this program is made possible through an

Enhanced Subspecialist Deck: Recommendations for the

Diagnosis and Management of Gout and

Hyperuricemia

This CME 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 This program is made possible through an educational grant from Savient Pharmaceuticals, Inc. educational grant from Savient Pharmaceuticals, Inc.

and URL Pharma, Inc.and URL Pharma, Inc.

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.

Accreditation

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) approach13 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

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

Gout - a Progressive and Disabling Disease One Chronic Disease - 4 Stages

Necessary butnot sufficient for gout

asymptomatichyperuricemia

GoutAsymptomatichyperuricemia1

Gout2

Acute flares Intercritical Period

Persistent or Progressive gout

Disease Progression

sUA ≥ 7 mg/dl

Intermittent inflammatory arthritis

First MTP Joint

Increasing frequency and duration of attacksPolyarticular presentation

Chronic synovitisVisible tophi

Chronic Arthropathy and Tophi

Progression togout: 20 – 30%

~32million in US ~5 million~8 million ~300-800k

1. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S5662. Zhu Y, et al. Arth. & Rheumatism. 2010 ;62(10 suppl.):S901-2

Stages of Gout

AsymptomaticHyperuricemia

Acute Gout with Intercritical

Periods

Advanced Gout

Years

Pai

n

Lev

el

rachelf

remove the line that seperates the title from the figure

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

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

Pathogenesis of Hyperuricemia

Endogenous purine synthesis

Tissue nucleic acids

Dietary purines

600 mg

100 mg

1200 mg

SUA x Blood Volume

500 mg

200 mg

Renal excretion

Intestinal uricolysis

Purine Sources

Total Body Uric Acid Pool

Miscible urate pool

Purine Elimination

Sources and distribution of uric acid

Endogenous purine synthesis

Tissue nucleic acids

Dietary purines

600 mg

100 mg

1200 mg

500 mg

200 mg

Renal excretion

Intestinal uricolysis

Purine Sources

Total Body Uric Acid Pool

Miscible urate pool

Purine Elimination

300 mgMiscible urate pool

2000 mg300 mg

Insoluble urate pool

1 to >100 grams

1200 mg

Miscible urate poolMiscible urate pool

2000 mg

Insoluble urate pool

1 to >40 grams

Consequences of Expanded Urate Pools

Asymptomatic hyperuricemia

Gouty arthritis

Urate tophi

Renal Manifestations

?Hypertension, kidney & heart

disease

URIC ACID AND THE KIDNEY

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 Processes

Proximal Tubule

Renal Proximal Tubular Epithelium

Peritubular Interstitium

Nephron Lumen

SECRETION

OAT1 OAT3

MRP4 UAT

ABCG2

NTP1

Urate

Urate

Urate

Na+

Anions

Urate

REABSORPTION

L-GLUT9

OAT4 OAT10

URAT1

S-GLUT9

Anions

Anions

Urate

Urate

Urate

Urate

To Blood To Urine

Renal Transport of Urate

Edwards NL, ACP Medicine, 2012

Proximal Urate Absorption

David Bruce Mount

? Include as alternative

Proximal Urate SECRETION

Inhibition AND Activation of Urate Exchange by the Same Anions

David Bruce Mount

Would include this if you include the statements in the next slide

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 Recommendations

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

Co-Morbid Conditions

Metabolic Syndrome7(63%)

• Hypertension

• Diabetes Mellitus

• Obesity

Cardiovascular Disease

• Myocardial Infarction

• Peripheral artery disease

• Congestive heart failure

Impaired Renal Function8-11

(10 -50%)

Risk Factors & Co-Morbid Conditions

1. Bieber JD, Terkeltaub RA. Arthritis & Rheumatism. 2004;50(8):2400-24142. Wallace KL et al. J Rheumatol. 2004;31:1582-1587.3. Weaver AL. Cleveland Clinic Journal of Medicine. 2008;75(Sup 5):S9-S12.4. Choi HK et al. Arch Intern Med. 2005;165:742-748.5. Williams. Am J Clin Nutr. 2008;87:1480.6. Smith RG. US Pharm. 2009;34(5):40-47.

Risk Factors

Modifiable1-6

• Obesity

• Serum urate

• High-fructose corn syrup

• Purine-rich diets

– Meats (organ meats), Seafood

• Alcohol consumption

• Medications

– Diuretics, Low-dose aspirin, Cyclosporine, Ethambutol

Non-modifiable

• Age

• Gender

– Male

– Postmenopausal females

7. Choi et al. Arthritis Rheum. 2007;57:1098. Keenan RT, et al. Am. J. Med. 2010:Article in Press. 9. KRYSTEXXA™ (pegloticase) for intravenous infusion, Briefing

Document for Arthritis Advisory Committee.10. Becker MA, et al. New Engl. J. Med. 2005;353(23):2450-2461.11. 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):2049-2055Choi 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 hoursChoi HK, Atkinson K, Karlson WE, Willett W, Curhan G. NEJM 2004;350:1093-1101Choi HK, Atkinson, K, Karlson WE, Willett W, Curhan G. Lancet 2004;353: 1277-1281Lotito 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

Culleton BF, et al. Ann Int Med 1999;131:7-13. Fang J, Alderman M. JAMA 2000;283:2404-2410.

Bickel C, et al. Am J Cardiol 2002; 29:12-17. Niskanen LK, et al. Arch Int Med 2004;164:1546-1551.

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

Diagnostic Recommendation: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)

• Strength of recommendation: 93 (95% CI, 91–94)

• Highly or strongly recommend: 96%

• Quality of evidence: Moderate, grade 1 recommendation

Diagnostic Recommendation: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

Midfoot

Gout flares or attacks can occur

in bursae, tendons, and joints

Olecranon Bursa

Elbow

Wrist

Knee

AnkleSubtalar

1st MTP(eventually affected in ~ 90% of individuals

with gout)

Fingers

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

• Systemic illness

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

Diagnostic Recommendation: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)

• Strength of recommendation: 92 (95% CI, 91–93)• Highly or strongly recommend: 95%• Quality of evidence: Very low, grade 1 recommendation

Diagnostic 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)


Diagnostic Recommendation: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)



• Quality of evidence: Very low, grade 2 recommendation

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

• Synovial fluid (SF) crystal analysis requires a polarized light microscope*

• All monosodium urate crystals (MSU) birefringent

• 1/5 calcium pyrophosphate dihydrate (CPPD) crystals birefringent

2

• 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.

Diagnostic Recommendation: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)




Diagnostic Recommendation: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

Diagnostic Recommendation: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.

Max Hamburger

What is WRT?

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

Diagnostic Recommendation: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. 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.

1

21

3

http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=%5Cwebsites%5Cemedicine%5Cmed%5Cimages%5CLarge%5C3893Gout;Tophi-ear.jpg&template=izoom2

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.

A

B

Ultrasound in the Diagnosis of Gout

Normal

Gouty Arthritis

“Double Contour Sign”

Management Recommendations

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.

Controlling Pain and Inflammation

Acute Flare Pain

Antiinflammatory Prophylaxis

Optimal Pharmacologic Gout Management

Reducing Urate Burden

NSAIDsColchicineGlucocorticoidsIL-1 inhibitors

Approach to 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)


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)




Management Recommendation:Importance of Patient Education

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)



• Quality of evidence: Moderate, grade 1 recommendation

Management Recommendation:Address Modifiable Risk Factors and Comorbidities

• 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)

• Strength of recommendation: 97 (95% CI, 96–98)• Highly or strongly recommend: 100%• Quality of evidence: Low, grade 1 recommendation

Management Recommendation:Colchicine, NSAIDs, and Corticosteroids Useful for Acute

Attacks

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)

MSU Crystals CD14

TLR2/4

MyD88

NFκB Mediated Cell Activation

Pro-IL1ß Gene Transcription

Pro-IL1β

NALP3

Pro-caspace 1

ASC

Caspace 1

IL-1β

IL-1R

Endothelial Activation

Leukocyte Migration

Monocyte

Endothelium/Leukocyte

Synovial Fluid

Edwards NL. Crystal-Induced Joint Disease, ACP Medicine Textbook, 2012

Reproduced with permission Edwards ML

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:

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

Pain reduction at 72 hours

Cannukinumab 150 mg s.c.

Triamcinolone 40 mg IM

>75% 78% 45%

>50% 96% 61%

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

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

• 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)




Management Recommendation:Low Dose Colchicine is Effective and Best Tolerated

RANDOMIZED

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

High-dose colchicine1 (n=52) (4.8 mg: 1.2 mg, then 0.6 mg/h × 6)High-dose colchicine1 (n=52) (4.8 mg: 1.2 mg, then 0.6 mg/h × 6)

Placebo(n=58)

Placebo(n=58)

1 24Hours

Patients with acute gout (N=184)

Low-dose colchicine1 (n=74) (1.8 mg: 1.2 mg, then 0.6 mg in 1

h)

Low-dose colchicine1 (n=74) (1.8 mg: 1.2 mg, then 0.6 mg in 1

h)

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

AGREE: Responder Analysis at 24 Hours*

(n=74) (n=52) (n=58)

40

30

20

10

38%

33%

15%

*†

Low-dose PlaceboHigh-dose0

* P=0.034 versus placebo.†P=0.034 versus placebo.

*A responder is defined as a patient who achieved a ≥ 50% reduction in pain score and didnot take rescue medication prior to the 24-hour post dose assessment.*A responder is defined as a patient who achieved a ≥ 50% reduction in pain score and didnot take rescue medication prior to the 24-hour post dose assessment.

AGREE: Adverse Events

0

10

20

30

40

50

60

70

80

90

AEs GI AEs Diarrhea Nausea Vomiting Severe AEs Severe diarrhea

% o

f Pa

tien

ts w

ith A

dve

rse

Eve

nts

* * *

* * *

High-dose (n=52)

Low-dose (n=74)

Placebo (n=59)

*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 administration

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




Management Recommendation:Intra-articular Steroids May Be Effective

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)



• Quality of evidence: Low, grade 1 recommendation

Management Recommendation:Indications for 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)



• Quality of evidence: Low, grade 1 recommendation

Management Recommendation:Goals of ULT

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 TherapyImportant Considerations

• Prophylaxis against gout flares• Increased risk of flares with

urate lowering therapy• Colchicine or NSAIDs;

sometimes glucocorticoids

• Treating to target• serum urate to <6 mg/dl

• May be<4mg/dl in patients with tophi

• DON’T TREAT ASSYMPTOMATIC HYPERURICEMIA

• Patient education

• Duration of therapy – indefinite• Lifelong risks of ULT

• Adherence is often sub-optimal

• Uncertainty in chronic kidney disease

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.

Management Recommendation: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, 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)


Management Recommendation:Probenecid

• 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)


Management Recommendation:Xanthine Oxidase Inhibitors

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 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)


Management Recommendation:Allopurinol

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: 47-56Stamp,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.

Management Recommendation: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 AllopurinolPhase 3 Clinical Trial Primary End Points

0

10

20

30

40

50

60

70

80

90

Allopurinol 300 mg

Febuxostat

80 mg

Febuxostat 120 mg

Sub

ject

s w

ith S

UA

<6.

0 m

g/dL

, %

*

*

*

*

*P<.05 for each febuxostat group vs allopurinol group.

Last 3 SUA <6.0 mg/dL

Week 52 SUA <6.0 mg/dL

Primary end points

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

Randomized, double-blind, 52-week, multicenter trial of 760 patients

CONFIRMS Efficacy in Renally Impaired Subjects

Proportion of Subjects With Mild-to-Moderate Renal Impairment With sUA 6 mg/dL at Final Visit

*p.05 vs allopurinol.

**p.05 vs ULORIC 40 mg.

Renal impairment was defined as baseline estimated CLcr 90 mL/min.

50%

72%

42%

0

10

20

30

40

50

60

70

80

% o

f S

ub

ject

s

***

*

Febuxostat40 mg

(n=479)

Febuxostat 80 mg

(n=503)

Allopurinol 300/200 mg

(n=501)

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

Uricase Enzymes

Allantoin

NHN

NN

OHHO N

N

NH

OH

N

OH

Uric acid

N

N

NH

OH

HO

N

OH

H2O + O2H2O2 + CO2

HO

OH

Uricase Uricase

NH

OH

Management Recommendation: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

PegloticaseResolution of Tophi

Baseline Week 15Sundy 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

Phase Three Trial

Risks

Gout flares

Infusion related events (reactions)

Anaphylaxis

Adverse Events

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, 2011January 25, 2011 May 3, 2011May 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

Tophus Resolution

26 September 200726 March 2007

Reduction in Gout Flares

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

Management Recommendation: 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 address risk reduction behavior

• Initiate urate lowering therapy (ULT) in patients with two or more attacks a year

• Do not start ULT during an acute attack

• Do not discontinue ULT if patient on ULT has an acute attack

• Allopurinol is drug of choice for initial ULT

• Uricosurics useful in allopurinol allergic patients with normal renal function, under-excretion, and no history of nephrolithiasis

• Uricosurics – not indicated in overproducers

• Use concomitant prophylaxis when initiating ULT to prevent treatment induced attacks

• Measure serum uric acid levels • every 3-6 months. Adjust

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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