Annual Rheumatology & Therapeutics Review for Organizations & Societies

Transcription

1 Annual Rheumatology & Therapeutics Review for Organizations & Societies

2 Gout: New Updates on an Old Disease

3 Learning Objectives Understand the epidemiology of gout Describe the challenges and the role of the rheumatologist in managing gout Discuss new therapies approved and in progress for the management of gout Review new ACR guidelines for gout management

4 Outline Epidemiology Challenges in gout management Hyperuricemia, risks, metabolic syndrome Immunobiology of Gout New ACR Guidelines Mgmt Gout New Therapies: approved/in progress Role of the Rheumatologist

5 Hippocratic Aphorisms on Gout Eunuchs do not take the gout, nor become bald A woman does not take the gout, unless her menses be stopped A youth does not get gout before sexual intercourse In gouty affections, inflammation subsides w/in 40 d (studies show 7d) Gouty affections become active in spring and in autumn Hippocrates 5 th century BC Adapted from Nuki and Simkin Arthritis Research & Therapy (Suppl 1):S1`

6 Gout: Extent of the Problem Prevalence of gout has doubled in last 30 yrs. 2008, prevalence to 8.3 million (3.9% pop) 1,2 Males: 5.9% (6.1 million) Females: 2.0 % (2.2 million) Hyperuricemia affects 43.3 million (21%) adults Kim et al estimates the annual cost of Acute Gout is $27,378,494 in the USA (Probable underestimate as women excluded & not all indirect and intangible costs included) 3.9 million outpatient visits in 2002 ~70% to PCP and only 1.3% to rheumatologists Zhu Y, et al. Arthritis Rheum 2011 Kim Clin Ther.2003;25: Lawrence RC, Felson DT, Helmick CG et al. Arthritis Rheum. 2008;58: Qazi Y, Lohr JW. emedicine.

7 Hyperuricemia and Gout Serum Urate mg/dl Gout attack/yr/ year cumulative < > (4.9%) 220 (22%) Incidence of gout increases with uric acid level Majority of pts with hyperuricemia will remain asymptomatic < >10 mg/dl Campion EW. Am J Med Mar;82(3):421-6

8 Why Are We Seeing More Gout? Baby boomers Dietary trends (Atkins) Prevalence of metabolic syndrome, obesity, diabetes, HTN, CRD Increase use of meds (aspirin, diuretics)

9 ARS: In Your Opinion, What Has Been Most Disappointing in the Care of Gout Patients? A. Lack of new/effective therapy B. Noncompliance C. Treatment by nonrheums D. Limited available treatment for tophaceous gout E. Lack of data on how to manage these patients

10 Survey of 484 US Rheumatologists Most Disappointing in the Care of Gout pts? Lack New Rx Noncompliance Rx by nonrheums Rx Toph.Gout Milestones in Rheumatology Survey Percent

11 PCPs and Gout Management 86% PCPs comfortable managing Gout <3% refer their Gout pts to Rheumatology PCP Rx allopurinol to everyone <1/3 routinely monitor SUA while on ULT+ PCPs LESS likely to use prophylaxis when initiating uric acid-lowering therapy Mean post-treatment SUA were higher for PCP patients vs. Rheum patients (6.0 vs 5.0 mg/dl) PCP don t do arthrocentesis (3%) J Clin Rheumatol Feb;3(1):24-7. Rheum2008:35:498 #Roberts C, et al. Rheumatology 2002; 41:503 +Owens D, etal. Ir Med J. 2008;101:147

12 Who Should Manage Gout: PCP vs Rheums Difference in Rheum vs PCP management? Rheum referral more accurate dx Shorter Sx duration (3.1 days) Shorter hospitalization (7.4 days) Lower hospitalization costs ($5995 less) Higher rate of patient compliance *Solomon DH. Ann Int Med 12:52, 1997 Krishnan E, J Rheum2008:35:498 #Roberts C, et al. Rheumatology 2002; 41:503 +Owens D, etal. Ir Med J. 2008;101:147

13 Surveys of Patients Regarding Gout Patient surveys shows a knowledge deficit on the causes and consequences of gout Only 17% compliant with allopurinol Few were aware of common food triggers Many think gout is part of normal aging Most pts (and MDs) focus on acute Rx (not ULT and disease prevention) Spencer Ann Rheum Dis. 2012;71: Zandman-Goddard G Rheumatology (Oxford) Feb 7 Harrold L, BMC Musculoskelet Disord. 2012;13:180

14 Management Rx Challenges Misdiagnosis Asymptomatic hyperuricemia Colchicine use Allopurinol dosing: treat to target ULT without prophylaxis Rx Tophaceous gout Comorbidities (eg, CRI, CHF) Noncompliant patients 30% patients don t fill their Rx s Neogi T. J Rheumatol 2006;33:104-9.

15 What's a Normal Uric Acid Level? Normative Aging Study 2046 men followed 14.9 years Creatinine (mg/dl) Normal Uric acid level (mg/dl) mg/dl* 1.5 mg/dl 9 mg/dl mg/dl >2.0 or HD 12 mg/dl *lab ref range Am J Med 1987 Mar;82(3):421-6.

16 Total uric acid (undissociated + urate): mg/l How Hyperuricemia Cause Disease 1800 Uric acid K Urate 200 Na Urate Urinary ph Fig. 3. Solubility of total uric acid. Na urate and K urate as a function of urinary ph. Uric acid is a weak acid (pka = 5.8) existing as urate at physiologic ph Solubility of uric acid decreases with temperature and ph Campion EW. Am J Med Mar;82(3):421-6

17 Comorbidities Associated With Gout & Hyperuricemia That Warrant Consideration Comorbidity Freq. Obesity 1,2 53% Metabolic syndrome 3 76% Diabetes mellitus 4 26% Heart failure 5 11% Hypertension 6,7 76% Renal disease 71% Hyperlipidemia 1 63% 1. Nakanishi. Int J Epidemiol. 1999;28: Denzer. J Ped Endo Met. 2003;16: Ford. JAMA. 2002;287: Boyko. Diabetes Care. 2000;23: Anker. Circulation. 2003;107: Gavin. Am J Cardiovasc Drugs. 2003;3: Feig. Hypertension. 2003;42: Zhu Y. Am J Med. 2012;125: Keenan RT Am J Med. 2011; Pandya B. Arthritis Rheum. 2010;62(sup10):879.

18 Gout, Hyperuricemia and Chubby Outcomes

19 Percentage of patients with metabolic syndrome Gout and Metabolic Syndrome Metabolic Syndrome is found up to 76% of gout patients BMI>35 assoc > 3-7X risk Gout 76% gout patients have metabolic syndrome 34% increase in DM among men with gout Abbott J Clin Epidemioll :237 Niskanen LK. Arch Int Med :1546 Choi H. Am J Med.2007 ;120: Gout associated with higher prevalence of metabolic syndrome across age groups Gout No gout Age (yr) Frequency of Metabolic Syndrome < >10 Serum Uric Acid

20 Cumulative incidence (%) Gout, Hyperuricemia and CVD 100 Survival (%) sua & MI UA (N=755; 20 deaths) UA (N=802; 28 deaths) UA (N=751; 36 deaths) UA (N=790; 72 deaths) Framingham: independent risk factor for MI and stroke Carotid ASVD risk rises w/ sua MRFIT: sua risk carotid plaque Gout & sua increases risk of peripheral arterial disease Years Coronary Artery Ca++ w/ sua NHANES sua correl w/ CVdeath High risk CVD pts. sua is indep risk for all cause death No gout; n=3,987 Treated gout; n=129 Untreated gout; n=89 sua & CVD Krishnan E, et al. Hypertension 2007;49: Ioachimescu AG, et al. Arthritis Rheum. 2008;58(2): Klemp P et al. Annals of Rheumatic Diseases 1997;56: Krishnan E. Arthritis Res Ther. 2012; 14(1): R10 0 All-cause death CHD mortality Coronary incidence Stroke

21 Survival, % Heart Failure Relationship Between Serum Urate and Survival Kaplan-Meier Survival Curves SUA 6.72 mg/dl SUA mg/dl SUA mg/dl SUA >13.44 mg/dl Mortality Risk Ratios vs SUA < **** P<.0001 * P= A study of 294 chronic heart failure patients were assessed **** Anker et al. Circulation. 2003;107: Time, years * ****

22 0.00 Proportion of men without hypertension Gout, Hyperuricemia and HTN Adjusted for age Age and risk adjusted sua & HTN sua & CVD Follow-up in years Follow-up in years SUA=<7 mg/d 803 men with baseline hyperuricemia Time to HTN shorter when SUA>7 mg/dl Hyperuricemia 80% excess risk for HTN SUA=>7.0 mg/di Krishnan E, et al. Hypertension 2007;49: Ioachimescu AG, et al. Arthritis Rheum. 2008;58(2): Klemp P et al. Annals of Rheumatic Diseases 1997;56: Krishnan E. Arthritis Res Ther. 2012; 14(1): R10

23 Gout, Hyperuricemia and HTN ARIC: sua risk for HTN (RR 1.10) Normative Aging: sua risk HTN Metanalysis of 18 studies (55,607 pt) Hyperuricemia assoc w/ risk for incident HTN (adjusted RR 1.41) 1 mg/dl sua HTN RR 1.13 Krishnan E, et al. Hypertension 2007;49: Ioachimescu AG, et al. Arthritis Rheum. 2008;58(2): Klemp P et al. Annals of Rheumatic Diseases 1997;56: Krishnan E. Arthritis Res Ther. 2012; 14(1): R10

24 Alterations in Uric Acid and the Pathophysiology of Hypertension, CHF, CVD A Postulated Explanation for the Link Sympathetic outflow Hyperinsulinemia Altered renal sodium handling Arterial pressure Renal blood flow Uric acid excretion Serum Urate Purine oxidation Reactive oxygen species AT 1 receptor activation Early hypertensive nephrosclerosis Hypertensive vascular injury Ward. Lancet. 1998;352:

25 Diastolic Blood Pressure, mm Hg Diastolic Blood Pressure, mm Hg Allopurinol Rx of BP in Adolescents w/ Newly Diagnosed Essential HTN RDBPCT: 30 Adolescents w/ HTN & SUA > % were obese or overweight Rx w/ Placebo vs Allopurinol 400 mg/d SUA dropped w/ Allopurinol Rx PBO 97%; Placebo 24hr mean Diastolic BP Allopurinol Allop 33% Feig, et al JAMA. 2008; 300(8): Pretreatment End of Placebo Phase 60 Pretreatment End of Allopurinol Phase

26 Approaches to Managing Hyperuricemia/Gout Lifestyle Treat to target ULT: approved/in development Prophylaxis

27 2012 ACR Guidelines Part I Address education, diet, lifestyle & comorbidities. Allopurinol, febuxostat (XOI) are 1 st line ULT Decr. serum urate to improve signs & symptoms, with the target <6 mg/dl at a minimum. Rx allopurinol 100 qd & titrate upward (even w/ CKD) Test HLA B*5801 (PCR) in high risk pts* Combination ULT w/ uricosuric Rx may be needed Pegloticase is appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, appropriately dosed oral ULT options. * Severe allopurinol hypersensitivity rxns (e.g., Koreans, Han Chinese and Thai populations) Khana D. Arthritis Care Res 2012;64:1447.

28 2012 ACR Guidelines Part II ACUTE GOUTY ARTHRITIS: Rx and Prophylaxis Initiate therapy within 24 hrs of acute attack Continue ULT, w/o interruption, during acute flares Use NSAIDs, corticosteroids, or oral colchicine 1st line & combination therapy for severe or unresponsive pts PO colchicine or low-dose NSAIDs - when initiating ULT Khana D. Arthritis Care Res 2012;64:1447.

29 2012 ACR Guidelines Rx of Acute Gout Mild-Moderate Pain, Particularly For anattack Affecting Only 1 or a Few Small Joints, or 1-2 Large Joints Assess severity Monotherapy A Severe Pain, Particularly For a Polyarticular Attack or an Attack Affecting Multiple Large Joints Option: Initial combination therapy See Table 1 C NSAID A (^or COX-2 inhibitor) Systemic A Corticosteroids Supplement with Topical Ice as needed B Colchicine A Consider alternative diagnosis Inadequate response Treatment Outcome Successful Outcome Switch to alternate Option: Add-on C monotherapy C combination therapy Table 1 Treatment outcome Inadequate response Patient Education: including diet and lifestyle; role of uric acid excess in B gout and as key treatment target; prompt self-treatment of subsequent acute gout attacks Consider indications for ULT or adjustment of ongoing ULT C See Part I of Guidelines Off-Label Therapies in Development > Khana D. Arthritis Care Res 2012;64:1447.

30 Dietary Influence Choi HK NEJM 2004;350: Choi HK BMJ. 2009; 336(7639): Choi HK. Lancet 2004;363:

31 Modify Lifestyle Risks Diet is usually impractical, ineffective and rarely adhered to in clinical practice

32 Adjunctive Urate Lowering Interventions Calcium Channel blockers Losartan Fenofibrate Leflunomide Avoidance of unnecessary meds: diuretics, ASA Crittendon, Pillinger. Bull NYU Hosp Jt Dis. 2011;69:257

33 Gout Treatment When to start urate lowering therapy? After a first attack, 40% of patients will experience another attack within the first year; 80% will experience a further attack within 2 years. British Society for Rheumatology Guidelines: Treat if risk for further attacks or damage by tophi is high EULAR guidelines: ULT indicated in patients with recurrent acute attacks, arthopathy, tophi, or radiographic changes ACR 2012 Guidelines: Treat when >1 attack/yr Ferraz MB. J Rheumatol 1995;22: Jordan KM. Rheumatology 2007;46: Zhang W. Ann Rheum Dis 2006;65:

34 Why Target Uric Acid < 6.0 mg/dl? 6 mg/dl (360 μmol/l) is below the saturation point of MSU (6.8 mg/dl) <6.0 in most gout pts; 4-5 mg/dl in tophaceous pts Prevent crystal formation; promote tophus dissolution Benefits of T2T: frequency of attacks tophus volume urate crystal in synovial fluid Consequences of Gout, sua Examples of Taking aim: HTN, Diabetes, CAD/ASHD, hyperlipidemia Edwards L.U S M U S C U L O S K E L E T A L R E V I E W

35 Incidence of recurrent gouty attack more than one year after each patient s first visit (%) A Retrospective Study of the Relationship Between Serum Urate Level and Recurrent Attacks of Gouty Arthritis: Evidence for Reduction of Recurrent Gouty Arthritis with Antihyperuricemic Therapy N=267 Gout pts w/ 3 yrs F/U Attacks in 91 patients 80.0 observed logistic regression Group SUA Attacks 7.01 No Attacks average serum urate during the whole investigation period* (mg/dl) Shoji A. Arthritis Rheum Jun 15;51(3):321-5.

36 18 Gout pts Starting ULT Underwent q 3 Month Arthrocentesis of the Asymptomatic Joint Reduction of SUA # MSU Crystals sua 9.2 MSU Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial fluid after successful hypouricaemic treatment relates to the duration of gout. Ann Rheum Dis 2007;66: Perez-Ruiz F Rheumatology 2009;48:ii9-ii14

37 sua level (mmol/l) (mg/dl) Change in volume (cc) Does ULT & T2T in Gout Reduce Tophi? Short term: non-significant trends seen* Long-term: sustained sua < 6.0 (,5.0) shows significant reduction in tophi # and volume Lower sua leads to more Rapid Tophus Reduction Tophus Volume in12 mos: Related to sua level Velocity of tophi reduction (mm/month) R Sq Linear= Perez-Ruiz F Arthritis Rheum 2002;47: Perez-Ruiz F. J Rheumatol 2007;34: Average sua (mg/dl)

38 Success of T2T in Gout 1 yr T2T study of 125 Asian Gout pts starting ULT Mean time to achieve SUA<6 was 36.9 wks Survival Analysis: how many achieved SUA < 3 mos = 6 mos = 12 mos = 72% More likely w/ q 2 mos visits Without a T2T approach in Gout? Few Achieve the Target (21-47% SUA < 6.0) Lim Scand J Rheumatol. 2012;41:450 Tausche. Dtsch Arztebl Int. 2009;106:549 Chohan Curr Opin Rheum. 2009;21:143

39 Pharmacotherapy for Gout Treatment Goal Categories Action Examples Xanthine oxidase inhibitors Prevents formation of uric acid Allopurinol 1 Febuxostat 1 Oxypurinol Treatment of hyperuricemia Uricosuric agents Increases excretion of uric acid Probenecid 1 *Sulfinpyrazone 1 *RDEA594 Uricase Uric acid allantoin Urate disolution Pegloticase 5 Treatment of gouty arthritis Anti-inflammatory agents Interleukin-1 targeted therapy Reduce inflammation Manage acute attack Use for prophylaxis Binds IL-1β or IL-1R Use for Prophylaxis NSAIDs 1 Colchicine 1 Steroids 1 *Anakinra 2 *Canakinumab 3 *Rilonacept 4 *agents not yet FDA approved in for gout Tausche AK. Dtsch Arztebl Int. 2009;106:549; Anakinra [package insert]. Sobi 2012; Canakinumab [package insert; Novartis Pharmaceuticals.; Hoffman. J Allergy Clin Immunol. 2009;124:1129; Chohan. Curr Opin Rheum. 2009;21:143

40 Urate Lowering Therapy (ULT) 95% of all allopurinol Rxs are for < mg/d < 50% achieve SUA <6.0 UK Analysis 63,105 gout patients in practice 25% NO adjustments for AZA/6MP 26% No adjustments for renal impairment 57% inappropriate Rx of asymptomatic hyperuricemia 64% poor compliance by 9753 gout pts Likely w/ Young, AA, Rx by PCP Better compliance when Rx by rheumatologists or nephrologists 26% of 4357 pts creatinine not monitored Mikuls Rheumatology. 2005;44:1038. Am J Med 1984;76: Can J Hosp Pharm 1992;45:21.J Qual Clin Pract 2000;20:42. Aust N Z J Med 2000;30: Solomon D. ARD. 2008;67:609 Raebel MA. Ann Pharmacother. 2006;40:386-91

41 Allopurinol Use with Renal Impairment Allopurinol Package Insert Allopurinol can substantially reduce uric acid in gout refractory pts, even in the presence of renal damage Some w/ pre-existing renal dz have shown a rise in BUN w/ allopurinol monitor renal function early on Renal failure only seen w/ neoplasia, myeloma, CHF Pts w/ decreased renal function may require lower doses No mention of a ceiling dose for CRI Dose allopurinol according to effect, not renal funx If dosed to CrCl, sua not controlled Bryant PrimHealthCare 2011;3:323 Chao Curr Rheum Rep 2009;11:135 Stamp A&R2011;63:412 Dalbeth Rheum :1646

42 Febuxostat Selective xanthine oxidase inhibitor Phase II, III trials; doses of mg Use w/ renal insufficiency metabolised by hepatobiliary conjugation 60% (n=1673) rx w/ Mild-mod CRI (30-89 cc/min)?safe in pts with mild-mod hepatic dysfunction Can be safely given with colchicine, naproxen, indomethacin, hydrochlorothiazide or warfarin Incr. mortality, CV & thromboembolic events 1 st eval (RCT/LTE): 9 Deaths FEB vs 0 Placebo

43 FACT: Febuxostat vs Allopurinol 52 wk RCT Outcome Serum urate <6.0 mg/dl Gout flares weeks 1-9 Gout flares weeks 9-52 Reduction in tophus area Febux 80mg Febux 120mg Allopurinol 300mg 53% 62% 21% 22% 36% 21% 64% 70% 64% 83% 66% 50% P Value <0.001 FEB 80/120 vs ALLOP More flares if Prophylaxis Withdrawn 0.08 FEB 80 vs ALLOP Becker MA et al. N Engl J Med 2005; 353:

44 Proportion of Subjects (%) APEX Trial NO Signif reduction in 28 5 yr F/U study, tophus resolution was achieved in 69% (18/26) of patients Febuxostat Versus Allopurinol and Placebo in Reducing Serum Urate in Gout: A 28 week, Phase III, Randomized, Double blind, Parallel group Trial All Subjects Normal Renal Function Impaired Renal Function 126/262 b,c,d,e,f 122/253 4/9 175/269 b,c,d 170/258 5/11 92/134 b,c,d 88/129 3/5 80/258 b 60/ /134 0/129 0/5 0/10 Placebo Febuxostat 80 mg Febuxostat 120 mg Febuxostat 240 mg Allopurinol 300 a mg Treatment Schumacher R, Arthritis Rheum.2008 Nov 15;59(11): Schumacher R Rheumatology 2009 Feb;48(2):

45 % of subjects Febuxostat vs Allopurinol in the Treatment of Gout in Subjects >65 Years 295 pts >65 years of age from FACT or APEX Demographic features and comorbidities similar in all treatment groups Endpoint: proportions of subjects with sua <6.0 mg/dl at the last 3 visits and at the final visit % Subjects Achieving sua <6.0 mg/dl Last 3 visits Final visit Placebo Febuxostat 80 mg QD Febuxostat 120 mg QD Febuxostat 240 mg QD Allopurinol 300 mg QD Febuxostat: well-tolerated up to doses of 240 mg/day Phase III studies to be repeated due to concerns re: CVS toxicity Schumacher HR et al. EULAR 2007, Barcelona, #THU0353.

46 Subjects, % CONFIRMS: sua <6 mg/dl at Final Visit *# Febuxostat 40 mg Febuxostat 80 mg Allopurinol More flares with higher doses of febuxostat Flares gradually decreased over time Fewer flares w/ prophylaxis given for 6 months CV events: FBX 40=0%, FBX 80=0.4%, allopurinol=0.4% * P<0.001 vs allopurinol # P<0.001 vs febuxostat 40 mg Non-inferior to allopurinol FDA Arthritis Advisory Committee Nov 24, 2008

47 Febuxostat and the Frequency of Cardiovascular (ATPC) Events Prior RCTs CONFIRMS (F153) Febuxostat (total) 9/1177 (0.8%) 3/1513 (0.2%) Allopurinol 1/521 (0.2%) 3/756 (0.4%) FDA Arthritis Advisory Committee Nov 24, 2008

48 Chronic Tophaceous Gout Associated with early age of onset, long duration of untreated disease, frequent attacks, upper extremity involvement, polyarticular disease and elevated serum uric acid. 30% of patients will develop tophaceous gout in 5 years if left untreated Gutman AB. Arthritis Rheum 1965; 8:

49 Pegloticase: Mechanism of Action Pegloticase is a pegylated modified porcine recombinant uricase It converts uric acid to allantoin Uric acid is sparingly soluble whereas allantoin is highly soluble Allantoin is excreted efficiently by the kidneys Xanthine Uric acid Allantoin Pegloticase Terkeltaub R. Nat Rev Rheumatol. 2010;6(1): Chohan S. Curr Opin Rheumatol. 2009;21:

50 % w/ SUA <6.0 IV Pegloticase in Chronic Refractory Gout FDA approved in 2010 based on 6 trials & 541 patients 2 DBRPCT: 225 pts w/ severe gout, allopurinol failure & sua> 8.0 mg/dl. (Prevalent comorbidities DM, CAD, etc) Immunogenicity 89%, infusion Rx 26-41%, anaphylaxis 6% Primary endpt sua<6mg/dl (80%) Mo 3-6 Placebo q 2 wk q 4 wk OL ext study of 149 pts, 28±18 PEG infusion, 25mos F/U 10 /11 pts: serious infusion rxn occurred if sua> 6 mg/dl. Sundy J. JAMAl. 2011,; 306 :306:711 Pegloticase is effective in Refractory Gout Pts

51 Pegloticase most developed antibodies to pegloticase with adverse effects on safety and efficacy ~90% tested positive for antibodies against (PEG) and the level of antibodies was correlated with infusion reaction (P<0.001) Elevation of SUA > 6.0mg/dl surrogate for Abs and Rxns Eight serious cardiac adverse events in the pegloticase groups, including 2 sudden cardiac deaths, 2 exacerbations of congestive heart failure, 2 cases of dysrhythmia, 1 MI, and 1 case of angina. None in the control group 1. Becker MA et al. ACR abstracts, 2008; FDA briefing document June 2009

52 Pegloticase Dose: 8mg IV q2weeks REQUIRED: Prophylaxis against infusion reactions Measure serum uric acid level prior to each infusion, consider d/c Rx if pre-treatment serum urate level > 6 mg/dl (esp. if this occurs > once) ULTs should be discontinued/not initiated prior to starting pegloticase. Safety Concerns: - G6PD deficiency - Infusion rxn/anaphylaxis - CHF - Flares

53 Pathophysiology: IL-1 and Gout Inflammasome: high molecular wt complexes that activate caspase-1 PAMP Colchicine PGN RNA MSU ATP DAMP NF-kB NLRP3 (Cryopyrin) activated by: Stimuli Crystals Pore-form. toxins Bacteria, Viruses DNA, RNA Response Inflammation Antimicrobial Adjuvant Autoinflammatry Pope R, Tschopp J. Arthritis Rheum. 2007;56: Inflammasome MSU and pathogen-associated molecular patterns (PAMP) or danger-associated molecular patterns (DAMP) may activate the NLRP4 (NALP3) inflammasome. Caspase Pro-IL-1b IL-1b release

54 Up-Regulation of Innate Immunity in Microarray Analysis Adaptive Immunity Innate Immunity Adaptive Immunity Erythropoiesis Inflammation Genes of the innate immune response are upregulated Healthy Inactive Active GOUT Rodriguez-Pla A. ACR 2012, Abstract # 1629 sojia

55 Potential IL-1 -Directed Treatment Options Targeted IL-1β blockade (canakinumab) IL-1 Trap (rilonacept ) IL-1 receptor antagonist (anakinra) Target IL-1β only IL-1β, IL-1, IL-1Ra IL-1R1 Mode of Action Antibody Soluble receptor Natural antagonist Prevents binding of IL- 1β to its receptor Prevents binding of IL-1β, IL-1 and IL-1 receptor antagonist Acts as an IL-1 receptor antagonist to bind to IL-1 and IL-1β Elimination t 1/2 3 4 weeks 6 days 4 6 hours Dose (CAPS): Every 8 weeks weekly daily Arcalyst (rilonacept) Prescribing Information, 2006; Kineret (anakinra) Prescribing Information, 2008 Novartis data on file. Note: Canakinumab is not FDA approved. Anakinra is used for CAPS off-label.

56 Open-Label Reports of Anakinra in Gout 10 pts OL Study - failed NSAID, colchicine, steroids 100 mg x 3d: 10/10 responded to anakinra in hours 24 hospitalized pts with acute gout + comorbidities Rx Anakinra 19/22 dramatic improve by1d, 3/22 by d2 10 pts hospitalized -failed steroids. Rx anakinra x3d 6 good response, 3 partial response 9 pts w/ recurrent flares after d/c anakinra (ranging from 3 to 45 days after) So et al. Arthritis Res Ther 9:R28, 2007 Cho, et al ACR 2010 #163 Chen Semin Arthritis Rheum. 2010;40:210-4

57 Canakinumab: Mechanism of Action Canakinumab is a human monoclonal anti-human IL-1β antibody IL-1b Canakinumab binds to human IL-1β and neutralizes its activity Inflammation Canakinumab IL-1R Adapted from Hoffman HM. J Allergy Clin Immunol. 2009;124:

58 Cumulative event rate (%) Canakinumab Reduces Flares w/ ULT Initiation 432 pts w/ active gout starting ULT with allopurinol Flare prophylaxis w/ colchicine vs CAN Single dose CAN or monthly x 4 CAN superior to daily colchicine ISR 6.2% Canakinumab 25 mg Canakinumab 300 mg Canakinumab 50 mg Canakinumab q4wk Canakinumab 100 mg Colchicine 0.5 mg Canakinumab 200 mg COL CAN Time post dose (weeks) Treatment Follow-up Schlesinger N. Ann Rheum Dis Jul;70(7):

59 CANAKINUMAB VS TRIAMCINOLONE IN ACUTE GOUT Canakinumab 10,25, 50, 90, 150 vs TCA IM Canakinumab rapid pain relief in acute gout & significantly reduces the risk of recurrent flares compared with triamcinolone IM Pain Relief Recurrent Flares So A. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study. Arthritis Rheum Oct;62(10):

60 LONG TERM SAFETY CANAKINUMAB 36 Weeks open label extension after the initial 12 week core study 397 patients in core study, 232 entered E1 (50% completed) On demand CAN-PFS 150 mg SQ with new Gout flare CAN-PFS delayed time to new flare compared to TCA patients RRR 55% (HR 0.45, 95%CI , p< 0.001) Incidence of infection after switching from TA to CAN was similar CAN-PFS SAE 3.4/100py 1 death (cardiac failure)- not related to study drug P Sunkureddi, ACR 2014 Abstract # 174

61 Rilonacept: Mechanism of Action Rilonacept is a recombinant fusion protein with high affinity for IL-1β It also binds to IL-1α, and IL-1Ra Rilonacept reduces gout-induced inflammation by binding to IL-1β and blocking its interaction with the IL-1 receptor IL-1b IL-1α Inflammation Rilonacept IL-1R Hoffman HM. J Allergy Clin Immunol. 2009;124: Gillespie J. Journal of Inflammation Research. 2010;3:1-8

62 Mean number of flares per patient, 95% CI Mean Change from Baseline to Averaged Pain at Hours (NRS) Rilonacept: Role in Gout? SURGE: RIL vs RIL/Indo vs Indomethacin 3d: Indo superior to rilonacept in pain reduction 241 new allopurinol starts: PBO vs RIL Pts:SUA 9, 4 attack/yr Fewer ULT flares and dropouts w/ RIL Terkeltaub. Arthritis Res Ther. 2013;15(1):R25 Schumacher Arthritis Care Res : SURGE: Study of Rilonacept in Gout Exacerbations SC Placebo + oral indomethacin (n=75) IND P= *P<0.001 versus placebo **P<0.002 versus placebo SC Rilonacept + oral indomethacin (n=74) * * * * * * Weeks IND/ RIL P< SC Rilonacept + oral Placebo (n=73) RIL PBO RIL * *

63 Basolateral surface Luminal surface Gout Pipeline Agents Drug Mechanism Action Lesinurad (RDEA594) Arhalofenat Tranilast BCX4208 Inhibitor of URAT 1 Inhibitor of URAT1,OAT4 and OAT10 Inhibits URAT1 & GLUT9a Inhibits purine nucleoside phosphorylase uricosuric uricosuric uricosuric Block purine metabolism Glomerular ultrafiltrate Tubule Lumen Urate Urate URAT1 Other resorbing OATs ABCG2, MRP4 Urate Membrane Potentialdependent Anions: e.g. CI, lactate, nicotinate, Pyrazinoate, dicarboxylates Dicarboxylates Urate A TP A DP+Pi GLUT9a OAT 1 OAT 3 Renal interstitium Urate NPT1, NPT4 Urate Bulletin of the NYU Hospital for Joint Diseases 2011;69(3): Tubular Epithelial cell

64 RDEA 594 a URAT1 Inhibitor 90% of gout pts are underexcreters Lesinurad (RDEA594 ): oral inhibitor of URAT1, a transporter in the kidney that regulates uric acid excretion RDEA594 shown to be effective in: allopurinol refractory gout As adjunctive therapy (FBX or allopurinol) Activity of RDEA594 is not diminished in patients with varying degrees of renal impairment. Fleischmann R, et al. EULAR 2011, London, #THU0026 Perez-Ruiz F, et al. EULAR 2011, London, #OP0111

65 Suggested Management of GOUT Education, Weight reduction, Lifestyle (alcohol, shellfish, etc), Comorbidity control patient self-help groups Acute disease Chronic disease Acute Rx, Prophylaxis (NSAID, STEROIDS, Colchicine) Uricosuric Tophace ous Gout Urate-Lowering Tx (allopurinol, febuxostat) Pegloticase Asympt. Hyperuric Treat to target uric acid

66 Goals of Gout Management Treat & avoid attacks Reduce total body urate burden Avoid damage, disability, comorbidity Foster education, compliance, control SUA < 6.0 mg/dl (SUSTAINED)

67 Education in Gout is Needed! Misguided/Overconfidence Colchicine #1 worldwide for Acute Gout Allopurinol Rx Underutilized? Under-dosed No monitoring of sua, Cr Uricosurics Misuse Newer Agents (FEB, PEG) Slow growth/no experience Safety issues limits use Educational Targets PCPs, NonRheums Rheumatologists Nephrologists Podiatrists Risk:Benefit Clarity Efficacy Safety Forums/Opportunities Advisories Local National Print, meetings, CME

68 <10% of Gout patient have crystal proven gout Anemia (10% population) pts 2x risk of gout Low dose ASA (81,325mg/d) gout attacks by 81% (RR 1.81). Effect nullified by Allopurinol use Allopurinol initiation during acute attacks is not associated with more/worse attacks/outcomes Cherries (+extract) consistently shown attacks CCB & losartan (ULT) have risk of incident gout Gout pts have Cancer risk and risk Parkinsons RA found in 2-3.8% of gout pts Zhu Y. Arthritis Rheum. 2011;63:3136; Zhang. Ann Rheum Dis Jan 23; Taylor. Am J Med. 2012;125:1126 Zhang. Arthritis Rheum. 2012;64:4004; Choi H. BMJ. 2012;12;344; Kuo CF. Joint Bone Spine. 2012;79:375.; DeVera Arthritis Rheum. 2008;59:1549