Gout Diagnosis and Management Update: Cases and Choices

1. Gout 2.0 Scott Vogelgesang, M.D. Division of Immunology: Rheumatology & Allergy

2. Case • 48 year old man presents with swollen, painful left toe that started overnight. Didn’t hurt when he went to bed. No trauma, never happened before. No fever, no family history of arthritis or gout. • PMH: Hypertension, Hyperlipidemia • Meds: HCTZ 25 mg daily, atorvastatin 20 mg daily, aspirin 81 mg daily • SH: No tobacco, ETOH – 5-10/week • Exam: • t36.8 p95 (increases to 115 when you use the word “needle”), bp148/91 • Rest (except right toe) unremarkable • Left toe ….

3. Case (continued) • CBC, Electrolytes, liver tests normal • Serum Uric Acid 5.2 mg/dl • X-ray of the foot shows only soft-tissue swelling. Now what? Next diagnostic step?

4. Arthrocentesis • Demonstrate crystals • Needled-shaped • Intracellular • Negatively birefringent (“parallel-yellow”) • Rule out septic joint

5. Alternate scenario • “…you want to poke a needle where?!! I came to see you to make this better, not make it hurt worse! Come on, can’t you tell me what this is without sticking a needle into my already sore toe?” • Your records indicate that when you started his statin, he had a serum uric acid of 10.2 mg/dl. • Can we make a diagnosis without aspiration?

6. Presumptive Diagnosis:(Unable to demonstrate crystals) • Rapid development of severe pain (≤ 24 hrs) • Pain, erythema, swelling – typical joint • Hyperuricemia • ~80% probability of having gout • Zhang w et al. Ann Rheum Dis 2006;65:1301

7. Dual Energy Computed Tomography(DECT) • Identifies urate deposits • Using chemical properties of urate • Yield 85-90% • False negative scans: • 1st episode of gout • Symptom duration < 6 weeks • False positive • Osteoarthritis • Similar to conventional CT • Radiation exposure • Expense Durcan L et al. Semin Arthritis Rheum 2015, http://dx.doi.org/10.1016/j.semarthrit.2015.09.008

8. Ultrasound • “Double Contour Sign” • Irregular echogenic line over the superficial layer of hyaline cartilage • No radiation • $< than CT • Performance • Specific • Not sensitive Durcan L et al. Semin Arthritis Rheum 2015, http://dx.doi.org/10.1016/j.semarthrit.2015.09.008

9. Case • “… you mean, you knew I had high levels of that gout chemical and you didn’t treat it? Could you have prevented this pain in my toe?” • Should we treat asymptomatic hyperuricemia?

10. (Asymptomatic) Hyperuricemia • Onset: • Men: puberty • Women: menopause • Level of SUA correlates with likelihood of acute gout, renal stones BUT only 1-10% of those with hyperuricemia will develop acute gout • Not treated

11. Case - Management Choices depend on severity and number of joints

12. Baseline Recommendations • Education, diet & lifestyle recommendations • Avoid high-purine foods, alcohol overuse • Encourage low/non-fat dairy products and vegetables • Weight loss • Smoking cessation • Increase exercise • Secondary Causes • Obesity • Excessive alcohol • Metabolic syndrome • Hypertension • Hyperlipidemia • History of urolithiasis • Chronic kidney disease • Genetic/acquired cause of urate overproduction • Lead intoxication

13. NSAIDs • Use any short-acting NSAID- Full dose • FDA: indomethacin, naproxen, sulindac • No functional difference in efficacy • Use at onset of symptoms • Keep Rx available so no need to call office • Continue until attack resolves • Usually better tolerated than colchicine

14. Colchicine:Oral • 1.2 mg then 0.6 mg 1 hour later • 12 hours later 0.6 mg qd or BID • Mechanism: • Inhibits microtubule formation • Decreases inflammatory response • Side Effects: NVD, marrow suppression, death, hepatitis, seizures, respiratory depression, alopecia,

15. Prednisone • 0.5 mg/kg x 5-10 days then stop –or- • 0.5 mg/kg x 2-5 days then taper over 7 days

16. Joint Injection • Rule out infection before injecting steroids • Not routinely done unless cultures negative for 24-72 hours

17. Case • Should we stop his HCTZ? • “The decision should be individualized, taking into consideration the degree to which the thiazide increases the serum urate level, whether this increase can be managed without overly complicating the patient’s hypouricemic therapy, and, most importantly, what effect switching to another drug will have on the control of the patient’s hypertension.” • “No study has directly addressed this issue.” • Should we stop his aspirin? • “…aspirin in low doses for cardioprotection (81 mg daily) also need not be stopped in patients with hyperuricemia or gout in an effort to better control the serum urate level. Low-dose aspirin increases the serum urate level by about 0.3 mg/dL. Since patients with gout have a higher risk of having cardiovascular disease, metabolic syndrome, and chronic kidney disease, many will benefit from low-dose aspirin therapy.” • Could we substitute losartan for HCTZ? • “Losartan is a weak uricosuric and can lower the serum urate level slightly, possibly making the addition of another hypouricemic agent unnecessary, while still controlling the blood pressure with a single pill. This decision must be individualized, taking into consideration the efficacy and cost of the alternative antihypertensive drug, as well as the potential but as yet unproven cardiovascular and renal benefits of lowering the serum urate with a more potent hypouricemic to a degree not likely to be attained with losartan alone.” • Mandel B. Cleveland Clinic Journal of Medicine. 2014 February;81(2):83, 86

18. Case • Same patient 10 years later… • Managed his “attacks” by taking ibuprofen 800 mg three times daily at the first “twinge” of toe pain for 5 days • Frequency of attacks has been increasing over the past few years – now he gets 4-5 attacks per year and the ibuprofen doesn’t completely abate the attacks anymore. • He returns to clinic for advice… • Exam: • T37.1 p82 bp 127/78 • Rest unremarkable (no tophi) • CBC, Liver tests, electrolytes normal. Serum Uric Acid 10.4 mg/dl

19. Chronic/Tophaceous Gout • Destructive, chronic arthritis • Rate of urate deposition  SUA level • Can be polyarticular with systemic features

20. Urate Lowering Therapy • Indications • 1 gout attack & chronic kidney disease • Tophi • ≥ 2 attacks/year • History of urolithiasis • Medications • Xanthine Oxidase Inhibitors (XOI) • Examples: Allopurinol, Febuxostat • Stop purine metabolism (inhibit xanthine oxidase) • Uric acid doesn’t form • Uricosurics: • Example: Probenecid • increase renal excretion of uric acid • Urate Transporter (URAT1) inhibitor • Example: Lesinurad • inhibits uric acid reabsorption • Uricase: converts uric acid to allantoin New!

21. Overall Approach to Therapy • Allopurinol or Febuxostat (XOI) • Treat to at least ≤ 6.0 mg/dl (< 5.0 mg/dl if tophi) • Increase intensity and re-evaluate • If not successful, consider adding lesinurad • Probenecid as alternative if XOI is contra-indicated or not tolerated • Add uricosuric with both agents titrate to max appropriate dose • If ineffective, consider pegloticase

22. Allopurinol • Xanthine oxidase (competitive) inhibitor • Consider HLA-B*5801 in Koreans with CKD 3, Chinese, Thai • Dose • Start 100 mg/day (50 mg/day in CKD 4) • Titrate up q 2-5 weeks • Max 800 mg/day • Side Effects: TEN, NVD, marrow suppression, hepatitis, fever, vasculitis, alopecia • Drug interactions: azathioprine • Any change in SUA can precipitate acute flare of gout • Beware of allopurinol hypersensitivity – TEN can be fatal

23. Febuxostat • Xanthine Oxidase inhibition (non-competitive) • 40 mg qd (max 80 mg) • Side Effects • Cardiovascular (MI, CVA) • Elevated LFTS • Gout Flare • Avoid combo with azathioprine

24. Probenecid • Uricosuric – monotherapy or combo with XOI • Rarely used anymore • Ideal candidate: • XOI not tolerated • < 60 years of age • normal renal function (GFR > 30-60 ml/min) • 24 hour urine uric acid < 800 mg • no history of stones • > 2 attacks/year • 250 mg BID (max 3g/day) • Side effects: rash, NVD, marrow toxicity

25. Lesinurad • Urate transporter (URAT1) inhibitor • 200 mg daily • Used in combination with XOI • Side Effects • Renal failure (stop if CrCl < 45) • Headache • GERD • Avoid with ASA, valproic acid, OCP

26. Other Options • Pegloticase (uricase): Persistent activity despite (or intolerance to) combination urate lowering therapy • IL-1 antagonists

27. Prophylaxis • Colchicine (or NSAIDs) to prevent an acute exacerbation while initiating hypouricemic therapy • Colchicine 0.6 mg qd - BID • indomethacin 25 mg qd – BID • Duration: Greater of… • 6 months –or- • 3 mos after target SUA (no tophi) • 6 mos after target SUA (with tophi that resolved)

28. Diagnosis of gout: Crystal identification Presumptive Dx Criteria Dual Energy CT Ultrasound Asymptomatic Hyperuricemia not treated. Acute treatment: NSAIDs Colchicine Prednisone Allopurinol: ≥ 2 attacks/yr, stones, GFR, tophi, TLL, Enzyme deficiency Take Home Points

29. Questions? • References • Neogi T. Clinical practice: gout. New Engl J Med 2011;364:443-52. • Khanna D, et al. 2012 American College of Rheumatology Guidelines for Management of Gout Part 1. Arthritis Care Res 2012;64(10): 1431-1446. • Khanna D, et al. 2012 American College of Rheumatology Guidelines for Management of Gout Part 2. Arthritis Care Res 2012; 64:1447-61. • Mandel B. Cleveland Clinic Journal of Medicine. 2014 February;81(2):83, 86 • Zhang w et al. Ann Rheum Dis 2006;65:1301