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Treatment Update For Gout The Future is Now

Treatment Update For Gout The Future is Now. Scott R. Burg, D.O. Orthopaedic and Rheumatologic Institute Cleveland Clinic. Gout…in 1799…. Flare: Classic Description.

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Treatment Update For Gout The Future is Now

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  1. Treatment Update For GoutThe Future is Now Scott R. Burg, D.O. Orthopaedic and Rheumatologic Institute Cleveland Clinic

  2. Gout…in 1799…

  3. Flare: Classic Description The victim goes to bed and sleeps in good health. About two o’clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle, or instep. The pain is like that of a dislocation, and yet the parts feel as if cold water were poured over them . . . Now it is a violent stretching and tearing of the ligaments – now it is a gnawing pain, and now a pressure of tightening. So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of the bedclothes nor the jar of a person walking in the room. The night is spent in torture. Sydenham, 1683 Sydenham, T: The Works of Thomas Sydenham, London, New Sydenham Soc. 1850 (translation)

  4. Gout Defined As… The deposition of monosodium urate crystals (MSU) in tissues at physiologic pH

  5. What is Gout? Gout is a disorder of uric acid metabolism This is NOT just a disease of the joints! Characterized by: Hyperuricemia Attacks of acute arthritis Tophi around joints Joint destruction Renal Disease (Glomerular, Interstitial, Tubular) Dz Uric Acid Urolithiasis

  6. Untreated Gout May Lead to… Tophaceous masses of MSU crystals in cartilage and joints Renal stones Urate nephropathy

  7. Peripheral Structure Involvement vs Relative Sparing of Central Joints Attacks due in part to temperatures <37 C peripherally Resulting in reduced solubility of urate

  8. Total Population of Several Rheumatic Conditions in the United States 8.3 Million* 9 7.1 Million† 8 7 5.0 Million‡ 6 5 Total Population (Millions) 2.7 Million§ 4 1.3 Million‡ 3 2 1 0 Gout Activity-limiting Fibromyalgia Carpal Tunnel Rheumatoid Back Pain Syndrome Arthritis *Based on patient-reported data from NHANES 2007-2008. †Estimated from 1997 NHIS and 2005 US Census Bureau data. ‡Estimated from 2005 US Census Bureau data.§Based on 1988 NHIS data.

  9. Who May Be the Patient With Hyperuricemia and Gout? Comorbidities Demographics • Advanced age • Male • Postmenopausal women • Hypertension • Cardiovascular disease • Chronic kidney disease • Diabetes mellitus • Dyslipidemia • Metabolic syndrome Lifestyle Commonly Used Medications • Obesity (high BMI) • Diet rich in meat and seafood • High alcohol intake • Frequent consumption ofhigh-fructose corn syrup • Diuretics • Low-dose aspirin (eg, <325 mg) • Cyclosporine • Niacin

  10. Risk Factors for Gout (Continued) • Generic Overproducers • Some patients have unusual shunt mechanism that converts glycine directly to uric acid • HPRT deficiency • Lesch-Nyhan Syndrome • Gout and Mental Retardation in Children • X-linked • PRPP hyperactivity • G6PD deficiency • Autosomal recessive • Von Gierke’s type-1 glycogen storage disease

  11. Fructose Intake and Urate Excretion Dominant dietary source – high-fructose corn syrup (HFCS) High concentration of fructose causes rapid accumulation of AMP Increases the body pool of purines Lactic acid is a by-product of fructose metabolism Lactate decreases urate excretion HFCS Purine Catabolism Fructose Pyruvate Uric Acid AMP Lactate ATP Fructose 1-Phosphate

  12. Diagnosing Gout Abrupt onset of severe pain, swelling, and tenderness that reaches its maximum within just 6–12 hours, especially with overlying erythema, is suggestive of crystal inflammation though not specific for gout A presumptive diagnosis is reasonably accurate for typical presentations, such as recurrent podagra with hyperuricemia Demonstration of MSU crystals in synovial fluid or tophus provides definitive diagnosis

  13. Acute Flares Flares occur without warning and may: Produce extreme pain Last hours to weeks Limit mobility Monoarticular in ~90% of initial presentations; ~50% are podagra Over time, flares may occur more often Temporary reduction in sUA levels can occur during a gout flare, making sUA measurements during a flare unreliable Courtesy of Theodore Fields, MD.

  14. Gout Radiograph http://www.pathguy.com

  15. Intervals Between 1st & 2nd Acute Flares Majority experience second acute flare within 1 year of first gout flare 1-2 yrs 16% 2-3 yrs- 6% 3-5 yrs - 5% Within 1 yr 62% After 10 yrs - 4% No 2nd in more than 10 yrs - 7% Yu et al. Ann Int Med. 1961;55:179-192

  16. Recommendations From the 2012 American College of Rheumatology Guidelines for Management of Gout ACR recommends a comprehensive treatment plan for the management of gout, including both nonpharmacologic and pharmacologic approaches1,2 Patient education including diet and lifestyle modifications is recommended along with the following pharmacologic approaches for the management of gout1,2 Acute Gout Flares Gout Flare Prophylaxis Chronic Gout Management • Treat an acute gout flare with pharmacologic therapy (NSAIDs, corticosteroids, or colchicine) within 24 hours of onset2 • For gout attack prophylaxis, initiate low-dose colchicine or low-dose NSAIDs when initiating urate-lowering therapy (ULT)2 • Anti-inflammatory prophylaxis should be continued from initiation of ULT for the greater of2: • At least 6 months, or • Following achievement of target serum urate, for 3 months in patients without or 6 months in patients with tophi on physical exam • When initiating ULT, begin anti-inflammatory gout flare prophylaxis1 • Initiate first-line ULT, febuxostat or allopurinol, or if at least one of these is contraindicated or not tolerated, probenecid can be used to treat to sUA target of <6 mg/dL1 • sUA should be monitored regularly (every 2-5 weeks) during ULT titration, then every 6 months once target sUA is achieved1

  17. Management of Gout RESOLVE Acute Flare INITIATEUrate-loweringTherapy MAINTAIN Treatment to Control sUA Continue ULT to maintain sUA levelsand reduce therisk of future flares Treat with anti-inflammatory agents Target sUA<6 mg/dLwith ULT Continuing prophylaxisfor 6 months reduced the frequency of gout flares in a clinical study Initiate concomitant anti-inflammatory prophylaxis for prevention of mobilization flares Track sUA levels

  18. NSAIDS Indomethacin (Indocin) has usually been used Lots of GI Toxicity / Renal Toxicity 25mg TID May use other NSAIDS Don’t use aspirin, competes with uric acid for excretion in the kidneys

  19. Evidence for the Use of Concomitant Anti-Inflammatory Prophylaxis • Anti-inflammatories are used for both acute flares and prophylaxis • Anti-inflammatory prophylactic therapy reduces the risk of mobilization flares, but is not a chronic treatment • ACR guidelines, as well as medical consensus and clinical evidence, support the use of anti-inflammatory prophylaxis when initiating ULT • In a clinical study, using colchicine with ULT for 6 months decreased the frequency of gout flares * 2.0 Colchicine 0.6 mg twice daily (n=21) Placebo (n=22) 1.5 † Mean Number of Flares1 1.0 0.5 0.0 0–3 3–6 Time Interval, Months *P=0.022; †P=0.033.

  20. Corticosteroids Indications for Steroids in the Management of Acute Gouty Arthritis Co morbid medical illnesses CHF, HTN Renal Insufficiency Peptic Ulcer, GI Bleed Hepatic Insufficiency Chronic Alcoholism Bleeding diathesis Advanced Age Anticoagulant use Post Op NSAID Hypersensitivity Severe attacks refractory to NSAIDs/Colchicine

  21. Corticosteroids Methods Parenteral Oral Intra-articular Prednisone 1mg/kg PO as a single dose -OR- 20-40 mg PO QD taper by 5-10mg every 3 days until D/C Methylprednisolone 40 mg intra-articular single dose Triamcinolone 40 mg intra-articular as a single dose

  22. Colchicine Alkaloid obtained from autumn crocus Minimal effect on uric acid synthesis and excretion Prevents release of chemotactic factors and cytokines from neutrophils Binds to microtubules in neutrophils Major use is in acute gouty attacks 0.6mg - two initially, then one every 2 hours until pain is relieved, you have reached 6mg or diarrhea, nausea or vomiting develop IV Colchicine no longer available NSAIDS have largely replaced colchicine

  23. Colchicine is approved for 2 gout indications: Treatment of gout flares Prophylaxis of gout flares Colchicine is not an analgesic medication and should not be used to treat pain from other causes Colchicine, USP Overview

  24. Colchicine, USP Dosing Considerations Usage Dosing Renal or hepatic impairment ClCr ≥30 mL/min No dose adjustment Patients receiving dialysis Reduce dose Severe impairment Reduce dose Coadministration with CYP3A4 Reduce colchicine dose (eg, clarithromycin, ritonavir) or P-gp inhibitors (eg, cyclosporine) Renal or hepatic impairment AND Contraindicated, as Concurrent P-gp inhibitors or life-threatening or fatal strong inhibitors of CYP3A4 toxicity has been reported with colchicine in this setting

  25. Colchicine Pharmacokinetics in AGREE Trial 10 High-dose colchicine (4.8 mg total) Low-dose colchicine (1.8 mg total) Single-dose colchicine (0.6 mg total) 8 6 Concentration (ng/mL) 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours

  26. Colchicine, USP Dosing and Administration: Acute Flares Usage Dosing Treatment of gout flares: 1.2 mg at first sign of flare, then 0.6 mg 1 hour later. Maximum dose 1.8 mg over a 1-hour period; higher doses have not been found to be more effective

  27. Colchicine, USP Dosing and Administration: Prophylaxis Usage Dosing Prophylaxis of gout flares: For the prevention of mobilization flares, 0.6 mg once or twice daily; maximum dose 1.2 mg/day

  28. Colchicine, USP Effectively Reduced the Pain of Acute Gout Flares Percentage of responders based on target joint pain score at 24 hours post first dose • The primary endpoint was the proportion of patients who experienced at least 50% reduction in pain scores from baseline at 24 hours, without rescue medication 40 38%* † 33% 30 Percentage of responders 20 16% 10 0 Low-dose High-dose Placebo Colchicine, USP (n=74) colchicine (n=58) (n=52) * P=0.005 vs placebo; †P=0.034 vs placebo.

  29. Colchicine, USP Had a Lower Incidence of Gastrointestinal Adverse Events Treatment-emergent adverse events (AEs) occurring in ≥2% of patients in any treatment group 100 † High-dose colchicine (n=52) * Low-dose COLCRYS (n=74) 77 77 77 80 Placebo (n=59) 60 Percentage of patients 37 40 27 26 23 20 19 17 17 20 14 8 5 4 2 1 0 0 0 0 0 Any AE Any gastrointestinal Diarrhea Nausea Vomiting General disorders Severe diarrhea disorder and administration- site conditions

  30. Colchicine, USP Dose Adjustments for Coadministration With CYP3A4 Inhibitors

  31. Colchicine, USP Dose Adjustments for Coadministration With P-gp or Protease Inhibitors

  32. Principal Potential Adverse Events with Colchicine Used to Treat Acute Gout Common with Excess Oral Colchicine • GI • Diarrhea (sometimes severe) • Nausea • Vomiting • Abdominal cramps • Dehydration Most common with Overdose of Oral Colchicine • Bone marrow depression: nadir at 7 days • Neuropathy-myopathy, elevated CK, and weakness: onset can be in weeks Less Common with Severe Overdose of Oral Colchicine • CV • Cardiac toxicity • Arrhythmia • Vascular collapse • Hepatotoxicity • Alopecia

  33. Management of Gout RESOLVE Acute Flare INITIATEUrate-loweringTherapy MAINTAIN Treatment to Control sUA Continue ULT to maintain sUA levelsand reduce therisk of future flares Treat with anti-inflammatory agents Target sUA<6 mg/dLwith ULT Continuing prophylaxisfor 6 months reduced the frequency of gout flares in a clinical study Initiate concomitant anti-inflammatory prophylaxis for prevention of mobilization flares Track sUA levels

  34. Gout Treatment Acute Treat the Pain! NSAIDS Indocin, Ibuprofen, Naproxen NOT Asprin! COX-2 Colchicine Corticosteroids Chronic/Ongoing Decreased production Probenecid Sulfinpyrazone Increase excretion Allopurinol Febuxostat Do not use these drugs during acute attack since these therapies may initially exacerbate the condition

  35. FDA-ApprovedUrate-Lowering Agents Drug Action Dose Range First-Line (Uricostatic) Allopurinol Xanthine Oxidase 100-800 mg daily (decrease inhibitor dose in renal impairment) Febuxostat Xanthine Oxidase 40-80 mg daily inhibitor Second-Line (Uricostatic) Probenecid URAT1 and GLUT9 500-2000 mg daily (carefully inhibitor adjust dose to 3000 mg maximum) For Severe, Treatment-Refractory Disease (Uricostatic) Pregloticase IV Recombinant, 8 mg IV every 2 weeks PEGylateduricase

  36. Allopurinol Historically the drug of choice in treatment of chronic tophaceous gout Competitive inhibitor of xanthine oxidase Xanthine and hypoxanthine are more soluble and better excreted renally Metabolized to oxypurinol Oxypurinol accumulates—may be responsible for antigout effects Oxypurinol is not well absorbed orally Decreases serum and urinary uric acid levels

  37. Correlation Between Allopurinol Dose and Serum Urate 14 12 10 8 Serum Uric Acid Level (mg/dL) 6 4 2 0 0 2 4 6 8 Dose (mg/kg/day) Takada M, et al. J Clin Pharm Ther. 2005;30:407-412

  38. Velocity of Tophus Size Reduction Accelerates as Serum Urate Drops Below 4 mg/dL 8 6 Serum Urate (mg/dL) 4 Allopurinol Benzbromarone Combined 2 0 0.0 0.5 1.0 1.5 2.0 2.5 Velocity of reduction in Size of Index Tophus (mm/mo) Perez-Ruiz F, et al. Arthritis Rheum. 2002;47)4):356-360

  39. Dose Adjustment of Allopurinol According to Creatinine Clearance Does Not Provide Adequate Control of Hyperuricemia in Patients With Gout 100 80 P <0.01 60 Gout Subject Achieving SUA <6.0 mg/dL (%) 38 40 19.1 20 15 0 Lower than recommended Recommended Higher than recommended Dalbeth N, et al. J Rheumatol. 2006;33:1646-1650

  40. Drugs Potentially Affected by Allopurinol Therapy • Ampicillin/amoxicillin (~20% risk of ampicillin/amoxicillin-related rash) • Azathiprine* • Chlorpropamide • Cyclophosphamide • Dilantin • Dilantin • 6-Mercaptopurine* • Probenecid • Theophylline* • Vidarabine • Warfarin • ACE inhibitors (suspected) *Potential for severe toxicity by impairment of drug clearance via suppression of xanthine oxidase. Potential for drug-drug interaction is also highly significant with the xanthine oxidase inhibitor febuxostat. Becker M, et al. Arthritis and Allied Conditions, 14th ed. Philadelphia, PA. Lippincott, Williams and Wilkins’ 2001:2323.

  41. Allopurinol Hypersensitivity Syndrome (AHS), A Variant of Drug Reaction With Eosinophilla and Systemic Symptoms (DRESS) Symptoms Cutaneous rash 92% Fever 87% Renal dysfunction 85% Eosinophilia 73% Hepatitis 68% Leukocytosis 39% Death 21% Epidemiology Median dose 300 mg (200-900) Median therapy duration 3 weeks (1-30) Prior renal dysfunction 81% Asymptomatic hyperuricemia 50% Concomitant thiazide diuretic 40% The DRESS syndrome usually commences symptomatically 1 to 8 weeks after exposure to the responsible drug. The symptom complex can be severe. The classic combination is rash, fever, and major internal organ involvement (most commonly hepatitis, but also can include nephritis and pneumonitis). The most common drugs inducing the DRESS syndrome include allopurinol, carbamazepine, phenobarbitol, phenytoin, minocycline, dapsoen, and sulfonamides. Hande KR, et al. Am J Med. 1984;769(1):47-56

  42. Approximate Prevalance of the Human Leukocyte Antigen (HLA) Allele HLA-B*5801 in Various Geographic Regions of the World Unshaded areas represent regions where prevalence of the gene has not been determined. Middleton D, et al. Tissue Antigens. 2003;61(5):403-407

  43. Risk Factors for Allopurinol Hypersensitivity Reaction Risk Factor Reference(s) Recent initiation of allopurinol 1,2,3,4 Renal impairment 1,2,4,5,6,7 Diurectic therapy 1,2,5,6,7 HLA-B*5801 4,8 Allopurinol dose (positive association) 1,2,5,9 Allopurinol dose (negative association) 4,10,11 • Hande KR, et al. Am J Med. 1984;76:47-56 • Lupton GP, et al. J Am Acad Dermatol. 1979,1:365-374 • Singer JZ, et al. Arthritis Rheum. 1986;29:82-87 • Hung SI, et al. Proc Nat Acad Sci USA. 2005,102:4134-4139 • Arellano F, et al. Ann Pharmacother. 1993;27:337-343 • Lang PG Jr, South Med J. 1979,72:1361-1368 • Young JL Jr, et al. Arch Intern Med. 1974;134:553-558 • Zinch I, et al. Pharmacogenomics. 2011,12:1741-1749 • Perez-Ruiz F, et al. J Clin Rheumatol. 2005,11:129-133 • Dalbeth N, et al. J Rheumatol. 2006;33:1646-1650 • Vazquez-Mellado J, et al. Ann Rheum Dis. 2001;60:981-983 Dalbeth N, et al. Semin Dial. 2007;20:391-395; Zinch I, et al. Pharmacogenomics. 2011,12:1741-1749.

  44. Febuxostat and Allopurinol CH3 O H3C N NC CH3 S CO2H Febuxostat Allopurinol H Structure N N N HN O Tablet Formulation 40 mg or 80 mg 100 mg or 300 mg Dosing Range 40 mg-80 mg 100 mg-800 mg Dosing Frequency Once daily Once daily for ≤300 mg Divided doses for >300 mg Drug Elimination Primarily hepatic Primarily renal Dose adjustment in None Yes Patients with mild to moderate renal impairment

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