BEYOND THE FLARE IMPLEMENTING SOLUTIONS FOR HYPERURICEMIA GOAL ACHIEVEMENT IN THE PRIMARY CARE PRACTICE

Transcription

1 BEYOD THE FLARE IMPLEMETIG SOLUTIOS FOR HYPERURICEMIA GOAL ACHIEVEMET I THE PRIMARY CARE PRACTICE Paul Doghramji, MD FAAFP Collegeville Family Practice Collegeville, PA 1

2 APPROXIMATELY HOW MAY GOUT PATIETS (I STUDIES) ACHIEVE URIC ACID GOAL OF 1. <6.0 MG/DL? 90% 2. 80% 3. 70% 4. 60% 5. Less than half 6. Unsure 2

3 APPROXIMATELY HOW MAY PATIETS I YOUR PRACTICE ACHIEVE THE GOUT URIC ACID GOAL OF <6.0 MG/DL? 1. 90% 2. 80% 3. 70% 4. 60% 5. Less than half 6. Unsure URATE LOWERIG THERAPY (ULT) USUALLY EXTED OVER WHAT PERIOD OF TIME? 1. 3 months 2. 6 months 3. 1 year 4. Remainder of life 5. Unsure 3

4 WHAT IS COSIDERED TREATMET SUCCESS FOR A GOUT PATIET? 1. Relief of flare pain 2. Reduction in flares 3. Reduction in uric acid 4. Reduction in uric acid to <6.0mg/mL or <5.0mg/mL 5. 1 & , 2 & , 2 & & 4 9. Unsure THE PRECIPITATIG FACTOR I A FIRST ACUTE EPISODE OF GOUT IS USUALLY: (CHOOSE BEST ASWER) 1. A beer binge 2. Ingestion of large quantities of seafood 3. Reduced kidney function 4. Hyperuricemia 5. A sore toe 6. All of the above 7. Unsure 4

5 GETTIG PATIETS TO GOAL IS DIFFICULT. IF A PATIET DOES OT ACHIEVE GOAL, FURTHER COSIDERATIO SHOULD BE GIVE TO: (SELECT THE BEST CHOICE) 1. Complete reduction of alcohol 2. Weight loss 3. Bland diet 4. Stronger anti-inflammatories 5. Increased exercise 6. Combination therapies 7. Unsure WHAT TOP PRACTICE CHAGE WOULD YOU COSIDER OVER THE EXT 3 MOTHS? 1. Place gout on the practice radar by incorporating a treat-to-target approach reinforced by practice enhancements and training 2. Utilize pharmacologic combinations to increase numbers of patients reaching goal 3. Set and Implement sua goals- education and discussion with both patients and the practice TEAM 4. Consider adding or switching medication when sua goals are not achieved 5. Follow-up patients through office monitoring every 6 months to assess adherence and goal achievement 5

6 EDUCATIOAL OBJECTIVES 1. Incorporate a treat-to-target approach and practice system for achieving SUA goals in practice 2. Expand the therapeutic armamentaria to reach target SUA by including new and emerging dual action/combination approaches 3. Educate office staff and patients regarding gout beyond pain relief, and provide focus on UA goals 4. Establish a practical gout management workflow that includes the patient, signals for therapeutic adherence, and practice systems for long-term monitoring and management. GOUT AD THE PROVIDER Most cases of gout are treated in the primary care setting 1 Recent audit shows that fewer than half of patients achieved target sua over 12 mos. 2 Another survey found opportunities for gout management and treatment 3 Education regarding achievement of gout goals Implement office monitoring SUA (serum uric acid): every 6 months Screening for comorbidities ULT considerations and proper monitoring 1. Becker MA, Schumacher HR, Romain PL Treatment of Acute Gout; 2016 UpToDate; UpToDate.com 2. Roddy E, Packham J, Obrenovic K, Ledingham JM. Rheumatology 2018 doi: /rheumatology/kex Zychowicz M, Howson A, Kim D. et al. Improving gout management in primary care AAFP ational Conference Poster. 6

7 GOUT RISK FACTORS Advancing age Male gender Family history of gout Obesity Certain drugs: diuretics, low dose aspirin, cyclosporin Alcohol, especially beer and binge drinking High fructose diet Organ transplants Thyroid problems Myeloproliferative disorders Singh JA, Reddy SG, Kundukulam J. Risk Factors for Gout and Prevention 2011 Curr Opin Rheum 23(2): COMORBIDITIES I GOUT Individuals in the US general population with gout and hyperuricemia have significantly higher comorbidities 1 Comorbidities Gout- Hyperuricemia o Gout- o Hyperuricemia Hypertension Obesity Diabetes ephrolithiasis Myocardial infarction Heart Failure Stroke Renal Impairment Zhu Y, et al. Am J Med Jul;125: e1. 7

8 CKD ASSOCIATED WITH GOUT 71% of US patients with gout have stage 2 or higher CKD 1 Annual reduction in GFR Healthy adults ml/min Untreated hyperuricemic adults 2.5 ml/min/1.73 m2 1 Martillo M, Karis E, Crittenden db, Pillinger MH Gout Co-Morbidities: Prev. and Mgmt Future Med CLIICAL GUIDELIES UDERUTILIZED I GOUT Only 52.8% of PCPs provide optimal medication therapy for acute gout attacks <20% of PCPs recommended optimal Tx for tophaceous gout <20% of PCPs use ULT with dose titration and prophylaxis Harrold LR, et al. Rheumatology. 2013;6: Edwards L. Curr Rheumatol Rep. 2011;13:

9 A COUPLE OF OTES Most common inflammatory arthritis in adults in the Western world 1 Characterized by hyperuricemia and effects of acute and chronic inflammation in joints and bursa Caused an an inflammatory response to MSU re hyperuricemia 2 Agonizing and chronically painful ew hope for patients with new drug discoveries- things are changing!! 1. Zhu Y et al. Arthritis Rheum 2011;63: Martinon F, et al. ature 2006:440; WHERE DOES URATE COME FROM? About two-thirds of uric acid is generated endogenously by the body, while one-third comes from purines in the diet 1 o Uricase in Humans and Higher Primates Purine Catabolism Fam AG. J Rheum. 2002;29: ; 2 Hediger MA, et al. Physiology. 2005;20: ; 3 Johnson RJ, et al. J Comp Physiol B. 2009;179:67-76; 4 Terkeltaub RA. In: Primer on the Rheumatic Diseases. 12 th ed. Atlanta, GA: Arthritis Foundation; 2001:

10 THE CRYSTALS AD THE PAI Purine catabolism= uric acid formation 98% of UA forms monosodium salts MSU crystals for in synovial fluid when solubility limits are exceeded Crystals cause an inflammatory reaction THE TREAT 2 TARGET DILEMMA >sua = Increased flares T2T sua = may cause increased flares initially Suboptimal treatment of sua can lead to more flares every year In the long haul, T2T is recommended for reduction of flares and prevention of joint destruction Singh JA, Uhlig T. Chasing crystals out of the body: will treat to serum urate target for gout help us get there? 2017 Ann Rheum Dis 76(4);

11 GOUT AD THE PATIET Significant morbidity Work-related disability Loss of productivity Increase healthcare costs All-cause hospital admissions Rimler E, Lom J, Higdon, Cosco D, Jones D. A Primary Care Perspective on Gout 2016 Open Urol & eph Journ: 9, (Suppl 1:M5) ACR: THERAPY AD PREVETIO OF ACUTE FLARES Gouty arthritis attack (acute flare) Reduce pain, inflammation, and disability quickly Treat with pharmacologic therapy within 24 hours of onset 11

12 TREATMET FOR ACUTE GOUTY IFLAMMATIO First-line options 1-3 SAIDs* Oral Colchicine Glucocorticosteroids* Intra-articular Parenteral* Combinations if severe or refractory 1 Terkeltaub RA. Eng J Med. 2003;349: Terkeltaub R. at Rev Rheumatol. 2010;6: Terkeltaub RA, et al. Arthritis Rheum. 2010;62: OW FOR sua- TREAT TO TARGET- WHAT DOES IT MEA?? T2T Recommendations 1,2,3 sua lowered and maintained at <6 mg/dl in all patients with gout (<5 mg/dl in those with tophi or frequent attacks) sua should be measured regularly for dose adjustments if needed 1. Richette P, Doherty M, Pascual et al EULAR Updates Mgmt of Gout Ann Rheum Dis 76: Zhang et al. EULAR Evidence-based recommendations for Gout P II 2006 Ann Rheum Dis 65: Khanna D, Fitzgerald JD, Khanna PP et al ACR guidelines for mgmt. of gout 2012 ArthCare Res 64:

13 WHY DO URIC ACID GOALS MATTER HRQOL is impaired compared to ageand sex-matched study controls 1 Reduce pain and disability 2 Prevent/limit joint destruction 3 Strong association between gout and metabolic syndrome 4 Independent risk factor for CV disease and mortality 5 1.Chandratre P, Mallen C, Richardson J, et al. HRQOL of life in primary care 2018 Sem in Arth Rheum 2. Osterhaus JT, et al. Patient reported outcomes associated with gout Arth Rheum 52(9 Suppl):S DAlbeth, Doyle AJ Imaging tools to measure treatment response in gout Rheum 57(suppl_1):i27-i McCracken E, Monaghan M, Sreenivasan S. Patho. Of the metabolic syndrome Clin Derm 36(1): Stack AG, Hanley A, Casserly LF et al. QIM 2013; 106: HOW DO YOU ACHIEVE GOAL, OR T2T? 1. Know gout- and place it on the practice radar (TEAM) 2. Know that treating an acute attack is EVER enough 3. Know that getting SUA < 6mg/dL (< 5mg/dL with tophi) is THE TARGET, and follow up tests every 6 months or more 4. Know how to use pharmacologics- both traditional and new,emerging- for optimal results 5. Know that >25% of patients will need combinations of meds to achieve goal 13

14 PHARMACOLOGIC URATE-LOWERIG OPTIOS AD STRATEGIES Xanthine Oxidase Inhibitors (XOI) ALLOPURIOL- PURIE-LIKE O O Available in US since 1966 Purine-like backbone, converted in liver to oxypurinol O O Hypoxanthine O Xanthine O Uric acid O O Allopurinol O Oxypurinol ormal half-life 24 hours Renal Elimination 14

15 ALLOPURIOL (ZYLOPRIM, ALOPRIM, LOPURI) Starting dosage of allopurinol should be no greater than 100 mg/day and less than that in moderate to severe CKD Gradual upward titration of the maintenance dose, which can exceed 300 mg daily even in patient with CKD Khanna D, et al. Arthritis Care Res. 2012;64: ALLOPURIOL Most common ULT in US Pruritic rash in ~2%; intolerance in 5%-10% (eg, hepatic enzyme elevation, GI, CS) Major cutaneous reactions (SJS, TE) linked with HLA- B58 Major allopurinol hypersensitivity syndrome has incidence of 0.1%-0.4%, up to 25% mortality GI, gastrointestinal CS, central nervous system SJS, Stevens-Johnson syndrome Riedel AA, et al. J Rheumatol. 2004;31: TE, toxic epidermal necrolysis Chao J, et al. Curr Rheumatol Rep. 2009;11: Terkeltaub R. Recent Advances in Difficult-to-Treat Gout: Medscape ACR 2008 Annual Mtg; San Francisco, CA 15

16 ALLOPURIOL DOSIG GUIDELIES ACR, EULAR and FDA Guidelines Start at 100 mg daily, lower in CKD Increase by 100 mg daily every 2 weeks until the target SUA level is reached ~400 mg daily is an average dose to achieve target level in subjects with preserved renal function Divide allopurinol dose to BID at >300 mg daily Allopurinol dose adjustment required in CKD FDA approved at doses up to 800 mg daily (monitor for toxicity) Chao J, et al. Curr Rheumatol Rep. 2009;11: Zhang W, et al. Ann Rheum Dis. 2006;65: IITIATIG ALLOPURIOL Prior to initiation of allopurinol HLA-B* 5801 screening - risk management High risk ratio Korean with stage 3 or worse CKD Han Chinese Thai HLA-B*5801, human leukocyte antigen Khanna D, et al. Arthritis Care Res. 2012;64:

17 FEBUXOSTAT (ULORIC) on-purine backbone Selective inhibitor of xanthine oxidase Primarily metabolized in the liver FEBUXOSTAT PHASE 3 TRIALS VS OTITRATED ALLOPURIOL: PRIMARY EDPOIT SERUM URATE <6 MG/DL Study Febuxostat 40 mg daily Febuxostat 80 mg daily Allopurinol 300 mg daily Placebo COFIRMS 1 (6 months) 45% (n=757) 67% *, ** (n=756) 42% (n=755) -- APEX 2 (6 months) -- 76% * (n=267) 41% *** (n=268) 1% (n=134) FACT 3 (12 months) -- 53% * (n=256) 21% (n=253) -- 1 Becker MA, et al. Arthritis Res Ther. 2010;12:R63. 2 Schumacher HR, et al. Arthritis Rheum. 2008;59: Becker MA, et al. Eng J Med. 2005;353: * P<.001 vs allopurinol ** P<.001 vs febuxostat 40 mg and placebo *** P<.001 vs placebo 17

18 FEBUXOSTAT DOSIG Label: 40 mg daily for 2 weeks. If serum urate does not normalize after 2 weeks, increase to 80 mg daily Dose reduction not needed in moderate renal or liver impairment (CrCL >29 ml/min) Most common side effects: rash (~2%), elevated LFTs (up to 3%), and arthralgia (~1%) In Europe, max dose is 120; as per ACR, can titrate to LFTs, liver function tests 120, off label in USA PRESERVATIO OF REAL FUCTIO WITH FEBUXOSTAT 6 Mean change egfr from BL, ml/min Expected Decline, untreated hyperuricemia All Subjects treated with febuxostat -12 Time, y Adapted from Whelton A, et al. Postgrad Med. 2013;125(1):

19 DPM1 PHARMACOLOGIC URATE-LOWERIG STRATEGIES Uricostatic Suppress uric acid formation: eg, target xanthine oxidase using allopurinol or febuxostat Uricosuric Increase uric acid elimination: eg, target proximal tubule epithelial cell transporters using probenecid Uricolytic biologic approach Directly degrade soluble urate: pegloticase Terkeltaub R. at Rev Rheumatol. 2010;6: URICOSURIC-PROBEECID (BEEMID, PROBALA) One of two FDA-approved agents currently available Typical dosing: 500 mg BID titrated up to 2.5 g a day Usage First line if XOI can t be used Second line: added to XOI if target not reached ot effective with egfr <50 1 Reinders MK, et al. Ann Rheum Dis. 2009;68: Contraindicated with uric acid overproduction Activity blocked by ASA Side effects common 1 Urolithiasis risk onspecific GI, CS side effects Rash, drug-drug interactions XOI, xanthine oxidase inhibitor egfr, estimated glomerular filtration rate ASA, aspirin 19

20 Slide 37 DPM1 Maybe this slide shoul be before teh first ALLOPURIOL slide Doghramji, Paul, MD, 3/21/2018

21 DPM2 LESIURAD [SIGLE AGET) (ZURAMPIC) Uricosuric SURI (selective uric acid reabsorption inhibitor) Approved as add-on therapy or as a single dual action/combination product (DUZALLO) GETTIG TO GOAL: COMBIIG URATE LOWERIG THERAPIES Many on XOI s do not achieve <6 mg/dl or <5 mg/dl Medical need for additional options Consideration may be given to combination therapies of meds with differing MOA 20

22 Slide 39 DPM2 If we put brand name here, don't we have to put brand name for all the meds? Doghramji, Paul, MD, 3/21/2018

23 EDPOIT Proportion of patients achieving sua <6mg/dL at Month 6 LESIURAD + ALLO- ICREASE I PATIETS ACHIEVIG SUA <6 MG/DL AT MOTH 6 60% 50% 40% 30% 20% 10% 28% 54% 23% 55% Placebo + ALLO Lesinurad ALLO P< % CLEAR 1 (n=603) CLEAR 2 (n=610) Lesinurad Prescribing Information; Ironwood. LESIURAD+ALLO EFFICACY I PATIETS WITH MILD OR MODERATE REAL IMPAIRMET- COSISTET WITH OVERALL TRIAL POPULATIO EDPOIT Proportion of patients achieving sua <6mg/dL at Month 6 70% 60% 50% 40% 30% 20% 10% 29% 57% 32% 59% 0% 60- <90 ml/min 45- <60mL/min Lesinurad Prescribing Information; Ironwood. Baseline renal function Placebo + ALLO Lesinurad ALLO P<

24 80.00% 70.00% LESIURAD PLUS FEBUXOSTAT: CRYSTAL Primary Endpoint: % of patients achieving sua Secondary: 1. Complete resolution of tophus ; 2. 50% resolution of tophus % 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% Primary Secondary-Complete Resolution of tophus Secondary-50% resolution Placebo + Febuxostat Lesinurad Febuxostat 80mg Lesinurad 400mg + Febuxostat 80mg LESIURAD AD LESIURAD/ALLOPURIOL COMBIATIO- SAFETY IFORMATIO Risk of acute renal failure- more common when used without a XOI Lesinurad should always be used in combination with a XOI 22

25 LESIURAD AD LESIURAD/ALLO DOSIG One 200mg lesinurad tablet daily in combination with an XOI, including allopurinol or febuxostat Lesinurad/Allo combos: Lesin 200/Allo 200, Lesin 200/Allo 300 Requires no dose adjustment for: Mild or moderate renal impairment (CrCl 45 ml/min) Moderate to severe (CrCl ml/min- do not initiate Severe renal impairment (CrCl / - End-stage renal disease- contraindicated Duzallo PI. Ironwood URICOSURICS: OTHERS Losartan, fenofibrate, atorvastatin: All off label Good added options in hyperlipidemia and hypertension if indicated Relatively weak effects 23

26 PATIETS AD PROVIDERS VIEW GOUT DIFFERETLY Providers view gout medication adherence as good - providing excellent relief In actuality, gout medication adherence is poor Less than 36% Patients discontinue gout meds Patients think ULT worsens or has no impact on gout Do not recognize long-term value DC therapy due to clinical and cost concerns Patients don t understand the concept of treatment goal Reach G. Joint Bone Spine. 2011;78: Harrold LR, et al. Chronic Illn : Coburn BW et al. Target Serum Urate- Do Gout Patients Know their Goal? 2016 Arth Care Res68(7): DC, discontinue ULT, urate lowering therapy DIET RECOMMEDATIOS Weight loss or 5%-10% goal Reduce or eliminate alcohol Drink lots of water and/or other nonalcoholic fluids Increase low- or non-fat dairy Increase plant-based proteins Beans, legumes Avoid high-purine foods Organ meats Oily fish Asparagus/cauliflower Mushrooms ACR Recommendations and Healthline 24

27 THE ECOOMICS BEHID ACHIEVIG GOUT GOALS Year Study Authors Title Factor Cost 2013 Rao S, Haji A, Burns L, Choi H The Economic Burden of Gout: A Systematic Review of Direct and Indirect Costs (Boston U. and Univ. of British Columbia) 2015 Rai SK, Lindsay CB, De Vera MA, Haji A, Giustini D, Choi HK 2016 Lim Sy, Lu, Oza A, Fisher M, Rai SK, Menendez ME, Choi HK The Economic Burden of Gout: A systematic review Trends in Gout & Rheumatoid Arthritis Hosps. In the US Work productivity loss with >3 flares/yr -Gout related healthcare costs with 6+ flares/yr All-cause direct costs Employed Elderly Treatment-refractory -Inflation-adjusted annual hospitalization costs for gout (+68%) Gout admissions $ 2,000+ per patient $ 12,000+ per patient Gout on-gout $ 4,400 $ 2,560 $ 17,000 $10,600 $ 18,400 $ 7,200 $ 58,003 Preventableinadequate or inefficient care KOWLEDGE GAPS I PATIETS Clear understanding of progression Untreated elevated SUA results in chronic joint damage Treatment options and duration of therapy for acute and chronic gout Concept of ULT to avoid complications and disability Treatment goals Khanna P et al. Knowledge Gaps In Patients with Gout- A Qualitative Study ACR/ARHP Annual Meeting. Coburn BW et al. Target Serum Urate- Do Gout Patients Know their Goal? 2016 Arth Care Res68(7):

28 PATIET EGAGEMET Accountability starts with an informed patient Improves patient satisfaction with therapy decision Promotes adherence to therapeutic regimen and medication PATIET EDUCATIO GOALS I GOUT Patients want to know more 1 Causes of gout Treatment goals Long-term consequences Exercise for overall health, joint mobility, and weight maintenance 2 Diet Medication adherence tips 1. Onna M, Hinsenveld E, de Vries H, Boonen A. Health Literacy in patients dealing with gout Clin Rheumatology 34(9): Khanna D, et al. Arthritis Care Res. 2012;64:

29 PHYSICAL ACTIVITY GOALS CDC 2015 Arthritis improves with physical activity Adult goals 150 minutes moderate-intensity/ week plus Muscle strengthening 2 or more days/week Older adult goals minutes moderate-intensity/ week plus Muscle strengthening 2 or more days/week Physical disability Refer to physical therapist CDC 2015 Gout Goals ACR: DIET RECOMMEDATIOS Avoid Limit Encourage Organ meats high in purine content (sweetbreads, liver, kidney) Serving sizes of: Low-fat or non-fat dairy products Beef, Lamb, Pork Seafood with high purine content B B B (sardines, shellfish) High fructose corn syrup - sweetened Servings of naturally sweet fruit juices Vegetables, Cherries sodas, other beverages, or foods Table sugar, and sweetened beverages and desserts Table salt, including in sauces C and gravies C C Alcohol overuse (defined as more than 2 servings per day for a male and 1 serving per day for a female) in all gout patients B Alcohol (particularly beer, but also wine and spirits) in all gout patients B Any alcohol use in gout during periods of frequent gout attacks, or advanced gout under poor control C Khanna D, et al. Arthritis Care Res. 2012;64:

30 MAAGIG THE GOUT PATIET LOG- TERM Prevent gout attacks with prophylaxis flare therapy for first 3-6 months of ULT Maintain normal serum UA with long-term ULT medication Support diet and lifestyle modifications Monitor side effect status of flare medication Measure SUA levels regularly (~every 6 months) Monitor ULT side effects Monitor renal function SUA: serum uric acid ULT: urate lowering therapy 28

31 WHAT TOP PRACTICE CHAGE WILL YOU IMPLEMET OVER THE EXT 3 MOTHS? 1. Place gout on the practice radar by incorporating a treat-to-target approach reinforced by practice enhancements and training 2. Utilize pharmacologic combinations to increase numbers of patients reaching goal 3. Set and Implement sua goals- education and discussion with both patients and the practice TEAM 4. Consider adding or switching medication when sua goals are not achieved 5. Follow-up patients through office monitoring every 6 months to assess adherence and goal achievement APPROXIMATELY HOW MAY GOUT PATIETS (I STUDIES) ACHIEVE URIC ACID GOAL OF 1. <6.0 MG/DL? 90% 2. 80% 3. 70% 4. 60% 5. Less than half 6. Unsure 29

32 URATE LOWERIG THERAPY (ULT) USUALLY EXTED OVER WHAT PERIOD OF TIME? 1. 3 months 2. 6 months 3. 1 year 4. Remainder of life 5. Unsure WHAT IS COSIDERED TREATMET SUCCESS FOR A GOUT PATIET? 1. Relief of flare pain 2. Reduction in flares 3. Reduction in uric acid 4. Reduction in uric acid to <6.0mg/mL or <5.0mg/mL 5. 1 & , 2 & , 2 & & 4 9. Unsure 30

33 THE PRECIPITATIG FACTOR I A FIRST ACUTE EPISODE OF GOUT IS USUALLY: (CHOOSE BEST ASWER) 1. A beer binge 2. Ingestion of large quantities of seafood 3. Reduced kidney function 4. Hyperuricemia 5. A sore toe 6. All of the above 7. Unsure GETTIG PATIETS TO GOAL IS DIFFICULT. IF A PATIET DOES OT ACHIEVE GOAL, FURTHER COSIDERATIO SHOULD BE GIVE TO: (SELECT THE BEST CHOICE) 1. Complete reduction of alcohol 2. Weight loss 3. Bland diet 4. Stronger anti-inflammatories 5. Increased exercise 6. Combination therapies 7. Unsure 31

34 Paul P. Doghramji, MD, FAAFP 32