Management

1. Management

2. Main Diagnosis Acute gouty arthritis on top of chronic tophaceous gout Ruptured tophi with secondary bacterial infection of the foot with osteomyelitis Anemia secondary to occult GI bleeding probably due to NSAID gastropathy Chronic kidney disease secondary to gout

3. Patient with ACUTE GOUT ARTHRITIS Panel B: Acute Gouty Arthritis • Identify and treat precipitants of gout flare* • Do NOT start Allopurinol • If the patient is already taking allopurinol, do not change its dose. • Ice compress (20 min x 4x/day up to one week) Any contraindications to colchicine/ NSAID/ COX-2 selective inhibitor Y • REFER TO RHEUMATOLOGIST • Start Prednisone 30 mg single dose on day 1, reduce dose by 5 mg daily and discontinue by day 7 • Intravenous or intramuscular steroids are options N Colchicine 0.5 mg/tab 1 tab TID-QID ± NSAID/ COX-2 selective inhibitor ± analgesic On day 7, is the arthritis RESOLVING Y • Discontinue NSAID/ COX-2 inhibitor/ Steroids • Start or adjust Colchicine 0.5 mg/tab 1 tab BID Go to Panel C (Intercritical and Chronic Gout N • Review adherence to meds • Recheck if precipitants have been adequately treated • REFER TO RHEUMATOLOGIST Li-Yu J, et al. (2008) Philippine Clinical Practice Guidelines for Management of Gout. Phil. J. Internal Medicine, 46:165-173

4. Known precipitants of gout flares • Stress • Hospital admission or surgery • Infection • Dehydration • Drugs/ Medication (aspirin <1g/day, pyrazinamide, ethambutol, diuretics, etc) • Irregular intake of urate lowering medications Li-Yu J, et al. (2008) Philippine Clinical Practice Guidelines for Management of Gout. Phil. J. Internal Medicine, 46:165-173

5. Panel C: Intercritical and Chronic Gouty Arthritis Patient with INTERCRITICAL/ CHRONIC GOUT • Start Colchicine 0.5 mg/tab 1 tablet BID • Prescribe lifestyle modifications* • Correct modifiable risk factors REFER TO RHEUMATOLOGIST/ NEPHROLOGIST Is there an INDICATION to start Allopurinol? Is crea clearance <80 mL/min? Y Y N N • Instruct patient on colchicine use to avert flare • Monitor/ observe for indications to start allopurinol • Baseline crea, uric acid every 1-3 months & ALT every 6 months • Start Allopurinol at 50-100 mg once daily, to be titrated by 50-100 mg every 2-4 weeks Li-Yu J, et al. (2008) Philippine Clinical Practice Guidelines for Management of Gout. Phil. J. Internal Medicine, 46:165-173

6. Maintain on allopurinol and colchicine • Check lifestyle • Check adherence to medications • REFER TO RHEUMATOLOGIST On periodic monitoring, is SUA <6mg/dL? Any flare in between visits? Y Y N N • Maintain allopurinol • May discontinue colchicine • Continue periodic monitoring of SUA, crea Has allopurinol 300 mg/day been used? Y • Review the diagnosis of GOUT • REFER TO RHEUMATOLOGIST N • Continue titration of allopurinol • Maintain colchicine Li-Yu J, et al. (2008) Philippine Clinical Practice Guidelines for Management of Gout. Phil. J. Internal Medicine, 46:165-173

7. Lifestyle modifications that should be prescribed to all patients with gout • Low to moderate purine diet • Intake of more fluid (at least 2 L/day if without contraindication) • Avoidance of alcoholic beverages • Maintenance of appropriate body mass index • Engagement in low-to-moderate aerobic exercises at least 45 minutes per day 4 times a week

8. Indications for starting urate lowering therapy • Recurrent arthritis, at least 2 episodes • Presence of tophaceous deposits • Radiographic evidence of chronic gout • Recurrent uric acid nephrolithiases

9. Febuxostat • inhibitor of xanthine oxidase, it is structurally different from allopurinol • has an alternate mechanism of enzyme inhibition, and is more potent Love, BL et al. (2010). Urate-lowering therapy for gout: focus on febuxostat. Pharmacotherapy 30(6):597-608

10. Febuxostat • Unlike allopurinol, which undergoes oxidation to the active metabolite oxypurinol and interacts chemically with the molybdenum center of xanthine oxidase • febuxostat remains unchanged and inhibits xanthine oxidase by binding in a narrow channel leading to the molybdenum center of the enzyme. • By this mechanism, febuxostat is able to inhibit both the reduced and oxidized form of xanthine oxidase to produce sustained reductions in sUA levels. Love, BL et al. (2010). Urate-lowering therapy for gout: focus on febuxostat. Pharmacotherapy 30(6):597-608

11. Gaffo, AL and Saag KG. (2009). Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout. Core Evid 4:25-36

12. Rilonacept Being evaluated as a therapeutic drug candidate for the prevention of gout flares in patients who are initiating uric acid- lowering therapy Fusion protein designed to attach to and neutralize IL-1 before IL-1 can bind to cell surface receptors and generate signals that trigger inflammation

13. Rilonacept Currently indicated in the U.S. for the treatment of Cryopyrin-Associated Periodic Syndroms (CAPS), including Familial Cold Auto-inflammatory Syndroms (FCAS) and Muckle-Wells Syndroms (MWS) in adults and children 12 and older

14. PRE-SURGE • PREventive Study against URate-lowering drug-induced Gout Exacerbations 1 and 2 • Evaluating the mean number of gout flares per patient over the first 16 weeks of initiation og allopurinol therapy. • Approximately 240 patients are being randomized on a 1:1:1 basis in each study to receive one of the following regimens: • Rilonacept 160mg as an initial loading dose, followed by weekly 80mg subcutaneous injections • Rilonacept 320mg as an initial loading dose, followed bu weekly 160mg subcutaneous injections • Weekly placebo injections

15. Preliminary results of PRE-SURGE 1 Patients who received rilonacept at a weekly dose of 160mg had an 80% decrease in mean number of gout flares compared to the placebo group over the 16 week treatment period (0.21 flares vs 1.06 flares, p<0.0001) Patients who received rilonacept at a weekly dose of 80mg had a 73% decrease compared to the placebo group (0.29 flares vs 1.06 flares, p<0.0001)

16. Preliminary results of PRE-SURGE 1 • Adverse events that occurred at a frequency of at least 5% in any study group were: • Injection site reaction • Upper respiratory tract infection • Lower respiratory tract infection • Musculoskeletal pain/discomfort • headache

17. Global RE-SURGE REview of Safety Using Rilonacept in preventing Gout Exacerbations study Evaluating the safety of rilonacept vs placebo over 16 weeks in 1,200 patients at risk for gout flares from uric-acid lowering treatment, including allopurinol, febuxostat, probenecid, or sulfinpyrizone About 300 patients receive placebo, 900 patients receive rilonacept as an initial 320mg loading dose, followed by weekly 160mg subcutaneous injections

18. Rilonacept with NSAIDs Compared to indomethacin, there was no significant benefit from combining indomethacin with rilonacept Measured by the primary endpoint of the average intensity of gout pain from 24-72 hours after initiation of treatment.

19. Wound Management • Debridement may be accomplished by sharp, mechanical, enzymatic, and/or autolytic measures. • Wounds should be cleaned initially and each dressing changed by a nontraumatic technique. • Use normal saline • Selection of a dressing should ensure that the ulcer tissue remains moist and the surrounding skin dry. • Give tetanus prophylaxis James, WD, et al. (2006). Andrews’ Diseases of the skin: Clinical Dermatology, 10th ed.

20. Cellulitis • Initial empiric therapy should cover both staphylococci and streptococci. • Intravenous penicillinase-resistant penicillins or a first-generation cephalosporin are usually effective James, WD, et al. (2006). Andrews’ Diseases of the skin: Clinical Dermatology, 10th ed.

21. Osteomyelitis • Empiric therapy guided by findings on Gram’s stain or chosen to cover the most likely pathogens • Should include agent active against anaerobes in the setting of a decubitus ulcer or diabetic foot infection Fauci, AS, et al. (2008). Harrison’s Principles of Internal Medicine, 17th ed

22. Fauci, AS, et al. (2008). Harrison’s Principles of Internal Medicine, 17th ed

23. initial empiric therapy to cover gonococci, S. aureus, and streptococci, pending culture results • ceftriaxone or cefotaxime Firestein, GS, et al. (2008). Kelley’s Textbook of Rheumatology, 8th ed PNDF Vol II, 3rd ed (2006)

24. 3rd gen cephalosporins • more stable to hydrolysis by beta-lactamases than 2nd generation cephalosporins. • wider spectrum and greater potency against gram-negative organisms especially for Enterobacteriaceae • treating serious gram-negative bacillary infections including sepsis and meningitis when microorganisms are resistant to customarily used drugs or when aminoglycosides are contraindicated • cefotaxime and ceftriaxone - gram-positive organisms and beta-lactamase producing Proteus, Klebsiella, Serratia, H. influenzae, Enterobacter, N. gonorrheae and S. typhi PNDF Vol II, 3rd ed (2006)

25. GI bleeding Feldman, M et al. (2006). Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed.

26. GI Bleeding • Treatment of patients with fecal occult blood depends on the underlying disorder. • NSAIDs should be discontinued if possible • PPIs are more effective than H2 receptor antagonists and misoprostol Feldman, M et al. (2006). Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed.

27. Anemia • Blood transfusion • normal daily blood loss of 0.5 to 1.5 mL/day, a stool weight of 150 g, and a circulating hemoglobin level of 15 g/dL, the usual stool hemoglobin concentration is 0.5 to 1.5 mg/g of stool. • under normal circumstances, a total of 0.25 to 0.75 mg of elemental iron is lost because of gastrointestinal bleeding daily. • A small amount of iron is also lost in sloughed intestinal cells and from minute amounts of bleeding, making the average daily iron loss approximately 1 mg • The absorptive capacity of the small intestine for iron can increase dramatically in response to iron depletion but normally is limited. Feldman, M et al. (2006). Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed.

28. iron deficiency results only when iron loss exceeds absorption, usually when blood loss exceeds 5 to 10 mL/day over many weeks. • When diagnosis of iron deficiency anemia is established • iron therapy should be instituted • Ferrous sulfate, 325 mg orally two to three times daily, is recommended

29. Hypertension • Diuretics – contraindicated in hyperuricemia, gout • Anti-adrenergics • Alpha Adrenoceptor Blockers - salt and/or water depleted may exhibit a sudden, drastic drop in standing BP after the first dose • Beta Adrenoceptor Blockers – relative contraindication insulin-requiring diabetes; renal failure; lipid disorders • Adrenergic Neuron Blockers – contraindicated in patient with PUD • Centrally Acting Anti-hypertensives – 2nd or 3rd line with multiple drug regimen Fauci, AS, et al. (2008). Harrison’s Principles of Internal Medicine, 17th ed PNDF Vol II, 3rd ed (2006)

30. Hypertension • Direct Vasodilators – precaution in renal or hepatic impairment • Calcium Channel Blockers • Angiotensin Converting Enzyme (ACE) Inhibitors – contraindicated in renal failure • Angiotensin 2 Receptor Blockers (ARB) – precaution in renal insufficiency Fauci, AS, et al. (2008). Harrison’s Principles of Internal Medicine, 17th ed PNDF Vol II, 3rd ed (2006)

31. Calcium Channel Blockers • Reduce vascular resistance through L-channel blockade, which reduces intracellular calcium and blunts vasoconstriction • NIFEDIPINE 5-10 mg q8h, • Amlodipine 5-10 mg daily • Felodipine Initially, 5 mg once daily, PO; titrated slowly to 10 mg once daily. • Nicardipine Start with 10 mg 3x/d PO • Nimodipine PO 60 mg q4h. Fauci, AS, et al. (2008). Harrison’s Principles of Internal Medicine, 17th ed PNDF Vol II, 3rd ed (2006)

32. Thank you!!!

33. Jordan, KM, et al. (2007). Guideline for Management of Gout. British Society for Rheumatology

34. Ice compress 20 min x 4x/day up to one week In the absence of contraindications 0.5 mg/tab TID-QID initially at 30 mg and rapidly tapered over 6 days can be given as alternative Allopurinol started at 100 mg/day 2 weeks after the pain and swelling has subsided. Dose is titrated by 50-100 mg/day every 2 to 4 weeks to achieve SUA <6 mg/dL. The maximum dose of allopurinol is 300 mg/day. SUA and serum creatinine should be periodically monitored. Li-Yu J, et al. (2008) Philippine Clinical Practice Guidelines for Management of Gout. Phil. J. Internal Medicine, 46:165-173 Jordan, KM, et al. (2007). Guideline for Management of Gout. British Society for Rheumatology

35. Jordan, KM, et al. (2007). Guideline for Management of Gout. British Society for Rheumatology

36. Absence of response after a week should prompt re-evaluation of the diagnosis and referral to a rheumatologist Li-Yu J, et al. (2008) Philippine Clinical Practice Guidelines for Management of Gout. Phil. J. Internal Medicine, 46:165-173 Jordan, KM, et al. (2007). Guideline for Management of Gout. British Society for Rheumatology

37. In the absence of contraindications, i.e.. renal impairment or gastrointestinal ulcers, the use of colchicines, traditional non-steroidal anti-inflammatory drugs (NSAIDs), OR selective cyclo-oxygenase 2 (COX-2) inhibitors is recommended for the treatment of acute gouty arthritis. • The expert panel recommends that colchicines (500 mcg tab) should not exceed 4 tablets in divided doses per day. • Prednisone, initially at 30 mg and rapidly tapered over 6 days can be given as alternative if colchicines, traditional NSAIDs or COX-2 inhibitors are contraindicated or not tolerated by the patient • Absence of response after a week should prompt re-evaluation of the diagnosis and referral to a rheumatologist Li-Yu J, et al. (2008) Philippine Clinical Practice Guidelines for Management of Gout. Phil. J. Internal Medicine, 46:165-173

38. Ice compress is recommended in combination with pharmacologic agents for relief of joint pain and swelling of acute gouty arthritis • Serum uric acid (SUA) level should be reduced to and maintained at <6 mg/dL (0.36 mmol/L) • Continuous long term therapy with allopurinol is advised to achieve a target SUA level of <6 mg/dL • Allopurinol should be started at 100 mg/day 2 weeks after the pain and swelling of gouty arthritis has subsided. The dose is titrated by 50-100 mg/day every 2 to 4 weeks to achieve SUA <6 mg/dL. The maximum dose of allopurinol is 300 mg/day. SUA and serum creatinine should be periodically monitored. Li-Yu J, et al. (2008) Philippine Clinical Practice Guidelines for Management of Gout. Phil. J. Internal Medicine, 46:165-173

39. A referral to an internist or rheumatologist is recommended if SUA persistently remains > 6 mg/dL despite maximum dose. • Colchicine should be used at 0.5 mg/tab OD BID to prevent gout flares when initiating urate-lowering therapy with allopurinol. This should be maintained for 3-6 months from the last occurrence of gout flare and after the optimal SUA target is achieved. In the event that adverse events like diarrhea occur, a lower dose of colchicines should be used. NSAIDs should not be used for prevention of gout flares. • Dietary modification (to promote weight loss) and avoidance of alcohol should be prescribed. • Low impact exercises (walking, biking, swimming, ballroom dancing) may also be advised. Li-Yu J, et al. (2008) Philippine Clinical Practice Guidelines for Management of Gout. Phil. J. Internal Medicine, 46:165-173

40. Management of acute gout (1) Affected joints should be rested and analgesic, anti-inflammatory drug therapy commenced immediately, and continued for 1–2 weeks. (2) Fast-acting oral NSAIDs at maximum doses are the drugs of choice when there are no contraindication. (3) In patients with increased risk of peptic ulcers, bleeds or perforations, co-prescription of gastro-protective agents should follow standard guidelines for the use of NSAIDs and Coxibs. (4) Colchicine can be an effective alternative but is slower to work than NSAIDs. In order to diminish the risks of adverse effects (especially diarrhea) it should be used in doses of 500g bd–qds. Jordan, KM, et al. (2007). Guideline for Management of Gout. British Society for Rheumatology

41. (5) Allopurinol should not be commenced during an acute attack but in patients already established on allopurinol, it should be continued and the acute attack should be treated conventionally. (6) Opiate analgesics can be used as adjuncts. (7) Intra-articular corticosteroids are highly effective in acute gouty monoarthritis and i.a., oral, i.m or i.v corticosteroids can be effective in patients unable to tolerate NSAIDs, and in patients refractory to other treatments. (8) If diuretic drugs are being used to treat hypertension, an alternative antihypertensive agent should be considered, but in patients with heart failure, diuretic therapy should not be discontinued. Jordan, KM, et al. (2007). Guideline for Management of Gout. British Society for Rheumatology

42. Given in ward • Omeprazole 40 mg tab OD • Amlodipine 10 mg tab OD • Clindamycin 300 mg cap q 6 • Ciprofloxacin 250 mg tab BID • Given Colchicine as follows to treat acute gout: 2 tabs now then 1 tablet after 6 hours • Cold compress x 10-15 mins TID on inflamed joints

43. ANTIGOUT • For acute gout • COLCHICINE Oral: 500 mcg tablet • NSAIDs • For chronic gout • ALLOPURINOL Oral: 100 mg and 300 mg tablet PNDF Vol. I, 7th ed. (2007)

44. 2.4 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) • 2.4.1 Non-selective COX inhibitors • IBUPROFEN • NAPROXEN • diclofenac • indometacin • ketoprofen • mefenamic acid • 2.4.2 Selective COX 2 inhibitor • CELECOXIB PNDF Vol. I, 7th ed. (2007)