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Low-Dose Allopurinol Promotes Greater Serum Urate Lowering in Gout Patients with Chronic Kidney Disease Compared with Normal Kidney Function
Toprover, Michael; Crittenden, Daria B; Modjinou, Dodji V; Oh, Cheongeun; Krasnokutsky, Svetlana; Fisher, Mark C; Keenan, Robert T; Pillinger, Michael H
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.
PMID: 31140959
ISSN: 2328-5273
CID: 3921572
Autoimmune Hepatitis A Case Report and Literature Review
Hong, Annie S; Desta, Muuz; Hong, Jenny M; Ohning, Gordon V; Pillinger, Michael H; Saxena, Amit; Modjinou, Dodji V
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.
PMID: 31128586
ISSN: 2328-5273
CID: 3921202
Gout and cardiovascular disease: crystallized confusion
Abeles, Aryeh M; Pillinger, Michael H
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.
PMID: 30601229
ISSN: 1531-6963
CID: 3563412
Come from away: Best practices in mini-sabbaticals for the development of young investigators: a White Paper by the SEQUIN (mini-Sabbatical Evaluation and QUality ImprovemeNt) Group
Pillinger, Michael H; Lemon, Stephenie C; Zand, Martin S; Foster, P Jeffrey; Merchant, Jeanne S; Kimberly, Robert; Allison, Jeroan; Cronstein, Bruce N; Galeano, Claudia; Holden-Wiltse, Jeanne; Trayhan, Melissa; White, Robert J; Davin, Amanda; Saag, Kenneth G
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.
PMCID:6676495
PMID: 31402988
ISSN: 2059-8661
CID: 4038752
Acide urique et arthrose : données en faveur d'une relation réciproque
Neogi, Tuhina; Krasnokutsky, Svetlana; Pillinger, Michael H.
SCOPUS:85076470808
ISSN: 1169-8330
CID: 4248312
Integrated safety studies of the urate reabsorption inhibitor lesinurad in treatment of gout
Terkeltaub, Robert; Saag, Kenneth G; Goldfarb, David S; Baumgartner, Scott; Schechter, Bruce M; Valiyil, Ritu; Jalal, Diana; Pillinger, Michael; White, William B
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.
PMID: 30124941
ISSN: 1462-0332
CID: 3246302
Limitations in assessing cardiovascular risk of febuxostat in patients with gout and cardiovascular morbidities: comment on the article by Choi et al [Letter]
Abeles, A M; Pillinger, M H
EMBASE:627259871
ISSN: 2326-5191
CID: 3825212
Febuxostat and Cardiovascular Events: A Systematic Review and Meta-Analysis
Cuenca, John A; Balda, Javier; Palacio, Ana; Young, Larry; Pillinger, Michael H; Tamariz, Leonardo
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.
PMCID:6378016
PMID: 30863448
ISSN: 1687-9260
CID: 3733152
Effect of colchicine on diabetes incidence among gout patients in a veterans' affairs population [Meeting Abstract]
Slobodnick, A; Pike, V; Toprover, M; Pillinger, M
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
EMBASE:626436156
ISSN: 2326-5205
CID: 3704532
Prevalence of urate-lowering therapy use and target urate level achievement among gout patients in the United States (national health and nutrition examination survey [NHANES] 2007-2014) [Meeting Abstract]
Chen-Xu, M; Yokose, C; Pillinger, M; Choi, H K
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)
EMBASE:626437271
ISSN: 2326-5205
CID: 3704862