Faculty Bibliography

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.

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.

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.

PURPOSE OF REVIEW/OBJECTIVE:Gout is associated with the risk of cardiovascular morbidity and mortality, but the biological relationship between the two remains uncertain. The demonstration of reduction of cardiovascular risk with appropriate gout treatment would argue for a causal role for gout in cardiovascular disease. We reviewed recent studies that address the relationship between gout and cardiovascular disease. RECENT FINDINGS/RESULTS:Studies are conflicting; some show that lowering serum uric acid levels leads to better cardiovascular outcomes, whereas others show no such benefit. Inconsistencies in study design may contribute to these variations in outcome. Additionally, different gout treatment strategies may affect cardiovascular outcomes differently. SUMMARY/CONCLUSIONS:Despite an abundance of data generated in the last 5 years, it remains unclear whether treating gout with urate-lowering therapy provides a cardiovascular benefit. Additionally, further studies are needed to clarify whether different urate-lowering drugs confer different cardiovascular risks or benefits. Nonurate-lowering agents used for gout or commonly used in gout patients, such as colchicine and statins, may also improve cardiovascular outcomes in this population.

OBJECTIVES/OBJECTIVE:Gout patients with chronic kidney disease (CKD) accumulate the active allopurinol metabolite oxypurinol, suggesting that allopurinol may promote greater serum urate (sU) lowering in CKD patients. METHODS:We identified all patientswith gout diagnoses on either 100 mg or 300 mg of allopurinol daily, with available pre- and on-treatment sU levels, in our system in a 1-year period. Mean sU decrement by dosing per CKD groups was determined by CKD stage. RESULTS:Of 1,288 subjects with gout, 180 met entry criteria, with 83 subjects receiving 100 mg and 97 receiving 300 mg allopurinol. Subjects with CKD stage 1 experienced less sU lowering with 100 mg than 300 mg of allopurinol. Subjects with stage 4 and 5 CKD had equivalent sU decreases across the 100 mg and 300 mg allopurinol groups. However, the 100 mg group started at a higher pre-treatment sU and ended at a higher final sU than the 300 mg group. CONCLUSIONS:The strategy of titrating allopurinol to sU in patients with kidney impairment may result in greater sU lowering at lower doses than in patients without CKD but may also pose a treatment challenge from a possible drug ceiling effect.

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.

Mini-sabbaticals are formal short-term training and educational experiences away from an investigator's home research unit. These may include rotations with other research units and externships at government research or regulatory agencies, industry and non-profit programs, and training and/or intensive educational programs. The National Institutes of Health have been encouraging training institutions to consider offering mini-sabbaticals, but given the newness of the concept, limited data are available to guide the implementation of mini-sabbatical programs. In this paper, we review the history of sabbaticals and mini-sabbaticals, report the results of surveys we performed to ascertain the use of mini-sabbaticals at Clinical and Translational Science Award hubs, and consider best practice recommendations for institutions seeking to establish formal mini-sabbatical programs.