Faculty Bibliography

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)

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: To date, most studies of gout and cardiovascular disease have been cross-sectional or retrospective, and have addressed the outcome of acute coronary syndromes. Less is known regarding the impact of gout on basic vascular health, including arterial endothelial function. We asked whether initiating gout treatment with colchicine and urate-lowering therapy (ULT) reduces inflammation (CRP), and improves endothelial function as measured by brachial artery flow-mediated dilation (FMD). Methods: Gout patients initiating treatment with their physicians were enrolled. Physicians agreed to follow a care strategy that sequenced colchicine and ULT (allopurinol or febuxostat) initiation. Demographics and cardiovascular risk factors were recorded, and CRP and FMD were measured at baseline, after 6 weeks of colchicine (0.6 mgs daily), and again 4 weeks after ULT had been titrated to clinical target (<6.0 mg/dL; <5.0 mg/dL for patients with tophi) in the presence of continuing colchicine. Results: 34 untreated male gout patients (mean age 57.9 years) were enrolled. To date, 32 have completed postcolchicine, and 22 have completed post-ULT assessments. CRP decline was observed from baseline to post-colchicine and further to post-ULT (total change from baseline, 0.207 mg/dL) (Figure). Overall we observed no net FMD improvement post-colchicine, but patients who experienced CRP reduction post-colchicine had higher rates of FMD improvement than CRP non-responders (58.8% versus 25.0% FMD response). We stratified the overall cohort based on smoking status, and observed greater rates of post-colchicine improvement in both FMD and CRP in the non-smoker, compared with the smoker group. FMD improvement occurred in 60.0% of non-smokers versus 38.1% of smokers; CRP improved in 75% of non-smokers versus 52.4% of smokers. Non-smokers with CRP improvement were also more likely than non-smoker CRP non-responders to demonstrate FMD improvement (66.7% versus 50% response rate). Baseline to post-ULT trends in CRP improvement were also more pronounced in the non-smoker group, with 75% of non-smokers versus 56% of smokers experiencing a CRP decrease. Analysis of FMD outcomes in patients post-ULT is ongoing. Conclusion: This prospective observational pilot study suggests that treatment with colchicine and ULT is associated with an overall reduction in CRP. Among patients whose CRP declined, FMD also tended to improve, suggesting a common beneficial effect. Smoking appears to hinder improvement in inflammation and vascular function in response to colchicine and ULT. Data from the third and final (ULT) stage of the study are still being collected with analyses ongoing. Larger and longer studies may be warranted to confirm the anti-inflammatory and pro-vascular benefits of colchicine and ULT in patients undergoing gout treatment initiation. (Figure presented)

Osteoarthritis (OA), the most common type of arthritis worldwide, is a degenerative disease of diarthrodial joints resulting in pain, reduced quality of life, and socioeconomic burden. Gout, the most common form of inflammatory arthritis, is a consequence of persistently elevated levels of urate and the formation of proinflammatory monosodium urate crystals in joints. Clinicians have long noted a predilection for both diseases to occur in the same joints. In this review, we provide an overview into research elucidating possible biochemical, mechanical, and immunological relationships between gout and OA. We additionally consider the potential implications of these relationships for OA treatment.

OBJECTIVE: Osteoarthritis (OA) and gout have each been associated with increased cardiovascular disease (CVD), but their relative impact is unknown. We compared CVD rates among patients with gout versus patients with OA and no gout (OA-only). METHODS: We identified male patients at the VA New York Harbor Healthcare System with gout (with or without concur - rent OA) and with OA-only between August 2007 and August 2008. For each group, we collected baseline demographic data and CVD risk factors. The primary outcome was a composite index (CV4) of any diagnosis of coronary artery disease (CAD), angina, myocardial infarction (MI), or coro- nary bypass surgery (CABG). Secondary outcomes included individual diagnoses within the CV4, CHF, and death. We subsequently divided the gout patients into those who did versus did not have concurrent diagnoses of OA (gout-only; gout+OA). Logistic regression was used to compare the associations of OA-only, gout-only, and gout+OA with CV outcomes. RESULTS: 1,280 gout subjects met inclusion criteria (983 gout- only and 297 gout+OA), along with 1,231 OA-only subjects. Gout subjects overall had more CVD risk factors at baseline, including hypertension, hyperlipidemia, and chronic kidney disease, versus OA-only. Compared with OA-only, gout subjects overall had increased rates of all outcomes except MI. Both the gout-only and gout+OA subgroups also had increased risk for all outcomes except MI, and CABG in the case of gout+OA subjects. After adjusting for traditional CVD risk factors, both gout-only and gout+OA subjects continued to have increased risk for multiple CVD outcomes. Gout+OA did not impart ad- ditional risk over gout-only for any outcome studied. CONCLUSION: Our data suggest that gout is associated with higher risk of CVD compared with OA, and that OA does not impart any additive CVD risk to patients who also have gout. Significance and Innovations: * In our dataset, gout subjects both with and without con- comitant OA had more cardiovascular disease (CVD) risk factors at baseline, and higher prevalence of CVD outcomes, than patients with OA only. * After adjusting for traditional CVD risk factors, gout-only and gout+OA subjects continued to have increased rates of multiple CVD outcomes, suggesting an intrinsic CVD risk to the diagnosis of gout, compared with OA. * These observations underline that gout patients represent a group at increased CVD risk, for whom both rheumatic disease management and CVD prevention need to be addressed.

Background: Unlike for coronary artery disease, the association between neutrophil-lymphocyte ratio (NLR) and peripheral artery disease (PAD) has not been well established. The aim of this study was to determine the association between neutrophil-lymphocyte ratio and the severity of lower extremity peripheral artery disease. Methods: A retrospective chart review analysis identified 928 patients referred for peripheral angiography at a tertiary care center between December 2012 and June 2015. NLR was assessed from routine pre-procedural hemograms with automated differentials and available in 733 (79%) patients. Outcomes of interest included extent of disease on peripheral angiography and target vessel revascularization. Median follow-up was 10.4 months. Odds ratio (OR) [95% confidence intervals] was assessed using a logistic regression model. Results: There was a significant association between elevated NLR and the presence of severe multi-level PAD versus isolated suprapopliteal or isolated infrapopliteal disease (OR 1.42 [1.18-1.70], p=<0.001). This association between NLR and severe multi-level PAD remained significant even after adjustment for age (OR 1.31 [1.09-1.58], p=0.004); age, sex, race, and body mass index (OR 1.27 [1.05-1.5], p=0.015); and age, sex, race, body mass index, hypertension, diabetes, coronary artery disease, and creatinine (OR 1.25 [1.03-1.53], p=0.024). In patients who underwent endovascular intervention (n=523), there was no significant difference in the rate of target vessel revascularization on follow-up 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

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

The NYC Rheumatology Objective Structured Clinical Examination (NYC-ROSCE) is held annually to assess fellow competencies. We recently redesigned our OSCE to better assess subspecialty trainee communication skills and professionalism by developing scenarios in which the patients encountered were psychosocially or medically complex. The objective of this study is to identify which types of verbal and non-verbal skills are most important in the perception of professionalism in the patient-physician interaction. The 2012-2013 NYC-ROSCEs included a total of 53 fellows: 55 MD evaluators from 7 NYC rheumatology training programs (Hospital for Special Surgery-Weill Cornell (HSS), SUNY/Downstate, NYU, Einstein, Columbia, Mount Sinai, and North Shore/Long Island Jewish (NSLIJ)), and 55 professional actors/standardized patients participated in 5 stations. Quantitative fellow performance assessments were made on the following: maintaining composure; partnering with the patient; honesty; professionalism; empathy; and accountability. Free-text comments were solicited regarding specific strengths and weaknesses. A total of 53/53 eligible (100 %) fellows were evaluated. MD evaluators rated fellows lower for professionalism than did the standardized patients (6.8 +/- 0.6 vs. 7.4 +/- 0.8, p = 0.05), suggesting that physicians and patients view professionalism somewhat differently. Fellow self-evaluations for professionalism (6.6 +/- 1.2) were concordant with those of the MD evaluators. Ratings of empathy by fellows themselves (6.6 +/- 1.0), MD evaluators (6.6 +/- 0.7), and standardized patients (6.6 +/- 1.1) agreed closely. Jargon use, frequently cited by evaluators, showed a moderate association with lower professionalism ratings by both MD evaluators and patients. Psychosocially challenging patient encounters in the NYC-ROSCE permitted critical assessment of the patient-centered traits contributing to impressions of professionalism and indicate that limiting medical jargon is an important component of the competency of professionalism.

The cardioprotective mechanisms of colchicine in patients with stable ischemic heart disease remain uncertain. We tested varying concentrations of colchicine on platelet activity in vitro and a clinically relevant 1.8-mg oral loading dose administered over 1 h in 10 healthy subjects. Data are shown as median [interquartile range]. Colchicine addition in vitro decreased light transmission platelet aggregation only at supratherapeutic concentrations but decreased monocyte- (MPA) and neutrophil-platelet aggregation (NPA) at therapeutic concentrations. Administration of 1.8 mg colchicine to healthy subjects had no significant effect on light transmission platelet aggregation but decreased the extent of MPA (28 % [22-57] to 22 % [19-31], p = 0.05) and NPA (19 % [16-59] to 15 % [11-30], p = 0.01), platelet surface expression of PAC-1 (370 mean fluorescence intensity (MFI) [328-555] to 333 MFI [232-407], p = 0.02) and P-selectin (351 MFI [269-492] to 279 [226-364], p = 0.03), and platelet adhesion to collagen (10.2 % [2.5-32.6] to 2.0 % [0.2-9.5], p = 0.09) 2 h post-administration. Thus, in clinically relevant concentrations, colchicine decreases expression of surface markers of platelet activity and inhibits leukocyte-platelet aggregation but does not inhibit homotypic platelet aggregation.