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.

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.

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.

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.

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/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: Many, but not all patients with chronic gout develop tophi, and the factors that govern tophus formation are not fully understood. Several studies have suggested impairment of renal function increases the risk for development of tophi, but others have not.
Method(s): This analysis addressed the relationship between estimated glomerular filtration rate (eGFR) and the presence of tophi in patients with chronic refractory gout, as well as effects of tophus resolution on eGFR using results from two randomized controlled trials of pegloticase in chronic gout patients.
Result(s): Overall, 73% of the 212 subjects in these trials had clinically apparent tophi at baseline and 27% did not. Subjects with tophi were significantly older than those without tophi (56.7 vs 51.9 years, P=0.034) and had a significantly longer disease duration (16.3 vs 11.7 years, P=0.0072). Subjects with tophi also had a significantly lower eGFR than those without tophi (59.8 vs 67.9 mL/min/1.73 m2, P=0.0495). Subjects with advanced renal disease were also more likely to have tophi. Persistent serum urate lowering and resolution of tophi in subjects treated with pegloticase had no significant effect on eGFR despite a significant decrease in the urinary uric acid:creatinine ratio.
Conclusion(s): These results indicate that chronic refractory gout patients may present with or without clinically apparent tophi and that there is a significant association between the presence of renal dysfunction measured by eGFR and the frequency with which chronic refractory gout patients manifested tophi. However, persistent serum urate lowering and tophus resolution had no significant effect on eGFR over the period of observation in this group of subjects

Background: Impaired renal function is a recognized comorbidity of gout and gouty tophi may be more frequent in those with renal dysfunction. It is not known however, whether the velocity of resolution of tophi in response to urate lowering therapy is affected by renal insufficiency.
Method(s): This analysis used results from two 6-month randomized controlled trials of pegloticase in patients with chronic refractory gout to address this issue. The velocity of tophus resolution was determined in 18 patients with chronic gout refractory to oral urate lowering therapy who responded to pegloticase administered at a dose of 8 mg every 2 weeks (q2w) with sustained serum urate reductions (<6 mg/dL) over 6 months. eGFR was determined at baseline and after 3 and 6 months of treatment. Tophi were photographed at baseline, 3, 4.5, and 6 months and measured using Computer-Assisted Photographic Evaluation technology. At baseline, the mean area of photographed tophi was 585.8 mm2.
Result(s): Complete resolution of all tophi photographed was achieved by 34.8% of the patients. Using linear regression analysis, the velocity of tophus resolution for all the patients was calculated to be 60.1 mm2 per month. There was no significant relationship between baseline eGFR and velocity of tophus resolution (p=0.5). In addition, there were no significant differences in the velocity of tophus resolution for patients with Stage 1 chronic kidney disease (CKD) vs Stage 2 CKD (P=0.7), Stage 3 CKD (P=0.9), or Stage 4 CKD (P=0.7).
Conclusion(s): The results from this analysis thus indicate that renal impairment does not compromise the ability of pegloticase to resolve tophi rapidly in patients who respond with sustained reductions in serum urate