G O U T. New Medications For New/Established Mechanisms AND. Old Medications With Novel Benefits

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1 G O U T New Medications For New/Established Mechanisms AND Old Medications With Novel Benefits Tawatchai (Kee) Paisansinsup, MD. Health Partners-Park Nicollet Health Services Twin Cities, Minnesota May 4, 2017 (paisat@parknicollet.com) Dr. Paisansinsup indicated no potential conflict of interest to this presentation. He does intend to discuss the unapproved/investigative use of Zyloprim (allopurinol) in patients with CKD, Arhalofenate, and anti-il 1 inhibitors for acute gout and prophylaxis. Financial Disclosure I have no financial disclosure.

2 You have been following a 58-year-old Caucasian male with history of frequent gout attacks (> 2 times in a year) over first MTP joint. He also has hypertension, obesity, chronic kidney disease stage III (GFR 45 ml/min). After a trial of life-style modification, he has continued to have frequent gout attacks. You decided to start allopurinol. You start the dose at low-dose 100 mg/d and slowly increase the dose by 100 mg every month. You also counseled the patient about symptoms of allopurinol hypersensitivity syndrome and put him on colchicine for gout prophylaxis 0.6 mg/d. SCOPEs OF THE TOPIC Pathogenesis of hyperuricemia and gout Management of gout - Treatment of the acute attack. - Long-term treatment with uric acid-lowering therapy (ULT). - Allopurinol doses in patients with chronic kidney disease. New medications with new/established mechanisms Old medications with novel benefits (only if there is time, slides are available for you to review) Uncertainties (Good slides/summaries to be printed out and posted on the walls in your office will have red dot on the right upper corners)

3 SCOPEs OF THE TOPIC Pathogenesis of hyperuricemia and gout Management of gout - Treatment of the acute attack. - Long-term treatment with uric acid-lowering therapy (ULT). - Allopurinol doses in patients with chronic kidney disease. New medications with new/established mechanisms Old medications with novel benefits. (only if there is time, slides are available for you to review) Uncertainties Prevalence of gout in seven representative countries Kuo, C.-F. et al. (2015) Global epidemiology of gout: prevalence, incidence and risk factors Nat. Rev. Rheumatol. doi: /nrrheum

4 MECHANISMs OF HYPERURICEMIA Genetics: Male, Ancestry, SLC2A9, ABCG2, SLC17A1/SLC17A3, GCKR Drugs: Diuretics, Cyclosporin, Tacroimus, ACE, Non-losartan ARB, Beta-lockers, Pyrazinamide, Ritonavir. Dietary: Red meat, Seafood, Beer, Spirits, Sugar-sweetened beverages. Others: Age, Menopause, Chronic kidney disease, Obesity, Hypertension, Hyperlipidemia, Hypertriglyceridemia, Congestive HF, Obstructive sleep apnea, Anemia, Psoriasis, Sickle Cell anemia, Hematologic malignancy, Lead exposure. (Modified from) Dalbeth N, et al. Lancet. 2016, 388; HYPERURICEMIA HYPERURICEMIA > 6 mg/dl INFLAMMASOME (Modified from) Dalbeth N, et al. Lancet. 2016, 388;

5 HYPERURICEMIA (Modified from) Dalbeth N and Stamp LK. Ann Rheum Dis. 2014;73:1598. MECHANISMs OF HYPERURICEMIA Genetics: Male, Ancestry, SLC2A9, ABCG2, SLC17A1/SLC17A3, GCKR Drugs: Diuretics, Cyclosporin, Tacroimus, ACE, Non-losartan ARB, Beta-lockers, Pyrazinamide, Ritonavir. Dietary: Red meat, Seafood, Beer, Spirits, Sugar-sweetened beverages. Others: Age, Menopause, Chronic kidney disease, Obesity, Hypertension, Hyperlipidemia, Hypertriglyceridemia, Congestive HF, Obstructive sleep apnea, Anemia, Psoriasis, Sickle Cell anemia, Hematologic malignancy, Lead exposure. Probenecid Lenisurad Arhalofenate Allopurinol Febuxostat (xanthine oxidase inh) Uricase Allantoin (Modified from) Dalbeth N, et al. Lancet. 2016, 388; HYPERURICEMIA

6 HYPERURICEMIA > 6 mg/dl NSAIDs Colchicine Steroids INFLAMMASOME Interleukin-1 inhs IL-1Ra (Anakinra) Anti-IL1 mabs (Canakinumab) IL1R-fusion protein (Rilonacept) (Modified from)dalbeth N, et al. Lancet. 2016, 388; SCOPEs OF THE TOPIC Pathogenesis of hyperuricemia and gout Management of gout - Treatment of the acute attack. - Long-term treatment with uric acid-lowering therapy (ULT). - Allopurinol doses in patients with chronic kidney disease. New medications with new/established mechanisms Old medications with novel benefits. (only if there is time, slides are available for you to review) Uncertainties

7 TREATMENT OF GOUT IS LIKE MELTING ICEBERGs (My own quote) Two tasks have to be accomplished: Tophi or Tissue uric acid deposits Serum Uric Acid Prevent new icebergs (crystals) to form. Allow the existing icebergs (crystals in tissues) to melt completely. Raise water temperature above 32 F. NO uric acid crystals, NO GOUT Reduce uric acid level below saturated point < 6 mg/dl. (no new crystals formed) Sustained urate reduction < 6 mg/dl. (allow existing crystals to melt) TREATMENT OF GOUT IS LIKE MELTING ICEBERGs (My own quote) Tophi or Tissue uric acid deposits Serum Uric Acid 1. While iceberg is melting, ice pieces can fall down. - Gout attacks are not uncommon during the first few months of starting hypouricemic Rx. - Gout attacks are not reduced during the first 6 months in the clinical trials (esp. without gout prophylaxis). - Gout prophylaxis during the first few months is recommended. 2. It takes time to melt icebergs - Gout attacks are reduced in most clinical trials after a year of treatment with hypouricemic Rx.

8 NSAIDs TREATMENT OF THE ACUTE GOUT ATTACK: A MATTER OF CONTRAINDICATIONS AND COST!!! (1) No one NSAIDs shown to be better than the others. (Most studied NSAIDs: Indomethacin 50 mg tid, Naproxen 500 mg bid) KEYs: Know contraindications, avoid in certain patients. Contraindications: Avoid: - Allergy to NSAIDs - Concurrent use of warfarin, factor Xa inh. - Recent GI bleeding/cerebral hemorrhages. - Patients more than 65 years. - Severe IHD, congestive heart failure. - Patients with GFR < 50 ml/min. (Indomethacin is lipophilic and can pass blood-brain barrier causing headache, drowsiness, mental changes/confusion in elderly patients.) COLCHICINE TREATMENT OF THE ACUTE GOUT ATTACK: A MATTER OF CONTRAINDICATIONS AND COST!!! (2) NO MORE HIGH-DOSE OLD REGIMEN COLCHICINE (2 tabs stat, 1 tab an hour later then 1 tab every hour until improved or until max 8 tabs (4.8 mg) is reached. (or you have diarrhea or die!!). LOW-INTENSITY colchicine has been shown to be efficacious and more tolerated. LOW-INTENSITY Dose: 1.2 mg as onset, followed by 0.6 mg an hour later, (followed by 0.6 mg once to twice a day for a few days or until it is over). Efficacy: 37.8% Vs 32.7% Vs 15.5% (p=0.005, low-dose Vs high-dose Vs placebo) Rescued med needed: 31.1% Vs 34.6% Vs 50% (p=0.027) Adverse events: OR 1.5, low-dose compared to placebo (95% CI ) Diarrhea: OR 21.3, high-dose compared to low-dose 95% CI ) Severe diarrhea: 19.2% Vs 0%, high-dose vs low-dose. Vomiting: 17.3% Vs 0%, high-dose vs low-dose. Terkeltaub RA, et al. Arthritis Rheumatol. 2010;62(4): Terkeltaub RA, et al. Arthritis Rheumatol. 2011;63(8):2226.

9 TREATMENT OF THE ACUTE GOUT ATTACK: A MATTER OF CONTRAINDICATIONS AND COST!!! (3) Colchicine Cost issue and insurance coverage Drug interactions Terkeltaub RA, et al. Arthritis Rheumatol. 2011;63(8):2226. TREATMENT OF THE ACUTE GOUT ATTACK: A MATTER OF CONTRAINDICATIONS AND COST!!! (4) STEROIDs Oral prednisone 0.5 mg/kg x 5-7 d, then stop or Oral prednisone 0.5 mg/kg x 2-5 d, then tapering over 7-10 d. IM triamcinolone mg (0.5-2 mg/kg), followed by oral prednisone. Intra-articular steroid (dose varies according to size of joint) Subcutaneous ACTH IU for NPO patients. DO NOT USE MEDROL DOSE PAK: Too low, taper too quickly. NOT IMPROVED Switch to different monotherapy Off-labeled use: IL1 blockers Combine: NSAIDs + Colchicine Steroid + Colchicine (Avoid steroid +NSAIDs) Khanna D, et al. Arthritis Care & Research. 2012;64:1431. Khanna D, et al. Arthritis Care & Research. 2012;64:1447. Richette P, et al. Ann Rheum Dis Jan;76(1): Qaseem A, et al. Ann Intern Med. 2016; doi: /M Reiner TH, et al. Ann Intern Med. 2016;164:464.

10 HYPOURICEMIC TRATMENT/URIC ACID LOWERING THERAPY (ULT) Xanthine Oxidase Allopurinol: Hypoxanthine isomer (purine analogue) - Generic, cheap (4$/month), long-term 60-year data available - Converted to active metabolite oxypurinol - Renal clearance - (Maintenance dose adjustment-controversial!!) - Maximal dose 800 mg/d (900 mg/d in Europe) Febuxostat: Non-nucleoside xanthine oxidase inhibitor - Generic is available outside US. Not yet in US (300$/month). - Metabolized by glucuronide formation and oxidation in liver. - No dose adjustment required in mild-to-moderate renal insufficiency. - Dose mg/d (up to 120 mg/d in Europe) -(Cannot be used together with allopurinol) HYPOURICEMIC TRATMENT/URIC ACID LOWERING THERAPY (ULT) Uricouric agents Probenecid - Increase renal uric acid excretion mg twice a day - GFR > 50 ml/min required to work - Can increase ASA, Methotrexate, penicillin levels - Drink water > 2 L/d to prevent kidney stone. Lesinurad: Recently FDA-approved to be used with a xanthine oxidase inhibitor. Arhalofenate: Anti-inflammatory uricouric agent. Ongoing phase III trial, not yet FDA-approved. (Benzbromarone: Not available in US, severe hepatoxicity)

11 ALLOPURINOL HYPERSENSITIVITY SYNDROME (AHS) AHS incidence is about %. Crude incidence of severe cutaneous reactions (AHS, SCAR, TEN/SJS/DRESS) is about 0.69 (95% CI ) per 1,000 person-years. The mortality of AHS ranges from 9%-20%...Very HIGH. Stamp LS et al. Nature Rev Rheumatol. 2016:12: 235 RENAL-ADJUSTED ALLOPURINOL MAINTENANCE DOSES (CrCL-ADJUSTED DOSES) 81% of patients (total n=78) with AHS had impaired renal functions. Assuming increased oxypurinol as the cause, recommend reducing allopurinol maintaining doses based on renal functions. Such strategy has never been shown to reduce AHS. Causes fears of providers to increase the allopurinol dose to attain SUA goal. As the result, gout is poorly controlled worldwide. Hande KR et al. American J Med. 1984;76:47.

12 RENAL-ADJUSTED ALLOPURINOL MAINTENANCE DOSES : CONTROVERSIAL AND WITH CLINICAL CONSEQUENCES Renal insufficiency is a risk factor for AHS but no data to suggest that the recommended renal-adjusted maintenance doses are associated with reduction of AHS. (Due to its rarity, data from a prospective randomized controlled study is unlikely available. Data are all from case-control, cohort studies.) A study suggested that starting dose (> 1.5 X GFR) NOT maintenance dose is associated with AHS. START LOW AND GO SLOWLY at the beginning In patients who did not develop AHS and tolerated allopurinol, increasing the dose above renal-adjusted maintenance doses were tolerated. Hande KR et al. American J Med. 1984;76:47. Stamp LK, et al. Arthritis Rheumatol. 2011;63:412. Reinders MK, et al. Ann Rheum Dis. 2009;68:892. Vazquez-Mellado J, et al. Ann Rheum Dis. 2001;60:981. Paisansinsup T, et al. J Clin Rheum. 2013;19: 180. Stamp LK, et al. Arthritis Rheumatol. 2012;64:2529. Dalbeth N, et al. J Rheumatol. 2006;33:1646. ShuengLu H, et al. PNAS. 2005;102:4134 Wen-Hung C. Ann Rheum Dis. 2015;74:2157. RISK FACTORS OF AHS The HLA-B*58:01 is most common in Asian descent, with a frequency of ~ 10-15% in the Han s Chinese ~ 12% in Koreans ~ 6-8% in Thai ~ 1-2% in Europeans and Japanese. The odds ratio for AHS/SCAR among HLA-B*58:01 carries in a meta-analysis was 73 using healthy controls, and 165 using allopurinol-tolerant controls. The presence of HLA-B*58:01 is the CONTRAINDICATION for allopurinol. Stamp LS et al. Nature Rev Rheumatol. 2016:12: 235 Dean L. In: Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US); 2012

13 Han s Chinese 92% of the population of China. 95% of Taiwan (Han Taiwanese) 76% of Singapore population. 23% of Malaysian population. 14% of Thai population. 1.3 billion people worldwide. 1% of US population. 3% of Canadian population. 3.5% of Australian population. 3.7% of New Zealand population. RISK FACTORS OF AHS CHECK HLA-B*58:01 The HLA-B*58:01 is most common in Asian descent, with a frequency of ~ 10-15% in the Han s Chinese ~ 12% in Korean ~ 6-8% in Thai ~ 1-2% in Europeans and Japanese. The odds ratio for AHS/SCAR among HLA-B*58:01 carries in a meta-analysis Was 73 using healthy controls, and 165 using allopurinol-tolerant controls. The presence of HLA-B*58:01 is the CONTRAINDICATION to take allopurinol. Stamp LS et al. Nature Rev Rheumatol. 2016:12: 235 Dean L. In: Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US); 2012

14 RANDOMIZED CONTROLLED TRIAL OF THE EFFICACY AND SAFETY OF ALLOPURINOL DOSE ESCLATION TO ACHIEVE TARGET SUA (TREAT-TO-TARGET, T2T) Patients with gout who had received CrCl-based renal doses for > 1 mo and SUA > 6 mg/dl: Randomized to - Continue the CrCl-based renal doses - Escalate allopurinol to reach the target of SUA < 6 mg/dl (Dose Escalation or DE) By 50 mg/d/month if CrCl < 60 ml/min By 100 mg/d/month if CrCl > 60 ml/min 12-mo follow-up ~50% patients had CrCl < 60 ml/min 11-15% patients had CrCl < 30 mlmin. Stamp LS, et al. Ann Rheum Dis. 2017;1-7. doi: /annrheumdis RANDOMIZED CONTROLLED TRIAL OF THE EFFICACY AND SAFETY OF ALLOPURINOL DOSE ESCLATION TO ACHIEVE TARGET SUA (TREAT-TO-TARGET, T2T) The mean SUA change was more in DE group (-1.5 Vs -0.34, p<0.001) More patients with SUA < 6 at final visit in DE group (69% Vs 32%, p<0.001) Gout flares are same in DE group as compared to control (54% Vs 59%, p=0.58) Same changes of tophus size reduction. Stamp LS, et al. Ann Rheum Dis. 2017;1-7. doi: /annrheumdis

15 RANDOMIZED CONTROLLED TRIAL OF THE EFFICACY AND SAFETY OF ALLOPURINOL DOSE ESCLATION TO ACHIEVE TARGET SUA (TREAT-TO-TARGET, T2T) Non-laboratory AEs Cardiac is most common,?causal relationship Mild, uncommon, comparable No allopurinol hypersensitivity Syndrome (AHS) 11 patients in control had rash. 5 patients in control had pruritus. 8 patients in DE had rash. - 1 resolved despite continuing. 10 patients in DE had pruritus. Stamp LS, et al. Ann Rheum Dis. 2017;1-7. doi: /annrheumdis RANDOMIZED CONTROLLED TRIAL OF THE EFFICACY AND SAFETY OF ALLOPURINOL DOSE ESCLATION TO ACHIEVE TARGET SUA (T2T) Laboratory AEs Elevated LFTs 5-10%, comparable (28 pts control Vs 32 pts DE)? Causal relationship 82 pts in control Vs 81 pts in DE with scr > 1-1.5x baseline. 28 pts in control Vs 34 pts in DE with > 20% decline of GFR. A similar proportion of patients with an increase in CrCL Escalating the allopurinol doses above CrCl renal doses in patients who tolerated allopurinol (with no AHS), EVEN IN PATIENTs with CKD, are safe and tolerated. START LOW AND GO SLOWLY Escalate the dose to keep SUA at the goal < 6 mg/dl Stamp LS, et al. Ann Rheum Dis. 2017;1-7. doi: /annrheumdis

16 RENAL-ADJUSTED ALLOPURINOL MAINTENANCE DOSES : CONTROVERSIAL AND WITH CLINICAL CONSEQUENCES Consequences: Only 35-40% of patients achieved SUA goal if following renal-adjusted maintenance dose recommendation. Renal-adjusted dose recommendation influences: - Clinical trials: Trials of new medications rarely allow allopurinol (comparator) doses more than 300 mg/d or to increase allopurinol doses more than renal-adjusted doses. - Claims of better uricemic controls than standard dose of allopurinol (fixed dose, not more than 300 mg/d or renal-adjusted doses) - Paucity of safety information of allopurinol (or newer medications!) in patients with GFR < 30 ml/min. Hande KR et al. American J Med. 1984;76:47. Stamp LK, et al. Arthritis Rheumatol. 2011;63:412. Reinders MK, et al. Ann Rheum Dis. 2009;68:892. Vazquez-Mellado J, et al. Ann Rheum Dis. 2001;60:981. Paisansinsup T, et al. J Clin Rheum. 2013;19: 180. Stamp LK, et al. Arthritis Rheumatol. 2012;64:2529. Dalbeth N, et al. J Rheumatol. 2006;33:1646. GUIDELINEs Management of acute gouty attacks Khanna D, et al. Arthritis Care & Research. 2012;64:1431. Khanna D, et al. Arthritis Care & Research. 2012;64:1447. Richette P, et al. Ann Rheum Dis Jan;76(1): Qaseem A, et al. Ann Intern Med. 2016; doi: /M Medication ACR 2012 EULAR 2016 ACP First lines: NSAIDs or Colchicine (Low-intensity)* or Same as ACR 2012 Corticosteroids (first line) NSAIDs (no NSAIDs preference) Steroid (Oral prednisone 0.5 mg/kg x 5-10 d stop or 2-5 d at full-dose,tapering in 7-10 d. or IM triamcinolone mg followed by oral prednisone or intra-articular steroid or IU ACTH subcut for NPO pts. Colchicine (Low-intensity, acknowledge that is now more expensive than corticosteroid and NSAIDs, multiple drug interactions) (NOT IMPROVED) Switch to different monotherapy Combination: NSAIDs + Colchicine or Steroid + Colchcine Off-label use: IL-1 blockers *Low-intensity colchicine: 1.2 mg at first sign, then 0.6 mg an hour later. - Colchicine is contraindicated in patients on dialysis. (Not dialyzable). Dose should be reduced in patients with renal insufficiency. - Colchicine dose should be reduced when used in combination with CYP3A4/P-glycoprotein inhibitors. Strong P-glycoprotein inhibitor: Cyclosporin/Tacrolimus: 0.6 mg 1 dose, to be repeated no earlier than 3 d. Strong CYP34A inhibitor: Ketoconazole, Clarithromycin, Ritonavir: 0.6 mg 1 dose or 0.3 mg bid, to be repeated no earlier than 3 d Medium CYP34A inhibitor: Verapamil, Diltiazem: 1.2 mg 1 dose, to be repeated no earlier than 3 d. Weak CYP34A inhibitor: Azithromycin: No dose reduction required: 1.2 mg at first sign, then 0.6 mg an hour later.

17 GUIDELINEs LONG-TERM HYPOURICEMIC AGENTs ACR 2012 EULAR 2016 ACP 2016 Medication - First lines (XOI): allopurinol or - First lines (XOI): allopurinol or Febuxostat Febuxostat When Khanna D, et al. Arthritis Care & Research. 2012;64:1431. Khanna D, et al. Arthritis Care & Research. 2012;64:1447. Richette P, et al. Ann Rheum Dis Jan;76(1): Qaseem A, et al. Ann Intern Med. 2016; doi: /M Second line (UUA): probenecid - Second lines (UUA): probenecid (only if CrCl>50 ml/min) or combined (only if CrCl>50 ml/min) or benzpro XOI with probenecid marone (only if CrCl>30 ml/min, unavailable in the US) or combined an XOI with a UUA - Frequent attacks > 2 x/yr - Presence of a tophus - Nephrolithiasis - CKD > stage II Allopurinol - Max. starting dose 100 mg/dl - No starting dose recommended in CKD for any patients with a lower but suggesting low dose. dose of 50 mg/dl in those with CKD > stage 4. - Max. dose adjusted to CrCl if target not achieved switch to febuxostat or - Gradually titrate the dose up by 50 benzbromarone with or without allopurinol to 100 mg every 2-5 wks to achieve (except in patients with GFR<30 ml/min) SUA goal as long as adequate patient education and monitoring drug toxicity are provided (eg. Pruritus, rash, elevated transaminase) - Frequent attacks > 2 x/yr - First attack, younger than 40 with SUA > 8 mg/dl - Presence of a tophus - Nephrolithiasis Target SUA - < 6 mg/dl for all - < 6 mg/dl for all - For severe or tophaceous - For severe gout (tophi, disease < 5 mg/dl frequent attacks) < 5 mg/dl - SUA < 3 mg/dl not recommended - No specific recommendation (Acknowledging available comparable effectiveness of both allopurinol and febuxostat) - Recommends against initiating long-term urate-lowering therapy after a first gout attack or in patients with infrequent attacks. -Recommends that clinicians discuss benefits, harms, costs, and individual preferences with patients before initiating urate-lowering therapy, including concomitant prophylaxis in patients with Recurrent gout attacks. - Treat-to-avoid-symptoms (meaning???, definition???) - Treat-to-avoid-symptoms, with no monitoring of urate levels (Acknowledging treat-to-target (T2T) commonly recommended by ACR and EULAR and requirement of comparative effectiveness studies that evaluate incremental benefits and harms of a T2T strategy over treat-to-avoid-symptoms strategy. SUBSEQUENT GOUT ATTACKs AFTER THE FIRST ONE Most untreated patients with gout will experience a second episode within two years. 62% percent of patients had a second attack within the first year. 78% percent of patients had a second attack within the second year. 93% percent of patients had a second attack within 10 years. Olmsted County data: - Mean follow-up 13.4 years (S.D. 8.5). - Mean SUA 8.1 mg/dl % developed at least a flare within the entire follow-up period. - Highest risks: Initial joint other than first MTP and high baseline SUA. Gutman AB. Gout and Goty arthritis. In: Text book of Medicine, Beeson PB, McDermott W (Eds), Saunders, Philadelphia p.595. Zleik N, et al. Arthritis Rheum 2013;65 Suppl 10:1998. Bongartz T, et al. Ann Rheum Dis 2013;72: A764. doi /annrheumdis-2013-eular.2263

18 GUIDELINEs for PROPHYLACTIC TREATMENT DURING URIC-ACID LOWERING TREATMENT Khanna D, et al. Arthritis Care & Research. 2012;64:1431. Khanna D, et al. Arthritis Care & Research. 2012;64:1447. Richette P, et al. Ann Rheum Dis Jan;76(1): Qaseem A, et al. Ann Intern Med. 2016; doi: /M ACR 2012 EULAR 2016 ACP First line: Colchicine* - First line: Colchicine or NSAIDs - Second line: NSAIDs (naproxen 220 mg bid, unless contraindicated) Duration: Duration: - At least 6 months - 6 months or - 3 months after achieving - Acknowledge that not all target SUA if no tophi patients may require or prophylaxis and discussion - At least 6 months after with patient recommended achieving target if tophi present or the last tophus has resolved - No specific recommendation - (acknowledging evidences available of using low-dose colchicine or low-dose NSAIDs for more than 8weeks-6 month) - Recommends that clinicians discuss benefits, harms, costs, and individual preferences with patients before initiating urate-lowering therapy, including concomitant prophylaxis in patients with recurrent gout attacks. *- Colchicine 0.6 mg once to twice a day. Lower dose is preferred in elderly patients and patients with CKD stage IV-V (0.3 mg/d or every other day). - Colchicine is contraindicated in patients on dialysis. (Not dialyzable) - Colchicine dose should be reduced when used in combination with CYP3A4/P-glycoprotein inhibitors Strong P-glycoprotein inhibitor: Cyclosporin/Tacrolimus: 0.3 mg/d or 0.3 mg every other day. Strong CYP34A inhibitor: Ketoconazole, Clarithromycin, Ritonavir: 0.3 mg/d or 0.3 mg every other day. Medium CYP34A inhibitor: Verapamil, Diltiazem: 0.6 mg/d or 0.3 mg once to twice a day.. Weak CYP34A inhibitor: Azithromycin: No dose reduction required: 0.6 mg once to twice a day. ACP GUIDELINE Vs ACR/EULAR GUIDELINEs: CONSERVATIVEs Vs LIBERALs ACP Guidelines are more conservative: review clinical evidences and make recommendations - Provide clinicians with recommendation based on THE BEST available evidence. (Meta-analyses, multiple RCTs) - To inform clinicians of when there is no evidence. - To help clinicians deliver the best health care possible - If no specific evidence exists to answer a clinical question within a topic, the ACP Clinical Guidelines Committee refrains from making a clinical recommendation. - Argue against serum uric acid (biomarker) as surrogate. Put more emphasis on final clinical outcome (less gout attack). (Failed studies to reduce mortality by using surrogate biomarkers as outcomes in DM, anemia in renal disease) Acknowledge that gout attack is more during initiation of ULT (and gout attacks are eventually less after more than a year of successful ULT.) Khanna D, et al. Arthritis Care & Research. 2012;64:1431. Khanna D, et al. Arthritis Care & Research. 2012;64:1447. Richette P, et al. Ann Rheum 7 Jan;76(1): Qaseem A, et al. Ann Intern Med. 2016; doi: /M Singh J, et al. Ann Rheum Dis. 2017;76:629 FitzGerald JD, et al. Arthritis Rheumatol. 2017;69:479.

19 ACP GUIDELINE Vs ACR/EULAR GUIDELINEs: CONSERVATIVEs Vs LIBERALs ACP Guidelines also suggested treatment without evidences: - Treat-to-avoid-symptoms : unclear definition, no data that this approach is better than T2T. Potential consequences: - Most gout patients are handled and managed in primary care. These data could potentially cause more confusion and more gout apathy. - Poor(er) control of gout. - More attacks, poorer functions, loss incomes, increased hospitalization, personal, medical and societal burdens. Khanna D, et al. Arthritis Care & Research. 2012;64:1431. Khanna D, et al. Arthritis Care & Research. 2012;64:1447. Richette P, et al. Ann Rheum 7 Jan;76(1): Qaseem A, et al. Ann Intern Med. 2016; doi: /M Singh J, et al. Ann Rheum Dis. 2017;76:629 FitzGerald JD, et al. Arthritis Rheumatol. 2017;69:479. ACP GUIDELINE Vs ACR/EULAR GUIDELINEs: CONSERVATIVEs Vs LIBERALs ACR and EULAR GUIDELINEs are more progressive and liberal: - Involve rheumatologists, internists, cardiologists, nephrologists and patients. - The best clinical evidences: meta-analyses, RCTs - Broader guidance on clinically relevant issues, at times in the absence of RCT data but with gaining benefit/harm information obtained from observation/ case-control trials, non-randomized prospective trials, ongoing RCTs/extension studies. - SUA of 6 as target: NO uric acid crystals, NO gout - Based on physiologic solubility of urate - Observation studies, ongoing and extension RCTs. Guidelines have to be tailored individually. (underlying medical problems, insurance situation, availability of medication in different parts of the world). Guidelines require ongoing update every few years with more available data. Khanna D, et al. Arthritis Care & Research. 2012;64:1431. Khanna D, et al. Arthritis Care & Research. 2012;64:1447. Richette P, et al. Ann Rheum 7 Jan;76(1): Qaseem A, et al. Ann Intern Med. 2016; doi: /M Singh J, et al. Ann Rheum Dis. 2017;76:629 FitzGerald JD, et al. Arthritis Rheumatol. 2017;69:479.

20 SCOPEs OF THE TOPIC Pathogenesis of hyperuricemia and gout Management of gout - Treatment of the acute attack. - Long-term treatment with uric acid-lowering therapy (ULT) - Allopurinol doses in patients with chronic kidney disease. New medications with new/established mechanisms Old medications with novel benefits. (only if there is time, slides are available for you to review) Uncertainties FEBUXOSTAT Non-purine oral selective xanthine oxidase inhibitor. Metabolized in the liver. Do not need dose adjustment for mild-to-moderate renal insufficiency. At dose mg/d in 6-12 mo RCTs, significant more effective in lowering SUA to goal level < 6 mg/dl than the-real-world, commonly prescribed allopurinol mg/d (>300 mg/dl not allowed), which was sustained in the extension studies. (The clinical outcomes gout flares and tophus size were similar to allopurinol.) Most common side effects (excluding gout flares during the first few months) - Nausea, diarrhea, headache, arthralgia, edema (1-5%) - Rash (5.6%) - Abnormal LFTs (3-7%), not worsening in pts with baseline liver disease No reported cross allergic reactions with febuxostat in patients with allopurinol allergy. Frampton JE. Drugs. 2015;75:427. Becker MA, et al. NEJM 2005;353:2450 Saag KG, et al. Arthritis Rheumatol. 2016;68:2035

21 FEBUXOSTAT The cardiovascular events were the most common serious adverse events during treatment with febuxostat.?? Causal relationship During phase III trials (> 5,000 patients), major adverse CV events (MACEs) were found in febuxostat (0.74/100 patient-years, 95% CI ), which was numerically higher than allopurinol (0.6/100 patient-years, 95% CI ). Ongoing trials in USA (CARES, ~7,500 patients, 5-yr) and UK/Denmark (FAST, ~5,706 patients, 3-yr) to address these MACEs. Most patients on clinical trials had mild-to-moderate renal insufficiency (GFR > 50 ml/min). Much less data with patients with GFR < 50 ml/min. Renal preservation and safety/efficacy data were available in patients with GFR ml/min (n=96) High cost (300$/mo Vs 4$/mo allopurinol), indicated in patients who are allergic to or cannot tolerate allopurinol or SUA not achieved with allopurinol and/or uricouric agent. Frampton JE. Drugs. 2015;75:427. Becker MA, et al. NEJM 2005;353:2450 Saag KG, et al. Arthritis Rheumatol. 2016;68:2035 MacDonald TM, et al. BMJ Open 2014;4:e doi: /bmjopen White WB, et al. Am heart J. 2012;164:14. MECHANISMs OF HYPERURICEMIA Genetics: Male, Ancestry, SLC2A9, ABCG2, SLC17A1/SLC17A3, GCKR Drugs: Diuretics, Cyclosporin, Tacroimus, ACE, Non-losartan ARB, Beta-lockers, Pyrazinamide, Ritonavir. Dietary: Red meat, Seafood, Beer, Spirits, Sugar-sweetened beverages. Others: Age, Menopause, Chronic kidney disease, Obesity, Hypertension, Hyperlipidemia, Hypertriglyceridemia, Congestive HF, Obstructive sleep apnea, Anemia, Psoriasis, Sickle Cell anemia, Hematologic malignancy, Lead exposure. Probenecid Lenisurad Arhalofenate Allopurinol Febuxostat (xanthine oxidase inh) Uricase Allantoin (Modified from) Dalbeth N, et al. Lancet. 2016, 388; HYPERURICEMIA

22 LESINURAD A new uric acid lowering therapy: Inhibitors of Urate/anion exchanger 1 (URAT1) and Organic transporter 4 (OAT4). Increase renal urinary uric acid excretion. Studies were in patients: - Standard dose of allopurinol (90-95% mostly < 300 mg/d). - Mostly male patients (92-95%). Caucasians (~75%). - Majority of patients had GFR > 60 ml/min. Only 14-20% patients with GFR ml/min. - Long-standing gout years. - Baseline tophi 14.3% - Gout prophylaxis (colchicine or NSAIDs) x 5 months. Primary end point: SUA < 6 mg/dl at 6 months Secondary end points: Gout flares requiring treatment Tophi resolution at 1 year. Perez-Ruiz F, et al. Ann Rheum Dis. 2016;75:1074. Saag KG, et al. Arthritis Rheumatol. 2017;69:203. Bardin T, et al. Ann Rheum Dis doi: /annrheumdis LESINURAD Efficacy Allop alone Allop + les 200 mg Allp + les 400 mg p value SUA <6 at 6 mo (primary) Gout flares (secondary) Tophi resol n at 1 yr (secondary) 27.9% 54.2% 59.2% < , % 0% 21.1% 0.02, 0.06 Perez-Ruiz F, et al. Ann Rheum Dis. 2016;75:1074. Saag KG, et al. Arthritis Rheumatol. 2017;69:203. Bardin T, et al. Ann Rheum Dis doi: /annrheumdis

23 LESINURAD Treatment Emergent Adverse Reactions (TEAEs) Most common non-renal TEAEs, comparable in all groups: - URI (2.5-8%) - Sinusitis (2-6%) - Headache (2.5-6%) Serious TEAEs (CVAs, CAD, MI): comparable (5.5% Vs 4.5% Vs 8%, allopurinol alone, allopurinol + lesinurad 200 mg, allopurinol + lesinurad 400 mg) Perez-Ruiz F, et al. Ann Rheum Dis. 2016;75:1074. Saag KG, et al. Arthritis Rheumatol. 2017;69:203. Bardin T, et al. Ann Rheum Dis doi: /annrheumdis LESINURAD Renal related TEAEs Allop alone Allop + les 200 mg Allp + les 400 mg Renal related TEAEs 3.5% 4% 10% Increased scr 1% 3.5% 7% scr > 1.5x baseline 1% 6% 15.9% scr > 2x baseline 0% 1% 6% Microcrystallization of uric acid. Mostly transient but can be irreversible (2 pts in les 200 mg, 6 pts in les 400 mg) Perez-Ruiz F, et al. Ann Rheum Dis. 2016;75:1074. Saag KG, et al. Arthritis Rheumatol. 2017;69:203. Bardin T, et al. Ann Rheum Dis doi: /annrheumdis

24 LESINURAD FDA approved only for 200 mg dose. (10$/pills with coupon) Only in combination with allopurinol standard dose and SUA not achieved. Drinks water at least 2 L/d. Monitor scr periodically. Discontinue if GFR < 30 ml/min. Contraindicated in: - End-stage renal disease - Kidney transplant recipients - On dialysis?risks Vs Rewards: -?Increase allopurinol above standard dose might just work - If GFR > 50 ml/min, probenecid is already available and cheaper (370$/mo with coupon) Perez-Ruiz F, et al. Ann Rheum Dis. 2016;75:1074. Saag KG, et al. Arthritis Rheumatol. 2017;69:203. Bardin T, et al. Ann Rheum Dis doi: /annrheumdis ARHALOFENATE (Not yet FDA-approved,?expected this year) Uricouric agent (URAT1 blocker) with anti-inflammatory property. Suppression of release of pro-inflammatory cytokines including IL-1β and prevention influx of neutrophils. Phase II data are from patients not on uricouric agents or together with febuxostat. Patients were mostly male (92-100%), Caucasians (62-70%). All patients have GFR > 60 ml/mins. The phase II data has been reported with 12-week data to demonstrate anti-flare property as primary outcome. Steinberg A, etal. Ann Rheum Dis 2015;74 Suppl 2: Poiley J, et al. Arthritis Rheumatol. 2016;68:2027.

25 ARHALOFENATE (Not yet FDA-approved) The flare incidence is decreased by 46% in arhalofenate 800 mg vs allopurinol alone (0.66 vs 1.24, p=0.0056), and placebo (0.66 vs 1.13, p=0.049). The flare incidence in arhalofenate 800 mg group is comparable to allopurinol plus colchicine (0.66 vs 0.4, p=0.091) Poiley J, et al. Arthritis Rheumatol. 2016;68:2027. ARHALOFENATE (Not yet FDA-approved) 65% Vs 39% experienced no flares, Arhalofenate 800 mg vs allopurinol alone. The mean change in SUA: % in arhalofenate 600 mg % in arhalofenate 800 mg % in placebo % in allopurinol alone % in allopurinol + colchicine Proportion of patients with SUA <6-13.2% in arhalofenate 600 mg % in arhalofenate 800 mg % in allopurinol alone - 34% in allopurinol + colchicine Poiley J, et al. Arthritis Rheumatol. 2016;68:2027.

26 ARHALOFENATE (Not yet FDA-approved) Side effects mild, minor, comparable with allopurinol alone. Phase III ongoing, together with xanthine oxidase febuxostat. If approved, most likely will be approved with a xanthine oxidase.? Role in practice: - Data on pts with GFR < 60 ml/min unavailable - If pts with GFR > 50 ml/min, generic probenecid, probenecid+colchicine tab are available. Poiley J, et al. Arthritis Rheumatol. 2016;68:2027. PEGYLATED RECOMBINANT MAMMALIAN URATE OXIDASE (PEGYLATED-URICASE) Genetically engineered, recombinant, PEG-conjugated mammalian (porcine) uricase which converts uric acid to allantoin with much better solubility. FDA-approved 8 mg/kg every 2 weeks in patients with refractory gout who failed, could not tolerate, or are contraindicated to other treatment. Very efficient, serum uric acid < 6 mg/dl within 6 hours, 87.5% reached SUA goal. Adverse reactions: (93% of patients) - Most common: nephrolithiasis (15%), arthralgia (12%), gout flares (88%) - Infusion-day adverse events (IDEs): (N&V, neck/back pain/muscle ache, SOB, chest pain, rash) happen in 12.7%. (12/18 pts withdrew due to IDEs) - 76% had a positive anti-pegloticase, associated with less efficiency. - IDEs usually preceded by increasing SUA..Cannot be used with other hypouricemic agents so that these pts are identified and repeated infusion is prohibited. Should NOT be used in the primary care setting..refer! Sundy JS, et al. Arthritis Rheumatol. 2007;56:1021. Sundy JS, et al. Arthritis Rhematol. 2008;58:2882. Richette P, et al. J Rheumatol. 2007;34:2093.

27 HYPERURICEMIA > 6 mg/dl NSAIDs Colchicine Steroids INFLAMMASOME Interleukin-1 inhs IL-1Ra (Anakinra) Anti-IL1 mabs (Canakinumab) IL1R-fusion protein (Rilonacept) (Modified from) Dalbeth N, et al. Lancet. 2016, 388; ANTI-IL 1 or ANTI-IL1R inhibitors

28 ANTI-IL 1 or ANTI-IL1R inhibitors Schett G, et al. Nature Reviews Rheumatology 2016, 12: Ghosh P, et al. Arthritis Care & Research. 2013, 65: Thueringer J, et al. Semin Arthritis Rheumatism. 2015, 45: Schlesinger N, et al. Ann Rheum Dis. 2012, 71: Terkeltaub R, et al. Ann Rheum Dis. 2009, 68: SCOPEs OF THE TOPIC Pathogenesis of hyperuricemia and gout Management of gout - Treatment of the acute attack. - Long-term treatment with uric acid-lowering therapy (ULT) - Allopurinol doses in patients with chronic kidney disease. New medications with new/established mechanisms Old medications with novel benefits. (only if there is time, slides are available for you to review) Uncertainties

29 ASYMPTOMATIC HYPERURICEMIA: NO TREATMENT IS RECOMMENDED MORE DATA NEEDED!!! Most patients with asymptomatic hyperuricemia do not develop gout. - 3-year risk of incident gout for a person with SUA ~10 is 18%. - 3-year risk of incident gout for a person with SUA ~7-9 is 2% What other factors required for patients with asymptomatic hyperuricemia to develop gout are not completely understood, thus difficult to identify high-risk (to develop gout) patients who will get benefits. What will be the target of SUA? (might be higher than patients with established gout--- < 6 mg/dl.? <6.8 mg/dl) Will treatment of patients with asymptomatic hyperuricemia reduce/alter natural history of other co-morbid CVD events (in addition to reduce gout)? Cost-effectiveness, risks associated with screening and treatment (or simply being labeled as having hyperuricemia ). Stamp L and Dabeth N. Nature Rev Rheumatology. 2014, 10:762. Adapted from Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med. 1987;82:

30 UNCERTAINTIES AND FUTURE RESEARCHES Treatment of asymptomatic hyperuricemia CVD benefits (or harms for febuxostat) of hypouricemic agents (Ongoing trials to address potential CVD harms of febuxostat: CARES in the USA and FAST in UK/Denmark) Safety of hypouricemic agents in patients with GFR < 30 ml/min Goal of serum uric acid: - < 6.8 mg/dl Vs < 6.0 mg/dl Vs others - Potential harms of very low serum uric acid < 3.0 mg/dl (Observation studies suggested association of SUA < 3 mg/dl neurodegenerative diseases such as Parkinsonian diseases) Duration of treatment with hypouricemic/uricouric agents Concept of drug holiday (Availabilities and prices of medications) SUMMARY (1) Asymptomatic hyperuricemia Acute gouty arthritis - No data to recommend treatment at this point. -? Treat in patients with multiple CVD risks: CKD stage II and higher, DM, HTN, hyperlipidemia, tobacco users, IHD, CVA, etc. -?Benefits vs Risks: Allopurinol hypersensitivity Syndrome, neurodegenerative disease (< 3mg/dL). - Life style modification, weight loss, identify CVD risks commonly found in patients. - Avoid diuretics, use meds with uricouric property (losartan, fenofibrate).

31 SUMMARY (2) Asymptomatic hyperuricemia Acute gouty arthritis - Indications Vs Contraindications Vs Drug interactions Vs Cost of medications: Steroid: oral, IM, intra-articular injection. NSAIDs: not with blood thinner, avoid in elderly/chf/ihd/ckd Colchicine (LOW-intensity): reduce dose in elderly patients, CKD. Avoid using/reduce dose with CY3A4/P-glycoprotein inhibitor. (Not sure: use steroid- short-course, decently safe) - Off-label: IL-1 blockades (always involve a specialist, insurance coverage issue) - Counseling and minimizing risks: Obesity, diuretic use, alcohol, diet/life style modification. Asymptomatic hyperuricemia SUMMARY (3) Acute gouty arthritis Chronic uric acid deposits - DO NOT stop hypouricemic agent during the attack. - Counsel the patient how to manage the acute attack. Offer hypouricemic agents when there is an indication: Frequent attacks at least 2 x a year, presence of clinical tophus, uric acid-containing nephroliathiasis. Xanthine oxidase is the first choice. - Allopurinol is the first choice even with renal insufficiency. COUNSEL the patient about AHS. If tolerated, titrate the dose up gradually to achieve SUA goal. If not tolerated, switch to febuxostat. - Start LOW and GO slowly to reduce flares and possible allopurinol hypersensitivity syndrome (AHS). - Consider checking HLA-5801 in Han s Chinese, Thai, Korean. If positive, allopurinol is CONTRAINDICATED. Switch to febuxostat. - Add uricouric agent (probencid, if GFR >50, lesinurad if GFR >30) to xanthine oxidase if higher dose xanthine oxidase is not tolerated and SUA goal is not achieved. - Provide prophylaxis to minimize flare and to re-inforce compliance with hypouricemic treatment. NSAIDs or Colchicine. Duration of prophylaxis 3-6 months.

32 SUMMARY (4) Asymptomatic hyperuricemia Acute gouty arthritis Chronic uric acid deposits Serum uric acid goal - Check uric acid after providing uric acid lowering therapy. - All patients, less than 6 mg/d, not less than 3 mg/dl (3.0 to 5.9). - Severe, with tophi, less than 5 mg/dl, not less than 3 mg/dl (3.0 to 4.9). Dalbeth N, et al. Lancet. 2016, 388;

33 SCOPEs OF THE TOPIC Pathogenesis of hyperuricemia and gout Management of gout - Treatment of the acute attack. - Long-term treatment with uric acid-lowering therapy (ULT). - Allopurinol doses in patients with chronic kidney disease. New medications with new/established mechanisms Old medications with novel benefits. Uncertainties INCREASED CARDIOVASCULAR RISKs/EVENTs WITH HYPERURICEMIA/GOUT Meta-analyses have concluded that hyperuricemia is the independent risk factor for CHD, stroke and mortality. Large epidemiologic studies have demonstrated that gout is an independent risks: - CHD - Peripheral arterial disease - Heart failure - Stroke - Death due to cardiovascular causes. The presence of baseline tophi is the independent risk factor of mortality after adjustment for baseline CV risks and baseline SUA. (SMR 1.98, 95% CI ) The risks associated with CVD complications are lower in asymptomatic hyperuricemia. Direct consequence of uric acid crystal formation/hyperuricemia: - Causes gout attack associated with pro-inflammatory environments. - Requirements of NSAIDs, which could negatively affect CVD system. - Low-grade inflammation around tophi and in asymptomatic joints with uric acid crystals. - Increased free radical formation during production of uric acid. Common co-existing co-morbid conditions: DM, HTN, CKD, dyslipidemia, metabolic synd. Richette P et al. Nat Review Rheumatol. 2014; doi: /nrrheumatol Perez-Ruiz F, et al. Ann Rheum Dis. 2014;73:177.

34 CARDIOVASCULAR BENEFITS WITH XANTHINE OXIDASE INHIBITORs:?Xanthine oxidase inhibitor lessens CVD risks/death. Xanthine oxidase inhibitor could potentially help lessen CVD risks. - Hypouricemic effects. Lessen gout attack, uric crystal formation. - Non-hypouricemic effects: reduce free radical formation, improve endothelial functions, lowering blood pressure, increased inosine/adenosine. - Upstream precursors (eg. inosine, adenosine) are beneficial. Kok VC, et al. PLOs One. 2014;9:e Taheraghdam AA, et al. Med Princ Pract 2014;23:134. Agarwal V, et al. J Clin Hypertens;15:435. Dubreuil M, et al. Ann Rheum Dis. 2015;74:168. Singh JA, et al. Arthritis Research&Therapy. 2016;18:209. Liu P, et al. Intern Med. 2015;54:2129. Singh JA, et al. Ann Rheum Dis. 2017;76:72. Singh JA, et al. Ann Rheum Dis 2017;133. Thanassoulis G, et al. Arch Intern Med. 2010;170:1358. Feig DI, et al. JAMA. 2008;27:924 Szwejkowski BR, et al. JACC;61(10):E1256 Kim SC, et al. Am J Med. 2015;128:e7-653.e16 Richette P et al. Nat Review Rheumatol. 2014; doi: /nrrheumatol CARDIOVASCULAR BENEFITS WITH XANTHINE OXIDASE INHIBITORs: THE JURY IS STILL IN! Most data are from allopurinol with gaining more data on febuxostat. Most data are derived from patients with hyperuricemia associated with gout, preexisting cardiovascular diseases. Observational case-control studies >> randomized controlled studies. - Reduce blood pressure - Reduce over-all mortality - Improve renal function and GFR The cardiovascular benefits are not always replicated: - Baseline presence or absence of CVD risks. - More or less CVD risks. More or less benefits might depend on the absence or more/less baseline CVD risks. NO DATA from patients with asymptomatic hyperuricemia. Kok VC, et al. PLOs One. 2014;9:e Taheraghdam AA, et al. Med Princ Pract 2014;23:134. Agarwal V, et al. J Clin Hypertens;15:435. Dubreuil M, et al. Ann Rheum Dis. 2015;74:168. Singh JA, et al. Arthritis Research&Therapy. 2016;18:209. Liu P, et al. Intern Med. 2015;54:2129. Singh JA, et al. Ann Rheum Dis. 2017;76:72. Singh JA, et al. Ann Rheum Dis 2017;133. Thanassoulis G, et al. Arch Intern Med. 2010;170:1358. Feig DI, et al. JAMA. 2008;27:924 Szwejkowski BR, et al. JACC;61(10):E1256 Kim SC, et al. Am J Med. 2015;128:e7-653.e16 Richette P et al. Nat Review Rheumatol. 2014; doi: /nrrheumatol

35 MORTALITY REDUCTION WITH ALLOPURINOL Gout is associated with 9-28% increased risk of premature death. The mortality benefits cannot be explained by hypouricemic action. (No similar reduced mortality or improvement of endothelial function with probenecid, benzbromarone) A VA observational study (99% male) showed 23% lower risk of death among individual with hyperuricemia. A nested case-control study showed 26% reduced all-cause mortality in patients with gout and congestive heart failure. Recent new case-(propensity score matched) control study suggested reduced all-cause mortality in hyperuricemia and/or gout patients in general population. Dubreuil M, et al. Ann Rheum Dis. 2015;74:1368. Luk AJ, et al. Rheumatology 2009;48:804. Thanassoulis G, et al. Arch Intern Med. 2010;170:1358. MORTALITY REDUCTION WITH ALLOPURINOL Allopurinol was associated with 11% reduced all-cause mortality in pts with hyperuricemia (HR 0.89, ) and 19% in pts with gout (HR 0.81, ).?No detail on cause-specific death. No data on pts with GFR < 30 ml/min. This overall survival benefit of allopurinol might outweigh the impact of rare, potentially serious AHS. Similar mortality reduction has not been shown yet with febuxostat. Dubreuil M, et al. Ann Rheum Dis. 2015;74:1368.

36 RENAL PROTECTION WITH XANTHING OXIDASE INHIBITORs: GROWING EVIDENCEs. (Except for AHS from allopurinol allergy), Allopurinol use is associated with an improved renal function in both randomized trials and observation studies. An ongoing 24.3$ million federally funded randomized study is ongoing to determine if allopurinol can prevent renal function loss in diabetes (with or without gout). Xanthine oxidase inhibitor: - Hypouricemic effects. Lessen gout attack, uric crystal formation. - Non-hypouricemic effects: reduce free radical formation, improve (renal)endothelial functions, lowering blood pressure, increased inosine/adenosine. Singh JA, et al. Ann Rheum Dis 2017;133. Levy GD, et al. J Rheum. 2014;41:955. Siu YP, et al. Am J Kidney Dis. 2006;47:51. Maahs DM, et al. Curr Diab Rep 2013;13:550. Richette P et al. Nat Review Rheumatol. 2014; doi: /nrrheumatol RENAL PROTECTION WITH XANTHING OXIDASE INHIBITORs: GROWING EVIDENCEs. In people with no known h/o renal failure, allopurinol exposures were associated with less incident renal failure, with dose-response relationship (dose 200 mg and higher). Singh JA, et al. Ann Rheum Dis 2017;76:133.

37 RENAL PROTECTION WITH XANTHING OXIDASE INHIBITORs: GROWING EVIDENCEs. In sensitivity analysis by extending baseline from 183 days to 365 days, longer duration of exposure than a year seems to be renal protective, with duration-response relationship. Singh JA, et al. Ann Rheum Dis 2017;76:133. COLCHICINE AND CARDIOVASCULAR BENEFITs Colchicine is anti-inflammatory: - Disrupting microtubule spindle formation - Disturbing inflammasome function. - Inhibiting cytokine production - Hindering neutrophil chemotaxis. An open-label un-blinded study showed benefits of colchicine in secondary CV prevention in general population. Gout patients have 30-65% increased risk of CV events.?colchicine might provide CV risk protection? Nidorf SM, et al. J Am Coll Cardiol 2013;61:404. Choi HK, et al. Circulation. 2007;116:894. Zhu Y, et al. Arthritis Rheumatol. 2012;125: e1. Solomon DH, et al Sep;75(9): doi: /annrheumdis Crittenden AB, et al. J Rheumatol. 212;39:1458.

38 COLCHICINE AND CARDIOVASCULAR BENEFITs Crittenden AB, et al. J Rheumatol. 2012;39:1458. COLCHICINE AND CARDIOVASCULAR BENEFITs 49% lower risks of primary outcomes (HR 0.51, 95% CI ) Solomon DH, et al Sep;75(9): doi: /annrheumdis % lower risks of all-cause mortality (HR 0.27, 95% CI ) Primary outcomes: MI, stroke, TIA Secondary outcomes: primary + procedures, All-cause mortality