Faculty Bibliography

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.

INTRODUCTION: Pegloticase is a highly effective therapy for patients with refractory and/or tophaceous gout, but has a high discontinuation rate (30-50%) due to development of anti-drug antibodies causing loss of efficacy and risk of infusion reactions. OBJECTIVE: To describe the use of azathioprine or other immunosuppressive therapies as a pegloticase adjunct to prevent pegloticase immunogenicity when treating gout. METHODS: Case report of azathioprine use in a patient receiving pegloticase therapy for refractory tophaceous gout, and review of the literature for the impact of immunosuppressive agents on development of anti-drug antibodies. RESULTS: A 56-year-old man with severe refractory tophaceous gouty arthritis was placed on low-dose azathioprine (50mg daily) in combination with pegloticase, with successful treatment after 98 weeks illustrated by significant improvement of caliper-measured tophi (77% decrease), resolution of gouty attacks, maintenance of low serum urate (sUA) level, absence of infusion reactions, and good toleration of the treatment by the patient. Two transient increases in sUA (maximal sUA 1.0 and 6.2mg/dL, respectively), were associated with azathioprine non-compliance and resolved with azathioprine reinstitution. Literature review confirmed successful use of DMARDs for prevention of anti-drug antibodies to anti-TNF-alpha therapies in RA, spondyloarthropathies, and inflammatory bowel disease. Additionally, one open-label trial of pegloticase for refractory tophaceous gout included 7 organ transplant recipients on immunosuppressive medications (mycophenolate mofetil, cyclosporine, azathioprine, and/or tacrolimus), only one of whom (14%) was noted to experience treatment failure (anti-pegloticase antibodies and loss of urate-lowering efficacy without infusion reaction), versus 52% (n =12) of non-immunosuppressed subjects (n = 23). CONCLUSIONS: Low doses of oral immunosuppressive therapy may provide a safe, cost-effective adjunct to prevent the development of anti-drug antibodies associated with infusion reactions and high rate of pegloticase failure in patients with refractory gout. Controlled studies to assess an immunosuppressive strategy when using pegloticase 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.

BACKGROUND: While strong associations are seen between serum uric acid levels and gout and cardiovascular disease (CVD), few studies have assessed differences between gout patients (pts) with and without CVD.
OBJECTIVE(S): To compare disease and comorbidity characteristics among gout pts with and without CVD, identifying differences in treatment patterns and healthcare utilization in a real-world cohort.
METHOD(S): Data were assessed from a survey of U.S. physicians and in-depth patient chart audits. Severity of gout was measured by physician global assessment, flares, organ/joint damage, and tophi. Type/dose of xanthine oxidase inhibitor, length of current treatment, sociodemographic factors, and physician type were identified. Multivariate and descriptive statistics described differences among pts with and without CVD and assessed urate-lowering therapy (ULT) use and gout disease control.
RESULT(S): 1159 patient charts were abstracted (738, CVD; 421, no CVD; 81% male; 38% >= 61 y; 71% white). Pts with CVD had longer duration of gout (52 vs. 34 mo; 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), severe gout (19% vs. 11%; P < 0.001), and more flares in the past 12 mo. (2.1% vs. 1.8%; P = 0.017). Time from gout diagnosis to start of ULT was delayed for those with CVD (24 vs. 16 mo.; P = 0.02), but these pts were more likely to be on ULT (83% vs. 59%; P < 0.001). Gout pts with CVD were more likely to have 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 pts with CVD were more likely to have an emergency department visit for gout in the past 12 mo. (12% vs. 7%; P = 0.003). Overall, ULT use was associated with better gout control. In a backward, stepwise logistic model in pts with CVD, those more likely be treated with ULT had organ/joint damage (odds ratio [OR] = 13.3), severe gout (OR = 1.5), or prostate disease (OR = 4.2), but these were not significant predictors for pts without CVD.
CONCLUSION(S): In this study, pts treated with ULT were more likely to have better gout control. Gout pts with CVD were more likely to be on ULT, despite delayed initiation of therapy. Given that gout pts with CVD were more likely to have additional comorbidities and more severe gout, the delay in treatment may be associated with the severity of disease in these pts. These data suggest that gout pts with CVD constitute a less healthy group in need of earlier, more aggressive therapy

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)

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)

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)