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

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Presentation on theme: "Treatment Update For Gout The Future is Now Scott R. Burg, D.O. Orthopaedic and Rheumatologic Institute Cleveland Clinic."— Presentation transcript:

1 Treatment Update For Gout The 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 (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



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

10 Total Population of Several Rheumatic Conditions in the United States 8.3 Million * 7.1 Million † 5.0 Million ‡ 2.7 Million § 1.3 Million ‡ *Based on patient-reported data from NHANES † Estimated from 1997 NHIS and 2005 US Census Bureau data. ‡ Estimated from 2005 US Census Bureau data. § Based on 1988 NHIS data GoutActivity-limiting Back Pain FibromyalgiaCarpal Tunnel Syndrome Rheumatoid Arthritis Total Population (Millions)

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

12 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

13 AMP ATP Lactate Pyruvate Fructose 1- Phosphate 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 Fructose Uric Acid Purine Catabolism

14 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

15 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.



18 Gout Radiograph

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



22 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 approaches 1,2ACR recommends a comprehensive treatment plan for the management of gout, including both nonpharmacologic and pharmacologic approaches 1,2 Patient education including diet and lifestyle modifications is recommended along with the following pharmacologic approaches for the management of gout 1,2Patient education including diet and lifestyle modifications is recommended along with the following pharmacologic approaches for the management of gout 1,2 Treat an acute gout flare with pharmacologic therapy (NSAIDs, corticosteroids, or colchicine) within 24 hours of onset 2 Acute Gout Flares 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 of 2 : 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 Chronic Gout ManagementGout Flare Prophylaxis When initiating ULT, begin anti-inflammatory gout flare prophylaxis 1 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/dL 1 sUA should be monitored regularly (every 2-5 weeks) during ULT titration, then every 6 months once target sUA is achieved 1

23 Continuing prophylaxis for 6 months reduced the frequency of gout flares in a clinical study Management of Gout RESOLVE Acute Flare INITIATE Urate-lowering Therapy MAINTAIN Treatment to Control sUA Target sUA <6 mg/dL with ULT Treat with anti- inflammatory agents Initiate concomitant anti-inflammatory prophylaxis for prevention of mobilization flares Continue ULT to maintain sUA levels and reduce the risk of future flares Track sUA levels

24 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

25 Evidence for the Use of Concomitant Anti-Inflammatory Prophylaxis Colchicine 0.6 mg twice daily (n=21) Placebo (n=22) *P=0.022; † P= Mean Number of Flares 1 0–33–6 † * Time Interval, Months 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

26 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

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

28 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

29 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

30 Colchicine, USP Dosing Considerations UsageDosing Renal or hepatic impairment Cl Cr ≥30 mL/minNo dose adjustment Patients receiving dialysisReduce dose Severe impairmentReduce dose Coadministration with CYP3A4Reduce colchicine dose (eg, clarithromycin, ritonavir) or P-gp inhibitors (eg, cyclosporine) Renal or hepatic impairment ANDContraindicated, as Concurrent P-gp inhibitors orlife-threatening or fatal strong inhibitors of CYP3A4toxicity has been reported with colchicine in this setting

31 Colchicine Pharmacokinetics in AGREE Trial Hours Concentration (ng/mL) High-dose colchicine (4.8 mg total) Low-dose colchicine (1.8 mg total) Single-dose colchicine (0.6 mg total)

32 Colchicine, USP Dosing and Administration: Acute Flares UsageDosing 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

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

34 Colchicine, USP Effectively Reduced the Pain of Acute Gout Flares 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 * P=0.005 vs placebo; † P=0.034 vs placebo. Percentage of responders † Colchicine, USP (n=74) (n=52) (n=58) 38% * 33% 16% Percentage of responders based on target joint pain score at 24 hours post first dose Low-doseHigh-dose colchicine Placebo

35 Colchicine, USP Had a Lower Incidence of Gastrointestinal Adverse Events Treatment-emergent adverse events (AEs) occurring in ≥2% of patients in any treatment group Percentage of patients † * Any AEAny gastrointestinal disorder DiarrheaNauseaVomitingGeneral disorders and administration- site conditions Severe diarrhea High-dose colchicine (n=52) Low-dose COLCRYS (n=74) Placebo (n=59)

36 Colchicine, USP Dose Adjustments for Coadministration With CYP3A4 Inhibitors

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

38 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

39 Continuing prophylaxis for 6 months reduced the frequency of gout flares in a clinical study Management of Gout RESOLVE Acute Flare INITIATE Urate-lowering Therapy MAINTAIN Treatment to Control sUA Target sUA <6 mg/dL with ULT Treat with anti- inflammatory agents Initiate concomitant anti-inflammatory prophylaxis for prevention of mobilization flares Continue ULT to maintain sUA levels and reduce the risk of future flares Track sUA levels

40 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

41 FDA-Approved Urate-Lowering Agents DrugActionDose Range First-Line (Uricostatic) AllopurinolXanthine Oxidase mg daily (decrease inhibitordose in renal impairment) FebuxostatXanthine Oxidase40-80 mg daily inhibitor Second-Line (Uricostatic) ProbenecidURAT1 and GLUT mg daily (carefully inhibitoradjust dose to 3000 mg maximum) For Severe, Treatment-Refractory Disease (Uricostatic) Pregloticase IVRecombinant,8 mg IV every 2 weeks PEGylated uricase

42 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

43 Correlation Between Allopurinol Dose and Serum Urate Takada M, et al. J Clin Pharm Ther. 2005;30: Dose (mg/kg/day) Serum Uric Acid Level (mg/dL)

44 Velocity of Tophus Size Reduction Accelerates as Serum Urate Drops Below 4 mg/dL Perez-Ruiz F, et al. Arthritis Rheum. 2002;47)4): Allopurinol Benzbromarone Combined Velocity of reduction in Size of Index Tophus (mm/mo) Serum Urate (mg/dL)

45 Dose Adjustment of Allopurinol According to Creatinine Clearance Does Not Provide Adequate Control of Hyperuricemia in Patients With Gout Dalbeth N, et al. J Rheumatol. 2006;33: Lower than recommended RecommendedHigher than recommended Gout Subject Achieving SUA <6.0 mg/dL (%) P <

46 Drugs Potentially Affected by Allopurinol Therapy Ampicillin/amoxicillin (~20% risk of ampicillin/amoxicillin- related rash) Azathiprine* Chlorpropamide Cyclophosphamide 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, 14 th ed. Philadelphia, PA. Lippincott, Williams and Wilkins’ 2001:2323.

47 Allopurinol Hypersensitivity Syndrome (AHS), A Variant of Drug Reaction With Eosinophilla and Systemic Symptoms (DRESS) Hande KR, et al. Am J Med. 1984;769(1):47-56 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. Symptoms Cutaneous rash92% Fever87% Renal dysfunction85% Eosinophilia73% Hepatitis68% Leukocytosis39% Death21% Epidemiology Median dose300 mg ( ) Median therapy duration3 weeks (1-30) Prior renal dysfunction81% Asymptomatic hyperuricemia50% Concomitant thiazide diuretic40%

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

49 Risk Factors for Allopurinol Hypersensitivity Reaction Dalbeth N, et al. Semin Dial. 2007;20: ; Zinch I, et al. Pharmacogenomics. 2011,12: Hande KR, et al. Am J Med. 1984;76: Lupton GP, et al. J Am Acad Dermatol. 1979,1: Singer JZ, et al. Arthritis Rheum. 1986;29: Hung SI, et al. Proc Nat Acad Sci USA. 2005,102: Arellano F, et al. Ann Pharmacother. 1993;27: Lang PG Jr, South Med J. 1979,72: Young JL Jr, et al. Arch Intern Med. 1974;134: Zinch I, et al. Pharmacogenomics. 2011,12: Perez-Ruiz F, et al. J Clin Rheumatol. 2005,11: Dalbeth N, et al. J Rheumatol. 2006;33: Vazquez-Mellado J, et al. Ann Rheum Dis. 2001;60: Risk FactorReference(s) Recent initiation of allopurinol1,2,3,4 Renal impairment1,2,4,5,6,7 Diurectic therapy1,2,5,6,7 HLA-B*58014,8 Allopurinol dose (positive association)1,2,5,9 Allopurinol dose (negative association)4,10,11

50 Febuxostat and Allopurinol N H N N HN O NC O S N CH 3 CO 2 H CH 3 H3CH3C FebuxostatAllopurinol Structure Tablet Formulation40 mg or 80 mg100 mg or 300 mg Dosing Range40 mg-80 mg100 mg-800 mg Dosing FrequencyOnce dailyOnce daily for ≤300 mg Divided doses for >300 mg Drug EliminationPrimarily hepaticPrimarily renal Dose adjustment in NoneYes Patients with mild to moderate renal impairment

51 Febuxostat Overview Febuxostat is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout Febuxostat is not recommended for the treatment of asymptomatic hyperuricemia Febuxostat may reduce elevated sUA in chronic gout patients who: - -Have sUA >6 mg/dL on existing therapy - -Are still flaring - -Have mild to moderate renal impairment * There are insufficient data in severe renal impairment (Cl Cr <30 mL/min). Caution should be exercised in those patients. Febuxostat is contraindicated in patients being treated with azathioprine or mercaptopurine.

52 Febuxostat Dosing and Administration An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including Febuxostat. If a gout flare occurs during treatment, Febuxostat need not be discontinued. UsageDosing 40 mg is the recommended starting doseOnce daily 80 mg is the recommended if sUA < 6 mg/dL is not achieved after 2 weeks with 40 mg dose Once daily Upon initiation of treatment, prophylaxis with and NSAID or colchicine may be beneficial Up to 6 months

53 Febuxostat Dosing Considerations – Warfarin – Hydrochlorothiazide – Colchicine –Naproxen –Indomethacin –Desipramine Special ConsiderationsDose Adjustment Febuxostat can be used in patients with mild 0 to moderate renal or hepatic impairment Febuxostat can be used in patients receiving 0 certain common medications

54 Febuxostat Efficacy: APEX, Fact, and Confirms 42% (n=610/145) Allopurinol 300/200 mg (n=242) Allopurinol 300 mg 36% (n=253/10) Allopurinol 300/100 mg 39% (n=253) Febuxostat 80 mg 72%* (n=249) Febuxostat 80 mg 74%* (n=756) Febuxostat 80 mg 67%* † (n=757) Febuxostat 40 mg 45% Proportion of Patients With sUA <6 mg/dL at Final Visit APEX (6 months) FACT (1 year) Patients, % CONFIRMS (6 months) *P<0.001 vs allopurinol; † P<0.001 vs Febuxostat 40 mg.

55 Confirms Efficacy in Patients With Mild to Moderate Renal Impairment *P≤0.05 vs allopurinol. Proportion of Patients With Mild to Moderate Renal Impairment with sUA <6 mg/dL at Final Visit Patients, % Confirms (6 months) (n=479) Febuxostat 40 mg 50%* (n=503) Febuxostat 80 mg 72%* (n=356/145) Allopurinol 300/200 mg 42% Renal impairment was defined as baseline estimated Cl Cr ≥30 mL/min and <90 mL/min.

56 Adverse Reactions Summary: Physician-Reported *At a ≥0.5% greater rate than with placebo. PlaceboFebuxostatFebuxostatAllopurinol Adverse Reactions40 mg80 mg300/200/100 mg (≥1% of Patients*)(n=134)(n=757)(n=1,279)(n=1,277) Liver Function0.7%6.6%4.6%4.2% Abnormalities Nausea0.7%1.1%1.3%0.8% Arthralgia0%1.1%0.7%0.7% Rash0.7%0.5%1.6%1.6%

57 Probenecid ColBenemid Inhibits tubular reabsorption of filtered urate in kidney Controls hyperuricemia and prevents tophus formation Salicylates interfere with action Use caution with decreased renal function Can impair renal secretion of : - -Sulfinpyrazone, - -Sulfonylureas - -Indomethacin - -Penicillin - -Sulfonamides

58 Drugs Potentially Affected by Probenecid Therapy Ampicillin Penicillin Nafcillin Cephradine Cephaloridin Salicylates Indomethacin Heparin Dapsone Methotrexate Rifampicin

59 Uricase Enzymes Uricase (uric acid oxidase) catalyzes the eventual conversion of uric acid to allantoin, a more soluble, readily renally excreted form. OH Uricase H 2 O + O 2 H 2 O 2 + CO 2 OH HO NHNH N N N N N OH NHNH N HO N N OH NHNH N Uric acidAllantoin

60 Uric Acid Production About two-thirds of uric acid is generated endogenously by the body, while one-third comes from purines in the diet Purine Catabolism 2-5 Xanthine Oxidase Xanthine Oxidase Urate Oxidase (Uricase) End product for humans, higher primates, reptiles, birds, and some mammals End product for the majority of mammals HypoxanthineXanthineUric AcidAllantoin

61 Reduction in Plasma Urate Levels With IV Pegloticase in Phase 3 Trials Replicate multicenter, phase 3, double-blind trials assigned to 128 patients with sever, refractory gout to receive either pegloticase 8 mg q2w, or a placebo infusion (n=43). The trials’ primary end point was a sustained plasma urate of <6.0 mg/dL in months 3 & 6. There is evidence for loss of efficacy overall overall over time in the treatment group. Mean PUA (All subjects) Week Mean PUA (mg/dL) (  SE) Placebo Pegloticase 8 mg q 2wk

62 Reduction in Plasma Urate Levels With IV Pegloticase in Phase 3 Trials Data are for those subjects in the q2w treatment arm of the phase 3 trials separating responders (ie, those who achieved the defined primary end point) vs nonresponders. Nonresponders were generally those subjects who developed high titers of pegloticase antibodies, and these antibodies correlated with infusion reactions. Week Mean PUA (mg/dL) Placebo Nonresponders Responders Mean PUA (Responders) Month 3Month 6

63 Pegloticase-Associated Infusion Reaction Relationship to Pre-infusion Serum Urate Level Data from phase 3 randomized controlled trials (RCT) and open-label extensions (OLE) demonstrate a marked relationship between an increased frequency of infusion reactions (IR) and the loss of effectiveness of pegloticase. For all infusions after the initial pegloticase infusion, the likelihood of IRs depends greatly on whether the pre- infusion serum urate determination is above or below 6.0 mg/dL <6 mg/dL>6 mg/dL IRs per 100 Infusions RCT OLE

64 Most Common Signs and Symptoms of Infusion Reaction to Pegloticase* Chest discomfort Flushing Dyspnea Nausea / vomiting Back / flank pain Erythema Blood pressure changes Muscle spasm / stiffness Hyperhidrosis *Data include all subjects in RCT and OLE in biweekly, monthly, and placebo arms.

65 Strategy for Lowering Uric Acid Initiate prophylaxis with low dose Colchicine or NSAID 1-2 weeks prior to urate lowering agent Initiate uricostatic agent at low dose (100 mg/day Allopurinol or 40 mg/day for febuxostat) Escalate dose every 2-4 weeks while monitoring for toxicity until serum urate is < 6.0 mg/dL If treat to target goal achieved maintain anti- inflammatory prophylaxis for 3-6 months after last gouty flair or longer when tophi persist

66 Strategy for Lowering Uric Acid Maintain urate-lowering agent indefinitely and check serum urate levels every 6-12 months If toxicity occurs with one uricostatic drug try the other agent. No evidence of cross- reactive toxicity. If target serum urate not achieved with uricostatic agent, a uricosuric can be added and titrated or Pegloticase can be tried No adjustment during gout flares

67 Study Showed Maintaining sUA <6 mg/dL Is Associated With Reduced Risk of Future Gout Attacks Incidence of recurrent gout attacks more than 1 year after each patient visit * Based on a retrospective analysis of 267 predominantly male gout patients for up to 3 years (Tokyo, Japan). Baseline mean sUA level >7.45 mg/dL. Urate-lowering therapies prescribed: allopurinol and benzbromarone. Incidence of Recurrent Gout Attack, % Average Uric Acid Level During Investigation Period (mg/dL) Observed Logistic regression (n=91) % of patients who achieved a serum uric acid level of <6 mg/dL (n=81) had no gout attacks during the observation period

68 Tracking sUA Levels The best time to measure sUA is after a flare has resolved, at least 2 weeks postflare - -sUA levels may be artificially low ~50% of the time during a flare Evaluate sUA in patients on therapy to ensure that the target level is achieved and maintained - -ACR guidelines recommend monitoring sUA level every 2-5 weeks during urate-lowering therapy titration, then every 6 months once sUA target has been achieved sUA Levels Over Time sUA Level Intercritical Period Gout Attack Intercritical Period ACR=American College of Rheumatology.


70 Limitations of Lifestyle Modifications on Reaching Target sUA Levels sUA levels may be reduced by making lifestyle changes including: - -Losing weight - -Limiting consumption of purine-rich meat and seafood - -Reducing alcohol intake, particularly beer - -Limiting high-fructose corn syrup intake - -Consuming dairy products

71 Singh JA, Jodges JS, Asch SM. Opportunities for improving medication use monitoring in gout. Ann Rheum Di. 2009;68: Medication prescription and monitoring of SUA in patients with a diagnosis of gout n/N%n/N% Continuous allopurinol prescription297/64346 SUA monitoring SUA checked and reached target126/64320 SUA checked but did not reach target127/64320 No SUA check390/64361 Colchicine/NSAID prophylaxisColchicineColchicine or NSAID ≥14 days before new allopurinol prescription66/ /64326 Before new allopurinol prescription80/ /64330 On or before new allopurinol prescription169/ /64348 ≤14 days after new allopurinol prescription180/ /64351

72 Take-Away Messages The goal of therapy in subjects with multiple recurrent gout flares or tophaceous gout is to prevent disease progression by reducing the body urate burden. Any patient presenting with advanced gout, or simply demonstrating tophi on physical exam, should clearly be started on ULT. Both allopurinol and febuxostate are effective in gout patients whose hyperuricemia is caused by either uric acid overproduction or underexctetion. Uricosurics should not be used in overproducers of uric acid or as monotherapy in those with a history of urolithiasis.

73 Take-Away Messages The uricostatics can be administered as once-daily medications, which increases compliance. Probenecid requires 2 to 3 doses per day for optimal function. The uricostatic agents function well in the face of renal insufficiency, whereas probenecid requires a GFR of at least 50 mL/min to be most effective. In fact, febuxostat appears to function better than many other options in subjects with mild-to- moderate renal insufficiency.

74 Take-Away Messages Rash will develop in at least 2% of patients started on allopurinol. Most rashes are benign and dose related, but allopurinol is one of the more common drug causes of severe cutaneous reactions in the form of SJS or TEN and rashes as a component of the DRESS syndrome, which is more commonly known as AHS. HLA-B*5891, which is by far most common in those of Southeast Asian ancestry, is a marked risk factor for severe allopurinol cutaneous reaction particularly in Koreans with CKD, and those of Han Chinese and Thai descent.

75 In essence, the appropriate strategy for ULT is termed “treat to target,” with the evidence-based target to begin to achieve superior outcomes being achievement of a serum urate of <6.0 mg/dL, at a minimum. This requires checking the serum urate level regularly (eg, every 6 months once the target has been achieved). In patients with one or more tophi detected on physical exam, the authors prefer a serum urate target of <5.0 mg/dL and in certain patients with advanced disease and multiple tophaceous deposits, lowering the serum urate level to <4.0 mg/day is the preferred strategy by the authors to help optimize therapy outcome. Take-Away Messages

76 In certain patients with advance disease and multiple tophaceous deposits, lowering the serum urate level to well below 6.0 mg/dL, such as in the range of 4.0 mg/dL, appears to help optimize therapy by accelerating resolution of tophi. The recombinant PEGylated uricase pegloticase is FDA-approved as in approach for potent and rapid reduction of serum urate and achieves rapid debulking of tophi (within 6 months) in drug responders (which were between 40% to 50% of subjects in phase 3 clinical trials, using 8 mg IV every 14 days).

77 The therapeutic program of urate-lowering measures, once initiated, should keep the serum urate less than 6.0 mg/dL (at a minimum) for the remainder of the patient’s life, even after tophi and gouty arthritis attacks are no longer present. Take-Away Messages


79 Uric Acid Overproducers and Underexcretors Uric Acid Underexcretion (~90%) Urate Overproduction (~10%) Primary Hyperuricemia Secondary Hyperuricemia Disordered urate transport Impaired renal function with urate transport Drug-induced renal toxicity Metabolic disorders Idiopathic Excessive purine intake Tumor lysis syndrome

80 Acute flares may be triggered by fluctuations in sUA levels, which can mobilize crystals Crystals released into the joint space undergo phagocytosis Phagocytosis can initiate a proinflammatory response, resulting in gout flares Gout Flares Occur When Crystals Trigger an Acute Inflammatory Response Supersaturation Crystal Formation Microcrystal Release Inflammatory Cascade Gout Flare Hyperuricemia Recurrences

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