Download Treatment approach to refractory gout

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