Gout in the 21st Century Gout: Disease Definition

JOAN M VON FELDT, MD, MSEd
Professor of Medicine
Division of Rheumatology
University of Pennsylvania
Philadelphia, PA
GARY M. OWENS, MD
President, Gary Owens Associates
Medical Management and Pharmaceutical Consulting
Glen Mills, PA
Gout in the 21st Century
• Gout has markedly increased in prevalence
and clinical complexity over the last 2 decades
• Prevalence rise is influenced by diet, aging,
comorbidities, and the obesity epidemic
• Diagnostic criteria and imaging tools are
evolving
• Treatment-refractory gouty arthritis and
hyperuricemia are growing challenges
• New treatments are available
Gout: Disease Definition
“Arthritis resulting from excess
uric acid in body”
• Can lead to:
• Gouty arthritis:
• Inflammation in joints;
frequently occurs in big toe
• Tophi:
• Deposits of urate crystals that form
subcutaneous nodules
• Renal disease:
• Kidney stones from uric acid crystals in the kidneys
• Chronic interstitial nephropathy (in severe cases)
1
Uric Acid,
Hyperuricemia, and Gout
• Hyperuricemia: A serum urate concentration
in excess of urate solubility (>6.8 mg/dL)
• Results from overproduction and/or
underexcretion of uric acid
• The most common cause of hyperuricemia is
renal insufficiency
• Does not always result in gout
• Gout: Results from deposition of monosodium
urate crystals in the synovium, with subsequent
release and resultant inflammation
Becker MA. In Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. 2001:2281–2313.
Gout: A Typical Case
• Middle-aged male
• Presentation with acute
and excruciatingly painful
arthritis associated with
swelling and redness
• Big toe, midfoot, ankle
involvement are classic
• Recurrent self-limited
episodes of arthritis
• Kidney stones can occur
• Serum urate is elevated
Source: American College of Rheumatology Slide Collection
Gout Epidemiology
• Affects up to 6 million individuals in US
• 1%–2% prevalence in adult males
• Renal insufficiency is the most
common cause of gout
• 9 times more common in young men
(<40) than pre-menopausal women
• Metabolic syndrome is a significant risk
factor and the prevalence of this
disease is dramatically increasing in
US population
2
Gout Epidemiology:
Emerging Populations
• Renal insufficiency is growing more
common in certain patient groups,
increasing the risk of gout in:
• Elderly
• Heart failure patients
• Transplant patients
• Patients with metabolic syndrome
• Once patients are on dialysis,
hyperuricemia eventually normalizes
Commonly
Underdiagnosed Groups
• Women
• Post-menopausal women have increasing risk
of gout with advancing age
• Patients with tophi
• Asymptomatic patients can be proactively identified
with a good musculoskeletal and skin exam
• Patients with hypertension (HTN)
• Diuretics, renal disease compounds hyperuricemia
• Patients with metabolic syndrome
• Insulin resistance and renal disease impair
excretion of renal uric acid
Schumacher HR. New Horizons. 2002;8:11–15.
"Perfect Storm"
Driving Increased Prevalence
and Clinical Complexity
• Increased longevity
• Improved cardiovascular disease survival rates
• Iatrogenesis: Diuretics, low-dose ASA, niacin,
major organ transplants
• Diet and alcohol use trends
• Increases in prevalence of comorbid conditions that
promote hyperuricemia including: obesity, metabolic
syndrome, DM, hypertension, CHF, CKD, and ESRD
ASA – aspirin • DM – diabetes mellitus • CHF – congestive heart failure
CKD – chronic kidney disease • ESRD – end-stage renal disease
Terkeltaub R. Bull NYU Hosp Jt Dis. 2006;64:82–86.
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Gout: Economic Burden
• Direct costs for new cases of acute gout: ~$27 million
• Care of chronic gout is approximately 6% of a
patient's all-cause yearly health care costs
• Diagnosis of gout is independently associated with
higher medical/arthritic comorbidity, higher utilization
of health care
• Significant costs to employers:
• Patients with acute gouty arthritis miss an average of 3–5
days of work annually
• Estimated total annual cost of gout to employer per
employee:
• Employee with gout
>$6500
• Employee without gout <$4000
Halpern R, et al. J Clin Rheumatol. 2009;15:3–7.; Kim KY, Schumacher HR. Clin Ther. 2003;25:1593–
1617.; Wu EQ, Patel PA. J Manag Care Pharm. 2008;14:164–175.;Singh JA, Strand V. Ann
Rheum Dis. 2008;67:1310–1316.; Kleinman NL, Brook RA. Value Health. 2007;10:231–237.
Gout: Utilization
National Ambulatory Medical Care and Hospital Ambulatory Care Surveys
• Total ambulatory visits/visits to
primary care vs specialties
• 973 million ambulatory care visits, 3.9 million
(0.4%) for gout
• 69% of gout visits to primary care
• 10% to cardiologists
• Up to 16% to other specialties or unknown
• <3% to rheumatologists
Adapted from Terkeltaub R. Arthritis Res Ther. 2009;11:236.
American College of Rheumatology
(ACR) Criteria (1977)
• >1 attack of acute arthritis
• Unilateral tarsal joint attack
• Maximum inflammation
develops within 1 day
• Tophus
• Monoarthritis attack
• Redness over joints
• Asymmetric swelling within
a joint on x-ray
• 1st MTP joint painful
or swollen
• Subcortical cysts without
erosions on x-ray
• Unilateral first MTP
joint attack
• Synovial fluid cultures (-)
for organisms
MTP: metatarsophalangeal
Wallace SL, et al. Arthritis Rheum.1977;20:895–900.
• Hyperuricemia
When using 6 ACR criteria,
diagnosis of gout is
correct only in ≤80%
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Netherlands Proposal:
Diagnosis Without Joint Aspiration
7 variables "easily ascertainable in primary care":
• Male gender
• Previous patient-reported arthritis attack
• Onset within 1 day
• Joint redness
• Involvement of the 1st MTP
• Hypertension or 1 or more cardiovascular diseases
• Serum uric acid level of more than 5.88 mg/dL
Janssens HJ, et al. Arch Intern Med. 2010;170(13):1120-1126.
OBSERVED PROBABILITY
Calibration Plot of the Final
Diagnostic Rule
EXPECTED PROBABILITY
Janssens HJ, et al. Arch Intern Med. 2010;170(13):1120-1126.
WAITING FOR
PERMISSION LANGUAGE
Pitfalls in Gout Diagnosis
• Hyperuricemia is not a reliable marker for
diagnosis
• Not all patients with elevated uric acid will
develop gout
• Uric acid levels may be normal during an
acute attack
• Other conditions that mimic gout should
be ruled out:
• Septic arthritis
• Pseudogout due to calcium pyrophosphate crystals
• Inflammatory arthritis
• Cellulitis
• Osteoarthritis
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The Role of Imaging in
Diagnosis of Tophaceous Gout
• Plain x-rays are insensitive in
early disease
• Although advanced imaging can
identify soft tissue collections,
there are no imaging modalities
than can specifically diagnose tophi
Diagnosis and
Treatment Caveats
• Clinically significant hyperuricemia
does not precisely predict which
patients will develop gout
• Treatment of asymptomatic
hyperuricemia is not currently
recommended except for tumor lysis
syndrome, or when serum uric acid
exceeds 12.0 mg/dL (increased risk of
nephrolithiasis); this may be changing
Long-Term Management Goals
in Gout Are Closely Linked
Identify and manage comorbidities
and causes of hyperuricemia
PATIENT
EDUCATION
AND
TREATMENT
ADHERENCE
Diagnose,
treat, and
prevent
acute flares
Urate-lowering
drugs:
Target SUA
<6 mg/dL
SUA – serum uric acid
6
Principles of
Gout Management
Acute attack
• Therapeutic goal is to reduce pain and
inflammation
• NSAIDs and colchicine can be used for
acute gout attacks
• Colchicine works best in early flares (<24 hrs)
• Comorbidities and medications should
guide choice
• Corticosteroids and IL-1 antagonists are
alternatives
NSAIDs – non-steroidal anti-inflammatory drugs
Schumacher HR, et al. Clev Clin J Med. 2008;75(suppl 5):S22–S25.
Case 1
• 47-year-old man presents with first
episode of gout
• No current medications
• Drinks 5 bottles of beer daily
• Physical exam: BMI 33; left 1st MTP
is swollen and tender
• Labs: Uric acid 6.9 mg/dL, Cr 1.0
• What would you recommend?
Case 1
• Counsel patient to decrease alcohol intake
and lose weight
• Prescribe indomethacin 50 mg TID for
acute attack
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Preventing Acute Attacks:
Diet to Reduce Serum Urate
• Moderation of portion size is critical
(including smaller meat and seafood portions)
• Diets tailored to insulin resistance and weight
reduction are preferred
• Diet reduces serum urate up to 1–2 mg/dL
• Not enough to avoid urate-lowering therapy (ULT)
in most
• Alcohol promotes hyperuricemia (and flares
of arthritis in established gout)
Dessein PH, et al. Ann Rheum Dis. 2000;59:539–543.
Fam AG. J Rheumatol. 2005;32:773–777.
Zhang Y, et al. Am J Med. 2006;119:800.e13–e18.
Lee SJ, et al. Curr Rheum Rep. 2006;8:224–230.
Case 2
• 65-year-old man with history of hypertension
presents to your office after a recent admission
for polyarticular arthritis of the right 1st MTP,
right ankle, and left knee
• Monosodium urate (MSU) crystals were identified
on aspirate of the left knee
• Discharged on indomethacin 50 mg TID
• He had a previous episode of
gout (pain and swelling of the
1st MTP) about 1 year ago
Case 2
• Current medications:
• ASA 81 mg daily
• Metoprolol 50 mg daily
• Indomethacin 50 mg TID
• Physical exam: Remarkable for
subcutaneous nodule within the
left olecranon bursa
• Labs: Uric acid 8.1 mg/dL,
Cr 1.4
• How would you treat?
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Case 2
• Start colchicine 0.6 mg daily
• Start allopurinol or febuxostat and titrate
until uric acid is <6 mg/dL
Concise Explanation of Disease
and Therapies to Patients:
“Gout is Like Matches”
Gout is like matches. Crystals of uric acid deposit
in and around joints like matches. Gout flares
happen when the matches catch on fire. A brief
course of drugs such as naproxen, indomethacin,
prednisone, or colchicine puts out the fire. A daily
low dose of colchicine keeps the matches moist so
they do not catch fire. Uric acid-lowering therapies
like allopurinol and febuxostat shrink and
ultimately get rid of the matches.
Adapted from Wortmann RL. Am J Med. 1998;105:513–514.
Treatment Options:
Acute Attacks
Cautions
NSAIDs
Colchicine
Corticosteroids
Heart Failure
√
√
Hypertension
√
√
Ulcer Disease
√
√
Diabetes
√
Infections
√
Drug interactions
Warfarin
Cyclosporine, statins,
clarithromycin and
erythromycin, disulfiram
√
√
ASA- or NSAID-induced asthma
√
Renal impairment
√
Liver impairment
√
√
Avoid abrupt withdrawal
√
√
Adapted from Schumacher HR, et al. Clev Clin J Med. 2008;75(suppl 5):S22–S25.
9
Gout:
Acute Attack Prescriptions
National Ambulatory Medical Care and
Hospital Ambulatory Care Surveys
• Gout patient-specific anti-inflammatory
prescriptions (2002)
• NSAIDs ~700 000
• Colchicine ~381 000
• Prednisone ~341 000
Adapted from Terkeltaub R. Arthritis Res Ther. 2009;11:236.
Principles of
Gout Management
Preventing attacks:
• Therapeutic goal is to reduce serum urate and
maintain serum uric acid <6.0 mg/dL
• Urate-lowering therapy (ULT) is life-long, as with
other metabolic diseases
• Intermittent therapy can lead to recurrent flares
• Acute attack (gout flare) prophylaxis for 3–6
months is essential when starting ULT
Schumacher HR, et al. Clev Clin J Med. 2008;75(suppl 5):S22–S25.
Strategies to Lower
Serum Urate to Complement
Urate-Lowering Drugs
• Eliminate non-essential use of
diuretics and niacin
• Optimally manage BP and renal function
• ARB’s are mildly uricosuric
• Modify lifestyle:
• Reduction in dietary and alcohol excesses
• Weight/BMI reduction decreases serum urate
Choi HK, et al. Rheumatology (Oxford). 2008;47:713–717.
Eggebeen AT. Am Fam Physician. 2007;76:801–808.
Cannella AC, et al. Am J Manag Care. 2005;11:S451–458.
10
Preventing Acute Attacks:
Urate-Lowering Therapy (ULT)
Goals of therapy
• Decrease total body burden of urate and
monosodium urate crystals so that tophi
resolve permanently
• Therapeutic goal: SUA <6.0 mg/dL
• Improved education for patients and PCPs
• Proposed slogans for patients*
• Keep gout away, check your SUA
• Do not let gout play tricks, keep your SUA below 6
*Ogdie AR, et al. Curr Opin Rheumatol. 2010;22(2):173-180.
Preventing Gout Flares
When Initiating ULT
• Start prophylaxis 1 week before initiating ULT
• Preferred regimen: oral colchicine
• 0.6 mg 1–2 times daily for 6 months
• Continue at least 6 months in patients with visible tophi
• Reduce colchicine dose in the following patient populations:
>70 years, ≥stage 3 CKD, potential drug-drug interactions
• Alternative regimen:
• Low-dose NSAID prophylaxis (eg, naproxen 250 mg BID) for
same time frame as described for colchicine
• Avoid use of low-dose prednisone: fails to prevent gout
flares and difficult to wean patients due to rebound flares
Quality Gaps in ULT
• Delayed initiation of ULT
• Inadequate dosing of ULT
• Failure to document treatment
response to ULT
• Failure to use gout flare prophylaxis
during initiation of ULT
• Initiation of ULT during acute
gout flares
Sundy JS. Curr Opin Rheumatol. 2010;22(2):188-193.
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Treatment Options: ULTs
Cautions
Allopurinol
Febuxostat
√
√
Contraindicated in patients on
azathioprine, mercaptopurine, or
theophylline
Other drug interactions
Probenecid
NSAIDs,
Certain
Antibiotics
Dose adjustment in CKD
+/-
Potentially fatal hypersensitivity (rare)
√
Monitor LFTs
√
+/-
√
Ineffective in stage 3 or worse CKD
√
Risk of nephrolithiasis
√
Adapted from Schumacher HR, et al. Clev Clin J Med. 2008;75(suppl 5):S22–S25.
Comparative Trials of
Febuxostat and Allopurinol
% patients achieving SU <6.0 mg/dL
Febuxostat
40 mg daily
Febuxostat
80 mg daily
Allopurinol
300 mg daily
Placebo
CONFIRMS
(6 months)
45%
67%
42%
–
APEX
(6 months)
–
72%
39%
1%
FACT
(12 months)
–
74%
36%
–
Study
Becker MA, et al. Arthritis Rheum. 2008;58:Late breaking abstract No: L11.
Becker MA, et al. N Engl J Med. 2005;353:2450–2461.
Schumacher HR Jr, et al. Arthritis Rheum. 2008;59:1540–1548.
Sundy JS. Arthritis Rheum. 2008;59:1535–1537.
SU: serum urate
Treatment: Refractory Gout
Classic features:
• Allopurinol-intolerant/resistant to appropriate doses
• CKD or urolithiasis ruling out uricosurics
• Abundant tophi
• Repeated flares or persistent gouty synovitis with
joint erosion, deformity, and functional incapacity
• CHF
• Hypertension
• Diabetes
• Advanced age
• Potential drug-drug interactions and toxicities
Edwards NL. Arthritis Rheum. 2008;58:2587–2590.
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Pegloticase
• Results of two studies:
• 8 mg bimonthly: 47% and 38% of patients achieved
plasma uric acid levels of <6 mg/dL for at least 80%
of the time (months 3 and 6, respectively) vs 0%
placebo (P < .001, both studies)
• Effects on tophi (present in 71% of patients
at baseline)
• 45% of patients receiving bimonthly therapy
achieved a complete response at month 6 vs
placebo, 8% (P < .02)
• Most common adverse event was gout flare
• Premedication with antihistamines and corticosteroids
is advised; colchicine prophylaxis
• Contraindicated in patients with G6PD deficiency
Sundy JS, et al. Arthritis Rheum. 2008;58(9):2882-2891.
Baraf HS, et al. Arthritis Rheum. 2008;58(11):3632-3634.
Monitoring Patients
With Gout
• Assess treatment efficacy
• Reduced gout flares
• Serum urate (SU) <6 mg/dL
• Monitor SU levels every 1–2
months when starting ULT, then
at least 1–2 times per year
• For treatment-refractory disease:
consider referral to rheumatologist
Terkeltaub RA. N Engl J Med. 2003;349:1647–1655.
Gout and Patient Nonadherence:
Major Cause of ULT Failure
% patients achieving adherence of ≥80%
Hypertension
72.3%
Hypothyroidism
68.4%
Type 2 Diabetes
65.4%
Seizure Disorders
60.8%
Hypercholesterolemia
54.6%
Osteoporosis
51.2%
Gout
36.8%
Decreased rates associated with patients <60 years
Higher rates associated with increased visits, comorbidities
Briesacher BA, et al. Pharmacotherapy. 2008;28:437–443.
Healthcare claims data 706 032 adults >18 years
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Adherence Tips
for Healthcare Professionals
• Address patient's physical and financial barriers
• Provide education and assess the patient’s
understanding of prescribed treatment regimen
• Notify prescribers when a patient falls behind
on refills
• Work with prescribers to simplify dosing regimens
• Explain risks and benefits of adherence
• Assess readiness to change and tailor
medications to patient’s goals and lifestyle
• Review medications to ensure contraindications
do not exist
Case 3
The complicated inpatient consult:
• 75-year-old s/p abdominal surgery 4 days ago
presents with temperature 100.8 and polyarticular
arthritis (knees, left ankle, right 1st MTP and left
wrist) of 2 days duration
• Arthrocentesis confirms urate crystals of both
knees, with inflammatory synovial fluid
• Cr 2.4 mg/dL
• Surgeons resistant to treating patient
with steroids
• What would you recommend?
On the Horizon:
IL-1 antagonists
• MSU crystals activate the NALP-3
inflammasome similar to cryopyrinassociated autoinflammatory
syndromes for which IL-1 blockade
is effective
• Anakinra, canakinumab, and rilonocept
antagonists of IL-1 signaling have all
be shown to be effective in acute gout
(with only 1 dose)
So A, et al. Arthritis Rheum .2010;62:3064-3076.
So A, et al. Arthritis Res Ther. 2007;9:R28.
Terkeltaub et al. Ann Rheum Dis. 2009;68:1613-1617.
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Community
Needs and Resources
• Arthritis Foundation - www.arthritis.org
• Patient Tutorials
• www.nlm.nih.gov/medlineplus/tutorials/gout/
htm/index.htm (interactive)
• http://nihseniorhealth.gov/gout/toc.html
• Medline Plus - www.nlm.nih.gov/medlineplus/gout.html
• Many resources in both English and Spanish
• Mayo Clinic
• Gout diet - www.mayoclinic.com/health/goutdiet/HQ00765/METHOD=print
Summary
• Gout is costly; proper diagnosis and management can
control costs
• Treat acute gout flares
• Identify/treat comorbidities and consider cause of
hyperuricemia
• Initiate ULT (after first flare has passed) in those with:
• Frequent flares (>3 in 2 years)
• Tophi
• Uric acid overproduction
• “Difficult to treat” gout
Do not stop ULT, or stop and start ULT, because of flares
Initiate gout flare prophylaxis
Monitor SU levels
Educate patients on role of diet and importance of
treatment adherence
• Refer poor responders to a rheumatologist
•
•
•
•
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