The Management of Gout and Hyperuricemiadbm

Enhanced Subspecialist Deck:
Recommendations for the
Diagnosis and
Management of Gout and
Hyperuricemia

 ThisCME activity is intended for practicing
physicians, and other health care providers who
may treat patients who have Gout and
Hyperuricemia.

 There is no fee for participation in this CME
activity.
This program is made possible through an
educational grant from Savient Pharmaceuticals, Inc.
and URL Pharma, Inc.

Accreditation

This activity has been planned and implemented in
accordance with the Essential Areas and policies of the
Accreditation Council for Continuing Medical Education
(ACCME) through the joint sponsorship of UHS-PEP of
Virginia Commonwealth University Health System and
Miller Professional Group. UHS-PEP is accredited by the
ACCME to provide continuing medical education for
physicians.

Disclosure of Significant Relationships with
Relevant Commercial Interests

 Neither VCU nor Miller Professional Group has any
commercial interests relevant to the content of this
activity. The content of this CME activity will not
contain discussion of off-label uses. Please consult the
product prescribing information for full disclosure of
labeled uses.

DISCLOSURES of FACULTY CONFLICTS OF
INTEREST

 These members of the faculty and /or VCU UHS-PEP faculty and staff disclose the following relevant relationships to
commercial interests:

 Thomas Adamson, III, MD is a member of the Speaker’s Bureau for Warner Chilcott and Pfizer; and participated in a one-time
speaking even for Interpace BioPharma.
 Herb Baraf, MD is a member of the Speaker’s Bureau for Savient and Takeda and is an Investigator for Savient, Takeda,
Ardea, Metabollix and Regeneron; and is a Consultant for Savient.
 Howard Blumstein, MD is a member of the Speaker’s Bureau for Abbott, UCB, Warner Chilcott and Genentech.
 Alan Brown, MD is a member of the Speaker’s Bureau for Takeda.
 Paul Doghramji, MD is a member of the Speaker’s Bureau and a Consultant for URL.
 N. Lawrence Edwards, MD is a Consultant for Takeda, Savient, Novartis, Ardea and Regeneron.
 Alan Epstein, MD is a member of the Speaker’s Bureau for Takeda and HGS.
 Madelaine Feldman, MD has no relationships to report.
 Germano Guadagnoli, MD is a member of the Speaker’s Bureau for Pfizer, Amgen, Takeda, URL and Savient.
 Max Hamburger, MD is a member of the Speaker’s Bureau for Amgen, BMS, Genentech and UCB; is a Consultant for Amgen
and BMS; and has obtained Med Ed grants on behalf of 3 rd parties from Abbott, Amgen, BMS, Centocor, Genentech and UCB.
Miller Professional Group (MPG), a medical education and communications company, owned by a family member; has been
the recipient of CME grants from Abbott, Amgen, BMS, Centocor, Crescendo, Genentech, Biogen Idec, Roche, and URL.
 Joseph Huffstutter, MD is a member of the Speaker’s Bureau for Takeda, HGSI and Savient.
 Richard Jimenez, MD is a member of the Speaker’s Bureau for Takeda.
 Joseph Lieberman III, MD has no relationships to report.
 Kenneth Miller, MD has no relationships to report.
 Eric Mizuno, MD has no relationships to report.

DISCLOSURES of FACULTY CONFLICTS OF
INTEREST

 Alan Morton, DO is a member of the Speaker’s Bureau for Pfizer, Amgen, UCB, URL, BMS, Takeda, Genentech, Abbott,
Warner Lambert and Savient; and is a Consultant for Pfizer, Amgen, URL, BMS, Savient and Novartis.
 David Mount, MD has no relationships to report.
 Richard Pope, PA-C is a member of the Speaker’s Bureau for Takeda and URL.
 Gregory Schimizzi, MD has no relationships to report.
 Paul Schulman, MD has no relationships to report.
 Katy Setoodeh, MD is a member of the Speaker’s Bureau for Amgen and HGS.
 Evan Siegel, MD is a member of the Speaker’s Bureau for Amgen and Abbott.
 John Skosey, MD is a Stockholder in Amgen and TheraTest Laboratories and is a Director of TheraTest Laboratories.
 Michael Weitz, MD is a member of the Speaker’s Bureau for Savient.

All conflicts of interest due to reported relationships above have been resolved according to VCU’s Policy on Conflict of
Interest and the Standards for Commercial Support of the ACCME.

All presenting faculty affirm that they will employ the best available evidence from all sources to support any clinical
recommendations made in their presentations.

After Participating in the Educational Activity,
Attendees should be able to:
• Describe the patho-physiology of hyperuricemia and gout

• Describe recent advances in the understanding of the epidemiology of
gout and hyperuricemia, and the relationship between hyperuricemia, risk
factors and co-morbidities

• Apply recommended guidelines for correctly diagnosing gout and
hyperuricemia

• Manage gout and hyperuricemia in accordance with recommended
guidelines and incorporate data on efficacy and safety

– Manage the acute attack
– Implement prophylaxis and urate lowering therapy
– Management of chronic hyperuricemia
– Manage the refractory or challenging patient

Updating the EULAR 2006 Guidelines-
Methods

• A multidisciplinary team with members specializing in rheumatology,
nephrology, cardiology, primary care, and allied health reviewed the diagnostic
and management recommendations published by EULAR in 2006. 11, 12

• The EULAR evidence hierarchy for diagnosis and management of gout
was based primarily on study design.

• The revised recommendations are based on the Grading of Recommendations
Assessment, Development, and Evaluation (GRADE) approach 13 as an evidence-
based strategy for rating quality of evidence and grading the strength of
recommendations formulated for use in clinical practice.

Strength of Recommendation
• Strength-of-recommendation scores express expert experience and
consensus.

• Each team member rated the strength of each agreed-on recommendation
on 2 scales:
• a categorical scale (as fully, strongly, moderately, weakly, or not
recommended)
• a visual analog scale (VAS) ranging from 60 (weak recommendation) to
100 (strong recommendation).

• Based on categorical data, the percentage of strongly and fully
recommended scores was calculated for each recommendation.

• Analysis of continuous data resulted in a mean VAS score with 95%
confidence intervals for each recommendation.

The numbered recommendations in this presentation
were taken with permission from:

2011 Recommendations for the Diagnosis and Management
of Gout and Hyperuricemia
Postgraduate Medicine
Volume 123 Issue 6 Supplement 1
Hamburger et al

Sir Thomas Sydenham: Description
of Acute Gout: 1848

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. This pain is like that of a dislocation. ...
Then it is a violent stretching and tearing of the ligaments. … now it is a
gnawing pain and now a pressure and tightening.

… He cannot bear the weight of bedclothes nor the jar of a person walking in
the room. The night is passed in torture, and perpetual change of posture; the
tossing about of the body being as incessant
as the pain of the tortured joint.
Sydenham T. The Works of Thomas Sydenham, MD Translated by RG Latham.
Vol II London: Sydenham Society; 1848:1224.

A Renaissance for Uric Acid?

 Increasing incidence of gout

 Mapping/characterization of genes associated with hereditary
hyperuricemic nephropathy, uric acid stones, hyperuricemia, and gout

 Evolving associations with hyperuricemia:
– Kidney stones
– Insulin resistance syndrome / metabolic syndrome
– Hypertension, renal disease
– Prognosis of vascular disease, heart failure, stroke
– Protection from Parkinson’s, multiple sclerosis, AD

Gout

• Gout: Acute arthritis, typically very severe

• Most common form of inflammatory joint disease.

• Disease Process

• Urate: End product of purine metabolism

• Blood level of urate > physiologic limit of solubility (6.8mg/dL):
Tissue crystallization

• Sodium in tissues: Conversion of urate to monosodium urate (MSU)

• Inflammatory response to the presence of MSU crystals: Acute Gout

Gout - a Progressive and Disabling Disease
One Chronic Disease - 4 Stages
Asymptomatic
asymptomatic Gout2
hyperuricemia
hyperuricemia1
Gout
sUA ≥ 7 mg/dl Acute flares Intercritical Persistent or Chronic
Period Progressive gout Arthropathy
and Tophi
~32million in US ~8 million ~5 million ~300-800k

Progression to Intermittent Increasing Chronic
gout: 20 – 30% inflammatory frequency and synovitis
arthritis duration of attacks Visible tophi
Necessary but Polyarticular
not sufficient First MTP Joint presentation
for gout

Disease Progression

1. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S566
2. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S901-2

Level Stages of Gout
Pain

Years

Asymptomatic Acute Gout with
Advanced Gout
Hyperuricemia Intercritical

Classification of Patients with Gout and
Hyperuricemia

• >90% are Under-excretors

• Enhanced net proximal tubular reabsorption of urate

• Renal insufficiency

• Medications impairing renal urate clearance

• <10% are Over-producers: de novo increased purine biosynthetic
rate

Scott JT, Pollard AC Ann Rheum Dis 1970:29:397-400

Pathogenesis of Hyperuricemia

Choi, H. K. et. al. Ann Intern Med 2005;143:499-516 (reprinted with permission)

Purine Total Body Uric Purine
Sources Acid Pool Elimination

Endogenous
purine
synthesis
Miscible urate pool Renal
500 mg
excretion
600 mg
Tissue
nucleic acids 1200 mg
SUA x Blood Volume 200 mg Intestinal
Dietary
100 mg uricolysis
purines

Sources and distribution of uric acid

Purine Total Body Uric Purine
Sources Acid Pool Elimination

Endogenous
purine
synthesis
Miscible urate pool
Miscible urate pool Renal
300
500 mg
excretion
600 mg
Tissue
nucleic acids 1200 mg
2000 mg Intestinal
Dietary 200 mg
300 mg
100 mg uricolysis
purines

Insoluble urate pool

1 to >100 grams

Consequences of Expanded Urate Pools

Asymptomatic
Miscible urate pool
Miscible urate pool hyperuricemia

Hypertension,
1200 mg ? kidney & heart
2000 mg disease
Renal Manifestations

Insoluble urate pool Gouty arthritis

1 to >40 grams Urate tophi

Overview

 Pathways for proximal tubular urate absorption and secretion;
relevance to hyperuricemia

 Genetics of renal urate transport
– Renal hypouricemia
– Hyperuricemia and gout – new genetic factors

 Hyperuricemia and renal disease
– Familial hyperuricemic nephropathy
– Nephrolithiasis and gout
– Progression of CKD
– Management issues for gout in CKD

Pathophysiology of Renal Urate Transport

 Renal under-excretion is the dominant mechanism for hyperuricemia in gout.

 Genetic syndromes of renal hyper/hypouricemia.
– Renal hypouricemia – deficiency in the absorptive transporters URAT1
and GLUT9
– Familial hyperuricemic nephropathy – mutations in uromodulin
– Genetic variation in urate transporters and associated proteins are the
dominant contributor to genetic risk of hyperuricemia and gout

 Strong correlation between proximal tubular reabsorption of Na+-Cl- and urate
→ hyperuricemia in volume depletion, hypouricemia in SIADH.

 Indirect evidence for regulation of renal urate reabsorption by:
– Insulin
– Angiotensin-II
– PTH

Renal Transport of Urate

Proximal Tubule
Peritubular Renal Proximal Nephron
Interstitium Tubular Epithelium Lumen

MRP4 Urate
Urate
OAT1 UAT
OAT3 Urate
Anions ABCG2

Urate
NTP1
SECRETION
Na+
OAT4 Anions
REABSORPTION OAT10
Urate
Anions
URAT1
L-GLUT9 Urate
Urate S-GLUT9
Urate

To Blood To Urine
Edwards NL, ACP Medicine, 2012

Inhibition AND Activation of Urate
Exchange by the Same Anions

TAKE HOME MESSAGES:
Proximal Tubular Apical Absorption

 URAT1, OAT4, and OAT10 function as apical, absorptive urate:anion
exchangers

 The Na+-anion transporters SLC5A8 and SLC5A12 activate urate
absorption via “trans-stimulation” of apical urate exchange.

 Many of the “trans-activating” anions can also “cis-inhibit”.

 The four-component model is imperfect
– Anti-uricosurics ↑ absorption, versus ↓ secretion

Genome-Wide Association Studies Have Revealed
Multiple Genetic Contributors to Variation in Urate

 SLC2A9 – encodes GLUT9, involved in urate absorption
 ABCG2 – apical urate secretory transporter: loss of function →
hyperuricemia
 SLC17A1/A3 – apical urate secretory transporters: loss of function →
hyperuricemia
 SLC16A9 – MCT9 – solute transporter, mechanism of hyperuricemia
unknown
 GCKR – regulator of glucokinase – contributes to risk of metabolic
syndrome
 SLC22A11 – encodes OAT4, absorptive urate transporter
 SLC22A12 – encodes URAT1, absorptive urate transporter
 PDZK1 – scaffolding protein for URAT1, OAT4, SLC5A8/A12, etc.

Most of this genetic variation affects net renal urate excretion

Gout and Chronic Kidney Disease

 CKD complicates the management of acute gout and urate-lowering therapy.

 Gout is much less common in ESRD/dialysis, but can resume or emerge after
transplant.

 Lowering urate in gout patients can ↑ GFR, ? partially secondary to ↓ in NSAID
use.

 Evolving interest in the role of urate in CKD and hypertension

 Inhibition of xanthine oxidase (XO) also exerts urate-independent effects on kidney
and vasculature.

Gout and Transplantation
 2-13% of renal transplants may develop new-onset gout; ~1/3
asymptomatic hyperuricemia.

 New-onset gout is associated with graft loss.

 Treatment issues
– Post transplant gout tends to be highly tophaceous.
– Risk of gout with CsA >>> than with tacrolimus.
– Allopurinol ↑↑ effect of azathioprine, but has less effect on MMF.
• Xanthine Oxidase inhibitors are contraindicated with allopurinol
– CsA ↑ risk of myoneurotoxicity from colchicine.

Diagnostic Recommendation:
Assess for Risk Factors

Risk factors for gout should be assessed, including features of
the metabolic syndrome (obesity, hyperglycemia,
hyperlipidemia, and hypertension), chronic kidney disease
(CKD), medications, family history, and lifestyle. (#10)

• Strength of recommendation: 97 (95% CI, 96–98)
• Highly or strongly recommend: 100%
• Quality of evidence: Moderate, grade 2 recommendation

Risk Factors & Co-Morbid Conditions
Risk Factors Co-Morbid Conditions
Modifiable1-6 Non-modifiable Metabolic Syndrome7(63%)
• Obesity • Age • Hypertension
• Serum urate • Gender • Diabetes Mellitus
• High-fructose corn syrup – Male • Obesity
• Purine-rich diets – Postmenopausal Cardiovascular Disease
– Meats (organ meats), females • Myocardial Infarction
Seafood • Peripheral artery disease
• Alcohol consumption • Congestive heart failure
• Medications Impaired Renal Function8-11
– Diuretics, Low-dose aspirin, (10 -50%)
Cyclosporine, Ethambutol

1. Bieber JD, Terkeltaub RA. Arthritis & Rheumatism. 2004;50(8):2400-2414 7. Choi et al. Arthritis Rheum. 2007;57:109
2. Wallace KL et al. J Rheumatol. 2004;31:1582-1587. 8. Keenan RT, et al. Am. J. Med. 2010:Article in Press.
3. Weaver AL. Cleveland Clinic Journal of Medicine. 2008;75(Sup 5):S9-S12. 9. KRYSTEXXA™ (pegloticase) for intravenous infusion, Briefing
4. Choi HK et al. Arch Intern Med. 2005;165:742-748. Document for Arthritis Advisory Committee.
5. Williams. Am J Clin Nutr. 2008;87:1480. 10. Becker MA, et al. New Engl. J. Med. 2005;353(23):2450-2461.
6. Smith RG. US Pharm. 2009;34(5):40-47. 11. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S365

Risk Factors for Development of Gout: Diet

• Risk from caffeine : 5+ caffeinated beverages/day ↓ risk of gout
• Risk from alcohol intake: Beer>liquor>wine
• High meat consumption: ↑ risk of gout
• High seafood consumption: ↑ risk of gout
• High dairy consumption: ↓ risk of gout
• High consumption of purine-rich vegetables or total protein:
no association

Choi HK, Willett W, Curhan G. Arthritis Rheum 2007;56(6):2049-2055
Choi HK, Atkinson K, Karlson EW, Willet W Curhan G. Lancet 2004:363:1277-1281.
Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. NEJM 2004;350:1093-1101.
.

Dietary Purine Intake and Serum Uric Acid Levels

• Severe reduction in dietary purine intake can
accomplish no more than a 1 mg/dl decrease in serum
uric acid.

• Exception: Reduction of dietary fructose
• Only carbohydrate that influences purine metabolism
• Implicated in insulin resistance, metabolic syndrome and
obesity
• An apple a day? Ingestion of 5 apples=35% increase in serum
uric acid within 6 hours
Choi HK, Atkinson K, Karlson WE, Willett W, Curhan G. NEJM 2004;350:1093-1101
Choi HK, Atkinson, K, Karlson WE, Willett W, Curhan G. Lancet 2004;353: 1277-1281
Lotito SB, Frei B Free Radic Biol Med. 2004;37:251-8

Medications Affecting Urate Excretion

• Thiazides and loop diuretics
• Low dose aspirin
• Cyclosporin A
• Anti-tuberculous medications
• pyrazinamide and ethambutol
• Niacin
• PTH therapy

Gonzalez EB, Miller ST, Agudelo CA. Drugs Aging 1994;4:128-134.

Secondary Causes of Gout and Hyperuricemia
Due to Uric Acid Overproduction

• Myeloproliferative syndromes
• Lymphoproliferative disorders
• Malignancy
• Hemolytic anemias
• Exfoliative psoriasis
• Tumor lysis syndrome
• Hyperparathyroidism
• Genetic disorders
• Deficient hypoxanthine-guanine phosphoribosyl
transferase
• Glycogen storage diseases

Hyperuricemia: Cardiovascular Risk
Factor?

• Chronic inflammation associated with chronic gout

• Stronger risk factor in those already at high risk for
cardiovascular disease

Bickel C, et al. Am J Cardiol 2002; 29:12-17.
Culleton BF, et al. Ann Int Med 1999;131:7-13. Niskanen LK, et al. Arch Int Med 2004;164:1546-1551.
Fang J, Alderman M. JAMA 2000;283:2404-2410.

Hyperuricemia and Hypertension

• Co-occurrence of hypertension with hyperuricemia

• Hyperuricemia predicts development of hypertension, in many
but not all studies

• ULT of hypertensive hyperuricemia in adolescents → ↓ bp

• Animal models – uricase inhibition → ↑ bp/renin

• In vitro effects of uric acid on endothelial and VSM cells;
intracellular pro-oxidant effect

Acute Gout

• Acute arthritis, typically
monoarticular and very severe
• Inflammatory response to the
presence of monosodium urate
(MSU) crystals
• Urate: end product of purine
metabolism

• Most common form of inflammatory
joint disease in men*

• Crystallization occurs when the
blood level of urate> physiologic
limit of solubility: 6.8mg/dl

* Terkeltaub RA. N Eng J Med 2003; 349:1647-1655

Know the Clinical Picture of Gout

In acute monoarticular attacks of the lower extremities,
the rapid development of severe pain, swelling, and
tenderness that reaches its maximum within 6 to 12 hours,
especially with overlying erythema, is highly suggestive of
crystal inflammation, though not specific for gout. (#1)


Normal Serum Uric Acid Levels Don’t Confirm or
Exclude Gout

While being the most important risk factor for gout, serum
uric acid (SUA) levels do not confirm or exclude gout, as
many people with hyperuricemia do not develop gout, and
SUA levels may be normal during acute attacks. (#3)

Elevated IL-6 levels are uricosuric, contributing to a drop
in SUA during acute attack

• Quality of evidence: Low, Grade 2 recommendation

Common Sites of Acute Gout Attacks

Olecranon Bursa

Elbow
Gout flares or attacks
can occur
in bursae, tendons, Wrist
and joints Fingers

1st MTP Knee
(eventually affected in
~ 90% of individuals
Ankle
Subtalar
with gout)

Midfoot

Precipitating Factors

• Trauma, including surgery

• Diuretics-other medications

• Dehydration or volume depletion for any reason

• Sudden rise or fall in SUA

• Dietary indiscretion

• Low temperature of affected limb

• Alcohol: Beer > Liquor > Wine

Special Considerations for Diagnosing
Gout

• Look for gout, even if
• Serum uric acid levels are normal
• The symptoms present in a woman
• The attack is polyarticular and chronic
• The involved joint is atypical

• Don’t diagnose based on response to treatment:
• Other types of acute arthritis may also respond to
colchicine

Differential Diagnosis of Gout

• Septic Joint

• Trauma, Hemarthrosis

• Pseudogout (CPPD/chondrocalcinosis)

 Rheumatoid or psoriatic arthritis

 Acute bursitis, tendonitis

Gout and Infection May Coexist

Gout and sepsis may coexist; therefore, when septic arthritis is
suspected, Gram staining and culture of synovial fluid should
still be performed, even if MSU crystals are identified. (#6)

• Quality of evidence: Very low, grade 1 recommendation

A Clinical Diagnosis Alone May Suffice
• Although only the demonstration of MSU crystals
in synovial fluid or tophus aspirates constitutes a definite
diagnosis of gout……

• a clinical diagnosis alone is a reasonable alternative
in patients with the typical presentation of gout. (#2)


Crystal Identification May Establish Diagnosis

When the diagnosis is in doubt, identification of MSU
crystals from asymptomatic joints may allow definite
diagnosis during intercritical periods.(#5)


Mono-sodium Urate Crystals during
Intercritical Periods

• MSU Crystals persist in
joints during intercritical
periods1,3
• Low-grade inflammation
often persists during
intercritical periods2,4
• Persistent MSU crystals
and low-grade
inflammation can lead to
progressive disease1-4
1. Pascual E, Batlle-Gualda E, Martínez A, Rosas J, Vela P. Synovial fluid analysis for diagnosis of intercritical gout. Ann Intern Med. 1999;131:756-
759. 2Pascual E. Persistence of monosodium urate crystals and low-grade inflammation in the synovial fluid of patients with untreated gout. Arthritis
Rheum. 1991;34:141-145. Pascual E, Pedraz T. Gout. Curr Opin Rheumatol. 2004;16:282-286. Schumacher HR. The pathogenesis of gout. Clev Clin
J Med. 2008;75(suppl 5):S2-S4.

Analysis of Synovial Fluid
2

• Synovial fluid (SF) crystal analysis requires
a polarized light microscope*
• All monosodium urate crystals (MSU)
birefringent
• 1/5 calcium pyrophosphate dihydrate
(CPPD) crystals birefringent
• Always culture SF
• Infected joints may also contain MSU and CPPD crystals*

• Search for MSU and CPPD crystals in all undiagnosed joint
effusions*

* Pascual et al. Clin Rheum. 2004;50:2400-2414.

Look For Crystals in Available Synovial Fluid

In available synovial fluid samples obtained from
undiagnosed inflamed joints, a routine search for MSU
crystals is recommended. (#4)


When to Measure Renal Uric Acid Excretion: Rarely

Assessment of renal uric acid (UA) excretion is rarely
necessary in patients with gout.

It should, however, be considered in those with early
onset gout (aged < 25 years) or a family history of early
onset gout. (#7)


Uric Acid Nephrolithiasis

 5-10% of stones in the U.S. are uric acid stones; varies from 4%
(Sweden) to 40% (Israel).

 Associated with obesity, metabolic syndrome, and type II DM; the “gouty
diathesis”.

 Yu and Gutman reported a 15-22% prevalence of stones in gout, versus
12% lifetime risk in the general population.

 Prevalence of reported gout with stones is 13.9%, but including
subclinical stone disease prevalence may be as high as 39%.

Risk Factors for Uric Acid Stones

 Low urinary pH
– Idiopathic uric acid nephrolithiasis
– Gout
– Obesity, type II DM
 Volume depletion
 Hyperuricemic hyperuricosuria
– Congenital enzyme defects
– Myeloproliferative disorders
 Normal/hypouricemic hyperuricosuria
– Uricosuric medications
– Renal hypouricemia

Liebman et al, Curr Rheum Reports, 2007

Do Lithogenic Workup in Patients with Stones

Patients with gout have a high incidence of renal
stones(>20%) and those with stones should have a
lithogenic workup.(#8)


Uric Acid Stones - Evaluation

 Standard chemistries, including Ca/Phosphate/PTH

 Stone analysis

 24 hour urine evaluation wrt volume, pH, other lithogenic
substrates (calcium, etc.)

 Noncontrast helical CT re stone burden, imaging characteristics,
etc.

Uric Acid Stones – Management

 Increase fluid intake to > 2 liters/day

 Urinary alkalinization – typically with K-citrate

 Moderation of animal protein intake

 Xanthine oxidase inhibitors for hyperuricosurics

 Avoid uricosuric agents

Little Role for Radiographs in Diagnosis of Acute Gout

Radiographs may be useful for differential diagnosis and
may show typical features in gout. They are not useful in
confirming the diagnosis of early or acute gout and should
only be performed if a fracture is suspected.(#9)


Advanced Gout: Clinically Apparent Tophi

1 2

1 3

1. Photos courtesy of Brian Mandell, MD, PhD, Cleveland Clinic. 3. ACR Clinical Slide Collection on the Rheumatic Diseases, 1998.
2. Photo courtesy of N. Lawrence Edwards, MD, University of Florida.

Advanced Gout: Radiographic Changes

• The characteristic gouty erosion is both destructive and hypertrophic,
leading to “overhanging edges.”
• The joint space is often preserved until very late in the disease process.

Photo courtesy ACR Clinical Slide Collection on the Rheumatic Diseases, 1998.

Ultrasound in the Diagnosis of Gout
A Normal

B Gouty
Arthritis
“Double Contour Sign”

Gout Treatment Goals

• Terminate the acute attack as rapidly as possible
• Colchicine, NSAIDs, or Corticosteroids (Oral, Intra-articular)

• Protect against further attacks
• Reduce the chance of crystal-induced inflammation
• Decrease the chances of joint destruction and other long-term
complications

• Treat hyperuricemia and prevent disease progression
• Long-term correction of the metabolic problem
• Lower serum uric acid sufficiently to deplete the total body urate
pool. Target: Serum uric acid < 6.0 mg/dl.

Approach to Gout Management

Controlling Pain and Inflammation Reducing Urate Burden

Acute Flare Antiinflammatory
Pain Prophylaxis

NSAIDs
Colchicine
Glucocorticoids
IL-1 inhibitors

Optimal Pharmacologic Gout Management

Edwards NL, Crystal-Induced Joint Disease in
ACPMedicine Textbook, 2012

Management Recommendation:
Optimize Treatment Outcomes
Optimal treatment of gout requires both nonpharmacologic and
pharmacologic modalities and should be tailored according to:

• Specific risk factors (levels of serum urate, previous attacks, radiographic
signs)

• Clinical phase (acute gout, intercritical gout, or advanced [ie, chronic
tophaceous] gout)

• General risk factors (age, sex, obesity, diet, alcohol consumption, urate-
elevating drugs, drug interactions, renal function, and comorbidities) (#1)


Importance of Patient Education

Patient education pertaining to beneficial lifestyle changes,
compliance with long-term therapy, and the prevention of
flares early in the course of ULT are core aspects of gout
management. (#2)


Address Modifiable Risk Factors and Comorbidities

Associated modifiable comorbidities and risk factors such as
hyperlipidemia, hypertension, hyperglycemia, obesity, and
smoking should be addressed as an important part of the
management of patients with gout. (#3)


Colchicine, NSAIDs, and Corticosteroids Useful for Acute
Attacks

• In patients with acute gout; oral colchicine, nonsteroidal anti-inflammatory
drugs (NSAIDs), and glucocorticoids may be used as first-line treatments.

• The choice will depend on patient and physician preference, with
consideration of comorbidities (especially a history of CKD and
gastrointestinal disease).

• It may be necessary to continue treatment for an additional 7 to 10 days.(#4)

• Quality of evidence: Low, grade 1 recommendation

Other Options for Acute Gouty Inflammation

• Other choices

• IA, IM or IV glucocorticoids

• Off Label: ACTH gel s.c.

• Off Label: IL-1 inhibitors

• Topical ice
Terkeltaub R. AR&T, 2009

IL-1 Inhibitors (not FDA approved)
 Anakinra

 Canakinumab

 Rilonacept

A Pilot Study of IL-1 Inhibition by Anakinra
in Acute Gout

 10 patient pilot, open-labeled trial of anakinra in patients who had failed other
anti-inflammatory therapy for acute gout.

 “All patients responded rapidly to the drug, with the most rapid onset observed
within 24 hours. In all patients, subjective symptoms of gout were greatly
relieved by 48 hours after the first injection.”

 “No side-effects were observed during the study period.”

So A, DeSmedt T, Revaz S, Tschopp J. Arthritis Research & Therapy 2007, 9: R28 (doi:10.1186/ar2143)

TLR2/4
MSU
Crystals CD14

Synovial Fluid
MyD88

NFκB Mediated
Cell Activation

NALP3 Endothelium/
Pro-IL1ß Gene
Transcription Leukocyte
Pro-caspace 1
ASC
Pro-IL1β
IL-1R

Caspace 1

IL-1β

Endothelial
Activation
Monocyte
Leukocyte
Migration

Edwards NL. Crystal-Induced Joint Disease, ACP Medicine Textbook, 2012
Reproduced with permission Edwards ML

Canakinumab (ACZ885) Relieves Pain and
Controls Inflammation Rapidly in Patients with
Difficult-to-Treat Gouty Arthritis.

 Purpose: Compare effect of IL-1β inhibition with Cannukinumab (CAN) to
triamcinolone acetonide (TA) in the treatment of acute gout flare.
 Methods: Patient with gouty flares who have contraindications to NSAIDs a/o
colchicine given 1 subcut dose of CAN or 1 IM dose of TA. Primary outcome:
pain intensity at 72 hr post dose.
 Results:

Pain reduction at 72 Cannukinumab 150 Triamcinolone 40 mg
hours mg s.c. IM

>75% 78% 45%

>50% 96% 61%

So A, et al. Abstract #145, ACR Annual Meeting, 2010

Conclusion: Cannukinumab vs
Triamcinolone

 Cannukinumab 150 mg sc is superior to IM triamcinolone
40 mg for pain relief in acute gouty flares.

 Markers of inflammation were suppressed by
Cannukinumab but not triamcinolone for 8 weeks after
injection.

Rilonacept and Gout Flare Prevention

 Conclusions: Phase III trial of IL-1 blockade with Rilonacept
demonstrated a marked reduction in acute gout flares during
the first 16 weeks of urate-lowering-therapy initiation and
escalation. Incidence of AEs similar in PLO and RIL groups
with no serious AEs

Low Dose Colchicine is Effective and Best Tolerated

• For acute gout, low-dose colchicine (ie, 1.2 mg administered as soon as
possible, followed by 0.6 mg 1 hour later) is effective and well tolerated.

• Colchicine should be continued (QD-BID as tolerated)for an additional 7
to 10 days or until the flare is resolved.

• High-dose colchicine is not indicated and should not be prescribed. (#5)


AGREE: Trial in Acute Gout
• Pivotal phase-3 trial examining the efficacy and safety of colchicine
• One of 17 clinical studies submitted to the FDA by URL Pharma
• Primary end point: 50% pain reduction at 24 hours without the use of
rescue medication
R High-dose colchicine1 1(n=52)
High-dose colchicine (n=52)
A (4.8 mg: 1.2 mg, then 0.6 mg/h ××6)
(4.8 mg: 1.2 mg, then 0.6 mg/h 6)
N
D
O Low-dose colchicine1 1(n=74)
Low-dose colchicine (n=74)
Patients with acute gout M (1.8 mg: 1.2 mg, then 0.6 mg in 11
(1.8 mg: 1.2 mg, then 0.6 mg in
h)
h)
(N=184) I
Z
E Placebo
Placebo
D (n=58)
(n=58)

1 24
Hours
1. Terkeltaub RA, et al. Arthritis Rheum 2010; 62:1060-1068. (Colchicine delivered as COLCRYS)

AGREE: Responder Analysis at 24 Hours*
40
*
38%
†
33%
30

20
15%

10

0
Low-dose High-dose Placebo
(n=74) (n=52) (n=58)

*A responder is defined as a patient who achieved a ≥ 50% reduction in pain score and did
not take rescue medication prior to the 24-hour post dose assessment.
* P=0.034 versus placebo.
†P=0.034 versus placebo.

AGREE: Adverse Events
90
High-dose (n=52)
Low-dose (n=74)
80 * * *
Placebo (n=59)
70

60

50

40

30
%

* *
w
E
A
P
d
h
n
e
a
o
v
s

*
r
t
f
i

20

10

0
AEs GI AEs Diarrhea Nausea Vomiting Severe AEs Severe diarrhea

*P ≤0.05 vs low-dose and placebo.
Terkeltaub RA, et al. Arthritis Rheum 2010; 62:1060-1068.

NSAIDs

• Equivalent efficacy in gout amongst all NSAIDs

• Relatively contra-indicated in many common comorbid conditions
• Peptic ulcer disease
• Cardiovascular disease and hypertension
• GI bleeds
• Aspirin- or NSAID-induced asthma
• Renal dysfunction
• Postoperative patients
• Warfarin

• Consider using PPI for gastric protection

Corticosteroids

• Effective as oral, intramuscular, or intra-articular agents

• Worsening of glycemic control in diabetics

• Infection risk

• Steroid “rebound” acute attack may recur if treatment not
followed by NSAID or colchicine

• All side effects likely minimized by intra-articular

Intra-articular Steroids May Be Effective

For an acute attack, after sufficient precautions have been
taken, intra-articular aspiration and injection of a long-
acting steroid is an effective and generally well-tolerated
treatment. (#6)

Rebound may occur and supplemental anti-inflammatory
therapy is often needed


Indications for ULT

Urate-lowering therapy is indicated in patients with any of
the following: recurrent attacks (> 1 attack per year),
chronic arthropathy, tophaceous deposits, nephrolithiasis,
or radiographic changes of gout.

Once initiated, ULT is considered a lifelong treatment
recommendation. (#7)


Goals of ULT

The therapeutic goal of ULT is to prevent acute flares,
prevent the development of tophi, help dissolve tophi, and
prevent the development of chronic gouty arthropathy.

This is achieved by maintaining an SUA level of < 6.0
mg/dL, well below the saturation point for MSU of 6.8
mg/dL. (#8)


Urate Lowering Treatments
• Urostatic agents: Xanthine oxidase inhibitors
• Allopurinol
• Febuxostat (Uloric ™)

• Uricosuric Agents
• Contraindicated in over-producers
• Probenecid
• Sulfinpyrazone

• Enzymatic-uricase
• Pegloticase (Krystexxa ™)

• Medications that incidentally lower SUA
• Losartan
• Fenofibrate

Urate Lowering Therapy
Important Considerations
• Prophylaxis against gout flares • Duration of therapy –
• Increased risk of flares with indefinite
urate lowering therapy
• Colchicine or NSAIDs;
• Lifelong risks of ULT
sometimes glucocorticoids
• Adherence is often sub-
• Treating to target optimal
• serum urate to <6 mg/dl
• May be<4mg/dl in patients with
tophi • Uncertainty in chronic
• DON’T TREAT ASSYMPTOMATIC kidney disease
HYPERURICEMIA

• Patient education

Protect Against Acute Attacks
While Implementing Urate Lowering Therapy

• Abrupt reduction in uric acid may cause acute attack
• Do not implement urate lowering therapy without prophylaxis
• Co-administer prophylactic agent prior to initiating urate
lowering therapy (usually 2 weeks before)
• Warn patient of potential for attacks, even in face of optimum
treatment
• Continue prophylactic therapy
• Colchicine 0.6 mg once or twice daily
– Or NSAID
• Duration: 6 months until after last attack and tophi if present have
resolved

Borstad GC, et al. J Rheumatol 2004;31:2429-2432.

Colchicine Is First Choice for Prophylaxis
• Prophylaxis against acute attacks during the first 6 to 12 months of ULT can be achieved by colchicine
(given as tolerated, 0.6 mg once or twice daily) or an NSAID (with gastroprotection if indicated).

• Prophylaxis should be initiated 2 weeks prior to the implementation of ULT.

• The choice for prophylaxis should include an analysis of the comorbidities of the patient as well as the
risks and benefits of the agent, which are shown below.

• Nonsteroidal anti-inflammatory drugs are currently not FDA approved for prophylaxis. (#13)


The expert panel recommends that colchicine be considered as the first choice
for prophylaxis. Nonsteroidal anti-inflammatory drugs and corticosteroids are
alternatives if colchicine is not tolerated or is not effective. Colchicine is the only
FDA approved medication for prophylaxis.

Probenecid
• Probenecid, a uricosuric agent, can be used as an alternative to a xanthine
oxidase inhibitor (XOI) in patients with normal renal function, but is relatively
contraindicated in patients with nephrolithiasis and ineffective in the presence
of renal insufficiency.

• Probenecid can be used together XOI, if necessary, to achieve the target goal of
lowering SUA to < 6.0 mg/dL.

• Dosing may begin at 500 mg daily, with titration monthly up to a maximum of 3
g per day in divided doses. (#12)


Xanthine Oxidase Inhibitors
• The xanthine oxidase inhibitors (allopurinol and febuxostat) are the agents of
choice for ULT to reach the therapeutic target SUA level of < 6.0 mg/dL.

• The dose should be titrated to optimize safety and minimize the chance of
precipitating an acute flare.

• Serum uric acid should be monitored to ascertain the achievement and
maintenance of this goal.

• Appropriate laboratory monitoring for toxicity is indicated.(#9)


The Target Level of SUA
 Saturation of uric acid occurs at >6.8 mg/dL at pH 7.4 and body temp
98.6.

 Achieving SUA of <6 mg/dL results in:
↓ MSU crystals in joints
↓ frequency of flares/attacks
↓ tophus size

 Lower target SUA levels are appropriate in patients with, tophaceous
disease.

 Median dose to goal for allopurinol is ~380 mg/day.

Allopurinol
• Allopurinol should be started at a low dose (100 mg daily) and increased by 100
mg every 2 to 4 weeks (to a maximum allowable dose of 800 mg/day) as
necessary to achieve the target SUA goal of < 6.0 mg/dL.

• If allopurinol toxicity occurs, it should be stopped immediately.

• Other treatment options include febuxostat or probenecid. (#10)


Allopurinol
• Administered as a daily dose of 50 to 800 mg daily
• Divide dose when >300mg daily
• Initiate at 50 mg/day in patients with renal insufficiency
• Titrate until Serum Uric acid < 6.0 mg/dl. It is commonly underdosed
• Get baseline laboratory tests
• Measure uric acid every month while titrating for 1st 3 months
• Monitor toxicity with exam, LFTs, RFTs, every 3-6 months while titrating
• CBC with manual differential to look for eosinophils

• About 2% incidence of mild allergic rash

• 0.4% incidence of severe reactions-20-25% mortality with allopurinol hypersensitivity
syndrome
• Steven Johnson Syndrome
• Toxic epidermal necrolysis
• Hepatitis
• Interstitial nephritis

• Reaction risk greatest in renal insufficiency and diuretics
Hande,KR, et al Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984;76: 47-56
Stamp,L, et al, the optimal use of allopurinol: An audit of allopurinol use in South Aukland. Aust NZ J Med 2000;30: 567-72

Dosing Above >300mg Allopurinol

89% of 90 patients reached goal with > recommended
dosing Arthritis Rheum. 2011 Feb;63(2):412-21

Allopurinol Hypersensitivity

 AHS occurs in ~0.4% of patients on allopurinol, with ~20% fatality.

 Renal dysfunction thought to be a risk factor, but there is minimal
evidence that reduction in CKD dose affects incidence of AHS.

 Molecular case control study suggests marked ↑ risk for those with
HLA-B*5801, i.e. immune factors may be > [oxypurinol].

 Dose reduction in CKD is associated with ↓ success in achieving
target urate.

Allopurinol Dose in CKD

Hande et al, Am. J. Med., 76, 1984
→ Allopurinol: Drug info, “UpToDate”, 2007

Conclusions: Renally-Adjusted
Allopurinol Dosing
 Allopurinol dosing in CKD has not traditionally been based on achieving a
target SUA.

 There is minimal evidence that dose reduction of allopurinol in CKD affects
risk of AHS.

 Problem: scant safety data for allopurinol dosing >300mg/d, vs. the
impediments (cost, insurance approval, etc.) to using febuxostat.
Febuxostat, however, does not cause an equivalent to AHS…

 Recommendation is to SLOWLY ↑ dose, with low-dose colchicine for flare
prophylaxis.

Febuxostat
• Febuxostat should be started at 40 mg daily and may be increased to 80 mg after
at least 2 weeks of treatment, if necessary to achieve the target SUA goal of < 6.0
mg/dL.

• If toxicity occurs, febuxostat should be stopped immediately.

• Other treatment options include allopurinol or probenecid.

• However, allopurinol and febuxostat should not be coadministered. (#11)


Febuxostat vs Allopurinol
Phase 3 Clinical Trial Primary End Points
Randomized, double-blind, 52-week, multicenter trial of 760
90 patients
80
Primary end points
Subjects with SUA <6.0 mg/dL, %

70
* *
60
50 * Last 3 SUA <6.0 mg/dL
Week 52 SUA <6.0 mg/dL
40 *
30
*P<.05 for each
20 febuxostat group vs
allopurinol group.
10
0
Febuxostat 120 Febuxostat Allopurinol
mg 80 mg 300 mg

Becker et al. ACR/ARHP Program Book Supplement. 2004;L18.Bec

CONFIRMS Efficacy
in Renally Impaired Subjects
Proportion of Subjects With Mild-to-Moderate Renal Impairment
With sUA <6 mg/dL at Final Visit
*
80 **
72%
70
50%
*
60
% of Subjects

50 42%
40
Febuxostat
Febuxostat
30 80 mg Allopurinol
40 mg 300/200 mg
20 (n=479) (n=503)
(n=501)
10
0
*p<.05 vs allopurinol.
**p<.05 vs ULORIC 40 mg.
Renal impairment was defined as baseline estimated CL cr <90 mL/min.

Enzymatic Uricolytic Drugs
• Uricase (urate oxidase) catalyzes uric acid to allantoin
• Allantoin is more soluble than uric acid
• Humans and other higher primates lack this enzyme

• Fast-acting, potent decrease in serum urate and in tophi

• Native and recombinant bacterial uricases are available outside the U.S. for
intravenous use
• To treat tumor lysis syndrome
• Not indicated for treatment of gout.

• Significant incidence of allergic reactions: all uricase of non-human origin

Effect of Urate-Lowering Therapy on the Velocity
of Size Reduction of Tophi in Chronic Gout

Perez-Ruiz F, Calabozo M, Pijoan JI, et al . Arthritis Rheum 47: 356-360, 2002

Uricase Enzymes
Uricase (uric acid oxidase) catalyzes the conversion of uric acid to allantoin: A more
soluble, readily excretable form

Uricase Uricase
OH
OH
H2O + O2 H2O2 + CO2
N
N
OH

HO N OH
N H
OH
N
N
N
N OH
OH
HO N
N H
HO N
N
N H
H Allantoin
Uric acid

Pegloticase

• For patients who have refractory gout and/or resistant
tophaceous disease, pegloticase is another treatment option.
Pegloticase is administered by infusion and has a significant risk
profile.

• Patients who may be candidates should be referred to health
care professionals with expertise in the use of pegloticase.


Ideal Candidate for Pegloticase

 Indication:
– gout refractory to conventional therapy occurs in patients
who have failed to normalize serum uric acid and whose
signs and symptoms are inadequately controlled with
xanthine oxidase inhibitors at the maximum medically
appropriate dose or for whom these drugs are
contraindicated*.

– *From Krystexxa Product Information Sheet

Ideal Candidate for Pegloticase

 Tophaceous disease, or

 Chronic synovitis, or

 Repetitive and frequent attacks of gout, or

 Unresponsive to standard ULT with one or more of the above
issues

 De-bulking agent

Pegloticase
Resolution of Tophi

Baseline Week 15
Sundy and Hershfield, unpublished data

Phase 3 Trials

 2 double blind replicate trials in 212 patients
– 2:2:1 randomization
• q2 vs q4 vs placebo
– 6 months RCT and 2 year OLE

Risks

 Gout flares

 Infusion related events (reactions)

 Anaphylaxis

Primary Endpoint

– Proportion of patients maintaining plasma
uric acid <6mg/dL in 80% of determinations
during month 3 and month 6

Infusion Reaction Relationship to SUA<
6mg/dL or >6 mg/dL

Among patients with SUA <6
mg/dL, fewer than 1 in 100
infusions were accompanied
by signs or sx of an infusion
reaction; placebo treated
patients had a 0.4% incidence
in the RCT

Most Common Signs and Symptoms of
Infusion Reactions to Pegloticase

Management of Infusion-Related
Events in RCT

 All reactions resolved with supportive measures

– slowing or stopping the infusion and/or other interventions that included

• antihistamines

• fluids

• corticosteroids

• analgesics

• Epinephrine: wheezing, lip swelling of “infusion reaction without BP
change - 1 each

Management of Infusion-Related
Events in Phase 3

 In the clinical studies no patient with an infusion related event required
resuscitation, intubation, mechanical ventilatory support, pressors or
hospitalization

 There was no shock among patients meeting definition of anaphylaxis

 There were no infusion-related deaths

Infusion Reaction Summary

 Risk of reaction and anaphylaxis is higher in patients who
have lost a therapeutic response (and will not benefit from
additional rx).
 Risk of reaction is low (under 1% of infusions) when SUA
is <6 mg/dL.
 Risk of reaction during rx can be mitigated:
– routine SUA measurement prior to each infusion
– stopping pegloticase treatment in patients with pre-
infusion SUA >6 mg/dL.
 All reactions resolved with conservative measures

January 25, 2011 May 3, 2011

Secondary Endpoints

 Tophus resolution

 Reduction in gout flares

 Reduction in tender and swollen joint counts

 Improvement in quality of life (SF-36)

 Improvement in functional status (HAQ-DI)

Tophus Resolution

26 March 2007 26 September 2007

Radiographic Outcomes

 No data was collected in the phase 3 program

 Radiographic scoring system recently proposed for gout*

 Virtually no data on radiographic outcomes in gout

*Dalbeth, et. al., Arthritis Care and Research, Vol 57, No. 6. August 2007

Radiographic Outcomes

Baraf, Matsumoto et al, A&R 2008

When to Refer

Considerations for referring a patient with gout to a rheumatologist or
nephrologist include:
• Confirmation of diagnosis, particularly in patients with atypical
presentation
• Management of refractory cases when
• An SUA level < 6.0 mg/dL cannot be achieved
• Recurrent flares occur despite apparent adequate treatment
• A patient presents with persistent and/or extensive tophaceous disease
• Management of patients with nephrolithiasis
• Consideration for complex treatment options (#16)


Treatment Pearls
• Treat associated co-morbidities and • Uricosurics useful in allopurinol allergic
address risk reduction behavior patients with normal renal function,
under-excretion, and no history of
• Initiate urate lowering therapy (ULT) nephrolithiasis
in patients with two or more attacks
a year • Uricosurics – not indicated in
overproducers
• Do not start ULT during an acute
attack • Use concomitant prophylaxis when
initiating ULT to prevent treatment
induced attacks
• Do not discontinue ULT if patient on
ULT has an acute attack
• Measure serum uric acid levels
• Allopurinol is drug of choice for initial • every 3-6 months. Adjust
ULT medications until a target uric acid
• of <6 mg/dl is obtained

Cannella AC, Mikuls TR. Res and Staff Phys 2005:51:21-28.

TAKE HOME MESSAGES:
Gout and CKD
 The kidney plays a dominant role in gout; SUA reflects the net balance of
urate reabsorption and secretion across the renal proximal tubule.

 Diuretic Rx ↑ SUA by multiple mechanisms.

 High prevalence of both CKD and renal stones in patients with gout.

 Think of FJHN in patients with a family history of gout and CKD.

 The target SUA in CKD is no different than in patients with normal renal
function.

TAKE HOME MESSAGES:
Gout Rx in CKD

 Dose reduction in allopurinol in CKD → ↓↓ likelihood of reaching SUA goal.

 In CKD, > recommended allopurinol dosage appears to be safe without ↑
risk of AHS. However, minimal safety data for >300 mg/day.

 Low-dose colchicine for acute gout and renally-adjusted colchicine for ULT
prophylaxis → expanded utility in CKD.

 High incidence of tophaceous gout in renal transplantation → consider
pegloticase.

Should Nephrologists Take a More
Active Role in Gout?
 High prevalence of CKD in gout.

 Increasing evidence of a role for hyperuricemia in progressive CKD.

 WRT dose titration of ULT, there is a built-in frequency of Nephrology
follow-up in patients with CKD III or worse.

 Minimal extra effort in achieving SUA goal along with bp and proteinuria
goals, PTH/calcium/phosphate/vitD goals, iron goals, etc.

Summary Points - 1
• Data continue to support the decision to diagnose gout using clinical characteristics
rather than mandating crystal identification.

• Although studies have shown that SUA levels of > 6.0 mg/dL are a significant risk
factor for gout,82-85 they are always a reliable diagnostic tool because approximately
14% of patients with acute gout presented with SUA levels of < 6.0 mg/dL. 109
Conversely, some people with high SUA may never develop gout. Serum uric acid
should be used in combination with clinical criteria and response to gout treatment
to arrive at a diagnostic decision.

• Research has focused on the interaction of gout with typically associated risk factors
and comorbid conditions. Strong associations have been demonstrated between
gout and metabolic syndrome,110-112 CVD,32, 33, 50, 113 and CKD.33

• Reference numbers are those from PostGraduate Medicine Reference

Summary Points - 2
• The use of nonpharmacologic measures in the treatment of patients with gout,
particularly dietary aspects, has become more sophisticated. 114

• Gout therapy relies on good patient education. Patients need to understand that
gout treatment requires a lifelong commitment. Patients also need to know that the
initiation of ULT results in acute gout attacks (mobilization flares) and that these
attacks are a sign of effective therapy. Finally, they need to understand the
importance of adhering to prophylaxis regimens.

• For effective management of an acute gout attack, treatment should begin within
hours of first symptoms. Low-dose colchicine (1.2 mg as soon as possible, followed
by 1 dose of 0.6 mg 1 hour later, for a total dose of 1.8 mg) is as effective and better
tolerated than high-dose colchicine (1.2 mg followed by 0.6 mg every hour for 6
hours, resulting in a total dose of 4.8 mg).68

Summary Points - 3
• The benefits of reaching a target SUA level of < 6.0 mg/dL have been confirmed. For
most patients, a target SUA between 5.0 and 6.0 mg/dL is safe and effective.
Patients with incapacitating, severe, tophaceous gout may require SUA levels of <
4.0 mg/dL to see improvement.87,115, 116

• Allopurinol has been found to be safe and more effective at higher doses. It should
be started at a low dose of 100 mg per day but can (with appropriate monitoring) be
titrated up to 800 mg per day as necessary for a patient to achieve the target SUA
level of 6.0 mg/dL.92-94 It has been recommended that patients with renal impairment
receive lower doses but recent studies report that this might not be required clinical
practice.

Summary Points - 4
• For patients who have not responded to or were not eligible to receive allopurinol,
febuxostat (also a xanthine oxidase inhibitor with a slightly different mechanism of
action) can be prescribed at unchanged doses for patients with mild-to-moderate
renal or hepatic impairment.89, 90 Intravenous pegloticase is indicated for patients with
refractory and/or resistant tophaceous gout.108

• Timely referral from primary care to rheumatology or nephrology may be the best
option for patients with an uncertain diagnosis or in cases of severe disease.

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