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Treatment approach to refractory gout Worawit Louthrenoo, M.D. Division of Rheumatology Chiang Mai University Disclosure Speaker: Roche, Pfizer, MSD, Sanofi-Aventis, Boehringer Ingelheim, Rottapharm, TRB chemedica, ATB, Actelion, J&J Investigator: Roche, Pfizer, MSD, TRB chemedica, Actelion, Sanofi-Aventis, BMS, J&J, GSK, Anthrena Advisory board: Pfizer, MSD, Sanofi-Aventis, BMS, GSK, Actelion, J&J Clinical features of gout Evolution of hyperuricemia and gout Painless inter-critical segment Asymptomatic hyperuricemia Acute flares Time Klippel et al. Primer on the rheumatic diseases. 12 th ed. 2001. Advanced gout Clinical course of gout Asymptomatic hyperuricemia Acute flares Inter-critical segments Uncontrolled hyperuricemia Advanced or tophaceous gout Renal and cardiovascular complications Traditional treatment of gout 1. 2. 3. 4. Treatment of acute attack Prevention of recurrent attack Treatment of hyperuricemia Treatment of associated conditions Medications currently approved for acute gouty arthritis Agent Advantage NSAIDS and COX-2 • Equally effective in specific inhibitors appropriate dose Disadvantage • AE: GI, renal, cardiovascular, fluid retention Colchicine • Fast-acting when use early • Synergism when use with other agents • • AE: diarrhea, toxicity in CKD Ineffective in late use Corticosteroids and ACTH • Useful in patients with renal and GI contraindication to other treatment • Able to use multiple dose • ACTH might have nonsteroid action • AE: increase risk of infection, aggravation of DM, HT, lipids Medications used to prevention of recurrent attack Prevention of recurrent attack should be prescribed in all patients who are going to receive hypouricemic therapy or those who have frequent recurrent attack Dosing Complication in chronic use Colchicine 0.3-1.2 mg/day, adjusted according to renal function, and GI side effects • Reversible axonopathy • Rhabdomyolysis NSAIDS Lowest effective dose • NSAIDS induced gastropathy • Renal insufficiency Corticosteroids < 10 mg/day of prednisolone • • • • • • Metabolic abnormality Cataract Adrenal suppression Hypertension Skin bruise Osteoporosis Currently available urate lowering agents Agents Advantage Disadvantage Uricosuric agents (Probenecid, benzbromarone, sulfinpyrazone) • Reverse the most common physiologic abnormality in gout • (90% of gout patients are under-excretors) • Renal impairment is an issue • Renal calculi Allopurinol Febuxostat (not yet avalilable in many countries) • Effective in both over production and underexcreter • Convenience for single daily dose • Effective in patients with renal insufficiency • Hypersensitivity is an issue for allopurinol Pegloticase (not yet available in many countries) • Effective in resistant case • Coverts uric acid to allantoin and then to NH3 and CO2 • Effective in patients with renal insufficiency • Contraindicate in G6PD deficiency Why do we still see refractory gout? • Difficult: not easy; requiring effort, skill or ability • Complicate: make complex (difficult to ….); make difficult to …… • Refractory: resisting control, discipline; not yielding to treatment; hard to work Dictionary of current English. Oxford University Press. 1963 Refractory gout • Clinical: ongoing of clinical manifestation with treatment (arthritis, tophus) • Laboratory: failure to achieve serum uric acid below therapeutic target (< 6 mg/dL) Refractory gout Physicians: • • Delay in prescribing uric lowering drugs (ULD) Failure to titrate ULD to achieve therapeutic target Patients: • • • Poor compliance of the patients to talk ULD Intolerance to ULD Presence of co-morbidities, particularly CKD, that prohibits the use of anti-anti-inflammatory and ULD Clinical characteristic of refractory gout 1. Long standing gout, presence of tophi 2. Renal impairment 3. Presence of co-morbidities, eg. obesity, hypertension, ASHD, etc. 4. Impair joint function and quality of life Approach to refractory gout • • Confirm the diagnosis of gout – indentified MSU crystals in SF or tissue Aware the complication of acute gout • • Infectious arthritis : bacteria, TB, etc. Look for gout mimickers • • • Acute CPP arthritis CPPD or BCP arthropathies Spondyloarthropathies Concomittant septic joint Psoriatic arthritis Gout diagnostic criteria: Sensitivity and specificity Criteria Sensitivity (%) Specificity (%) New York, 1961 64-80 99 Rome, 1966 64-82 99 ARA, 1977 70-85 64-97 Mexico, 2010 88-97 96 Percent changes in diagnosis after SF analysis Final diagnosis same Final diagnosis less likely % changes Osteoarthritis 31 6 16 Rheumatoid arthritis 24 5 17 Gout 25 9 26 Infectious arthritis 11 3 21 Pseudogout 9 1 10 Traumatic arthritis 7 2 22 Initial diagnosis Eisenberg JM. Arch Intern Med 1984;144:715-9. Practical point in treatment of acute arthritis • Start treatment as soon as possible • Start medication with high/maximum dose to get the highest benefit • Select appropriate drugs for each patients Suggestion • Colchicine – if normal renal function, arthritis onset within 48 hours • NSAIDs – if normal renal and GI, arthritis onset at any duration • Corticosteroid – if contraindicate for NSAIDs and colchicine • ACTH – similar to corticosteroid but with concurrent infection Role of NALP3 inflammasome and IL-1B in acute gout IL-1B MSU MSU TLR2/TLR4 IL-1R TIRAP MyD88 MyD88 IRAK4 NALP3 inflammasome TRAF6 NF-kB MAPKs Pro-IL-1B IL-1B AP-1 Gene expression of pro-inflammatory cytokine TNF-α, IL-6, IL-8 Akahoshi T. Curr Opin Rheumatol 2009:16:146-50. Anakinra in acute gout Open label study of 10 patients, with acute gout, treated with anakinra subcut. 100 mg/day for 3 days All failed NSAIDs, colchicine or corticosteroids treated for 48 hours So A. Arthritis Res Ther 2007;9:R28 Canakinumab in acute gout (pool 2 studies) 456 acute gouty attack < 5 days, contraindicate to NSAIDs or colchicine Received canakinumab 150 mg vs triamcinolone 40 mg q 14 days Primary outcome 72 hour post dose Physician assessment OR (95% CI) vs triamcinolone Tenderness 72 hr 2.16 (1.5-3.1)* 7 Days 2.15 (1.5-3.2)* Swelling 72 hr 1.74 (1.2-2.5)* 7 Days 1.57 (1.1-2.3) Erythema Pain (VAS) 72 hr 0.57 (0.4-0.9) 7 days 0.5 (0.3-0.9) Schlesinger N. Ann Rheum Dis 2012;71:1839–1848 Rilonacept in the prevention of recurrent attack 241 gouty arthritis, attacks > 2 /yr., uric > 7.5 mg/dL Received placebo, rilonacept 80 or 160 mg q wk for 16 wk Schumacher HR. Arthritis Care Res 2012;64:1462-70. Canakinumab in prevent recurrent gout 432 gout patient initiaing allopurinol were randomized to receive colchicine or various dose of canakinumab for 165 wks. Schlesinger N. Ann Rheum Dis 2011;70:1264–1271 Treatment of hyperuricemia (T2T) • Initiating urate lowering therapy at ideal time for each individual – Start after acute arthritis subside for a few weeks (Recent study showed no different in pain, recurrent flares) • Choosing the appropriate agent – Patients preference – Patients co-morbidity • Protecting against flares • Lower serum urate < 6.0 mg/dL or less to deplete urate pool (<5.0 in tophaceous gout) • Requires life-long therapy (intermittent therapy lead to recurrent of flares and tophi) • Monitor SUA q 2-4 weeks until achieve the desired level • Then monitor SUA q 6-12 months Taylor TH. Am J Med. 2012 Nov;125(11):1126-1134 Indication and selection of uric lowering drugs Organizato n Year BSR 2007 • Two or more flares a year • Renal insufficiency • Urolithiasis Tophi • Allopurinol (F)a • Uricosuric (S) < 5 mg/dL EULAR 2011 • Physician’s and Patient’s decision • XOIs (F) • Probenecid (S) • Combination (S) < 6 mg/dL ACR 2012 • Two or more flares a year • CKD Ccr < 90 cc/min or lower • Urolithiasis • Tophi (in physical examination or imaging studies) • XOIs (F) • Probenecid (F) • Other uricosurics (S) • Combination (S) • Pegloticase (S)b < 6 mg/dL < 5 in more severe case Indication of ULDs First/second line Target a = febuxostat was not approved in EU and US until 2008 b = pegloticase was not approved in EU, but in US in 2010 Jordan KM. Rheumatology (Oxford). 2007;46:1372–4. Hamburger M. Phys Sportsmed. 2011;39:98–123. Khanna D. Arthitis Rheum. 2012;64:1431–46. Urate excretion kinetic in gout vs nongout • Patients with primary gout have less efficient excretion kinetics, resulting in greater retention of uric acid • 40% less uric acid excretion in gouty compared with non-gouty subject • 90% of gouty subject are under-excretion Koopman W. Arthritis and allied condtions. 14 th. 2001, 2316. Simkin. Adv Exp Med Biol 1977;76B:41-5. Louthrenoo W. J Med Assoc Thai 2003;86:868-75. Urate transport at proximal tubules Basolateral membrane Probenecid Benzbromarone Sulfinpyrazone Urate anion Apical membrane Organic anions, Organic anions, monocarboxylates monocarboxylates URAT1 Urate anion Tubular lumen (SLC22A12) GLUT9 Urate anion reabsorbtion SLC2A9 Urate anion Probenecid Benzbromarone Sulfinpyrazone Peritubule interstitium ABCG2 Urate anion secretion Urate anion SLC22A6 SLC22A8 blood Urate anion Urate anion Urate anion Urate anion SLC17A1 Terkeltaub R. Arthritis Res Ther 2009;11:236 Allopurinol hypersensitivity syndrome Mucocutaneous reaction is seen in 2-3% of cases 0.4% of the reaction can be severe and fatal (TEN, Steven Johnson syndrome) High mortality rate (25%) Increase risk in patient with renal impairment, allergic to sulfa compound, concomitant use ampicillin and diuretics • Increase risk in Asian population with HLAB*5801 • • • • McInnes et al Ann Rheum Dis 1981;40:245-9 Ramasamy SN. Drug Saf 2013 (epub) Starting Dose Is a Risk Factor for Allopurinol Hypersensitivity Syndrome Review 54 cases of AHA and 15 1 Control and compared the starting dose with eGFR Stamp L. Arthritis Rheum 2012;64:2529-36 Allopurinol dosing guideline Keenan RT. Rheum Dis Clin NA 2012;38:663-80. Hande KR. Am J Med 1984;76:47–56. Stamp LK. Arthritis Rheum 2012;64:2529–36. Dose adjustment of allopurinol according to CCr usually not able to achieve SUA < 6 mg/dL Dalbeth N. J Rheumatol 2006;33:1646-50 Stamp LK. Arthritis Rheum 2011;63:412-21.. Limitations • Only 20% of patients achieve SUA < 6 mg/dL with allopurinol 300 mg/day in one study • Increase dose of allopurinol can increase in toxicity in the presence of renal impairment • A combination with uricosuric drugs might not be possible in those with significant renal impairment or the presence of renal calculi Combination allopurinol and probenecid Open study, gout patients who were taking 100-400 mg allopurinol were given probenecid 500 mg/day to max 2 gm/day to achieve SUA < 6 mg/dL. Adding probenecid - Decrease SUA 25% -Increase urate clearance 60% - Decrease oxycpurinol 26% -Increase renal oxypurinol clearance 24% Stocker SL. J Rheumatol J Rheumatol 2011;38:904–10 Targeting SUA < 5 mg/dL in controlling gout Perez-Ruiz F. J Rheumatol 2007;34:1888–93 Newer uric acid lowering drugs • Febuxostat • Pegloticase Febuxostat vs allopurinol in gout 1072 gout, mean disease duration 10 years, normal or mild impaired renal function 28 wk study Target = SUA < 6 mg/dL Schumacher HR. Arthritis Care Res 2008;59:1540-8. Pegloticase in refractory gout 225 refractory gout, SUA > 8 mg/dL, at least one tophi, and had > 3 flares during past 18 months, and contraindicate to allopurinol Treatment: placebo vs pegloticase 8 mg q 4 wk or q 2 wk Sherman M. Adv Drugs Deli Rep 2008 Sundy JS. JAMA. 2011;306(7):711-720 Other medication with uric acid lowering property • Losartan • Fenofibrate • Amlodipine Co-morbidities associated with gout • • • • HT DM Dyslipidemia ASHD Look for secondary cause of hyperuricemia in gout Non-pharmacological approach to reduce serum uric acid 1. Avoid alcohol, beer 2. 3. 4. 5. Dietary therapy, avoid high purine diet Control body weight Drink a lot of water Drink milk and diary product • Reduce weight by 8 kg can reduce SUA 11% in 80% of cases • Balanced diet: 1600 Kcal, with carbohydrate: protein: fat (mainly unsat) = 40:30:30 % can reduce SUA18% Purine free diet can decrease urinary uric acid excretion by 200-400 mg/day and serum uric acid by 1 mg/dL Nicolls A. Lancet 1972;2:1223-4. Dessein PH. Ann Rheum Dis 2000;59:539-43. Adherence with the therapy USA: 4166 paitents start ULDs • 56% of patients were not adherent Israel: • 83% were not adherent Harrold LR. Arthritis Res Ther 2009;11:R46 Zandman-Goddard G. Rheumatology 201352:1126-32 Other under-investigated ULD • Lesinurad (DHEA594) - a potent URAT1 inhibitor is now in many phase III program • Ulodesine (BCX4208) - purine nucloside phosphorylase inhibitor - complete phase IIb with favorable results Conclusions • Management of refractory gout requires a good co-operation between physician and patients • The diagnosis should be confirmed by the demonstration of MSU crystals in SF or body tissue • Anti-inflammatory should be started, with a maximum dose, as soon as possible • IL-1B inhibitor has been shown a promising results in difficult acute arthritis and prevention of recurrent attack • Prophylaxis should be prescribed to prevent recurrent attack during hypouricemic therapy • Hypouricemic therapy, when prescribed, should be aim to achieve SUA < 6 mg/dL or less • Non-pharmacological therapy – weight reduction, avoid alcohol and beer, and purine rich diet – should be implement • Adherence to the treatment is crutial for the successful outcome