AH prevalence was 17.9% (confidence interval (CI) 15.3-20.5). RKOA prevalence was 37.7% overall (CI 35.0-40.3), and was 44.0% for AH vs 36.3% for normouricemic adults (p = 0.056). symptomatic radiographic knee osteoarthritis (sRKOA) was more prevalent in AH vs normouricemic adults (17.4% vs 10.9%, p = 0.046). In multivariate models adjusting for obesity, model-based associations between AH and knee OA were attenuated (for RKOA, prevalence ratio (PR) = 1.14, 95% CI 0.95, 1.36; for sRKOA, PR = 1.40, 95% CI 0.98, 2.01). In stratified multivariate analyses, AH was associated with sRKOA in adults without obesity (PR = 1.66, 95% CI 1.02, 2.71) but not adults with obesity (PR = 1.21, 95% CI 0.66, 2.23). CONCLUSIONS:Among adults aged 60 or older, AH is associated with knee OA risk that is more apparent in adults without obesity.

Background: The standard approach to monitor subjects with gout is to measure serum urate. The assumption is that the signs and symptoms of disease will improve if serum urate is maintained below the target level of 6 mg/dL. However, there has been little emphasis on whether lowering urate transiently would have a prolonged impact on the clinical manifestations of advanced gout.
Objective(s): Assess the clinical benefit in patients with advanced gout who had transient lowering of serum urate resulting from treatment with pegloticase, a pegylated recombinant uricase.
Method(s): A post hoc analysis was carried out using the results from two randomized controlled trials (RCTs) of 6 months duration to assess the efficacy of treatment with 8 mg of pegloticase every 2 weeks (q2w)1. Serum urate was measured before each infusion and the serum urate area under the curve (AUC) was calculated as described2 for the first and second three-month periods of time in the RCTs. The following clinical outcomes were assessed: gout flares, tophus reduction, patient global assessment (PtGA), tender and swollen joints (TJC and SJC), pain measured with a 100-mm visual analog scale (VAS) and a variety of patient reported outcomes (36-Item Short Form Health Survey [SF-36] Physical Component Score [PCS] and Arthritis-Specific Health Index Score [ASHIS]).
Result(s): The analysis included 85 subjects treated with q2w pegloticase and 43 patients who received placebo. Of the 85 pegloticase-treated subjects, 49 had only a transient decrease in serum urate owing to the development of anti-pegloticase antibodies. The mean length of time these subjects experienced a serum urate <6 mg/dL was approximately 6 weeks3. Despite the transient reduction in serum urate, the serum urate AUC for the first and second 3 months of the RCTs was significantly (p=0.008) decreased compared to placebo-treated subjects. However, it was significantly (p<0.0001) less reduced compared with those with persistent urate lowering throughout the 6 month RCTs (Table 1). Results for both the subjects with persistent and transient lowering of serum urate to <6 mg/dL indicated significant reduction in tophi and improvements from baseline in PtGA, TJC, SJC, pain, and ASHIS after 6 months of the RCT. No significant improvements were observed in the patients who received placebo.
Conclusion(s): A transient reduction in serum urate resulting from pegloticase therapy can result in significant clinical benefit lasting through the 6 months of the RCTs. These results suggest that transient lowering of urate can alter the trajectory of the clinical manifestations of advanced gout. Moreover, estimates of serum urate AUC may be more helpful in assessing the impact of urate lowering therapy than individual measurements of serum urate. (Table Presented)

OBJECTIVES/OBJECTIVE:To estimate the contemporary prevalences of gout and hyperuricemia and their decadal trends in the US, as well as the prevalence of urate-lowering therapy (ULT) use among gout patients, using data from the latest and prior nationally-representative samples of US men and women (National Health and Nutrition Examination Survey [NHANES] 2007-2016). METHODS:Using data from 5,467 participants from NHANES 2015-2016, we estimated the latest prevalence of gout and hyperuricemia. During the NHANES, all participants were asked about a history of health professional-diagnosed gout and medication use. Hyperuricemia was defined as a serum urate level >7.0 mg/dL in men and >5.7 mg/dL in women. We examined decadal trends in these estimates using data from the NHANES 2007-2016 and ULT usage trends using the NHANES 2007-14 (the latest data available to date). RESULTS:The prevalence of gout was 3.9% (9.2 million) among US adults in 2015-2016 (5.2% [5.9 million] and 2.7% [3.3 million] among men and women, respectively). Mean serum urate levels were 6.0 mg/dL among men and 4.8 mg/dL among women, with hyperuricemia prevalences of 20.2% and 20.0%, respectively. The prevalences of gout and hyperuricemia remained stable over the past decade (P for trend >0.05). The prevalence of ULT use among patients with gout was 33% during 2007-2014 and remained stable over time (P for trend >0.05). CONCLUSION/CONCLUSIONS:In this nationally-representative sample of US adults, the prevalences of gout and hyperuricemia remain substantial albeit unchanged over the past decade. Despite this burden, only one-third of gout patients are receiving ULT.

To the Editors: We agree with Drs. Choi, et al, and their insightful analysis of the limitations of the CARES trial. [1] They point out that the dropout rate for the study was nearly 60%, and that when a post-hoc analysis included data on as many dropped-out patients as could be identified, the adverse CV signal for febuxostat was no longer significant. Additionally, most of the CV events (and deaths) occurred after drug discontinuation, making it difficult to impute causation.

INTRODUCTION/BACKGROUND:Autoimmune hepatitis (AIH) is a cause of chronic liver disease. It is usually suspected based on clinical presentation and laboratory findings, but the diagnosis relies on the presence of specific autoantibodies and characteristic histology. Other unexplained findings should always prompt investigation for coexisting syndromes. CASE PRESENTATION/METHODS:The patient is a 60-year-old Hispanic female with a history of mild asthma presented with exertional and pleuritic chest pain with weight loss, arthralgia, subjective fever, and night sweats for the last 3 months. Given the nonspecific nature of the presentation, further workup was pursued. Laboratory results indicated pancytopenia, elevated INR, and positive autoimmune panel including ANA, anti-chromatin, anti-histone, and rheumatoid factor as well as abnormal C3 and C4. Subsequent liver biopsy with interface hepatitis lead to a diagnosis of AIH with concurrent systemic lupus erythematosus suspected. CONCLUSION/CONCLUSIONS:The diagnostic work up for AIH is multimodal and aims to differentiate other etiologies such as congestive hepatopathy, iron overload, viral hepatitis, and other autoimmune liver diseases. In this particular case, unusual clinical and laboratory findings led to diagnosis of the overlap syndrome. Treatment for both was necessary to prevent further progression of disease.