Gout: Develop treatment plan in William Jones, MS, RPh

Transcription

1 Gout: Develop treatment plan in 2013 William Jones, MS, RPh

2 Objectives Describe acute gouty arthritis Tx Describe Tx of chronic gouty arthritis. Define the target serum uric acid concentration for Tx a patient with chronic gouty arthritis.

3 What will be discussed? Cases Develop a plan Determine optimal therapy Describe monitoring

4 Focus on new CPG from ACR Part 1. Approach to treating hyperuricemia. Arthritis Care & Res 2012; 64: Part 2. Acute Gouty Arthritis. Arthritis Care & Res 2012; 64: BUT NOT EXCLUSIVELY The process is not entirely evidenced based ~30% of recommendations from >1 RCT

5 Their assumptions Assess evidence of treatment, but do not account for cost-effectiveness Common scenarios No specific drug choices Dx of gout is correct

6 Questions to ask each time What are the patients needs? How can information be gathered? What are the goals of therapy? What are the recommendations? Anything more important than anything else? What are monitoring parameters & endpoints? What is the frequency of monitoring?

7 Gout Affects about 4% of US population INCREASING prevalence Maybe related to: Obesity CKD T2DM Diuretics

8 Gout typical presentation Man years Women > 60 years 80-90% monoarticular first attack VERY painful sudden 1 st attack (less later) Self-resolving early (3-14 days) Repeat attacks last longer (~2 months)

9 I confidently affirm that the greater part of those who are supposed to have died of gout, have died of the medicine rather than the disease - a statement in which I am supported by observation. Thomas Sydenham September 10, 1624 December 29, 1689

10 Phases of gout Impacts treatment decisions Hyperuricemia Acute gouty arthritis Intercritical period Chronic gout

11 Drug-induced hyperuricemia Evaluate for drug-induced lab changes Diuretics Tacrolimus Cyclosporine Ethambutol Pyrazinamide Cytotoxic chemotherapy Niacin Ethanol Salicylates (low dose) Levodopa Ribavirin and interferon Teriparatide

12 45 yo male w/o compliants PE: Normal, BP 110/70 mm Hg Lab: NL, except uric acid 9 mg/dl Dx: HTN Meds: HCTZ 25 mg qd, lisinopril 10 mg qd Treatment plan: What do we know?

13 What do we know? What are the patient's needs? What are the endpoints of therapy?

14 What do we know? What are the patient's needs? Hypertension and hyperuricemia What are the endpoints of therapy? Controlled BP No attacks of gout

15 Normative Aging Study AJM 1987; 82: healthy men, yo; f/u 15 years 84 new gout cases (4.1%)/15 years Cumulative incidence UA > 9 = 5 y 94 patients with UA > 9 Cumulative incidence UA 7-8 = 5 y Rate higher among HTN patients (HCTZ) Rate low overall conservative approach

16 What are the implications? Drug-induced hyperuricemia is NOT a disease Treat patients with gout WHY NOT treat hypericemia?

17 Allopurinol Hypersensitivity Arthritis Rheum 1986; 29: J Am Acad Dermatol 1979; 1: Characteristic % of patients Gout Asymptomatic Inc UA Renal insufficiency Diuretic therapy Death Hepatitis Worse renal function 60 95

18 Toxic Epidermal Necrolysis

19 Allopurinol hypersensitivity Arthritis Rheum 2012; 64: 2529 More common with higher dose USUALLY < 30 days (but can be ~1 yr) Higher with lower CrCl Higher if HLA-B*5801 hetrozygous Han Chinese, Thai, & Korean with CKD Genetic testing recommended in this group of patients

20 What should be done? Has hyperuricemia and CONTROLLED BP Could stop HCTZ Expect BP to be controlled & UA ~ 1 mg/dl Could replace Lisinopril with LOSARTAN Lowers uric acid ~ 0.5 mg/dl Assess diet including EtOH (NO DATA) May lower UA ~ mg/dl

21 45 yo male c/o severe pain great left toe starting 6 hours ago. No history of trauma. PE: Hot/red 1 st MTP joint, Pain 10/10 Lab: Renal panel nl, CBC nl, uric acid 8 mg/dl PMH: HTN Meds: HCTZ 25 mg qd, diltiazem XR 240 qd What do we know?

22 Podagra CLASSIC presentation

23 X-ray feet: No fracture asymmetric swelling R MTP

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25 What are the implications? Acute gout is classically very painful Treatment is needed What is the endpoint?

26 Does everyone with podagra have gout? NO

27 Can uric acid be normal and have acute attack of gout? YES

28 What needs to be known? Arthrocentesis: crystals in fluid? Past history of acute arthritis? What is BP? Does patient have any drug intolerance? Does patient have CKD/liver disease? Does patient have normal bone marrow?

29 ACR Presumptive diagnosis: No crystals Must have > 6 findings > 1 acute attack tophi maximum pain < 24 hours hyperuricemia monarticular arthritis asymmetric swelling on x-ray redness subcortical cysts on x-ray podagra sterile cultures of aspirated synovial fluid. unilateral involvement of MTP or tarsal joint

30 What do we know? What are the patient's needs? Hypertension and hyperuricemia What are the endpoints of therapy? Controlled BP Stop acute attack of gout No recurrence of gout

31 What is present? Has 6 gout findings and should PRESUME has gout. POSSIBLE to find fluid in larger joint and find crystals even if not painful.

32 Other imaging Ultrasound Hyperechoic areas Contour sign Dual Energy CT scan Color changes with urate

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35 What should be done? Has presumed gout based upon clinical signs and symptoms What are the options?

36 Acute Gout Treatment Goal is treat pain & inflammation Arthritis Care Res 2012; 64: 1447 Choices are NSAID, colchicine, corticosteroid All NSAID, but ASA, work If severe pain can use 2 drugs (opinion) Colchicine + NSAID or corticosteroid NOT recommended is NSAID + corticosteroid Can use intra-articular steroid

37 Combination may be common J Rheum 2006; 33: % of 518 surveyed use combination 43% NSAID + IA corticosteroid 33% NSAID + PO corticosteroid 32% NSAID + Colchicine

38 Acute Gout Treatment Goal is treat pain & inflammation Arthritis Care Res 2012; 64: 1447 Monotherapy for mild-moderate pain and only few small joints or 1-2 large joints Combination for severe pain (>6/10) ACR did not relate treatment to renal or hepatic disease or drug-interactions. THIS IS A MAJOR ISSUE

39 Acute Gout Treatment Goal is treat pain & inflammation Earlier treatment better <12 hours in RCT. <36 hours in ACR CPG Can use topical ice as adjunct (weak evidence) Opioids NOT considered Since analgesia is important, giving analgesic makes sense! Is considered in Kelly s Rheumatology text

40 Risks/Contraindications NSAID CV, kidney, GI disease, interactions Steroids HTN, DM, GI disease, osteoporosis, infection Colchicine Kidney, hepatic disease, interactions

41 Acute Gout Treatment Goal is treat pain & inflammation Arthritis Care Res 2012; 64: 1447 No contraindications NSAID (not aspirin) for 5-10 days Naproxen 750 mg x1 & 250 mg 3 times daily. Indomethacin 50 mg 3 times daily Sulindac 200 mg 2 times daily Celecoxib 800 x1 & 400 mg 2 times daily NOT ketorolac IM ALL WORK (ibuprofen 800 mg 3 times daily)

42 Acute Gout Treatment Goal is treat pain & inflammation Arthritis Care Res 2012; 64: 1447 No contraindications Colchicine 1.2 mg and 0.6 mg one hour later Continue 0.6 mg q 12 h if not resolved CKD (arbitrary, but Cr 2 or CrCl < 30 ml/min) and hepatic dysfunction BETTER to find another therapy! NOT DO USE if treated in last 14 days

43 Acute Gout Treatment Goal is treat pain & inflammation Arthritis Care Res 2012; 64: 1447 Prednisone 0.5 mg/kg/day x 5-10 days Could use tapering dose Special case is NPO IV (e.g., methylprednisolone mg/kg x 1) IM (e.g., triamcinolone acetonide 60 mg x1) Can repeat dose IF NEEDED h Large joint, can use intra-articular steroid (e.g., triamcinolone hexacetonide + lidocaine: dose varies with size of joint)

44 Colchicine Unapproved before 2009 Risks of serious/fatal toxicity identified NONE of the reports included renal or hepatic function CONTRAINDICATED to give with P- glycoprotein or strong CYP 3A4 inhibitors + renal/hepatic dysfunction

45 Colchicine interactions Some DEATHS associated with these P-glycoprotein transport inhibitors Digoxin, Cyclosporine, Tacrolimus, Ranolazine CYP 3A4 strong inhibitors Claritromycin, protease inhibitors, itra/ketoconzole CYP 3A4 moderate inhibitors Diltiazem, verapamil, erythromycin, fluconazole, grapefruit & juice (1 liter/day)

46 High & low colchicine dose Arthritis Rheum 2010; 62: mg 4.8 mg Placebo Response Rescue All ADE Severe ADE

47 Visual Analog Scale PAIN (mm) Naproxen vs. Prednisolone Treatment of acute gout Lancet 2008; 371: Naproxen 500 bid Prednisolone 35 qd Hours

48 What do we know? DOES NOT HAVE renal or hepatic dysfunction. known contraindications DOES TAKE diltiazem that can colchicine metabolism HCTZ that can be inhibited by NSAID (short term might not matter)

49 What should be done? Has presumed gout based upon clinical signs and symptoms Colchicine? NSAID? Prednisone?

50 45 yo male c/o severe pain great left toe starting 6 hours ago. No history of trauma. PE: Hot/red 1 st MTP joint, Pain 10/10 Lab: Renal panel nl, CBC nl, uric acid 8 mg/dl PMH: T2DM Med: Metformin 1000 mg BID What do we know?

51 Physician performs arthrocentesis Lab reports no microorganisms on GS Under polarized microscopy see

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55 What is known? Has crystal proven gout Does not have CKD No potential drug interactions

56 What needs to be known? UNKNOWN if any other risks UNKNOWN if liver disease

57 What should be done? Can be any of the three options if no other issues Colchicine? NSAID? Prednisone?

58 81 yo male admitted for hemorrhoidectomy. Wt 50 kg, Ht 5 9, PE normal 0400 post-op day 1 c/o acute, severe L ankle pain (9/10) PE: hot, erythematosus L ankle Labs: WBC 9K, Cr 2.0, lytes NL, H/H normal Aspirate of L ankle = neg birefringent needle shaped crystals.

59 Order received in pharmacy Colchicine 0.6 mg every hour until pain relieved, has n/v/d, or has taken 10 doses. What is your assessment of the order? What are the alternatives?

60 What needs to be known? Has crystal proven gout. Has renal insufficiency Acute or chronic? Need more information IN HOSPITAL so should have pre-op lab

61 12 hours later severe L ankle pain (8/10), almost cannot stand to walk Diarrhea PE: hot, erythematosus L ankle Medication profile shows 6 colchicine doses given

62 How can you tell if effective? Define inadequate response of acute gout to pharmacologic therapy: either < 20% improvement in pain score within 24 hours or < 50% improvement in pain score 24 hours after initiating pharmacologic therapy. Consider NOT GOUT Change drugs or COMBINE

63 What should be done? Has gotten colchicine and developed diarrhea NO RESPONSE yet Should therapy be changed? WHAT IS THE ENDPOINT?

64 What happens? Therapy is changed Patient has 4/10 pain 12 hours later NOW WHAT?

65 72 yo male with acute painful R knee and both elbows. Wt 50 kg, Ht 5 9, PE normal PE: hot, erythematosus R knee, L/R elbows PMH: s/p MI 2006, CHF with EF 20%, Gout x 2 Meds: furosemide 240 mg BID, lisinopril 40 mg/d, carvedilolol 25 mg BID, ASA 81 mg/d, Atorvastatin 40 mg/d Labs: WBC 9K, Cr 1.7, lytes NL, H/H normal UA 10.1 Aspirate of R knee = neg birefringent needle shaped crystals.

66 What is known? Has crystal proven gout Does not have CKD Potential drug interactions Furosemide, lisinopril, carvedilol all might be inhibited by NSAID Atrovastatin may colchicine metabolism

67 What needs to be known? UNKNOWN if any other risks UNKNOWN if liver disease

68 What should be done?

69 Now what? Should all get chronic therapy? Debatable whether patients with single attack of acute gout need chronic treatment

70 Should all get long-term therapy? Recurrence of Gout Years after first attack % of patients < never (> 10) 7

71 Choices Do nothing Try prevention Give hypouricemic therapy

72 Intercritical/interval period Time between acute attacks Chronic therapy Colchicine 0.6 mg 1-2 times/day Alternative is low dose NSAID (PPI?) naproxen 250 mg or ibuprofen 200 mg bid Prednisone <10 mg/day (last option) > 6 months or 3 months after target UA

73 Intercritical period Can start any hypouricemic therapy during acute gout attack MAKE SURE taking anti-inflammatory daily Also can wait to start after acute event IF recurrent attack while taking hypouricemic therapy CONTINUE that treatment

74 Starting allopurinol during attack AJM 2012; 125: 1126 Allopurinol 300 mg daily during acute attack versus day 10 in 51 total patients All treated with indomethacin x 10 days and colchicine x 90 days Gout flares lower early/late 90 days 7.7% vs. 12.0% (ONE MORE FLARE)

75 Chronic Gout Treatment Arthritis Care Res 2012; 64: 1431 SOME diet modifications/small impact Avoid high purine meat (e.g., liver) Avoid high fructose cost syrup drinks EtOH < 2 drinks/day (beer worse than other)

76 Chronic Gout Treatment Arthritis Care Res 2012; 64: 1431 Consider if > 1 attack/year & tophi Xanthine oxidase inhibitor (XOI) Allopurinol or Febuxostat LESS SAFETY DATA ABOUT FEBUXOSTAT Probenecid Alternative if XOI intolerance AND CrCl > 50

77 Chronic Gout Treatment Arthritis Care Res 2012; 64: 1431 Allopurinol and febuxostat may be substituted for each other if not tolerated or did not get to target uric acid at maximum dose (weak evidence)

78 Last patient meets this definition and should be treated since >1 acute event

79 Chronic Gout Treatment Goal is preventing recurrent attacks Allopurinol Adjust dose with renal failure CrCl < 10 ml/min = 100 mg every 2-3 days CrCl ~50 ml/min = 100 mg/day Initial target dose 300 mg/day Increase to 800 mg/day if UA >6.0mg/dl

80 REMEMBER Allopurinol hypersensitivity Arthritis Rheum 2012; 64: 2529 More common with higher dose Life threatening (20-25% mortality) Higher if HLA B*5801 (Han Chinese, Thai, & Korean)

81 Chronic Gout Treatment Goal is preventing recurrent attacks Allopurinol interferes with metabolism of azathioprine and mercaptopurine MARKEDLY. Must reduce dose of other drugs to about 25%-35% of current dose. MORE patients get skin rash taking ampicillin + allopurinol versus ampicillin.

82 Chronic Gout Treatment Goal is preventing recurrent attacks Febuxostat Dosage adjustment not needed if dose with renal failure CrCL > 30 ml/min = mg/day Increase to 120mg/day if UA >6.0mg/dl

83 Chronic Gout Treatment Goal is preventing recurrent attacks Febuxostat (non-purine XOI) Marketing is more effective More CV events (including MI) vs. allopurinol No drug interaction studies done, but contraindicated with azathioprine and mercaptopurine Post-marketing hepatitis (some fatal)

84 % of Patients Uric acid < 6 mg/dl comparison Arthritis Rheum 2008; 59: Febuxostat Febuxustat Febuxostate Allopurinol

85 % of Patients Febuxostat versus Allopurinol Treatment flares of gout NEJM 2005;353: Feb 120 mg Feb 80 mg Allo 300 mg Weeks

86 Chronic Gout Treatment Goal is preventing recurrent attacks Probenecid 250 mg twice daily; adjust dose 7-14 days 500 mg twice daily if uric acid > 6 mg/dl CAN TITRATE to g twice daily DOES NOT WORK if CrCL < 25 ml/min TARGET DOSE to uric acid < 6.0 mg/dl NOT if urate kidney stones! Give colchicine or low dose NSAID for 6 weeks (intercritical period)

87 61 yo male c/o severe pain great left toe PE: Hot, red L knee, tophi present, Fingers and toes are painful, but not inflammed Lab: NL, uric acid 10.7 mg/dl PMH: Chronic gout for 15 years Meds: None (allopurinol in past, but none in 10 years) Dx: acute on chronic gouty arthritis Treatment plan:

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90 What do we know for this patient? Treated in past for acute gout. What was used? USE THAT unless has new contraindication

91 This patient Start allopurinol 100 mg/day could be every other day Adjust every 2-5 weeks to uric acid target < 5 mg/dl since tophi. Needs preventive therapy Colchicine 0.6 mg 1-2 x daily Naproxen 250 mg BID

92 Alternative Febuxostat 40 mg daily Adjust every 2-5 weeks to uric acid target < 5 mg/dl since tophi. FDA limits to 80 mg; ACR to 120 mg Needs preventive therapy Colchicine 0.6 mg 1-2 x daily Naproxen 250 mg BID

93 This patient Allopurinol titrated and UA is 6.3 mg/dl while taking 800 mg daily What else to consider?

94 Chronic Gout Treatment Arthritis Care Res 2012; 64: 1431 Can add probenecid to XOI Titrate dose Fenofibrate & losartan UA & options Needed for another reason makes sense Uric acid < 6 mg/dl once tophi resolved

95 Persistence with taking meds Joint Bone Spine 2011; 78: studies and > 41,000 patients Medication possession <80% 18-44% About 25% with uric acid < 6 if <80% About 55% with uric acid < 6 if > 80% BEFORE DECIDING REFRACTORY make sure taking allopurinol. IF NOT, figure out why.

96 What if patient gets Rx on 2/13/13 for allopurinol 300 mg to take 2 tablets daily and 100 mg to take 2 tablets daily? Or 4/13/13 for allopurinol 300 mg to take 2 tablets daily and 100 mg to take 2 tablets daily?

97 What if? This should make you suspicious that not taking 800 mg daily since 3/13/13 is 90 days from 6/29/13 (today) Or This MIGHT make you wonder if taking. Would like to see what happened to uric acid as dose was titrated.

98 What if? Taking allopurinol 800 mg daily and probenecid 1 g twice daily and tophi still present and uric acid is 6.3 mg/dl? What is the target uric acid NOW?

99 Pegloticase RCT (12 infusions) JAMA 2011; 306: mg/2 wks 8 mg/4 weeks Placebo N = 85 N = 84 N = 43 Resolve > 1 tophi 40% 20% 2% Gout flare 76% 84% 35% Serious ADR 24% 23% 12% CV death 2% 1% 0%

100 REFRACTORY Gout Treatment Goal is preventing recurrent attacks Pegloticase approved by FDA for treating gout NOT RESPONDING to highest doses of xanthine oxidase inhibitor. >90% develop antibodies to drug ~5% developed anaphylaxis Cost is $2300/2 weeks

101 REFRACTORY Gout Treatment Goal is preventing recurrent attacks Arthritis Rheum 2012; 64: 2529 ACR guideline recommendation Pegloticase as appropriate only in cases of severe gout disease burden and refractoriness to, or intolerance of, appropriately dosed oral urate lowering therapy options.

102 Can treatment be discontinued? Arthritis Rheum 2011; 63; 4002 Study of 211 patients with gout and treated for 5 years IF uric acid < 7 mg/dl recurrence rate 0% Might be possible to withdraw treatment MORE LIKELY to succeed if lose weight, treated with losartan, not treated with diuretic. RECHECK URIC ACID!

103 Questions? Comments?