Treatment approach to refractory gout. Worawit Louthrenoo, M.D. Division of Rheumatology Chiang Mai University

Treatment approach to refractory gout Worawit Louthrenoo, M.D. Division of Rheumatology Chiang Mai University Disclosure Speaker: Roche, Pfizer, MS...
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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 ( 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

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