Treatment Update For Gout
The Future is Now
Scott R. Burg, D.O.
Orthopaedic and Rheumatologic Institute
Cleveland Clinic
Gout…in 1799…
Flare: Classic Description
The victim goes to bed and sleeps in good health. About two
o’clock in the morning he is awakened by a severe pain in
the great toe; more rarely in the heel, ankle, or instep. The
pain is like that of a dislocation, and yet the parts feel as if
cold water were poured over them . . . Now it is a violent
stretching and tearing of the ligaments – now it is a gnawing
pain, and now a pressure of tightening. So exquisite and
lively meanwhile is the feeling of the part affected, that it
cannot bear the weight of the bedclothes nor the jar of a
person walking in the room. The night is spent in torture.
Sydenham, 1683
Sydenham, T: The Works of Thomas Sydenham, London, New Sydenham Soc. 1850 (translation)
Gout Defined As…
The deposition of monosodium urate
crystals (MSU) in tissues at physiologic pH
What is Gout?
• Gout is a disorder of uric acid metabolism
• This is NOT just a disease of the joints!
• Characterized by:
- Hyperuricemia
- Attacks of acute arthritis
- Tophi around joints
- Joint destruction
- Renal Disease (Glomerular, Interstitial,
Tubular) Dz
- Uric Acid Urolithiasis
Untreated Gout May Lead to…
• Tophaceous masses of MSU
crystals in cartilage and joints
• Renal stones
• Urate nephropathy
Peripheral Structure
Involvement vs Relative
Sparing of Central Joints
• Attacks due in part to temperatures
<37 C peripherally
• Resulting in reduced solubility of urate
Total Population (Millions)
Total Population of Several Rheumatic
Conditions in the United States
9
8.3
Million*
8
7
7.1
†
Million
5.0
‡
Million
6
5
2.7
§
Million
4
3
2
1.3
‡
Million
1
0
Gout
Activity-limiting
Back Pain
Fibromyalgia
*Based on patient-reported data from NHANES 2007-2008.
†Estimated from 1997 NHIS and 2005 US Census Bureau data.
‡Estimated from 2005 US Census Bureau data.
§Based on 1988 NHIS data.
Carpal Tunnel
Syndrome
Rheumatoid
Arthritis
Who May Be the Patient With
Hyperuricemia and Gout?
Comorbidities
Demographics
• Advanced age
• Male
• Postmenopausal women
•
•
•
•
•
•
Lifestyle
Commonly Used Medications
•
•
•
•
Diuretics
Low-dose aspirin (eg, <325 mg)
Cyclosporine
Niacin
Hypertension
Cardiovascular disease
Chronic kidney disease
Diabetes mellitus
Dyslipidemia
Metabolic syndrome
•
•
•
•
Obesity (high BMI)
Diet rich in meat and seafood
High alcohol intake
Frequent consumption of
high-fructose corn syrup
Risk Factors for Gout (Continued)
Generic Overproducers
Some patients have unusual shunt mechanism
that converts glycine directly to uric acid
HPRT deficiency
Lesch-Nyhan Syndrome
Gout and Mental Retardation in Children
X-linked
PRPP hyperactivity
G6PD deficiency
Autosomal recessive
Von Gierke’s type-1 glycogen storage disease
Fructose Intake and Urate Excretion
HFCS
Pyruvate
Purine
Catabolism
Fructose
AMP
Lactate
Uric Acid
ATP
Fructose 1Phosphate
• Dominant dietary source – high-fructose corn syrup (HFCS)
• High concentration of fructose causes rapid accumulation of AMP
- Increases the body pool of purines
• Lactic acid is a by-product of fructose metabolism
- Lactate decreases urate excretion
Diagnosing Gout
• Abrupt onset of severe pain, swelling, and
tenderness that reaches its maximum within just
6–12 hours, especially with overlying erythema,
is suggestive of crystal inflammation though not
specific for gout
• A presumptive diagnosis is reasonably accurate
for typical presentations, such as recurrent
podagra with hyperuricemia
• Demonstration of MSU crystals in synovial fluid
or tophus provides definitive diagnosis
Acute Flares
• Flares occur without warning and may:
- Produce extreme pain
- Last hours to weeks
- Limit mobility
• Monoarticular in ~90% of initial
presentations; ~50% are podagra
• Over time, flares may occur more often
• Temporary reduction in sUA levels can
occur during a gout flare, making sUA
measurements during a flare unreliable
Courtesy of Theodore Fields, MD.
Gout Radiograph
http://www.pathguy.com
Intervals Between 1st & 2nd
Acute Flares
Majority experience second acute flare
within 1 year of first gout flare
1-2 yrs
16%
2-3 yrs- 6%
3-5 yrs - 5%
Within 1 yr
62%
After 10 yrs - 4%
No 2nd in more than 10 yrs - 7%
Yu et al. Ann Int Med. 1961;55:179-192
Recommendations From the 2012 American College of
Rheumatology Guidelines for Management of Gout
• ACR recommends a comprehensive treatment plan for the management of gout,
including both nonpharmacologic and pharmacologic approaches1,2
• Patient education including diet and lifestyle modifications is recommended along
with the following pharmacologic approaches for the management of gout1,2
Acute Gout Flares
• Treat an acute gout
flare with
pharmacologic
therapy (NSAIDs,
corticosteroids, or
colchicine) within
24 hours of onset2
Gout Flare Prophylaxis
• For gout attack prophylaxis,
initiate low-dose colchicine or lowdose NSAIDs when initiating uratelowering therapy (ULT)2
• Anti-inflammatory prophylaxis
should be continued from
initiation of ULT for the greater of2:
•
At least 6 months, or
•
Following achievement of
target serum urate, for
3 months in patients without
or 6 months in patients with
tophi on physical exam
Chronic Gout Management
• When initiating ULT, begin
anti-inflammatory gout flare
prophylaxis1
• Initiate first-line ULT, febuxostat
or allopurinol, or if at least one of
these is contraindicated or not
tolerated, probenecid can be used
to treat to sUA target of <6 mg/dL1
• sUA should be monitored
regularly (every 2-5 weeks) during
ULT titration, then every 6 months
once target sUA is achieved1
Management of Gout
RESOLVE
INITIATE
MAINTAIN
Acute Flare
Urate-lowering Therapy
Treatment to Control sUA
Treat with
antiinflammatory
agents
Target sUA
<6 mg/dL
with ULT
Initiate concomitant
anti-inflammatory
prophylaxis for
prevention of
mobilization flares
Continue ULT to
maintain sUA levels
and reduce the
risk of future flares
Continuing prophylaxis
for 6 months reduced the
frequency of gout flares
in a clinical study
Track sUA levels
NSAIDS
• Indomethacin (Indocin) has usually been used
• Lots of GI Toxicity / Renal Toxicity
• 25mg TID
• May use other NSAIDS
• Don’t use aspirin, competes with uric acid for
excretion in the kidneys
Evidence for the Use of Concomitant
Anti-Inflammatory Prophylaxis
• Anti-inflammatories are used for
both acute flares and prophylaxis
• ACR guidelines, as well as medical
consensus and clinical evidence,
support the use of antiinflammatory prophylaxis when
initiating ULT
• In a clinical study, using colchicine
with ULT for 6 months decreased
the frequency of gout flares
2.0
Mean Number of Flares1
• Anti-inflammatory prophylactic
therapy reduces the risk of
mobilization flares, but is not a
chronic treatment
*
Colchicine 0.6 mg
twice daily (n=21)
Placebo (n=22)
1.5
†
1.0
0.5
0.0
0–3
3–6
Time Interval, Months
*P=0.022; †P=0.033.
Corticosteroids
• Indications for Steroids in the
Management of Acute Gouty Arthritis
• Co morbid medical illnesses
-
CHF, HTN
Renal Insufficiency
Peptic Ulcer, GI Bleed
Hepatic Insufficiency
Chronic Alcoholism
Bleeding diathesis
Advanced Age
Anticoagulant use
Post Op
NSAID Hypersensitivity
Severe attacks refractory to NSAIDs/Colchicine
Corticosteroids
• Methods
- Parenteral
- Oral
- Intra-articular
• Prednisone
- 1mg/kg PO as a single dose -OR- 20-40 mg PO QD taper by 5-10mg every 3 days until D/C
• Methylprednisolone
- 40 mg intra-articular single dose
• Triamcinolone
- 40 mg intra-articular as a single dose
Colchicine
• Alkaloid obtained from autumn crocus
• Minimal effect on uric acid synthesis and
excretion
• Prevents release of chemotactic factors and
cytokines from neutrophils
• Binds to microtubules in neutrophils
• Major use is in acute gouty attacks
• 0.6mg - two initially, then one every 2 hours until
pain is relieved, you have reached 6mg or
diarrhea, nausea or vomiting develop
• IV Colchicine no longer available
• NSAIDS have largely replaced colchicine
Colchicine, USP Overview
• Colchicine is approved for 2 gout
indications:
- Treatment of gout flares
- Prophylaxis of gout flares
• Colchicine is not an analgesic
medication and should not be used
to treat pain from other causes
Colchicine, USP Dosing
Considerations
Usage
Renal or hepatic impairment
ClCr ≥30 mL/min
Patients receiving dialysis
Severe impairment
Dosing
No dose adjustment
Reduce dose
Reduce dose
Coadministration with CYP3A4
(eg, clarithromycin, ritonavir) or
P-gp inhibitors (eg, cyclosporine)
Reduce colchicine dose
Renal or hepatic impairment AND
Concurrent P-gp inhibitors or
strong inhibitors of CYP3A4
Contraindicated, as
life-threatening or fatal
toxicity has been reported
with colchicine in this setting
Colchicine Pharmacokinetics
in AGREE Trial
Concentration (ng/mL)
10
High-dose colchicine (4.8 mg total)
Low-dose colchicine (1.8 mg total)
Single-dose colchicine (0.6 mg total)
8
6
4
2
0
0
2
4
6
8
10
12
Hours
14
16
18
20
22
24
Colchicine, USP Dosing
and Administration: Acute Flares
Usage
Treatment of gout flares:
1.2 mg at first sign of flare,
then 0.6 mg 1 hour later.
Maximum dose 1.8 mg over
a 1-hour period; higher
doses have not been found
to be more effective
Dosing
Colchicine, USP Dosing
and Administration: Prophylaxis
Usage
Prophylaxis of gout flares:
For the prevention of
mobilization flares, 0.6 mg
once or twice daily;
maximum dose 1.2 mg/day
Dosing
Colchicine, USP Effectively Reduced the
Pain of Acute Gout Flares
Percentage of responders
Percentage of responders based on target joint
pain score at 24 hours post first dose
40
30
38%*
†
33%
20
16%
10
0
Low-dose
Colchicine, USP
(n=74)
High-dose
colchicine
(n=52)
* P=0.005 vs placebo; † P=0.034 vs placebo.
Placebo
(n=58)
• The primary endpoint was
the proportion of patients
who experienced at least
50% reduction in pain
scores from baseline at 24
hours, without rescue
medication
Colchicine, USP Had a Lower Incidence
of Gastrointestinal Adverse Events
Treatment-emergent adverse events (AEs) occurring in
≥2% of patients in any treatment group
Percentage of patients
100
80
77
77
†
High-dose colchicine
(n=52)
* (n=74)
Low-dose COLCRYS
Placebo (n=59)
77
60
40
37
27
26
20
20
23
14
17
19
17
4
5
8
0
0
1
2
0
0
0
Any AE
Any gastrointestinal
disorder
Diarrhea
Nausea
Vomiting
General disorders Severe diarrhea
and administrationsite conditions
Colchicine, USP Dose Adjustments for
Coadministration With CYP3A4 Inhibitors
Colchicine, USP Dose Adjustments for
Coadministration With P-gp or Protease Inhibitors
Principal Potential Adverse Events with
Colchicine Used to Treat Acute Gout
Common with Excess Oral Colchicine
• GI
-
Diarrhea (sometimes severe)
Nausea
Vomiting
Abdominal cramps
Dehydration
Most common with Overdose of Oral Colchicine
• Bone marrow depression: nadir at 7 days
• Neuropathy-myopathy, elevated CK, and weakness: onset
can be in weeks
Less Common with Severe Overdose of Oral Colchicine
• CV
-
•
•
Cardiac toxicity
Arrhythmia
Vascular collapse
Hepatotoxicity
Alopecia
Management of Gout
RESOLVE
INITIATE
MAINTAIN
Acute Flare
Urate-lowering Therapy
Treatment to Control sUA
Treat with
antiinflammatory
agents
Target sUA
<6 mg/dL
with ULT
Initiate concomitant
anti-inflammatory
prophylaxis for
prevention of
mobilization flares
Continue ULT to
maintain sUA levels
and reduce the
risk of future flares
Continuing prophylaxis
for 6 months reduced the
frequency of gout flares
in a clinical study
Track sUA levels
Gout Treatment
• Acute
- Treat the Pain!
- NSAIDS
• Indocin,
Ibuprofen,
Naproxen
• NOT Asprin!
- COX-2
- Colchicine
- Corticosteroids
• Chronic/Ongoing
- Decreased production
• Probenecid
• Sulfinpyrazone
• Increase excretion
• Allopurinol
• Febuxostat
- Do not use these drugs
during acute attack since
these therapies may
initially exacerbate the
condition
FDA-Approved
Urate-Lowering Agents
Drug
Action
First-Line (Uricostatic)
Allopurinol
Xanthine Oxidase
inhibitor
Febuxostat
Xanthine Oxidase
inhibitor
Second-Line (Uricostatic)
Probenecid
URAT1 and GLUT9
inhibitor
Dose Range
100-800 mg daily (decrease
dose in renal impairment)
40-80 mg daily
500-2000 mg daily (carefully
adjust dose to 3000 mg
maximum)
For Severe, Treatment-Refractory Disease (Uricostatic)
Pregloticase IV
Recombinant,
8 mg IV every 2 weeks
PEGylated uricase
Allopurinol
• Historically the drug of choice
in treatment of chronic tophaceous gout
• Competitive inhibitor of xanthine oxidase
• Xanthine and hypoxanthine are more soluble
and better excreted renally
• Metabolized to oxypurinol
• Oxypurinol accumulates—may be responsible
for antigout effects
• Oxypurinol is not well absorbed orally
• Decreases serum and urinary uric acid levels
Serum Uric Acid Level (mg/dL)
Correlation Between Allopurinol
Dose and Serum Urate
14
12
10
8
6
4
2
0
0
2
4
6
8
Dose (mg/kg/day)
Takada M, et al. J Clin Pharm Ther. 2005;30:407-412
Velocity of Tophus Size Reduction
Accelerates as Serum Urate Drops
Below 4 mg/dL
Serum Urate (mg/dL)
8
6
4
Allopurinol
Benzbromarone
Combined
2
0
0.0
0.5
1.0
1.5
2.0
2.5
Velocity of reduction in Size of Index Tophus (mm/mo)
Perez-Ruiz F, et al. Arthritis Rheum. 2002;47)4):356-360
Gout Subject Achieving SUA
<6.0 mg/dL (%)
Dose Adjustment of Allopurinol According to
Creatinine Clearance Does Not Provide Adequate
Control of Hyperuricemia in Patients With Gout
100
80
P <0.01
60
38
40
20
19.1
15
0
Lower than
recommended
Recommended
Higher than
recommended
Dalbeth N, et al. J Rheumatol. 2006;33:1646-1650
Drugs Potentially Affected by
Allopurinol Therapy
• Ampicillin/amoxicillin
(~20% risk of
ampicillin/amoxicillinrelated rash)
• Azathiprine*
• Chlorpropamide
• Cyclophosphamide
• Dilantin
•
•
•
•
•
•
•
Dilantin
6-Mercaptopurine*
Probenecid
Theophylline*
Vidarabine
Warfarin
ACE inhibitors
(suspected)
*Potential for severe toxicity by impairment of drug clearance via suppression
of xanthine oxidase. Potential for drug-drug interaction is also highly
significant with the xanthine oxidase inhibitor febuxostat.
Becker M, et al. Arthritis and Allied Conditions, 14th ed. Philadelphia, PA. Lippincott, Williams and Wilkins’ 2001:2323.
Allopurinol Hypersensitivity Syndrome (AHS), A
Variant of Drug Reaction With Eosinophilla and
Systemic Symptoms (DRESS)
Symptoms
Cutaneous rash
Fever
Renal dysfunction
Eosinophilia
Hepatitis
Leukocytosis
Death
92%
87%
85%
73%
68%
39%
21%
Epidemiology
Median dose
300 mg (200-900)
Median therapy
duration
3 weeks (1-30)
Prior renal dysfunction
81%
Asymptomatic hyperuricemia
50%
Concomitant thiazide diuretic
40%
The DRESS syndrome usually commences symptomatically 1 to 8 weeks after exposure
to the responsible drug. The symptom complex can be severe. The classic combination
is rash, fever, and major internal organ involvement (most commonly hepatitis, but also
can include nephritis and pneumonitis). The most common drugs inducing the DRESS
syndrome include allopurinol, carbamazepine, phenobarbitol, phenytoin, minocycline,
dapsoen, and sulfonamides.
Hande KR, et al. Am J Med. 1984;769(1):47-56
Approximate Prevalance of the Human
Leukocyte Antigen (HLA) Allele HLA-B*5801 in
Various Geographic Regions of the World
Unshaded areas represent regions where prevalence
of the gene has not been determined.
Middleton D, et al. Tissue Antigens. 2003;61(5):403-407
Risk Factors for Allopurinol
Hypersensitivity Reaction
Risk Factor
Recent initiation of allopurinol
Renal impairment
Diurectic therapy
HLA-B*5801
Allopurinol dose (positive association)
Allopurinol dose (negative association)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Reference(s)
1,2,3,4
1,2,4,5,6,7
1,2,5,6,7
4,8
1,2,5,9
4,10,11
Hande KR, et al. Am J Med. 1984;76:47-56
Lupton GP, et al. J Am Acad Dermatol. 1979,1:365-374
Singer JZ, et al. Arthritis Rheum. 1986;29:82-87
Hung SI, et al. Proc Nat Acad Sci USA. 2005,102:4134-4139
Arellano F, et al. Ann Pharmacother. 1993;27:337-343
Lang PG Jr, South Med J. 1979,72:1361-1368
Young JL Jr, et al. Arch Intern Med. 1974;134:553-558
Zinch I, et al. Pharmacogenomics. 2011,12:1741-1749
Perez-Ruiz F, et al. J Clin Rheumatol. 2005,11:129-133
Dalbeth N, et al. J Rheumatol. 2006;33:1646-1650
Vazquez-Mellado J, et al. Ann Rheum Dis. 2001;60:981-983
Dalbeth N, et al. Semin Dial. 2007;20:391-395; Zinch I, et al. Pharmacogenomics. 2011,12:1741-1749.
Febuxostat and Allopurinol
Febuxostat
Allopurinol
CH3
Structure
H3C
H
O
N
N
NC
S
CH3
CO2H
Tablet Formulation
Dosing Range
Dosing Frequency
40 mg or 80 mg
40 mg-80 mg
Once daily
Drug Elimination
Primarily hepatic
Dose adjustment in
None
Patients with mild to
moderate renal impairment
N
N
HN
O
100 mg or 300 mg
100 mg-800 mg
Once daily for ≤300 mg
Divided doses for >300 mg
Primarily renal
Yes
Febuxostat Overview
• Febuxostat is a xanthine oxidase (XO) inhibitor
indicated for the chronic management of
hyperuricemia in patients with gout
• Febuxostat is not recommended for the treatment
of asymptomatic hyperuricemia
• Febuxostat may reduce elevated sUA in chronic
gout patients who:
- Have sUA >6 mg/dL on existing therapy
- Are still flaring
- Have mild to moderate renal impairment*
There are insufficient data in severe renal impairment
(ClCr <30 mL/min). Caution should be exercised in those patients.
Febuxostat is contraindicated in patients being treated with
azathioprine or mercaptopurine.
Febuxostat Dosing and
Administration
Usage
Dosing
• 40 mg is the recommended starting dose
Once daily
• 80 mg is the recommended if sUA
< 6 mg/dL is not achieved after 2 weeks
with 40 mg dose
Once daily
• Upon initiation of treatment,
prophylaxis with and NSAID or
colchicine may be beneficial
Up to 6 months
An increase in gout flares is frequently observed during initiation
of anti-hyperuricemic agents, including Febuxostat. If a gout flare
occurs during treatment, Febuxostat need not be discontinued.
Febuxostat Dosing Considerations
Special Considerations
Dose Adjustment
• Febuxostat can be used in patients with mild
0
to moderate renal or hepatic impairment
• Febuxostat can be used in patients receiving
0
certain common medications
– Warfarin
– Hydrochlorothiazide
– Colchicine
– Naproxen
– Indomethacin
– Desipramine
Febuxostat Efficacy:
APEX, Fact, and Confirms
Proportion of Patients With sUA <6 mg/dL at Final Visit
Patients, %
APEX
(6 months)
80
70
60
50
40
30
20
10
0
FACT
(1 year)
74%*
72%*
(n=253/10)
Febuxostat Allopurinol
80 mg
300/100 mg
67%*†
45%
39%
(n=253)
CONFIRMS
(6 months)
42%
36%
(n=249)
(n=242)
Febuxostat Allopurinol
80 mg
300 mg
*P<0.001 vs allopurinol; †P<0.001 vs Febuxostat 40 mg.
(n=757)
(n=756)
(n=610/145)
Febuxostat Febuxostat Allopurinol
300/200 mg
80 mg
40 mg
Confirms Efficacy in Patients With Mild to
Moderate Renal Impairment
Proportion of Patients With Mild to Moderate
Renal Impairment with sUA <6 mg/dL at Final Visit
Confirms (6 months)
80
Patients, %
70
72%*
60
50
40
50%*
42%
30
20
10
0
*P≤0.05 vs allopurinol.
(n=479)
(n=503)
(n=356/145)
Febuxostat
40 mg
Febuxostat
80 mg
Allopurinol
300/200 mg
Renal impairment was defined as baseline estimated ClCr ≥30 mL/min and <90 mL/min.
Adverse Reactions Summary:
Physician-Reported
Placebo
Adverse Reactions
(≥1% of Patients*)
(n=134)
Febuxostat Febuxostat
40 mg
80 mg
(n=757)
(n=1,279)
Allopurinol
300/200/100 mg
(n=1,277)
Liver Function
Abnormalities
0.7%
6.6%
4.6%
4.2%
Nausea
0.7%
1.1%
1.3%
0.8%
0%
1.1%
0.7%
0.7%
0.7%
0.5%
1.6%
1.6%
Arthralgia
Rash
*At a ≥0.5% greater rate than with placebo.
Probenecid
• ColBenemid
• Can impair renal
secretion of :
• Inhibits tubular
- Sulfinpyrazone,
reabsorption of filtered
- Sulfonylureas
urate in kidney
- Indomethacin
• Controls hyperuricemia
- Penicillin
and prevents tophus
- Sulfonamides
formation
• Salicylates interfere
with action
• Use caution with
decreased renal function
Drugs Potentially Affected
by Probenecid Therapy
• Ampicillin
• Indomethacin
• Penicillin
• Heparin
• Nafcillin
• Dapsone
• Cephradine
• Methotrexate
• Cephaloridin
• Rifampicin
• Salicylates
Uricase Enzymes
Uricase
Uricase
H 2O + O2
H2O2 + CO2
OH
N
N
HO
OH
N
N
H
OH
OH
N
N
N
N
OH
HO
N
Uric acid
N
H
OH
HO
N
N
H
Allantoin
Uricase (uric acid oxidase) catalyzes the eventual conversion of uric acid
to allantoin, a more soluble, readily renally excreted form.
Uric Acid Production
• About two-thirds of uric acid is generated
endogenously by the body, while one-third
comes from purines in the diet
Xanthine
Oxidase
Urate
Oxidase
(Uricase)
Xanthine
Oxidase
Purine
Catabolism2-5
Hypoxanthine
Xanthine
Uric Acid
End product for humans,
higher primates, reptiles,
birds, and some mammals
Allantoin
End product for the
majority of mammals
Reduction in Plasma Urate Levels
With IV Pegloticase in Phase 3 Trials
Mean PUA (All subjects)
Mean PUA (mg/dL) (SE)
14
Placebo
Pegloticase 8 mg q 2wk
12
10
8
6
4
2
0
0
3
6
9
12
15
18
21
24
27
Week
Replicate multicenter, phase 3, double-blind trials assigned to 128 patients with sever,
refractory gout to receive either pegloticase 8 mg q2w, or a placebo infusion (n=43). The
trials’ primary end point was a sustained plasma urate of <6.0 mg/dL in months 3 & 6.
There is evidence for loss of efficacy overall overall over time in the treatment group.
Reduction in Plasma Urate Levels
With IV Pegloticase in Phase 3 Trials
Mean PUA (Responders)
Month 3
Placebo
Nonresponders
Responders
Mean PUA (mg/dL)
14
12
Month 6
10
8
6
4
2
0
1
3
5
7
9
11 13
15 17
19 21
23
25
Week
Data are for those subjects in the q2w treatment arm of the phase 3 trials separating
responders (ie, those who achieved the defined primary end point) vs nonresponders.
Nonresponders were generally those subjects who developed high titers of pegloticase
antibodies, and these antibodies correlated with infusion reactions.
Pegloticase-Associated Infusion Reaction
Relationship to Pre-infusion Serum Urate Level
IRs per 100 Infusions
6
5
5.5
RCT
OLE
4.8
4
3
2
1
0
0.8
0.5
<6 mg/dL
>6 mg/dL
Data from phase 3 randomized controlled trials (RCT) and open-label extensions (OLE)
demonstrate a marked relationship between an increased frequency of infusion
reactions (IR) and the loss of effectiveness of pegloticase. For all infusions after the
initial pegloticase infusion, the likelihood of IRs depends greatly on whether the preinfusion serum urate determination is above or below 6.0 mg/dL.
Most Common Signs and Symptoms
of Infusion Reaction to Pegloticase*
•
•
•
•
•
Chest discomfort
Flushing
Dyspnea
Nausea / vomiting
Back / flank pain
• Erythema
• Blood pressure
changes
• Muscle spasm /
stiffness
• Hyperhidrosis
*Data include all subjects in RCT and OLE in biweekly,
monthly, and placebo arms.
Strategy for Lowering Uric Acid
• Initiate prophylaxis with low dose
Colchicine or NSAID 1-2 weeks prior to
urate lowering agent
• Initiate uricostatic agent at low dose
(100 mg/day Allopurinol or 40 mg/day for
febuxostat)
• Escalate dose every 2-4 weeks while
monitoring for toxicity until serum urate is
< 6.0 mg/dL
• If treat to target goal achieved maintain antiinflammatory prophylaxis for 3-6 months after
last gouty flair or longer when tophi persist
Strategy for Lowering Uric Acid
• Maintain urate-lowering agent indefinitely and
check serum urate levels every 6-12 months
• If toxicity occurs with one uricostatic drug try
the other agent. No evidence of crossreactive toxicity.
• If target serum urate not achieved with
uricostatic agent, a uricosuric can be added
and titrated or Pegloticase can be tried
• No adjustment during gout flares
Study Showed Maintaining sUA <6 mg/dL Is Associated
With Reduced Risk of Future Gout Attacks
Incidence of Recurrent
Gout Attack, %
Incidence of recurrent gout attacks more
than 1 year after each patient visit*
80
86% of patients who achieved a
serum uric acid level of <6 mg/dL
(n=81) had no gout attacks during
the observation period
60
40
Observed
Logistic regression
(n=91)
20
0
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
Average Uric Acid Level During Investigation Period (mg/dL)
• Based on a retrospective analysis of 267 predominantly male gout patients for up to 3 years (Tokyo, Japan).
Baseline mean sUA level >7.45 mg/dL. Urate-lowering therapies prescribed: allopurinol and benzbromarone.
Tracking sUA Levels
sUA Levels Over Time
sUA
Level
Intercritical
Period
Gout
Attack
Intercritical
Period
• The best time to measure sUA is after a flare has resolved,
at least 2 weeks postflare
- sUA levels may be artificially low ~50% of the time during
a flare
• Evaluate sUA in patients on therapy to ensure that the target
level is achieved and maintained
- ACR guidelines recommend monitoring sUA level every
2-5 weeks during urate-lowering therapy titration, then
every 6 months once sUA target has been achieved
ACR=American College of Rheumatology.
Limitations of Lifestyle Modifications on
Reaching Target sUA Levels
• sUA levels may be reduced by making lifestyle
changes including:
-
Losing weight
Limiting consumption of purine-rich meat and seafood
Reducing alcohol intake, particularly beer
Limiting high-fructose corn syrup intake
Consuming dairy products
Medication prescription and monitoring of
SUA in patients with a diagnosis of gout
n/N
%
297/643
46
SUA checked and reached target
126/643
20
SUA checked but did not reach target
127/643
20
No SUA check
390/643
61
Continuous allopurinol prescription
n/N
%
SUA monitoring
Colchicine/NSAID prophylaxis
Colchicine
Colchicine
or NSAID
≥14 days before new allopurinol prescription
66/643
10
166/643
26
Before new allopurinol prescription
80/643
12
191/643
30
On or before new allopurinol prescription
169/643
26
311/643
48
≤14 days after new allopurinol prescription
180/643
28
329/643
51
Singh JA, Jodges JS, Asch SM. Opportunities for improving medication use monitoring in gout. Ann Rheum Di. 2009;68:1265-1270
Take-Away Messages
• The goal of therapy in subjects with multiple
recurrent gout flares or tophaceous gout is to
prevent disease progression by reducing the
body urate burden.
• Any patient presenting with advanced gout, or
simply demonstrating tophi on physical exam,
should clearly be started on ULT.
• Both allopurinol and febuxostate are effective in
gout patients whose hyperuricemia is caused by
either uric acid overproduction or underexctetion.
• Uricosurics should not be used in overproducers
of uric acid or as monotherapy in those with a
history of urolithiasis.
Take-Away Messages
• The uricostatics can be administered as
once-daily medications, which increases
compliance. Probenecid requires 2 to 3 doses
per day for optimal function.
• The uricostatic agents function well in the face of
renal insufficiency, whereas probenecid requires
a GFR of at least 50 mL/min to be most effective.
In fact, febuxostat appears to function better than
many other options in subjects with mild-tomoderate renal insufficiency.
Take-Away Messages
• Rash will develop in at least 2% of patients
started on allopurinol. Most rashes are benign
and dose related, but allopurinol is one of the
more common drug causes of severe cutaneous
reactions in the form of SJS or TEN and rashes as
a component of the DRESS syndrome, which is
more commonly known as AHS.
• HLA-B*5891, which is by far most common in
those of Southeast Asian ancestry, is a marked
risk factor for severe allopurinol cutaneous
reaction particularly in Koreans with CKD, and
those of Han Chinese and Thai descent.
Take-Away Messages
• In essence, the appropriate strategy for ULT is
termed “treat to target,” with the evidence-based
target to begin to achieve superior outcomes
being achievement of a serum urate of <6.0 mg/dL,
at a minimum. This requires checking the serum
urate level regularly (eg, every 6 months once the
target has been achieved).
• In patients with one or more tophi detected on
physical exam, the authors prefer a serum urate
target of <5.0 mg/dL and in certain patients with
advanced disease and multiple tophaceous
deposits, lowering the serum urate level to <4.0
mg/day is the preferred strategy by the authors to
help optimize therapy outcome.
Take-Away Messages
• In certain patients with advance disease and
multiple tophaceous deposits, lowering the serum
urate level to well below 6.0 mg/dL, such as in the
range of 4.0 mg/dL, appears to help optimize
therapy by accelerating resolution of tophi.
• The recombinant PEGylated uricase pegloticase
is FDA-approved as in approach for potent and
rapid reduction of serum urate and achieves rapid
debulking of tophi (within 6 months) in drug
responders (which were between 40% to 50% of
subjects in phase 3 clinical trials, using 8 mg IV
every 14 days).
Take-Away Messages
• The therapeutic program of urate-lowering
measures, once initiated, should keep the serum
urate less than 6.0 mg/dL (at a minimum) for the
remainder of the patient’s life, even after tophi
and gouty arthritis attacks are no longer present.
Uric Acid Overproducers and Underexcretors
Uric Acid
Underexcretion
Urate
Overproduction
(~90%)
(~10%)
Primary
Hyperuricemia
• Disordered urate
transport
• Metabolic disorders
Secondary
Hyperuricemia
• Impaired renal
function with urate
transport
• Excessive purine
intake
• Drug-induced renal
toxicity
• Idiopathic
• Tumor lysis
syndrome
Gout Flares Occur When Crystals Trigger
an Acute Inflammatory Response
Hyperuricemia
• Acute flares may be triggered by
fluctuations in sUA levels, which
can mobilize crystals
Supersaturation
• Crystals released into the joint
space undergo phagocytosis
Crystal
Formation
• Phagocytosis can initiate a
proinflammatory response,
resulting in gout flares
Microcrystal
Release
Recurrences
Inflammatory
Cascade
Gout Flare