Uric Acid, Hyperuricemia, and Gout • Uric acid

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School of Pharmacy
and Pharmaceutical
Sciences and
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and Pharmaceutical Sciences,
and The TCL Institute.
This activity is supported by an
educational grant from Takeda
Pharmaceuticals North America,
Inc.
Speaker : Dr. Randolph V. Fugit is an Internal Medicine Clinical Specialist at the Denver
Veterans Affairs Medical Center as well as Adjoint Assistant Professor in the Department of
Pharmacy Practice at the University of Colorado Health Sciences Center School of Pharmacy.
Dr. Fugit received his Doctor of Pharmacy degree from the University of New Mexico College
of Pharmacy. His areas of research include pharmacoeconomics and outcomes research
(including clinical pathway development) involved in the management of both acute and
chronic disease states in gastroenterology, rheumatology, infectious diseases, cardiology,
and pulmonology.
Speaker Disclosure:
Dr. Fugit reported that he is a consultant to Takeda Pharmaceuticals North America,
Inc. and Cubist Pharmaceuticals, Inc. He also reported that he is a speaker for Pfizer
Inc.; Boehringer Ingelheim Corporation; Cubist Pharmaceuticals, Inc.; Astellas
Pharma US, Inc.; and sanofi-aventis U.S. LLC.
Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical
Education Consultants (PharmCon) or the companies that support educational programming. A qualified
healthcare professional should always be consulted before using any therapeutic product discussed.
Participants should verify all information and data before treating patients or employing any therapies
described in this educational activity
This activity is supported by an
educational grant from Takeda
Pharmaceuticals North America,
Inc.
Accreditation:
Pharmacist –798-999-08-075-L01-P
Technicians- 798-999-08-075-L01-T
Learning Objectives
•
Recognize the general clinical presentations of gout,
differentiating between acute attacks and chronic underlying
disease
•
Advise patients about lifestyle interventions for the prevention
and management of gout, focusing on the importance of weight
loss and dietary modifications
•
Implement a patient education program for gout to improve
knowledge about the disease state, the importance of
adherence to medications, and patient commitment to
treatment
•
Counsel patients about the appropriate medications to be used
for acute and chronic gout, with a special focus on
comorbidities, medication contraindications, and drug
interactions, and advise when a physician visit is necessary
CE Credits:
1.0 Credit hour or 0.1 CEU for pharmacists/technicians
Target Audience: Pharmacists & Technicians
Program Overview: Gout is an enigma facing health care professionals today. Although it is an
ancient disease with centuries of clinical experience, gout’s incidence and prevalence continues
to rise owing to risk factors such as obesity from today’s more sedentary lifestyles. New
epidemiological issues such as the association between hyperuricemia and cardiovascular
disease also are now coming to the forefront in gout diagnosis and management.
Objectives:
•
Recognize the general clinical presentations of gout, differentiating between acute attacks and
chronic underlying disease
•
Advise patients about lifestyle interventions for the prevention and management of gout, focusing
on the importance of weight loss and dietary modifications
•
Implement a patient education program for gout to improve knowledge about the disease state,
the importance of adherence to medications, and patient commitment to treatment
•
Counsel patients about the appropriate medications to be used for acute and chronic gout, with a
special focus on comorbidities, medication contraindications, and drug interactions and advise
when a physician visit is necessary
How Prevalent Is Gout Compared
to Other Common Conditions?
Uric Acid, Hyperuricemia, and Gout
Lupus
Rheumatoid arthritis
Prostate cancer
Gout affects
5 million adults in
the United States1
Breast cancer
Liver disease
Kidney disease
Fibromyalgia
• Uric acid (urate) is the end product of purine
degradation in humans1
• Hyperuricemia is a serum urate
concentration in excess of urate solubility
(≥ 6.8 mg/dL)2
– Results from underexcretion and/or overproduction of
uric acid3
Gout
Stroke
0
1
2
3
4
5
6
7
Adults in the United States (millions)1-6
• Gout is the disease state resulting from
deposition of MSU crystals in tissues4
Gout is the most common inflammatory joint disease in men aged > 40 years7
1Kramer
HM and Curhan G. Am J Kidney Dis. 2002;40:37-42. 2Lethbridge-Cejku M, et al. Vital Health Stat. 2006;10(228).
RC, et al. Arthritis Rheum. 2008;58:26-35. 4Helmick CG, et al. Arthritis Rheum. 2008;58:15-25. 5Rahman A and
Isenberg DA. N Engl J Med. 2008;358:929-939. 6American Heart Association Web site.
http://www.americanheart.org/downloadable/heart/1200078608862HS_Stats%202008.final.pdf.
Accessed November 19, 2008. 7Roubenoff R. Rheum Dis Clin North Am. 1990;16:539-550.
3Lawrence
1Hahn
3Becker
PC, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2341-2355.
2Schumacher HR Jr. Cleve Clin J Med. 2008;75(suppl 5):S2-S4.
MA, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2303-2339.
4Eggebeen AT. Am Fam Physician. 2007;76:801-808.
Uric Acid: End Product of Purine
Degradation in Humans
Distribution of Serum Urate Values and
Hyperuricemia
40
Solubility decreases
OH
N
N
Purine
nucleosides
Xanthine
oxidase
Xanthine
oxidase
OH
OH
N
N
N
N
HO
N
N
H
OH
Hypoxanthine
N
H
N
OH
N
H
N
• Decreased
solubility of urate
(temperature)
• Trauma or tissue
injury
Uric acid
Xanthine
Uricase
O
Uricase:
Uricase:
▪ Humans lost enzyme
during evolution
O
Development of
MSU crystals
associated with1
NH
Men
30
Urate crystallizes
at a level of
6.8 mg/dL3
25
20
15
10
5
O
H2N
N
H
0
N
H
0 1 2
Hahn PC, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2341-2355.
Medications Altering Urate Levels
Pyrazinamide
Nicotinate
Lactate, β-hydroxybutyrate,
acetoacetate
Salicylate (low dose)
Ethambutol
3
4
5
6
7 8 9 10 11 12 13
Serum urate (mg/dL)*
Allantoin
Urate-Increasing Agent1
Laboratory range
for population
defined “normal”3,4
Women
35
Distribution (%)2
Purine
nucleotides
1Dalbeth
N, et al. Rheumatology. 2005;44:1090-1096. 2Lin K-C, et al. J
Rheumatol. 2000;27:1045-1050. 3MedlinePlus Web site.
http://www.nlm.nih.gov/medlineplus/ency/article/003468.htm. Accessed
March 11, 2009. 4Mandell BF. Cleve Clin J Med. 2008;75(suppl 5):S5-S8.
* Serum urate levels in 1515 men
and 1670 women aged ≥ 30 years in
Taiwan; 1991-1992
The Hyperuricemia Cascade
Dietary
purines
Urate-Decreasing Agent1
Tissue
nucleic acids
Endogenous
purine synthesis
Uricosurics:
Probenecid
Losartan
Salicylate (high dose)
Fenofibrate
Amlodipine
Urate
Overproduction
5%-10% of all gout
patients
Underexcretion
80%-90% of all gout
patients!
Hyperuricemia
Most common
cause of
hyperuricemia
Diuretics
Cyclosporine
Xanthine oxidase inhibitor:
Tacrolimus
Allopurinol
Febuxostat
β-blockers
Uricase
Silent
tissue
deposition
Gout
Other components may also affect uric acid clearance1-3
excessive alcohol intake, niacin, levodopa, cytotoxic drugs, and vitamin B12
2Quiceno
• Male gender1
• Postmenopausal women2,3
• Longevity/improved
survival of comorbidities2
• Diet:
– High alcohol intake:
• (Beer > hard liquor >
wine)2,4,5
– Red/organ meats and
seafood2,4,6
– High-fructose corn syrup7
• Drugs2
– Diuretics
– Cyclosporine
• Major organ
transplantation2
• End-stage renal disease
(ESRD)2
• Genetic influences4
Associated
cardiovascular
events
and mortality
Becker MA, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2303-2339.
Wortmann RL. In: Harrison’s Principles of Internal Medicine. 14th ed. 1998:2158-2165.
Hahn PC, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2341-2355.
Pittman JR and Bross MH. Am Fam Physician. 1999;59:1799-1806, 1810.
1Choi HK, et al. Ann Intern Med. 2005;143:499-516.
GA and Cush JJ. Rheum Dis Clin North Am. 2007;33:123-134. 3Peronato G. Contrib Nephrol. 2005;147:1-21.
Risk Factors
for the Development of Gout
Renal
Renal
manifestations
manifestations
Some Comorbidities Associated With
Hyperuricemia Warrant Consideration
• Obesity1,2
• Hyperlipidemia1-3
• Metabolic
syndrome3
• Hypertension2,6-8
• Diabetes mellitus1,4
• Heart failure5,6
• Renal disease6,9
• Cardiovascular
disease6,9
No reliable predictor that gout will develop in a given
hyperuricemic patient10
Currently, asymptomatic hyperuricemia is not treated
But, higher serum urate levels are more likely to lead to gout
1Kramer
HM and Curhan G. Am J Kidney Dis. 2002;40:37-42. 2Bieber JD and Terkeltaub RA. Arthritis Rheum.
2004;50:2400-2414. 3Hak AE and Choi HK. Arthritis Res Ther. 2008;10:R116. 4Fam AG. J Rheumatol. 2005;
32:773-777. 5Choi HK, et al. Lancet. 2004;363:1277-1281. 6Choi HK, et al. N Engl J Med. 2004;350:1093-1103.
7Nakagawa T, et al. Am J Physiol Renal Physiol. 2006;290:F625-F631.
7Feig
1Fam AG. J Rheumatol. 2005;32:773-777. 2Campion EW, et al. Am J Med. 1987;82:421-426.
3Choi HK, et al. Am J Med. 2007;120:442-447. 4Choi HK, et al. Rheumatology. 2008;47:1567-1570.
5Anker SD, et al. Circulation. 2003;107:1991-1997. 6Baker JF, et al. Am J Med. 2005;118:816-826.
DI and Johnson RJ. Hypertension. 2003;42:247-252. 8Alper AB Jr, et al. Hypertension. 2005;45:34-38.
9Zhou X, et al. Curr Hypertens Rep.2006;8:120-124. 10Lin KC, et al. J Rheumatol. 2000;27:1501-1505.
Slide 8
M70
Add Schumacher Cleve Clin J Med 2008 to verify this.
MOng, 10/6/2008
Hyperuricemia and Incidence of
Hypertension Among Men Without Metabolic
Syndrome Multiple Risk Factor Intervention Trial
Control of Metabolic Syndrome Components
Essential to Reduce Cardiovascular Disease Risk
in Patients With Hyperuricemia and Gout
Percent of patients with
metabolic syndrome
100
Gout
•
No gout
•
80
60
High prevalence of the
metabolic syndrome in
hyperuricemic patients1-3
Baseline hyperuricemia and risk
of subsequent hypertension
1.00
Patients with gout have an
approximately 30% elevated
cardiovascular disease (CVD)
risk3,4
40
Hyperuricemia3,4
20
0
20-39
40-59
Increases cardiovascular
mortality in patients at
high cardiovascular risk
≥ 60
Age (years)
* NHANES III (1988-1994)
Proportion of men
without hypertension
Higher prevalence of
metabolic syndrome associated
with gout across age groups*1,2
Adjusted for age
Hyperuricemia
increases the risk
of developing
hypertension by
approximately 80%
0.75
SUA ≤ 7 mg/dL (n = 2270)
SUA > 7 mg dL (n = 803)
0.50
0.25
0.00
0
1
AL. Cleve Clin J Med. 2008;75(suppl 5):S9-S12.
HK, et al. Arthritis Rheum. 2007;57:109-115.
3Puig JG and Martínez MA. Curr Opin Rheumatol. 2008;20:187-191.
4Krishnan E, et al. Arch Intern Med. 2008;168:1104-1110.
2
3
4
5
6
7
8
Follow-up in years
1Weaver
2Choi
Log rank P < 0.001 for both survivor functions
Hyperuricemia Increases Risk
of Renal Manifestations
Increased risk of renal failure
with hyperuricemia*
†
8
P < 0.01 vs moderate
SUA level
†
6
4
2
0
Clinical Stages of Gout
Hyperuricemia
predicts ESRD‡
10
Cumulative incidence of
ESRD per 1000 screenees
Relative risk of renal failure
10
Elevated serum urate with no
clinical manifestations of gout
Crystal deposition may be
starting
1
Asymptomatic
Hyperuricemia
•
Acute inflammation in the joint
caused by urate crystallization
and crystal phagocytosis
2
Acute Gouty
Arthritis
•
•
Intervals between acute flares
Crystals persist in joints
3
Intercritical
Periods
•
•
8
6
4
2
0
Low
(0.3-4.9)
Moderate
(5.0-6.4)
Slightly
high
(6.5-8.4)
High
(> 8.5)
SUA (mg/dL) < 7.0
Screenees (n) 15,617
ESRD cases (n) 19
SUA level (mg/dL)
* Prospective cohort study of 49,413 Japanese men
‡ Screened cohort of Japanese men and women
≥ 7.0
7332
34
< 6.0
21,795
19
Men
≥ 6.0
3433
31
Women
•
•
Long-term complications of
uncontrolled hyperuricemia
Chronic arthritis and tophi
Edwards NL. Cleve Clin J Med. 2008;75(suppl 5):S13-S16.
Tomita M, et al. J Epidemiol. 2000;10:403-409.
Iseki K, et al. Am J Kidney Dis. 2004;44:642-650.
Lower extremities most often involved1
– Most common initial site (~90%): first metatarsophalangeal joint
(podagra)1
– 80% of first attacks are monoarticular
•
•
Fever in some patients1,4
•
Can occur in bursae, tendons, and joints1
Feature
Untreated, an initial acute gout attack resolves completely
within 3 to 14 days4
– Majority of patients experience second acute flare within 1 year of first
gout flare5
1Becker MA, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2303-2339.
HR Jr. Cleve Clin J Med. 2008;75(suppl 5):S2-S4. 3Terkeltaub R. Bull NYU Hosp Jt Dis. 2006;64:82-86.
BF. Cleve Clin J Med. 2008;75(suppl 5):S5-S8. 5Yu TF and Gutman AB. Ann Intern Med. 1961;55:179-192.
2Schumacher
4Mandell
Intercritical
periods diminish
Chronic pain and
polyarticular gout
Typical Gout
Elderly Onset Gout
Peak in mid-40s
Over 65
Sex
Distribution
Men > women
Men = women
Presentation
Acute monoarthritis
Lower extremity (podagra 60%)
More often:
Polyarticular onset
Upper extremity affected
After years of attacks
Elbows > fingers
May occur early or
without history of prior attacks
Possibly more often over fingers
Obesity
Hyperlipidemia
Hypertension
Alcohol use, heavy
Renal insufficiency
Diuretic use, especially in women
Alcohol use less common
Age of
Onset
– Rarely affects shoulders, sternoclavicular joints, hips, spine, sacroiliac
joints
•
Advanced
Gout
Flares are
longer lasting
and more severe
Typical Clinical Features of Gout
Differ With Age of Onset
Pain and inflammation1-4
– Dramatic inflammatory response
4
Uncontrolled
Hyperuricemia:
Becker MA, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2303-2339.
Features of Acute Gouty Attacks
•
Krishnan E, et al. Hypertension. 2007;49:298-303.
Tophi
Associated
Features
Courtesy of the Clinical Slide Collection on the Rheumatic Diseases,
American College of Rheumatology, 1996; with permission.
Wise CM. Rheum Dis Clin North Am. 2007;33:33-55.
Images courtesy of Charles Goldberg, MD.
Diagnosing Gout: Why Aspirate the Joint?
Diagnosing Gout: Aspirate the Joint
Separate Septic Arthritis From Gout
The Gold Standard
• Does the patient have gout?
• Are current inflammatory symptoms due to gout?
Inflammatory Joint Fluids (> 4000-5000 white blood cells [WBCs] per
Synovial fluid analysis1-4
• Examine for MSU crystals
• Culture and Gram stain
analysis
mm3)
Septic arthritis
– Differential for septic arthritis
Crystal-induced monoarthritis (eg, gout, pseudogout)
Other potential causes:
Rheumatoid arthritis
Spondyloarthropathy
Systemic lupus erythematosus
Other inflammatory arthritides
Adapted from Siva C, et al. Am Fam Physician. 2003;68:83-90.
• Perform WBC count:
This superolateral approach may be
best when there is a large effusion5
Normal synovial fluid4
•
– Viscous, straw-colored substance (small amounts in joints, bursae, tendon
sheaths)
– 1-2 mL of fluid sufficient for studies3
1Rott KT and Agudelo CA. JAMA. 2003;289:2857-2860. 2Schlesinger N. Drugs. 2004;64:2399-2416.
3Wheeless' Textbook of Orthopaedics. http://www.wheelessonline.com/ortho/synovial_fluid.
Accessed November 20, 2008. 4MedlinePlus Web site. http://www.nlm.nih.gov/MEDLINEPLUS/ency/article/003629.htm.
Accessed November 20, 2008. 5Zuber TJ. Am Fam Physician. 2002;66:1497-1500, 1503-1504, 1507.
Differential Diagnosis:
Advanced Gout
MSU (Gout) or CPPD (“Pseudogout”) Crystals?
•
MSU crystals: strong
negative birefringence:
– Usually needle shaped
under compensated
polarized light1-3
MSU crystals3
•
Calcium pyrophosphate
dihydrate (CPPD) crystals:
weak positive birefringence1,4,5
– Rhomboid, rods, squares, or
irregular under compensated
polarized light; frequently missed;
consider septic arthritis5
CPPD crystals6
Direction of
polarized light
1Schumacher HR and Reginato AJ. Atlas of Synovial Fluid Analysis and Crystal Identification.
Philadelphia, PA: Lea & Febiger; 1991. 2Dore RK. Cleve Clin J Med. 2008;75(suppl 5):S17-S21. 3Reprinted with permission from ‘Gout
and Hyperuricemia,’ February 151999, American Family Physician. Copyright © 1999 American Academy of Family Physicians. All
Rights Reserved. 4Siva C, et al. Am Fam Physician. 2003;68:83-90. 5Pascual E and Jovaní V. Best Pract Res Clin Rheumatol.
2005;19:371-386. 6Image reprinted with permission from eMedicine.com, 2008. Available at:
http://www.emedicine.com//med/topic1938.htm. Accessed November 20, 2008.
Long-term Consequences
of Chronic MSU-induced Inflammation
Chronic
Chronic synovitis
synovitis
Low-grade
Low-grade synovitis
synovitis
in
in involved
involved joints
joints
can
can persist
persist after
after acute
acute
attacks
attacks
Factors
Factorsinvolved
involvedin
inacute
acute
attacks
attacksalso
alsocontribute
contributeto
to
chronic
inflammation:
chronic inflammation:
Cytokines
Cytokines
Chemokines
Chemokines
Proteases
Proteases
Oxidants
Oxidants
•
Risk factors include1
– Long duration of
hyperuricemia
– High serum urate levels
– Long periods of active,
untreated gout
• Subcutaneous gouty tophi
occur frequently at sites of
friction or trauma1
• Be careful: Chronic gout
can mimic rheumatoid or
psoriatic arthritis!2
Tophi
Tophion
oncartilage
cartilagesurface
surface
may
maycontribute
contributeto
tochondrolysis,
chondrolysis,
which
whichcan
canoccur
occurdespite
despite
adequate
adequatetreatment
treatment
Choi HK, et al. Ann Intern Med. 2005;143:499-516.
Helices of
the ear
Olecranon bursae
Extensor surface
of the forearms
Wrists
Finger pads
Principal
Sites
of
Tophi
Knees
Achilles
tendons
1Becker MA, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2303-2339.
2Mandell BF. Cleve Clin J Med. 2008;75(suppl 5):S5-S8.
Reproduced with permission from The Hand Center Web site. http://www.handcenter.org. Accessed November 20, 2008.
Diagnosing Gout
Common Challenges and Pitfalls
History and
Physical
Examination
Bone
Bone erosion
erosion
Cartilage
Cartilageloss
loss
– 5000 to 50,000/µL
Serum
Urate Level
Some
Patients
Refuse
Tapping the
Joint
1Rott
Acute versus chronic state, atypical joint involvement1
Elderly onset gout, (postmenopausal) women1,2
Not a definitive test; normal SUA levels common during
acute attacks1
•
Laboratory SUA level of population-defined “normal” often
equivalent to significant hyperuricemia2
Alternative: presumptive clinical diagnosis3
•
•
History and physical examination for characteristic features4
Clinical diagnosis wrong in about 20% of the cases5
Sepsis may lead to joint destruction within 24-48 hours6,7
KT and Agudelo CA. JAMA. 2003;289:2857-2860. 2Mandell BF. Cleve Clin J Med. 2008;75(suppl 5):S5-S8.
3Harrold LR, et al. Arthritis Rheum. 2007;57:103-108. 4Dore RK. Cleve Clin J Med. 2008;75(suppl 5):S17-S21.
5Chen LX and Schumacher HR. J Clin Rheumatol. 2008;14(5 suppl):S55-S62.
6Siva C, et al. Am Fam Physician. 2003;68:83-90. 7Zhang W, et al. Ann Rheum Dis. 2006;65:1301-1311.
What Is the Evidence for Gout Diagnosis?
Question to Ask the Patient
Ten Recommendations From EULAR Modified to US
Standards
Presumptive Diagnosis of Gout
• When did the symptoms start? Was the onset
sudden?
1
In acute attacks, rapid development of severe pain, swelling, and
tenderness, reaching peak within 6-12 hours is highly suggestive of
crystal inflammation, though not specific for gout
• Was this the first time you experienced pain/swelling
at this joint? If not, which other joints have been
affected and how long ago has this been?
2
For typical gout presentations (eg, recurrent podagra), a clinical
diagnosis of gout is reasonably accurate but not definitive unless
crystal confirmed
3
Demonstration of MSU crystals in synovial fluid or tophus aspirates
permits a definitive gout diagnosis
4
A routine search for MSU crystals is recommended in all synovial
fluid aspirates from inflamed joints
5
Identification of MSU crystals from asymptomatic joints may allow
gout diagnosis between attacks
• Are you running a fever?
• Do you have relatives with similar complaints?
• Are you taking any medications, and which?
• What have you been eating and/or drinking?
Anything like red meat, shellfish, or beer?
Adapted from Becker MA and Chohan S. Curr Opin Rheumatol. 2008;20:167-172.
Adapted from Zhang W, et al. Ann Rheum Dis. 2006;65:1301-1311.
What Is the Evidence for Gout Diagnosis?
Clinical Picture and Radiographic Evidence
Ten Recommendations From EULAR Modified to US
Standards (Cont.)
6
Gout and sepsis may coexist; if sepsis is suspected, Gram stain and
culture of synovial fluid should be carried out even if MSU crystals
are identified
7
Although the most important risk factor for gout, serum urate levels
do not confirm or exclude gout
8
Renal uric acid excretion should be determined in selected gout
patients (family history of young onset gout, onset of gout under age
25, or with renal calculi); hyperuricemia as a marker in acute gout
9
Radiographs may be useful for differential diagnosis and may show
typical features in chronic gout; they are not useful in confirming a
diagnosis of early or acute gout
10
Risk factors for gout and associated comorbidity should be
assessed, including features of metabolic syndrome
Polyarticular, tophaceous gout in
a patient originally treated for
rheumatoid arthritis for 8 years1
MetacarpalMetacarpalphalangeal joints
of the hand with
calcification of the
tophus on the
ulnar side2
1Image courtesy of N. Lawrence Edwards, MD.
2Images reprinted with permission from Ferguson M.
http://uwmsk.org/residentprojects/gout.html. Accessed November 20, 2008.
Adapted from Becker MA and Chohan S. Curr Opin Rheumatol. 2008;20:167-172.
Adapted from Zhang W, et al. Ann Rheum Dis. 2006;65:1301-1311.
Considerations for the Treatment
of Acute Gout
Case Presentation
Matthew, 66 Years Old
• Matthew comes to the pharmacist for an
over-the-counter (OTC) pain reliever:
– He limps on the left foot using a cane
• Questioning the patient reveals:
– Swelling/erythema of first metatarsophalangeal joint on left foot
started last night; patient runs a light fever
– Patient cannot bear any weight on the painful toe
– No other symptoms/recent injury, but similar episode
in elbow a few months ago
Matthew adheres to medication schedule:
Hydrochlorothiazide 50 mg/day
Glipizide 10 mg/day
BMI 33 kg/m2
Enalapril 20 mg/day
Difficulties with dietary changes:
Aspirin 81 mg/day
Consumption of red meat, alcohol, and
caffeinated nondiet sodas
Advanced gout: joint destruction
from large erosions with
“overhanging”
overhanging” edges2
Agent
Anti-inflammatory
doses of NSAIDs
Considerations and Cautions
•
•
•
•
•
Colchicine (oral)
Corticosteroids
(oral, intraarticular,
intramuscular)
30
•
•
•
•
•
All NSAIDs equally effective1-4
Caution with: older patients, renal insufficiency, heart
failure, peptic ulcer disease, liver disease, anticoagulant
therapy2,4
Taper off after attack has resolved3
Can be effective with early use1,4
Avoid in patients with severe renal or hepatic
impairment1-4
Interacts with cyclosporine, statins, and macrolides5
Low-dose approach: similar efficacy without
gastrointestinal concerns with higher dose*6
Useful when renal and/or gastrointestinal
contraindications to other therapies3
Avoid in patients with joint sepsis1,4
Caution with diabetes patients1,4
* Unpublished or preliminary data
1Eggebeen AT. Am Fam Physician. 2007;76:801-808. 2Terkeltaub RA. N Engl J Med. 2003;349:1647-1655. 3Wortmann
RL. Curr Rheumatol Rep. 2004;6:235-239. 4Schlesinger N. Drugs. 2004;64:2399-2416. 5Schumacher HR Jr and Chen LX.
Cleve Clin J Med. 2008;75(suppl 5):S22-S25. 6Terkeltaub R, et al. ACR Meeting 2008. Presentation 1944.
Anti-inflammatory Prophylaxis Prior to
Urate-lowering Therapy
Urate-lowering Therapy to Prevent Disease
Progression
• Urate-lowering therapy (ULT) often
started at week 2-4 with continuous
prophylaxis, but no evidence from
studies2-4
• Prophylactic agents1-3
Achieve/maintain
SUA level < 6 mg/dL
→Deplete
serum urate pool and
deposited crystals1-4
– NSAIDs, low-dose, oral colchicine
– Useful for decreasing the frequency and severity
of acute flares
– Will not stop silent tissue deposition of crystals
Reduce pain
and
inflammation
Avoid
hyperuricemia
treatment
during the
acute attack
• Initiate prophylaxis prior to starting
urate-lowering therapy and continue for
6-12 months2,3
→Reduce
frequency of acute
attacks during ULT1-4
– Crystals often persist during intercritical periods3
– Risk for continued flares, low-grade persistent
inflammation, and progressive disease3,4
→Maintain/improve
quality of life (QOL)1-4
– Incidence of flares and SUA levels decline
over time with treatment
• Therapy should be lifelong3
– Do not discontinue if attack occurs during
therapy initiation (flux in urate levels likely)2
– Uricosurics and xanthine oxidase inhibitors 1,2
• Weigh potential drug interactions/adverse
events
Patient dialogue and consistent follow-up
Patient dialogue and consistent follow-up
1Terkeltaub
1Borstad
3Schumacher
2Schlesinger
GC, et al. J Rheumatol. 2004;31:2429-2432.
N. Drugs. 2004;64:2399-2416.
HR, et al. Cleve Clin J Med. 2008;75(suppl 5):S22-S25. 4Choi HK, et al. Ann Intern Med. 2005;143:499-516.
What Is the Evidence for Gout Management?
What Is the Evidence for Gout Management?
Twelve Recommendations From EULAR Modified to US Standards (1)
Twelve Recommendations From EULAR Modified to US Standards (2)
Utilize both nonpharmacologic and pharmacologic modalities; tailor
1 to risk factors and clinical phase
8
Therapeutic goal of urate-lowering therapy: promote crystal dissolution and
prevent crystal formation by maintaining the SUA level below the saturation
point for MSU (6.8 mg/dL), target for SUA level < 6.0 mg/dL
9
Allopurinol: appropriate long-term urate-lowering drug; start at a low dose (eg,
100 mg daily) and increase by 100 mg every 2-4 weeks, if required; adjust
dose in patients with renal impairment; options with allopurinol toxicity: other
xanthine oxidase inhibitors, uricosuric agent, allopurinol desensitization
(cases of mild rash)
10
Uricosuric agents (probenecid): alternative to allopurinol (with normal renal
function); relatively contraindicated in patients with urolithiasis
Stress patient education and lifestyle changes (eg, weight loss and
2 alcohol reduction)
Address comorbidities like hyperlipidemia, hypertension,
3
hyperglycemia, obesity, and smoking
Oral colchicine and/or NSAIDs are first-line agents for systemic
4 treatment of acute attacks
5 Side effects with high doses of colchicine; low doses (eg, 0.6 mg TID)
may be sufficient for some patients with acute gout
Prophylaxis against acute attacks during the first months of urate-lowering
11 therapy: colchicine (0.6-1.2 mg daily) and/or an NSAID (with gastro-protection,
if indicated)
Intra-articular aspiration and injection of long-acting steroid is
6 effective and safe for an acute attack
Gout associated with diuretic therapy: stop diuretic, if possible; hypertension
12 and hyperlipidemia: consider use of losartan and fenofibrate, respectively
(both have modest uricosuric effects)
Urate-lowering therapy: patients with recurrent acute attacks,
7
arthropathy, tophi, or radiographic changes
Adapted from Becker MA and Chohan S. Curr Opin Rheumatol. 2008;20:167-172.
Adapted from Zhang W, et al. Ann Rheum Dis. 2006;65:1312-1324.
Adapted from Becker MA and Chohan S. Curr Opin Rheumatol. 2008;20:167-172.
Adapted from Zhang W, et al. Ann Rheum Dis. 2006;65:1312-1324.
Adjunctive Therapy for Gout
and Associated Comorbidities
Urate-lowering Agents
Uricosurics
Dietary and Lifestyle Recommendations
Control weight with daily exercise1,2
Limit red meat consumption1,2
Replace fish consumption with omega-3 fatty acids1
– Or supplements of docosahexaenoic acid and eicosapentaenoic acid
Refrain from high-fructose–containing foods/drinks2,3
Consume 1-2 servings of dairy or calcium supplement daily1,2
Consume nuts and vegetables daily1,2
Supplementation with vitamin C 500 mg/day2,4
Some evidence for beneficial effect of coffee consumption2
•
•
•
•
•
•
•
•
RA. N Engl J Med. 2003;349:1647-1655. 2Schlesinger N. Drugs. 2004;64:2399-2416.
3Schumacher HR Jr and Chen LX. Cleve Clin J Med. 2008;75(suppl 5):S22-S25.
4Becker MA, et al. Nucleosides Nucleotides Nucleic Acids. 2008;27:585-591.
•
Health benefits may extend beyond gout1,5
•
Limited impact on SUA level (1-2 mg/dL)
– Preventive strategies alone in patients with existing disorders may not be sufficient5
Uricosurics correct renal urate
underexcretion by inhibiting
postsecretory SUA reabsorption1
• Probenecid1,2
•
•
Mild uricosurics as adjunctive approach:
– Losartan* and fenofibrate*2,3
– Lose effectiveness as renal function
deteriorates 2-4
Other agents with urate-lowering properties:
– Atorvastatin*5
– Amlodipine* (increased renal urate excretion)6
– Vitamin C (400-500 mg/day)6,7
– Less than 20% of patients make sustained lifestyle changes5
1Choi HK. Curr Rheum Rep. 2005;7:220-226. 2Hak AE and Choi HK.
Curr Opin Rheumatol. 2008;20:179-186. 3Nakagawa T, et al. Am J Physiol Renal Physiol. 2006;290:F625-F631.
4Huang H-Y, et al. Arthritis Rheum. 2005;52:1843-1847. 5Levinson W, et al. Ann Intern Med. 2001;135:386-391.
* Off-label
Steps
During Treatment2
Alkalinize
urine
Increase
fluid
consumption
Multiple
medication doses
required
Emphasize
Compliance
1Terkeltaub RA. N Engl J Med. 2003;349:1647-1655. 2Daskalopoulou SS, et al. Curr Pharm Des.
2005;11:4161-4175. 3Bardin T. Ann Rheum Dis. 2003;62:497-498. 4Gaffo AL and Saag KG. Am J Kidney Dis.
2008;5:994-1009. 5Lee SJ, et al. Curr Rheumatol Rep. 2006;8:224-230. 6Choi HK, et al. Ann Intern Med.
2005;143:499-516. 7Gao X, et al. J Rheumatol. 2008;35:1853-1858.
37
Xanthine Oxidase Inhibitor
Allopurinol
Optimizing Allopurinol Dosing
O
• Effective in overproducers
and underexcretors
Allopurinol
N
NH
• Maximal dose 800 mg/day
N
H
N
Limitations
• Drug interactions
• Rare but life-threatening hypersensitivity reaction
possible
• Dose adjustments required:
• Allopurinol
dose increase
3Perez-Ruiz
Extremely rare, occurs in < 1% of patients on allopurinol
Mild reactions usually subside with
discontinuation of allopurinol
•
Progression to Stevens-Johnson syndrome or
toxic epidermal necrolysis well reported:
– Hepatomegaly, jaundice, and renal and hepatic
dysfunction can accompany severe reactions
– Risk factors include: renal dysfunction, hepatic
disease, thiazide diuretics, and chronic alcohol abuse
50
32
30
24
17
20
10
0
– Unknown mechanism for this reaction
< 200 mg/day
n = 5942
Observational study of a managed care organization
Typical Prescribing Errors With Available
Xanthine Oxidase Inhibitor
Percent of patients receiving
incorrect prescription
Interacting Drug
30
25.9
Warfarin
20
0
•
48/185
13/52
267/471
Incorrect dosing
of allopurinol in
renal failure
Inadequate dose
adjustment with
concomitant allopurinol
+ AZA or 6-MP*
Treatment of
asymptomatic
hyperuricemia
Allopurinol is frequently prescribed inappropriately; more
common with advancing age, male gender, and presence of
polypharmacy
Anecdotal reports of increased potential for bleeding
Increased risk of allopurinol hypersensitivity
Cyclophosphamide
Increased risk of bone marrow suppression
Adapted from Mikuls TR, et al. Rheumatology. 2005;44:1038-1042.
Increased risk of rash
Antacids/aluminum salts
Chlorpropamide
Cyclosporine
Probenecid
Phenytoin
Theophylline
* Allopurinol enhances effects of AZA and 6-MP
W, et al. ACR Meeting 2005. Poster 362.
CA, et al. J Clin Rheumatol. 2006;12:61-65.
Angiotensin-converting
enzyme inhibitors
Ampicillin/amoxicillin
10
1Yang
2Sarawate
Potential Effect
Increased 6-MP serum concentration with
increased risk of bone marrow suppression;
reduce AZA dose to one-quarter
AZA/6-MP
25.0
≥ 300 to < 400
mg/day
Potential Drug Interactions With Allopurinol
56.7
40
≥ 200 to < 300
mg/day
Majority of gout patients on varying doses of allopurinol
therapy did not reach target SUA level of < 6.0 mg/dL1
Rechallenge with allopurinol should not be performed
50
1Dalbeth N and Stamp L. Semin Dial. 2007;20:391-395.
2Fels E and Sundy JS. Curr Opin Rheumatol. 2008;20:198-202.
F, et al. J Clin Rheumatol. 2005;11:129-133. 4Hande KR, et al. Am J Med. 1984;76:47-56.
Patients on pharmacotherapy with nontarget levels were 59%
(allopurinol: 75%) more likely to flare than those at target level
40
However, reactions delayed by > 2 years have
been reported:
Fels E and Sundy JS. Curr Opin Rheumatol. 2008;20:198-202.
Bohan KH, et al. In: Applied Therapeutics: The Clinical Use of Drugs. 9th ed.
Philadelphia, PA: Lippincott Williams and Wilkins; 2008:42.1-42.14.
100 mg every 3 days
100 mg every 2 days
100
150
200
mg⁄day
250
300
350
400
Median SUA level with allopurinol treatment
decreased from 8.7 to 7.1 mg/dL (P < 0.001)1,2
Percent of patients
reaching target SUA1
•
Data from United Kingdom
General Practice research
database
0
10
20
40
60
80
100
120
140
Maintenance Dose
Allopurinol
Target Serum Urate Levels Are Often Not
Achieved
Allopurinol Hypersensitivity Reaction
60
(mL⁄ minute)
• Inform patients
of the risks and benefits
trade off:
Hahn PC, et al. In: Arthritis and Allied Conditions. 15th ed. 2005:2341-2355.
Perez-Ruiz F, et al. J Clin Rheumatol. 2005;11:129-133.
Usually
•
appears within
first 5 weeks
of treatment
Creatinine
Clearance
– Potential allopurinol toxicity
versus gout progression1
– Concomitant azathioprine and 6-mercaptopurine
– Renal function
Can present
as mild
erythema
and progress
to fatal
reactions with
continued
therapy
Dosing Guidelines for Allopurinol
Dosing1,4
– Prevent flare risk in all gout
patients with gradual
introduction1
– Monitor titration in patients
with CKD, emphasize
target SUA level of ≤ 6
mg/dL1-3
Decreased absorption of allopurinol
Increased hypoglycemic effect
Increased cyclosporine concentrations
with potential for toxicity
Increased renal elimination of oxypurinol;
inhibition of probenecid metabolism
Inhibited metabolism of phenytoin resulting
in increased serum concentrations
Increase in theophylline AUC, t½,
and reduction in clearance
Tatro DS. 2008 Drug Interaction Facts™. St Louis, MO: Lippincott Williams & Wilkins; 2008.
Efficacy of Xanthine Oxidase Inhibitors in
Patients With Normal Renal Function
New Xanthine Oxidase Inhibitor
Phase III, Randomized, Controlled, Multicenter, Double-blind Trial
Febuxostat*
•
Nonpurine, selective
•
inhibitor of xanthine oxidase
for the treatment of
hyperuricemia associated
•
with gout
CH
3
•
H3
C
N
No dose adjustments in renal and
mild/moderate hepatic
insufficiency1,2
Different molecule, no
crossreactions in allopurinolintolerant patients observed
•
CO2
H
45
•
•
– Concomitant use of azathioprine,
6-mercaptopurine and theophylline3
1Khosravan R, et al. J Clin Pharmacol. 2006;46:88-102.
2Swan S, et al. Arthritis Rheum. 2003;48:S529. Abstract 1348.
US Food and Drug Administration Web site. http://www.fda.gov/cder/foi/label/2009/021856lbl.pdf. Accessed
February 23, 2009.
20
0
•
Mean changes in expected GFR after 5 years of treatment
with febuxostat 40, 80, and 120 mg/day (baseline mean SUA: 9.7 mg/dL)*
Mean changes in
expected GFR (mL/min)
Percent of patients
with CKD
50
42
40
20
0
40 mg
80 mg
300 mg
Allopurinol*
Febuxostat
•
•
•
Becker M, et al. ACR Meeting 2008.
Presentation L11.
•
OH
HO
N
N
H
Uric acid
Uricase
O
O
NH
O
H2N
N
H
N
H
Allantoin
(Kidney excretion)
1Bomalaski
Solubility increases
N
-1.5
-2.0
-5
Greater benefit on GFR with
increased SUA reduction from baseline
-10
-10.8
-15
≤3
> 3 to ≤ 4
> 4 to ≤ 5
< 5 to ≤ 6
>6
*Preliminary or unpublished data
n = 116; 91% male
Comorbidities: 52% hypertension and 23% CVD
Whelton A, et al. ACR Meeting 2008. Poster L7.
Intravenous Uricase Enzyme: Treatment
Response in Patients With TFG GOUT1/GOUT2
Phase III Randomized, Double-blind Efficacy and Safety Trials
• Rapid and effective
reduction in SUA levels and
tophus burden1-4
– Reduced tophus burden in
40% of patients in phase
III clinical trials
(pegloticase 8 mg IV every
2 or 4 weeks)*4
– Short- and long-term
effects?
– Role of immunogenicity
– Cardiac risk
– Hemolysis risk
* Investigational
Unpublished or preliminary data
Patients with plasma urate < 6.0 mg/dL after 6 months of
intravenous pegloticase*1
100
• Investigations needed1,2,5
JS and Clark MA. Curr Rheumatol Rep. 2004;6:240-247. 2Sundy JS, et al. Arthritis Rheum. 2008;58:2882-2891.
3Sundy JS, et al. ACR Meeting 2008. Presentation 635. 4Baraf HS, et al. ACR Meeting 2008. Presentation 22.
Today Web site. http://www.medpagetoday.com/MeetingCoverage/ACR/11470. Accessed January 23, 2009.
5Medpage
0.5
– 1.0 mL/min GFR improvement for each 1.0 mg/dL reduction in SUA (P = 0.02)
– Normal expected annual reduction in GFR: 0.8 mL/min in healthy adults
aged 30-80 years
Percent of patients
OH
N
0.6
0
Significant relationship between GFR improvement and SUA
reduction:
Investigational Recombinant
Pegylated Uricase Enzyme
Polyethylene glycol
(covalent uricase
binding)
5
Average SUA decrease from baseline (mg/dL)
CKD patients: efficacy of febuxostat 40 mg and 80 mg superior to
allopurinol 300 mg/200 mg
Febuxostat 80 mg efficacy superior to both febuxostat 40 mg and
allopurinol 300 mg
Comparable adverse event rates, including CV events, across study
groups or by renal function
n = 2269; randomized 1:1:1 to treatment groups
* 145 subjects with moderate CKD in allopurinol group received 200 mg
Comorbidities: mild/moderate CKD (65%; n = 1483), obesity (64%),
hyperlipidemia (42%), hypertension (53%)
Becker M, et al. ACR Meeting 2008.
Presentation L11.
SUA Reduction May Benefit Estimated
Long-term GFR in Hyperuricemic Patients
Patients achieving SUA levels < 6.0 mg/dL at final visit at 6 months
P < 0.021
P < 0.001
P < 0.001
72
60
300 mg
Allopurinol*
n = 2269; randomized 1:1:1 to treatment groups
* 145 subjects with moderate CKD in allopurinol group received 200 mg
Comorbidities: mild/moderate CKD (65%; n = 1483), obesity (64%),
hyperlipidemia (42%), hypertension (53%)
Phase III, Randomized, Controlled, Multicenter, Double-blind Trial
80
80 mg
Comparable efficacy of febuxostat 40 mg and allopurinol 300 mg/
200 mg
Febuxostat 80 mg efficacy superior to both febuxostat 40 mg and
allopurinol 300 mg/200 mg
Comparable adverse event rates, including CV events, across study
groups or by renal function
Efficacy of Xanthine Oxidase Inhibitors:
Patients With Mild/Moderate CKD
100
42
40
Febuxostat
Contraindication:
* Approved by US Food and Drug
Administration February 13, 2009
P < 0.001
67
60
40 mg
– Gout flares, CV events, and elevated
liver function tests3
3
S
P < 0.001
80
Adverse events:
CH
NC
Patients achieving SUA levels < 6.0 mg/dL at final visit at 6 months
100
– No safety studies available3
Febuxostat
O
Potent inhibition with significant
urate reduction1
Percent of patients with
normal renal function
•
Every 2 weeks
Every 4 weeks
Placebo
80
60
42.5 †
34.5
40
20
0
0
Every 2 weeks
Every 4 weeks
Placebo
* Investigational; unpublished or preliminary data
P value was significant versus placebo (mean values from GOUT1 and GOUT2 depicted)
Treatment failure gout (TFG) was defined as: ≥ 3 flares in the previous 18 months, or ≥ 1 tophus,
or gouty arthropathy; serum urate > 8.0 mg/dL; and prior failure of maximum medically
appropriate dose of allopurinol or contraindication to allopurinol
†
2Baraf
1Sundy JS, et al. ACR Meeting 2008. Presentation 635.
HS, et al. ACR Meeting 2008. Presentation 22. 3Edwards NL, et al. ACR Meeting 2008. Presentation 27.
Immunoreactivity and Clinical Response to
Intravenous Uricase Enzyme
Percent of patients on
pegloticase 8 mg IV*
Pooled Data From GOUT1 and GOUT2
Infusion reactions and high antipegloticase titers are
increased with every 4 weeks in treatment group1
100
80
Every 2 weeks
67
Every 4 weeks
52
60
38
40
Managing Inflammatory
Manifestations of Gout
• Relative contraindications to symptomatic therapies
frequent in refractory gout patients1,2
– eg, NSAIDs or corticosteroids
• Potential benefit of biologic therapies*1
– Pain assessment, reduction of tender and swollen joint and creactive protein levels
24
20
• Use not established in large trials1
0
Infusion reactions
High antipegloticase and infusion
reactions
• Main adverse events were gout flares and infusion
reactions2
– Infusion reactions associated with anti–polyethylene glycol and
high antipegloticase titers1
* Investigational; unpublished or preliminary data
Response: plasma urate < 6 mg/dL for ≥ 80% of the time in months 3 and 6
1Becker
MA, et al. ACR Meeting 2008. Presentation 1945. 2Sundy JS, et al. ACR Meeting 2008. Presentation 635.
Case Discussion
1Fels
E and Sundy JS. Curr Opin Rheumatol. 2008;20:198-202.
MH, et al. Bull NYU Hosp Joint Dis. 2007;65:215-221.
3So A, et al. Arthritis Res Ther. 2007;9:R28.
4Terkeltaub R, et al. ACR meeting 2007. Poster 518.
5Fiehn C and Zeier M. Rheumatol Int. 2006;26:274-276.
6Tausche AK, et al. Ann Rheum Dis. 2004;63:1351-1352.
2Pillinger
* Investigational; unpublished
or preliminary data
• Hyperuricemia is defined as an SUA level > 6.8 mg/dL
• An acute gout attack has
been confirmed by
MSU crystal analysis:
• The target goal of uric acid treatment is < 6.0 mg/dL
– SUA levels can be normal, especially during the attack:
Previous medications:
Hydrochlorothiazide 50 mg/day
Glipizide 10 mg/day
Enalapril 20 mg/day
Aspirin 81 mg/day
Question to consider:
• Should this patient be started on urate-lowering
therapy at this point?
Questions and
Answers
– Interleukin-1 inhibition (anakinra, rilonacept)1-4
– Tumor necrosis factor-α inhibition (etanercept, infliximab, and
adalimumab)1,5,6
Conclusions
Matthew, 66 Years Old
– The patient returns to the
pharmacist with new
prescriptions
• Small uncontrolled trials
• Lifestyle modifications may benefit overall treatment
• Proper timing, dosing, and adherence to
pharmacotherapy important:
– Anti-inflammatory treatment and when to initiate urate-lowering
therapy
– Counsel on potential adverse events with therapy
– Ensure that contributory comorbidities are addressed
• New therapies are available and may benefit patients