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 ( 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