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

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 ….

Case (continued) Now what? Next diagnostic step? 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?

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

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?

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

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

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

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?

(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

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

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

NSAIDs Use any short-acting NSAID- Full dose Use at onset of symptoms 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

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,

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

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

Case Should we stop his HCTZ? Should we stop his aspirin? “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

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

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

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!

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

Allopurinol Xanthine oxidase (competitive) inhibitor Dose 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

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

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

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

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

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)

Take Home Points 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

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