Treatment approach to refractory gout - Worawit Louthrenoo, M.D. Division of Rheumatology Chiang Mai University
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Treatment approach to
refractory gout
Worawit Louthrenoo, M.D.
Division of Rheumatology
Chiang Mai UniversityDisclosure
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&JClinical features of gout
Evolution of hyperuricemia and gout
Painless inter-critical segment
Asymptomatic Acute flares Advanced gout
hyperuricemia
Time
Klippel et al. Primer on the rheumatic diseases. 12 th ed. 2001.Clinical course of gout
Asymptomatic Acute flares Inter-critical Advanced or
hyperuricemia segments tophaceous gout
Renal and
cardiovascular
complications
Uncontrolled hyperuricemiaTraditional treatment of gout 1. Treatment of acute attack 2. Prevention of recurrent attack 3. Treatment of hyperuricemia 4. Treatment of associated conditions
Medications currently approved
for acute gouty arthritis
Agent Advantage Disadvantage
NSAIDS and COX-2 • Equally effective in • AE: GI, renal, cardiovascular,
specific inhibitors appropriate dose fluid retention
Colchicine • Fast-acting when use early • AE: diarrhea, toxicity in CKD
• Synergism when use with • Ineffective in late use
other agents
Corticosteroids • Useful in patients with renal • AE: increase risk of infection,
and ACTH and GI contraindication to aggravation of DM, HT, lipids
other treatment
• Able to use multiple dose
• ACTH might have non-
steroid actionMedications 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 • Reversible axonopathy
according to renal • Rhabdomyolysis
function, and GI side
effects
NSAIDS Lowest effective dose • NSAIDS induced gastropathy
• Renal insufficiency
Corticosteroids < 10 mg/day of • Metabolic abnormality
prednisolone • Cataract
• Adrenal suppression
• Hypertension
• Skin bruise
• OsteoporosisCurrently available urate lowering agents
Agents Advantage Disadvantage
Uricosuric agents • Reverse the most common • Renal impairment is an
(Probenecid, physiologic abnormality in issue
benzbromarone, gout • Renal calculi
sulfinpyrazone) • (90% of gout patients are
under-excretors)
Allopurinol • Effective in both over • Hypersensitivity is an issue
Febuxostat (not yet avalilable production and under- for allopurinol
in many countries) excreter
• Convenience for single daily
dose
• Effective in patients with
renal insufficiency
Pegloticase (not yet available • Effective in resistant case • Contraindicate in G6PD
in many countries) • Coverts uric acid to allantoin deficiency
and then to NH3 and CO2
• Effective in patients with
renal insufficiencyWhy 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. 1963Refractory 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
ULDClinical 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.
Acute CPP arthritis
• Look for gout mimickers
• CPPD or BCP arthropathies
• Spondyloarthropathies
• Concomittant septic joint
Psoriatic arthritisGout 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 96Percent changes in diagnosis after SF
analysis
Initial diagnosis Final diagnosis Final diagnosis % changes
same less likely
Osteoarthritis 31 6 16
Rheumatoid 24 5 17
arthritis
Gout 25 9 26
Infectious 11 3 21
arthritis
Pseudogout 9 1 10
Traumatic 7 2 22
arthritis
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 infectionRole of NALP3 inflammasome and IL-1B in
acute gout
IL-1B
MSU
MSU
TLR2/TLR4 IL-1R
TIRAP
MyD88
MyD88
IRAK4
TRAF6 NALP3
inflammasome
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:R28Canakinumab 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 OR (95% CI) vs
assessment 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
72 hr 0.57 (0.4-0.9)
Pain (VAS)
7 days 0.5 (0.3-0.9)
Schlesinger N. Ann Rheum Dis 2012;71:1839–1848Rilonacept 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;70:1264–1271Treatment 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 (Indication and selection of uric
lowering drugs
Organizato Year Indication of ULDs First/second line Target
n
BSR 2007 • Two or more flares a year • Allopurinol (F)a < 5
• Renal insufficiency • Uricosuric (S) mg/dL
• Urolithiasis Tophi
EULAR 2011 • Physician’s and Patient’s • XOIs (F) < 6 mg/dL
decision • Probenecid (S)
• Combination (S)
ACR 2012 • Two or more flares a year • XOIs (F) < 6 mg/dL
• CKD Ccr < 90 cc/min or • Probenecid (F) < 5 in
lower • Other uricosurics more
• Urolithiasis (S) severe
• Tophi (in physical • Combination (S) case
examination or imaging • Pegloticase (S)b
studies)
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 Apical membrane
Probenecid
Benzbromarone Organic anions, Organic anions,
Sulfinpyrazone monocarboxylates
monocarboxylates
Urate anion Urate anion URAT1 Tubular
lumen
GLUT9 (SLC22A12)
Urate anion reabsorbtion Urate anion
SLC2A9
Probenecid
Benzbromarone
Sulfinpyrazone
Peritubule
interstitium
ABCG2
Urate anion secretion Urate anion
Urate anion Urate anion
Urate anion Urate anion
SLC22A6
SLC22A8 SLC17A1
blood Terkeltaub R. Arthritis Res Ther 2009;11:236Allopurinol 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;64:2529-36Allopurinol 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 calculiCombination 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;38:904–10Targeting SUA < 5 mg/dL in controlling gout
Perez-Ruiz F. J Rheumatol 2007;34:1888–93Newer uric acid lowering
drugs
• Febuxostat
• PegloticaseFebuxostat 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. Dietary therapy, avoid high purine diet
3. Control body weight
4. Drink a lot of water
5. 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 201352:1126-32Other 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 outcomeYou can also read
