Faculty Bibliography

BACKGROUND:Gout, hyperuricemia, and cardiovascular disease (CVD) are prevalent conditions in the United States, and while they share common risk factors such as obesity, hypertension, hypercholesterolemia, and type 2 diabetes mellitus, relatively little is known about what patient and disease characteristics may link CVD with hyperuricemia and gout and how the presence of both diseases affects management decisions differently than for patients with gout alone. OBJECTIVE:To identify differences in patient characteristics, patterns of urate-lowering therapy (ULT) use, and gout control in gout patients with and without cardiovascular comorbidity. METHODS:Data were assessed from a survey of U.S. physicians who performed in-depth patient chart audits of their last 5 consecutive adult patients with confirmed gout as determined by the medical record and clinical notes. Comorbidities, gout symptoms, length of current treatment, sociodemographic factors, and physician type were identified from the chart review. Descriptive statistics and logistic regression described differences among patients with and without comorbid CVD and assessed ULT use and gout control. RESULTS:Of the 1,159 patient charts that were reviewed, 738 patients had CVD and gout, and 421 had gout alone. Patients with CVD had longer duration of gout (mean [SD] = 52 [68.2] vs. 34 [47.2] months; P < 0.001) and were more likely to have clinician-reported tophi (28% vs. 15%; P < 0.001), organ/joint damage (19% vs. 9%; P < 0.001), and more flares (2.1% vs. 1.8%; P = 0.017) in the previous 12 months. Time from gout diagnosis to start of ULT was delayed for those with CVD (mean [SD] = 24.3 [56.6] vs. 15.5 [33.2] months; P = 0.023), but these patients were more likely to be receiving ULT (83% vs. 59%; P < 0.001). Gout patients with CVD were more likely to have a variety of additional comorbidities than those without CVD, such as obesity (28% vs. 18%; P < 0.001), diabetes (26% vs. 12%; P < 0.001), osteoarthritis (25% vs. 11%; P < 0.001), chronic kidney disease (17% vs. 5%; P < 0.001), and prostate disease (males, n = 933; 10% vs. 2%; P < 0.001). Gout patients with CVD were more likely to have an emergency department visit (12% vs. 7%; P = 0.003) for gout in the previous 12 months. In patients with CVD, ULT use was associated with better gout control. CONCLUSIONS:Gout patients with CVD were more likely to have additional comorbidities, more gout-related symptoms, and a delay in initiating treatment, which may be associated with the greater severity of disease in these patients. These data suggest that gout patients with CVD may constitute a less healthy group in need of earlier, more aggressive therapy. DISCLOSURES/UNASSIGNED:This study was supported by AstraZeneca. Pillinger reports consultancies at AstraZeneca, SOBI, Crealta/Horizon; investigator-initiated grants from Takeda (closed 2016); and was an investigator on industry-sponsored clinical trials for Takeda. Klein is employed by AstraZeneca. At the time of this study, Baumgartner was employed by Ardea Biosciences, a wholly owned subsidiary of AstraZeneca and owns stock in AstraZeneca. Baumgartner and Morlock are consultants to Ardea Biosciences. Morlock reports consulting fees from Genentech, Ironwood Pharmaceuticals, Astellas, and Abbot Medical Optics outside of this study. Bangalore reports consultancies at Pfizer, Merck, Abbott Vascular, Medicines Company, AstraZeneca, and the National Heart, Lung, and Blood Institute. The authors did not receive any honoraria for this publication. Study concept and design were primarily contributed by Morlock, along with the other authors. Morlock collected the data, and data interpretation was performed by all the authors. All authors equally contributed to preparation and revision of the manuscript. Preliminary results from this study were presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2016; San Francisco, California; April 19-22, 2016.

BACKGROUND: To characterize the differences between women and men with gout. METHODS: We analyzed a US national cohort of gout patients cared for by rheumatologists. RESULTS: Compared with the 1012 men with gout, women with gout (n = 262) were older (71 vs. 61 years, p < 0.001) and had a greater burden of comorbid conditions (p < 0.001 for hypertension, diabetes, renal disease and obesity). Risk factors for gout differed with women more often taking diuretics (p < 0.001), while men more frequently had dietary triggers (p < 0.05). CONCLUSIONS: The profiles of women and men with gout are markedly different, suggesting a need to tailor treatment recommendations.

BACKGROUND: The aim of this study was to determine the association between neutrophil-lymphocyte ratio (NLR) and severity of lower extremity peripheral artery disease (PAD). METHODS: A retrospective chart review identified 928 patients referred for peripheral angiography. NLR was assessed from routine pre-procedural hemograms with automated differentials and available in 733 patients. Outcomes of interest were extent of disease on peripheral angiography and target vessel revascularization. Median follow-up was 10.4months. Odds ratio (OR) [95% confidence intervals] was assessed using a logistic regression model. RESULTS: There was a significant association between elevated NLR and presence of severe multi-level PAD versus isolated suprapopliteal or isolated infrapopliteal disease (OR 1.11 [1.03-1.19], p=0.007). This association remained significant even after adjustment for age (OR 1.09 [1.01-1.17], p=0.02); age, sex, race, and body mass index (OR 1.08 [1.00-1.16], p=0.046); and age, sex, race, body mass index, hypertension, diabetes mellitus, coronary artery disease, and creatinine (OR 1.07 [1.00-1.15], p=0.049). After additional adjustment for clinical presentation, there was a trend towards association between NLR and severe multi-level PAD (OR 1.07 [1.00-1.15], p=0.056), likely limited by sample size. In patients who underwent endovascular intervention (n=523), there was no significant difference in rate of target vessel revascularization across tertiles of NLR (1st tertile 14.8%, 2nd tertile 14.1%, 3rd tertile 20.1%; p=0.32). CONCLUSION: In a contemporary cohort of patients undergoing peripheral angiography with possible endovascular intervention, elevated NLR was independently associated with severe multi-level PAD. Larger studies evaluating the association between this inexpensive biomarker and clinical outcomes are warranted.

BACKGROUND: An independent association between gout and coronary artery disease is well established. The relationship between gout and valvular heart disease, however, is unclear. The aim of this study was to assess the association between gout and aortic stenosis. METHODS: We performed a retrospective case-control study. Aortic stenosis cases were identified through a review of outpatient transthoracic echocardiography (TTE) reports. Age-matched controls were randomly selected from patients who had undergone TTE and did not have aortic stenosis. Charts were reviewed to identify diagnoses of gout and the earliest dates of gout and aortic stenosis diagnosis. RESULTS: Among 1085 patients who underwent TTE, 112 aortic stenosis cases were identified. Cases and non-aortic stenosis controls (n=224) were similar in age and cardiovascular comorbidities. A history of gout was present in 21.4% (n=24) of aortic stenosis subjects compared with 12.5% (n=28) of controls (unadjusted OR 1.90, 95% CI 1.05-3.48, p=0.038). Multivariate analysis retained significance only for gout (adjusted OR 2.08, 95% CI 1.00-4.32, p=0.049). Among subjects with aortic stenosis and gout, gout diagnosis preceded aortic stenosis diagnosis by 5.8 +/- 1.6 years. The age at onset of aortic stenosis was similar among patients with and without gout (78.7 +/- 1.8 vs. 75.8 +/- 1.0 years old, p=0.16). CONCLUSIONS: Aortic stenosis patients had a markedly higher prevalence of precedent gout than age-matched controls. Whether gout is a marker of, or a risk factor for the development of aortic stenosis remains uncertain. Studies investigating the potential role of gout in the pathophysiology of aortic stenosis are warranted and could have therapeutic implications.

Gout is the most common crystal arthropathy and the leading cause of inflammatory arthritis. It is associated with functional impairment and, for many, a diminished health-related quality of life. Numerous studies have demonstrated the impact of gout and its associated conditions on patient morbidity and mortality. Unfortunately, gout remains under-diagnosed and under-treated in the general community. Despite major advances in treatment strategies, as many as 90% of patients with gout are poorly controlled or improperly managed and their hyperuricemia and recurrent flares continue. The introduction of novel urate-lowering therapies, new imaging modalities, and a deeper understanding of the pathogenesis of gout raise the possibility of better gout care and improved patient outcomes. Here, we spotlight recent advances in the diagnosis and management of gout and discuss novel therapeutics in gout treatment.

Objective The Rheumatology Research Foundation's Clinician Scholar Educator (CSE) Award is a 3 year career development award supporting medical education research while providing opportunities for mentorship and collaboration. Our objective was to document the individual and institutional impact of the award since its inception as well as its promise to strengthen the subspecialty of rheumatology. Methods All 60 CSE Award recipients were surveyed periodically. 56/60 (90%) of CSE awardees responded to requests for survey information which included post-award activities, promotions and further funding. Data was also collected from yearly written progress reports for each grant. Results Of the total CSE recipients to date, 48/60 (80%) are adult rheumatologists, 11/60 (18%) are pediatric rheumatologists and 1 is adult and pediatric. Two-thirds of survey respondents spend up to 30% of their total time in educational activities, and a third spend greater than 30%. 31/60 (52%) of CSE recipients have published a total of 86 medical education papers. 26/52 (50%) had received an academic promotion following the award. 11 awardees earned advanced degrees. Conclusions We describe the creation and evolution of a grant program from a medical subspecialty society foundation and the impact on producing education research, individual identity formation and ongoing support for educators. This community of rheumatology scholar educators now serves as an important resource at the national level for the American College of Rheumatology (ACR) and its membership. We believe that this grant may serve as a model for other medical societies that want to promote education scholarship and leadership within their specialties

Background/Purpose: Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and European Union at 200 mg daily dose in combination with a xanthine oxidase inhibitor (XOI) for treatment of hyperuricemia associated with gout in patients unable to achieve target serum uric acid on XOI (allopurinol or febuxostat) alone. Approval of lesinurad was based on three pivotal, placebo-controlled, 12-month phase III (core) studies evaluating lesinurad 200 mg (LESU200) and 400 mg (LESU400) in combination with XOI. Patients completing core studies were eligible to enter extension studies, continuing LESU+XOI at the same dose or randomized from placebo to LESU200 or LESU400 plus XOI. Methods: Renal-related and kidney stone safety data were pooled from core studies to compare LESU200+XOI and LESU400+XOI with XOI alone and from core studies + extension studies to evaluate the impact on renal safety of extended LESU+XOI treatment. Renal-related treatment-emergent adverse events (TEAEs) were a customized list of 36 preferred terms selected from the Medical Dictionary for Regulatory Activities (MedRA) Renal and Urinary Disorders System Organ Class (SOC), the Investigations SOC and the Acute Renal Failure MedRA Standardized MedRA Query (SMQ). Descriptive statistics are provided for patients receiving >1 dose of study medication. To adjust for varying treatment duration, TEAEs are expressed as exposure-adjusted incidence rates (EAIRs; subjects with events per 100 person-years). Results: In the core studies, EAIRs for any renal-related TEAE, serious renal-related TEAEs, and renal-related TEAEs leading to discontinuation were similar with XOI alone and LESU200+XOI and lower than with LESU400 +XOI (Table 1). Similar results were found for kidney stone and serious kidney stone TEAEs. The most common renal-related TEAE was increased serum creatinine (sCr). EAIRs for sCr elevations >1.5x baseline were higher with LESU+XOI than XOI alone (Table 1). Overall, 75% and 84% of sCr elevations in the XOI alone and LESU+XOI groups, respectively, were resolved at last study assessment; 75% and 66% resolved without interruption of medication. Exposure to extended LESU+XOI treatment in core+extension studies did not show an increase from core studies in EAIRs for any renal-related or kidney stone adverse event category (Table 2). Conclusion: Lesinurad at the approved dose of 200 mg once-daily combined with XOI demonstrated comparable rate of adverse events to XOI alone. There was no clinically relevant increase in these adverse events with the extension of treatment beyond 1 year. (Table presented)

Background/Purpose: Osteoarthritis (OA) etiopathogenesis includes an inflammatory component. Published reports indicate that synovial fluid urate levels, even in patients without gout, associate with OA prevalence/severity. Whether serum urate (sUA), the precursor for gout and a biomarker for cardiovascular and kidney disease, may serve as a biomarker to convey or predict OA risk is not known. We investigated whether sUA levels associate with knee OA radiographic severity and contrast MRI-measured quantitative synovial volume (SV), and whether sUA levels predict radiographic progression, in a gout-free knee OA cohort. Methods: We assessed sUA in 88 gout-free subjects who completed a 24-month prospective, natural history knee OA study. Subjects had symptomatic medial knee OA, met ACR knee OA criteria and had BMI <33 at study entry. sUA was measured (enzyme-colorimetry) in serum frozen and banked at baseline. At baseline and 24 months, patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiographs (SynaFlexerTM). Twenty-seven subjects additionally had a dynamic gadolinium-enhanced 3.0T knee MRI that was read for quantitative synovial volume (SV). A musculoskeletal radiologist, blinded to subject data, determined joint space width (JSW) and Kellgren-Lawrence (KL) grades at each time point. Joint space narrowing (JSN) was determined as JSW change from baseline to 24 months. Pearson's correlations, student's t-tests, one-way ANOVA with post hoc Tukey-Kramer tests, ROC and AUC curves were used in statistical analyses, as appropriate. Results: sUA correlated with JSN in both univariate (r=0.40, p<0.01) and multivariate analyses (adjusting for age, gender and BMI, r=0.28, p=0.010). There was a significant difference in mean JSN after dichotomization of sUA at 6.8mg/dL, the solubility point for serum urate, even after adjustment for age, gender and BMI (JSN [+/-SEM] of 0.90mm+/-0.20mm for sUA>6.8; JSN [+/-SEM] of 0.31mm+/-0.09mm for sUA<6.8, p<0.01). Baseline sUA distinguished progressors (JSN>0.2mm), and fast progressors (JSN>0.5mm), from non-progressors (JSN<0.0mm) in multivariate analyses (area under the receiver operating characteristic curve [AUC] 0.626, p=0.027; AUC 0.620, p=0.045, respectively). sUA also correlated with SV (r=0.44, p=0.0040), a possible marker of JSN, though this correlation did not persist after controlling for age, gender and BMI (r=0.13, p=0.562). Conclusion: In non-gout patients with knee OA, sUA levels predict JSN and may serve as a biomarker for OA progression. (Figure presented)

Background/Purpose: Gout is an independent risk factor for cardiovascular disease (CVD). Investigators studying the relationship between gout and CVD have focused on acute coronary outcomes, with limited evidence available regarding peripheral arterial function. Using high-resolution ultrasound imaging of the brachial artery, we examined endothelial and smooth muscle arterial function in gout subjects versus healthy controls. Methods: 34 untreated male gout subjects and 64 healthy control males were included. By enrollment criteria some gout subjects, but no healthy controls, had coronary artery disease (CAD) or diabetes, or were current smokers. Demographics and medical history were recorded. Participants underwent brachial artery flow-mediated dilation (FMD; arterial response to blood flow after transient interruption using a distal blood pressure cuff) and nitroglycerine-mediated dilation (NMD) to assess endothelium-dependent and independent arterial smooth muscle responsiveness, respectively. Dynamic ultrasound images were assessed by two independent observers, with results reported as percentage change in arterial diameter from baseline. Results: Compared with healthy controls, gout subjects had a higher prevalence of CAD (21% vs 0%, p<0.05), chronic kidney disease (76% vs 0, p<0.05), hypertension (71% vs 22%, p<0.05) and hyperlipidemia (50% vs 18%, p<0.05), but a similar low prevalence of diabetes (6% vs 0%, p=0.12). 29% of gout patients were current smokers (p vs control<0.05). Gout subjects were slightly older (58.9 vs 53.2 years, p<0.05), and significantly more gout patients were African American (44% vs 8%). Both FMD (2.20+/-3.12 vs 3.56+/-2.50, p=0.021) and NMD (16.69+/-9.01 vs 24.51+/-7.18, p=0.00002) were significantly reduced in the gout group vs controls. Gout nonsmokers, white gout patients, and gout patients lacking specific co-morbidities persisted in having decreased FMD and NMD compared with controls. Gout patients with versus without specific co-morbidities had similar degrees of impaired FMD and NMD. Analysis of the gout group showed an inverse Pearson correlation between FMD and CRP (R=-0.42, p=0.017), a trend for inverse Pearson correlation between FMD and serum urate (R=-0.31, p= 0.08); but no correlation between NMD and CRP or serum urate. Conclusion: Compared with healthy controls, patients with gout have reduced arterial function as measured by FMD and NMD. While the increased prevalence of comorbidities among gout patients may contribute to diminished arterial function, it appears to be insufficient to explain the endothelial and smooth muscle dysfunction observed. Hyperuricemia and chronic inflammation may contribute to endothelial dysfunction among gout patients, but do not appear to contribute to smooth muscle dysfunction. Whether appropriate gout therapy may improve FMD and NMD in gout patients remains to be determined. (Figure Presented)