Faculty Bibliography

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.

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.

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.

Objective/UNASSIGNED:Lesinurad (LESU) is a selective urate reabsorption inhibitor approved at 200 mg daily for use with a xanthine oxidase inhibitor (XOI) to treat hyperuricaemia in gout patients failing to achieve target serum urate on XOI. The aim of the study was to investigate the long-term safety of LESU + XOI therapy. Methods/UNASSIGNED:Safety data were pooled from three 12-month phase III (core) trials evaluating LESU 200 and 400 mg/day combined with an XOI (LESU200+XOI and LESU400+XOI), and two 12-month extension studies using descriptive statistics. To adjust for treatment duration, treatment-emergent adverse events (TEAEs) were expressed as exposure-adjusted incidence rates (patients with events per 100 person-years). Results/UNASSIGNED:In the core studies, exposure-adjusted incidence rates for total and total renal-related TEAEs were comparable for XOI alone and LESU200+XOI but higher with LESU400+XOI. Exposure-adjusted incidence rates for serum creatinine (sCr) elevations ⩾1.5×baseline were 2.9, 7.3 and 18.7, respectively. Resolution (sCr ⩽1.2×baseline) occurred in 75-90% of all events, with 66-75% occurring without any study medication interruption. Major adverse cardiovascular events were 3, 4 and 9 with XOI, LESU200+XOI and LESU400+XOI, respectively. Longer exposure in core+extension studies did not increase rates for any safety signals. Conclusion/UNASSIGNED:At the approved dose of 200 mg once-daily combined with an XOI, LESU did not increase renal, cardiovascular or other adverse events compared with XOI alone, except for sCr elevations. With extended exposure in the core+extension studies, the safety profile was consistent with that observed in the core studies, and no new safety concerns were identified.

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