Faculty Bibliography

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: 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)

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)

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.

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: 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: The relationship between gout and cancer remains unclear. Whereas some studies have reported possible anti-cancer benefits of uric acid and monosodium urate crystals, others have found an increased risk of cancer in gout patients. Our study aimed to clarify the relationship between gout and colon metaplasia, including cancer and polyps. Methods: We conducted a retrospective study of patients in a VA hospital system using two distinct approaches. To obtain a historical, cross-sectional view of colon cancer prevalence, we assessed the presence of physiciancoded diagnoses of colon cancer and/or polyps in gout patients, versus patients with osteoarthritis (OA) but no gout, with active records in our computerized patient record system (CPRS) between 2007 and 2008. Lung and prostate cancer prevalence were recorded for comparison. In the second approach, we included only patients with documented colonoscopy reports in CPRS, and performed a retrospective cohort study of colon cancer and polyp incidences in gout versus OA patients over a ten-year period (2001-2010). In addition, colon cancer and polyp incidences were compared between patients who had undergone screening versus diagnostic colonoscopy, those who used aspirin or NSAIDs and those who did not, and between gout patients who used allopurinol and/or colchicine and those who did not. Results: 1287 gout patients and 1287 OA patients were included. Gout and OA patients were similar in age, ethnicity, BMI and smoking history. Gout patients had a lower physician-coded prevalence of all colonic lesions (cancer or polyp: 1.8 versus 9.6%, p<0.001), and a lower prevalence of colon cancer (1.0 versus 1.9%, p<0.001), than OA patients (Figure A). Lung and prostate cancer were similar between the two groups. Among 581 gout patients and 598 OA subjects with documented colonoscopies, the ten-year incidence of colon cancer was lower in gout patients than in patients with OA (0.8 versus 3.7%, p=0.0008) (Figure B). This difference in colon cancer incidence remained significant after accounting for NSAID and/or aspirin use. Among gout patients, the use of colchicine and/or allopurinol, as well as the presence or absence of concomitant of OA, did not appear to influence colon cancer prevalence. Differences in colon cancer incidence were significant between gout and OA patients undergoing diagnostic colonoscopy (0.5% in gout patients versus 4.6% in OA patients, p<0.001) but not those undergoing screening colonoscopy (0.9% in gout patients versus 1% in OA patients, p=1.0). No protective effect of gout was observed for prostate or lung cancer. Conclusion: Patients with gout had decreased physician-reported prevalence, and colonoscopy-documented incidence of colon cancer compared to patients with OA, suggesting a possible protective effect of gout or a goutassociated clinical, epidemiological or genetic factor. (Figure Presented)

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.