Gout: Let s Be Crystal Clear. Dr. Philip A. Baer Seacourses Asia CME December 2017

Transcription

1

2 Gout: Let s Be Crystal Clear Dr. Philip A. Baer Seacourses Asia CME December 2017

3 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

4 Objectives Diagnose crystal-induced arthritis correctly Correctly treat acute gout Prevent recurrences of gout Deal with comorbidities associated with gout

5 Gout facts The most common inflammatory arthritis in men Increasingly common cause of inflammatory arthritis in women More common overall than RA

6 Gout: The disease of kings James Gillray( ): The Gout George Cruikshank ( ): The Gout, The King, and the Doctors

7 The victim goes to bed and sleeps in good health. About 2 a.m. in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle or instep. This pain is like that of a dislocation, and yet the parts feel as if cold water were poured over them. Then follow chills and shivers and a little fever. The pain, which was at first moderate, becomes more intense. After a time this comes to its full height, accommodating itself to the bones and ligaments of the tarsus and metatarsus. Violent stretching and tearing of the ligaments and the gnawing feeling of a dog. So exquisite the pain that it cannot bear the weight of bedclothes or the jar of a person walking in the room. The night is passed in torture, sleeplessness and the perpetual change of posture. T. Sydenham 1717

8

9 Gout: Clinical and X-ray Findings

10 Gout: Misdiagnosis is Common 9,108 Patients 1.7% Had gout 1.8% Had been misdiagnosed as having gout 76% treated with allopurinol Wolfe and Cathey, J. Rheum. 1991

11 Mathematics of Gout Elevated Serum Uric Acid Joint Pain GOUT

12 Gout not a priority in training Diagnostic methods not optimal Long-term complications underestimated Treatment not titrated to target serum uric acid levels Patients need more information Management guidelines not followed

13 Incidence of Gout: Doubled in 20 Years Increased longevity Increased prevalence of hypertension Dietary trends Increased obesity and metabolic syndrome Increased end-stage renal disease Increased survival in CAD and CHF

14 Percent of population Epidemiology: Prevalence of Gout 20% 16% 12% 8% 4% 0% Protective effect of estrogen in premenopausal women through increased renal clearance of uric acid 5.9% 2.0% 0.4% 12.6% Men Women years 80+ years Zhu Y, et al. Arth Rheum 2011; 63(10):

15 Pathophysiology of Gout Renal excretion (2/3) Alimentary excretion (1/3) HYPERURICEMIA Serum urate > 360 μmol/l URIC ACID XO Xanthine XO Over-production ~10% Under-excretion ~90% Urate crystal deposit in joint & tissue Inflammation Hypoxanthine Purine Acute Gout Attacks/flares Chronic Gout Tophi Chronic synovitis Bone erosion Cartilage loss Other Comorbidities Nephrolithiasis Nephropathy Metabolic S. XO = xanthine oxidase Hochberg MC. et al, eds. Rheumatology. 4th ed. Philadelphia, Pa: Mosby; 2007; Koopman WJ, ed. Arthritis and Allied Conditions. 15th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005.

16 Uric Acid in Steady State Uric Acid level Steady State: Production = Excretion Sink is working perfectly

17 Hyperuricemia: Overproduction % of cases: Diet Malignancy Hemolysis Psoriasis Obesity Enzyme defects

18 Hyperuricemia: Underexcretion % of cases: Drugs: Low dose ASA, diuretics (increasing use) Toxins: Lead, ethanol Renal disease Endocrine disease Hypothyroidism Dehydration, starvation, ketosis Idiopathic

19 Underexcretion of Uric Acid Uric Acid level Under Excretion The Sink is Clogged The most common reason for hyperuricemia Lots of people with hyperuricemia but not acute gout

20 Gout: The Sink Overflows! Uric Acid level Acute Gout: When the sink overflows!

21

22 Nonpharmacologic ULT Measures in Gout Establish Diagnosis of Gout General Health, Diet and Lifestyle Measures for Gout Patients C Weight loss for obese patients achieve BMI that promotes general health Healthy overall diet Exercise (achieve physical fitness) Smoking cessation Stay well hydrated

23

24

25 Dietary Measures in Gout Avoid Limit Encourage Organ meats high in purine e.g. sweetbreads, liver, kidney B Serving sizes of: Beef, lamb, pork Seafood with high purine content e.g. sardines, shellfish B Low fat or non-fat dairy products B High fructose corn syrup foods sweetened sodas other beverages or foods C Servings of: Naturally sweet fruit juices Table sugar (beverages and desserts) Table salt (sauces and gravies) C Vegetables C Alcohol overuse in all gout patients Male >2 servings per day Female >1 serving per day B Alcohol Particularly beer Also wine and spirits B ANY alcohol use during periods of: Frequent gout attacks Advanced gout under poor control C

26 DASH Diet Lowers Serum Uric Acid The DASH diet can lower uric acid by 1.3 mg/dl in adults with an elevated uric acid, an effect similar to that of medication, where allopurinol, for example, the first-line urate-lowering medication, lowers uric acid by about 2 to 3 mg/dl. DOI: /art , American College of Rheumatology

27 Gout and Alcohol

28 What is the serum uric acid level at which the risk of gout starts to increase?

29 The relationship between serum uric acid levels and the incidence of gout 360 µmol/l = 6 mg/dl

30 Gout: Tip of the Uric Acid Iceberg

31 Stages of Gout

32 Dual Contour Sign on Ultrasound

33 Dual Energy CT (DECT)

34 X-ray: Typical Gouty Erosions The characteristic gouty erosion is both destructive and hypertrophic, leading to overhanging edges The joint space often preserved until very late in the disease process

35 Acute Gout

36 Acute Gout: Mechanism

37 Chronic Tophaceous Gout

38 Chronic Tophaceous Gout

39 Gout: Tophi

40 Milk of Urate Bulla

41 NEJM 2016

42 Gout: Diagnosis Typical presentation Monosodium urate crystals in joint fluid Elevated serum uric acid X-ray changes

43 Pathophysiology of Gout: Acute Flares Common Characteristics Acute inflammation with rapid development of intense pain and tenderness, swelling, and with overlying shiny erythema Monoarticular ~ 90% of first attacks Podagra ~ 50% of first attacks Frequently involving lower extremities Often occurring at night Possible + family history As disease progresses, attacks occur more frequently and can become polyarticular and chronic Common Sites Frequency: Big toe 76% Ankle/foot 50% Knee 32% Finger 25% Elbow/wrist 10% >1 site simult.11% Mandell BF. Cleve Clin J Med. 2008;75:S5-S8. Gibson T. In Rheumatology. 4th ed. Mosby Elsevier limited 2008:

44 Gout: Synovial Fluid Analysis Compensated Polarized Light Microscopy Gold standard in diagnosis Urate crystals identified by Strong negative birefringence Needle and rod shapes 1

45 Clinical Diagnosis of Gout Establish Diagnosis of Gout Without Joint Fluid Analysis Predefined variable Clinical score Male sex 2.0 Previous patient-reported arthritis attack 2.0 Onset within one day 0.5 Joint redness st MTP involvement 2.0 Hypertension or 1 cardiovascular disease 1.5 Serum uric acid level >350 µmol/l 3.5 Maximum score 13.0 Janssens HJ et al,arch Intern Med (13)

46 Clinical Diagnosis of Gout Establish Diagnosis of Gout Gout confirmed in 80% of patients with score 8 Predefined variable Clinical score Male sex 2.0 Previous patient-reported arthritis attack 2.0 Onset within one day 0.5 Joint redness st MTP involvement 2.0 Hypertension or 1 cardiovascular disease 1.5 Serum uric acid level >350 µmol/l 3.5 Maximum score 13.0 Janssens HJ et al,arch Intern Med (13)

47 ACR-EULAR Gout Calculator

48 sua Levels as a Diagnostic Marker sua levels may be normal ~50% of the time during a flare Normal sua at the time of a flare does not rule out a gout diagnosis The best time to measure sua is after a flare has resolved, which may take up to 2 weeks Laboratories often report hyperuricemia based on population norms Population norms may be higher than biologically significant hyperuricemia ( 360 µmol/l) Best Time to Measure sua 0 Days (start of flare) 4 Days 8 Days 14 Days 20 Days Urano W. et al. J Rheumatol. 2002; 29: Zhang W. et al. Ann Rheum Dis. 2006; 65:

49 Gout Treatment Goals: From Toe Pain to No Pain Urate-lowering therapies Treat the acute attack

50

51 Management of an Acute Gout Attack General Principles Acute gouty arthritis attacks should be treated with pharmacologic therapy. C To provide optimal care, pharmacological treatment should be initiated within 24 hours of acute gout attack onset. C Ongoing pharmacologic ULT should not be interrupted during an acute gout attack. C

52 Management of an Acute Gout Attack Assess Severity Mild-moderate pain, particularly for an attack affecting only 1 or a few small joints, or 1-2 large joints Severe pain, particularly for a polyarticular attack or an attack affecting multiple large joints Monotherapy A Option: Initial combination therapy C NSAID (^or COX-2 inhibitor) A A A Systemic Corticosteroids Supplement with topical ice as needed B Colchicine COX=cyclooxygenase Colchicine was recommended as an appropriate option for acute gout if started within 36 hours of symptom onset. COX-2 inhibition therapy with celecoxib (Evidence B) requires high doses and has unclear risk-benefit ratio at this time.

53 Management of an Acute Gout Attack: NSAID or Selective COX-2 Inhibitor A Full FDA- or EMA-approved dose of NSAID or a COX-2 inhibitor C Continue initial treatment at full dose** until the gouty attack has fully resolved C FDA=Food and Drug Administration; EMA=European Medical Agency ** The option to taper the dose in patients with multiple comorbidities/hepatic or renal impairment was reinforced by the TFP, without specific TFP voting or more prescriptive guidance.

54 What is the recommended colchicine dose schedule for acute gout?

55 Management of an Acute Gout Attack: Oral Colchicine Is patient on prophylactic colchicine already? Yes No Oral Colchicine^ 1.2mg, then 0.6mg 1 hour later, then gout attack prophylaxis dosing can be started, beginning 12 hours or later, and continued until the acute attack resolves B Has patient received acute gout regimen colchicine therapy in the last 14 days? No Choose other therapy (NSAID or corticosteroid) B Yes ^The doses recommended need to be adjusted down in the presence of significant drug interactions, and moderate to severe renal or hepatic impairment.

56 Gout: Colchicine Therapy AGREE Trial: 1.8 mg vs 4.8 mg Colchicine Arthritis & Rheumatism Vol. 62, No. 4, April 2010, pp

57 Management of an Acute Gout Attack: Corticosteroids Extent of joint involvement Options: For all cases of gout Option: 1-2 large joints Consider IA corticosteroids B Start Initial Treatment Oral: Prednisone 0.5mg/kg per day A Duration of Rx: 5-10 days at full dose then stop OR for 2-5 days at full dose then taper for 7-10 days then stop IA: Dose depends on joint size (with or without oral treatment) IM: Triamcinolone acetonide 60mg, then oral prednisone as above* B C C IA = intra-articular; IM=intramuscular *IM triamcinolone acetonide monotherapy lack of consensus

58 PAIN GENERAL DISABILITY WALKING DISABILITY Prednisone 35 mg/day x 5 days vs. Naproxen 500 mg BID x 5 days Janssens et al Lancet 2008; 371:

59 Gout: Indications for Pharmacologic ULT Indications for Pharmacologic ULT Any patient with established diagnosis of gouty arthritis and Tophus or tophi by clinical exam or imaging study Frequent attacks of acute gouty arthritis ( 2 attacks/year) Chronic kidney disease (CKD) stage 2 or worse Past urolithiasis C C A A

60 Chronic Kidney Disease: Definitions

61 EULAR 2016: Gout Guideline ULT should be considered and discussed with every patient with a definite diagnosis of gout from the first presentation. ULT is indicated in all patients with recurrent flares, tophi, urate arthropathy and/or renal stones. Initiation of ULT is recommended close to the time of first diagnosis in patients presenting at a young age (<40 years) or with a very high SUA level (>8.0 mg/dl; 480 mmol/l) and/or comorbidities (renal impairment, hypertension, ischemic heart disease, heart failure). Patients with gout should receive full information and be fully involved in decision-making concerning the use of ULT.

62

63 Gout: Individual Targets TREAT TO SERUM URATE TARGET defined for individual patient The minimum serum urate target is <360µmol/L Serum urate lowering below 300µmol/L may be needed to improve gout signs and symptoms

64

65

66 Gout: Urate Lowering Therapy (ULT) TREAT TO SERUM URATE TARGET defined for individual patient The minimum serum urate target is < 360µmol/L Serum urate lowering below 300µmol/L may be needed to improve gout S/S Select First Line ULT agent Xanthine Oxidase Inhibitor (XOI) A Allopurinol OR Febuxostat If at least one XOI is contraindicated or not tolerated Alternative First Line ULT B Uricosuric Agent Probenecid* C *Probenecid is not recommended as a first line or alternative first line ULT agent if the CrCl is <50

67 Gout: ULT and Attack Prophylaxis TREAT TO SERUM URATE TARGET defined for individual patient The minimum serum urate target is < 360µmol/L Serum urate lowering below 300µmol/L may be needed to improve gout S/S Select First Line ULT agent Xanthine Oxidase Inhibitor (XOI) Allopurinol OR Febuxostat If at least one XOI is contraindicated or not tolerated Alternative First Line ULT B A Acute Gout Prophylaxis Initiate concomitant pharmacologic anti-inflammatory gout attack prophylaxis A Uricosuric Agent Probenecid* C *Probenecid is not recommended as a first line or alternative first line ULT agent if the CrCl is <50

68 Uric Acid Metabolism Xanthine XO X Uric Acid (insoluble) Xanthine Oxidase (XO) Inhibitors Uricase (inactive in humans and apes) Allantoin (soluble)

69 What is the starting dose of allopurinol?

70 Allopurinol Dosing and Titration Starting dosage should be no greater than 100 mg/day for any patient, and start at 50 mg/day in stage 4 or worse CKD. B Gradually titrate maintenance dose upward every 2 5 weeks to appropriate maximum dose in order to treat to chosen sua target. C sua=serum uric acid

71 Allopurinol Dosing and Pharmacogenetics Dose can be raised above 300 mg daily, even with renal impairment, as long as it is accompanied by adequate patient education and monitoring for drug toxicity (e.g., pruritus, rash, elevated hepatic transaminases). B Prior to initiation, consider HLA B*5801 in selected patients, specifically in subpopulations at higher risk for severe allopurinol hypersensitivity reaction (e.g. Koreans with stage 3 or worse CKD, and Han Chinese and Thai irrespective of renal function). A sua=serum uric acid

72 Febuxostat Nonpurine Selective XO Inhibitor OH OH OH N N N N N H C N N N H N N H OH N N H Hypoxanthine Allopurinol Oxypurinol O N NC CH 3 Febuxostat S COOH

73 % of Subjects Efficacy of XO Inhibitors Proportion of Subjects with sua Level < 360 µmol/l at Final Visit 67% % 42% Febuxostat 40 mg (n=757) Febuxostat 80 mg (n=756) Febuxostat Allopurinol 300/200 mg (n=755) *p<.001 vs. allopurinol. p<.001 vs. febuxostat 40 mg Allopurinol 300 mg efficacy: 44% Allopurinol 200 mg efficacy: 32% Becker MA. et al. Arth Res & Ther 2010; 12:R63.

74 Chronic Gout Management Benefits of Continuous ULT Intermittent therapy or cessation of therapy can lead to recurrent flares. Continuous urate-lowering therapy controls flares better than intermittent therapy Bull PW, Scott JT. J Rheumatol. 1989; 16:

75 Benefits of Long-Term ULT Before Urate-Lowering Therapy 22 years with gout After Urate-Lowering Therapy 1 year with sua <240 µmol/l Images Fernando Perez-Ruiz, MD. All rights reserved.

76 Pharmacologic Antiinflammatory Prophylaxis of Gout Attacks Initiate Prophylaxis With, or just prior to initiating ULT Medication choices: First Line: Low dose Colchicine : e.g. colchicine 0.6 mg once or twice daily OR C Low dose NSAIDs with PPI (where indicated): e.g. naproxen 250 mg twice daily A * *Second Line: Low dose Prednisone or Prednisolone ( 10mg/day) C (if colchicine and NSAIDs both are not indicated, contraindicated, or ineffective) * Lack of consensus: Prednisone/prednisolone at doses above 10mg/day. The TFP did not specifically address case scenarios involving renal impairment adjusted colchicine dosing for gout attack prophylaxis

77 Duration of Anti-inflammatory Prophylaxis of Acute Gout Attacks Evaluate gout symptoms while on ULT No signs/symptoms Activity of gout S/S^ Continue pharmacologic antiinflammatory prophylaxis Duration: Treatment for the greater of A At least 6 months OR 3 months after achieving target serum urate appropriate for the patient (No tophi detected on physical exam) 6 months after achieving target serum urate appropriate for the patient (One or more tophi detected on physical exam) B C ^Examples include: acute gouty arthritis in the past 3 months, presence of palpable tophus or tophi, chronic tophaceous gouty arthropathy (with chronic synovitis) in the past 3 months

78 Subjects, % Reduction in Gout Flares Febuxostat 40 mg Febuxostat 80 mg Allopurinol 300/200 mg Time interval (weeks) Prophylaxis Prophylaxis: colchicine (0.6 mg daily) or naproxen (250 mg BID) Becker MA. et al. Arth Res & Ther 2010; 12:R63.

79 Uric Acid is Associated with Many Cardiovascular Risk Factors hypertension ethnicity obesity Uric Acid renal disease diuretics insulin resistance post-menopausal female male

80 Gout and the Metabolic Syndrome

81 GOUT: What s Coming

82 Urate transport systems in the proximal tubule The kidney excretes 70% of the daily urate production Urate anion transport function of URAT1 in renal proximal tubule epithelial cells. The organic anion transporter URAT1 exchanges tubular lumen urate with anions inside proximal tubular epithelial cells. URAT1 is targeted by uricosuric and antiuricosuric agents.

83 Lesinurad: FDA Approved (Zurampic) A selective uric acid re-absorption inhibitor (SURI) Inhibits the URAT1 transporter, increasing uric acid excretion and thereby lowering serum uric acid (sua) Phase 3 studies (CLEAR, CRYSTAL, LIGHT): used in combination with allopurinol or febuxostat Not to be used as monotherapy Approved by FDA in Dec Duzallo, a fixed-dose oral combination of lesinurad 200mg and allopurinol 200 or 300 mg, approved by FDA in

84 Arhalofenate First developed as an insulin sensitizer for type 2 diabetes Showed significant reductions in serum urate of 13 29% Inhibits URAT1, OAT 4 and OAT 10 involved in renal urate reabsorption without any effect on xanthine oxidase Antiinflammatory activity through inhibition of interleukin-1beta? the first ULAFT urate-lowering, antiflare therapy.

85

86 Resources

87

88

89

90

91

92

93

94 EULAR 2016 Gout Guideline

95 BSR 2017 Gout Guideline

96 Gout: PEARLs Serum urate concentrations can go down to normal levels during an attack of gout Oral steroids may be a safer alternative to NSAIDs or colchicine for the management of acute gout Urate lowering drugs are usually needed only for patients with frequent attacks of gout Asymptomatic hyperuricemia does not require pharmacologic treatment

97 Barriers to Change: Gout Gout is more common and more complex than usually appreciated Crystal analysis is gold standard for diagnosis but rarely performed Confusion between treatment of acute gout and chronic gout Patient and physician reluctance to start and continue urate lowering therapy (ULT)

98

99 Questions??