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Nevada Chapter ACP Scientific Meeting 2013 Mitchell D. Forman, D.O., FACR, FACP, FACOI Dean & Professor Touro University Nevada College of Osteopathic

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Text of Nevada Chapter ACP Scientific Meeting 2013 Mitchell D. Forman, D.O., FACR, FACP, FACOI Dean &...

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  • Nevada Chapter ACP Scientific Meeting 2013 Mitchell D. Forman, D.O., FACR, FACP, FACOI Dean & Professor Touro University Nevada College of Osteopathic Medicine Mitchell D. Forman, D.O., FACR, FACP, FACOI Dean & Professor Touro University Nevada College of Osteopathic Medicine
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  • Hyperuricemia as an Independent Risk Factor for Atherogenesis =
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  • Objectives Discuss the myths & realities regarding gout Discuss the factors associated with hyperuricemia & gout Review compelling data re: hyperuricemia & its strong association with hypertension, MI, stroke & CKD Reinforce an awareness that patients presenting with gout should be evaluated for other risk factors associated with ASCVD
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  • Uric Acid Intelligence Alzheimers Parkinsons Disease Gout Stone MI The Good The Bad The Ugly Tophi CVA
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  • Whats irrefutable?
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  • Epidemiology Gout most common form of inflam. arthritis in men > 40 yoa Prevalence of gout 2007-08 of 3.9% 12 million persons w G & H 10 yr inc of 45% > 80 yoa, inc 100% Uric acid levels have inc signif over last 80 yrs Inc sua is the most highly correlated lab value with the metab. syndrome Zhu Y, Pandya BJ, Choi HK. Prevalence of gout & hyperuricemia in the US general population: the National Health & Nutrition Exam Survey 2007-08. Arth. Rheum. 2011 Oct; 63 (10): 3136-41.
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  • Perfect Storm more severe & complex cases due to a convergence of factors Prevalence of HBP Use of diuretics Use of ASA Obesity Inc consumption of Beer Fructose Corn syrup Inc life expectancy Ability to keep pts alive with: CAD CHF DM CKD Lack of effective therapy Kuo CF, Yu KH, See LC, et al. Elevated risk of mortality among gout pts: a comparison with the national population in Taiwan. Joint Bone Spine. 2011 Dec;78(6):577-80. Keenan RT, OBrien WR, Lee KH, et al. Prevalence of contraindications & prescription of pharmacologic therapies fof gout. Am J Med. 2011 Feb;124(2):155-63.
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  • Uric Acid & Evolution UA is the end prod of purine metab in humans due to loss of uricase activities What are the evolutionary advantages of uric acid? Anti oxidant inc life expect BP control in times of low salt ingestion Intelligence Neurodegenerative protective effects
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  • Epidemiology: Disease Burden Gout is expensive cost & work days Tx failure gout (> 6 attacks/yr) = > $25,000 Added costs ER & clinic visits Hospitalizations Mngt of comorbidities Loss of productivity 81 pt, < 65 yoa, 1 yr workdays lost = 30 60 Lost days of social activities & self care Wu EQ, Forsythe A, Guerin A, Yu AP, et al. Comorbidity burden, healthcare resource utilization & costs in chronic gout pts refractory to convent. urate lowering therapy. Am J Ther. 2011 Feb 10. (Epub ahead of print). Edwards NL, Sundy JS, Forsythe A, et al. Work productivity loss due to flares in pts with chronic gout refractory to conventional therapy. J. Med Econ. 2011;14(1):10-5.
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  • Hyperuricemia & Gout Pathogenesis of hyperuricemia Overproduction (10%) HGPRTase /PRPP synthetase (1%) Increased purine intake Alcohol Myeloproliferative Disease Psoriasis Underexcretion (90%) renal defect, dec. GFR, diuretics, tubular toxins (alcohol, low dose ASA, cyclosporine), lead, hypothyroidism
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  • Clinical Course of Classical Gout Stage I Stage II Stage III Asymptomatic Acute Intermittent Arthritis Chronic Arthritis with Hyperuricemia Acute Exacerbations No Arthritis Acute Attacks 1-2 Weeks Intervals 2-10 Years Joints 1-2 Acute Attacks 1-3 Weeks Intervals 6 months 2 years Joints 1-2 Acute Attacks 1 Week 2 Months Intervals 2-3 Wks, 3-4 Mos. Joints 4-5 Tophi Bone & Cartilage Continuous Arthritis Acute Attacks Superimposed ? Asymptomatic Atherogenesis
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  • Acute Gouty Arthritis Abrupt onset of monoarthritis Episodic disease Sudden changes in uric acid levels are best predictor Classically 1 st attack is podagra Attacks polyarticular with time Needle shaped negatively birefringent MSU crystals Tophi indicative of chronic urate overload
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  • Oligoarthritis
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  • MSU Crystals Light Microscopy Polarized Microscopy Compensated Polarized Microscopy PGY
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  • CPPD MSU
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  • Management of Crystal Disease Clinical presentation Arthrocentesis dx & tx NSAIDs Colchicine Corticosteroids - p.o., i.v., ACTH Uric Acid Lowering Agents not during acute attacks!
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  • Indications for Urate Lowering Tophacheous disease with erosions Uric acid nephrolithiasis Recurrent attacks despite prophylaxis Prevent Acute cell lysis - e.g., chemo. Allopurinal or febuxostat contraindicated in acute gout but do not stop during an attack Not for mild or asymptomatic hyperuricemia?
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  • Pegloticase Mech of Action: recomb porcine-like uricase able to metabolize uric acid to allantoin. In contract to rasburicase, it is pegylated with inc elimination half life. Given by slow infusion q 2-4 wks. Indications: Chronic refractory gout, i.e., failure to normalize serum uric acid & continued signs & sx despite xanthine oxidase inhibitors @ max. med. approp dose or for whom these drugs are contraindicated. Doseage: 8 mg as a slow infusion q 2-4 wks mixed in 0.9 or 0.45 saline over 2 hrs
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  • Myth: Gout is common among men but rare among women Reality Increases substantially after menopause & rises with age In kidney, URAT1 responsible for reabsorbtion of uric acid from proximal tubule Estrogen has a direct effect on expression Enomoto et al. Nature. 2002; 417.
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  • Myth: The uric acid is normal, it cant be gout Reality 339 pts (2 studies) comparing tx with etoricoxib or indometh for acute gout 14% uric acid < 6.0 mg/dL at baseline 32% < 8.0 mg/dL during acute attack A change in uric acid is a better predictor of acute gout than inc sua Schlessinger et al. J Rheum 2009; 36(6).
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  • Whats more controversial?
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  • Hyperuricemia as an Independent Risk Factor for Atherogenesis =
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  • Dr. Nathan Smith Davis 1887 AMA Address High arterial tension in gout is due in part to uric acid or other toxic substances in the blood which increases the tonus of the renal arterioles
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  • How can I prove that Hyperuricemia is a risk factor for atherosclerosis? Uric Acid pathologically assoc with vascular damage & inflamm. Data that hyperuricemia is associated with CVD & premature death from MI & stroke Lowering uric acid levels associated with reduced risk
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  • Pathophysiology of Vascular Damage Due to Hyperuricemia
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  • Inflammatory Mediators
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  • Oxidative Stress Caused by an imbal. betw. the prod. of reactive O2 & a biological systems ability to detoxify the reactive intermed or easily repair the damage. Disturbances produce peroxides & free radicals Oxidative stress causes ROS ROS can be beneficial by attack & kill pathogens & in cell signaling Xanth oxidase, NADPH oxid & cytochr P450 can produce superoxides
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  • The Two Faces of Uric Acid
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  • Uric acid highest [ ] anti-oxidant in blood Provide > 50% of total anti-oxidant Anti-oxidant effect complex Doesnt react with some oxidants, e.g SO Effects in AS, CVA & MI? Protective (compens) rxn vs primary cause Acitivated by oxidative stress Metab derangements - Cu++ & Fe++
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  • Uric Acid: A new look at an old risk marker for CVD, metabolic syndrome & type 2 DM: The urate redox shuttle Role of UA, oxidative redox stress, reactive O 2 species, dec endothelial nitric oxide & endothelial dysfunction cannot be over emphasized In the pro oxidative environment, the antioxidant properties of UA paradoxically become pro oxidant This contributes to the oxidation of lipoproteins within atherosclerotic plaques Elev of uric acid > 4 mg/ml should be a red flag to the inc risk of CVD & espec in those at risk for CVD Hayden, MR & Tyagi SC. Nutrition & Metab. 2004; 1:10, 1 - 15
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  • Mechanisms of vascular damage in gout & oxalosis: crystal induced, granulocyte mediated, endothelial injury Immune triggered PMN endothelial interactions implicated in the pathogenesis of vascular disease MSU crystal treated sera stimulate PMN to adhere to & induce endothelial cell inflammatory factors Plts & PDGF play an active role in this process Boogaerts MA et al. Thromb Haemost. 1983 Aug 30;50(2):576-580.
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  • Uncontrolled hyperuricemia results in afferent arteriole with thick wall & small lumen (B). When urate normalized, arteriole thinner & the lumen larger (C).
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  • Uric Acid, Vascular Smooth Muscle Cell Proliferation & Inflammation Uric acid induces COX-2, TXA2 & PDGF A, which induces vasc. smooth muscle cell proliferation 1 Soluble u.a. is pro inflammatory 2 Induces Mono. Chemoattract. Protein-1 MCP-1 is a chemokine important in vasc dx & atherosclerosis 3