Gout

Source: American Family Physician, September 2007

SORT: KEY RECOMMENDATIONS FOR PRACTICE
Clinical recommendation	Evidence rating	References
Serum uric acid measurements are useful in the evaluation of gout; however, they should not be used alone to confirm or exclude the diagnosis.	C	12, 17, 19
Nonsteroidal anti-inflammatory drugs, corticosteroids, and colchicine are effective treatments for acute gout.	B	20, 22-25
In patients with gout, modifiable risk factors such as obesity, diuretic use, high-purine diet, and alcohol intake should be addressed.	B	13, 14, 17
Urate-lowering therapy is recommended for patients with recurrent gout attacks, tophi, or ongoing arthropathy with joint damage seen on a radiograph.	C	20
When initiating urate-lowering therapy, prophylaxis with low-dose colchicine for three to six months may reduce the risk of flare-ups.	B	20, 28
During urate-lowering therapy, the target serum uric acid level is less than 6 mg per dL (355 µmol per L).	B	20, 29
Allopurinol (Zyloprim) is the recommended first-line agent for urate-lowering therapy.	C	20
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 749 or http://www.aafp.org/afpsort.xml.

Epidemiology and Pathophysiology

uric acid is a metabolic by-product of purine catabolism
in humans, uricase is dysfunctional
hyperuricemia (uric acid > 6.5) is common
gout is casued by altered purine metabolism leading to hyperuricemia
when the local solubility limits of uric acid are exeeded, monosiduum urate cyrstal deposition in the joints, kidneys, and soft tissues causes clinical manifestations, including arthritis, soft tissue masses (ie, tophi), nephrolithiasis, urate nephropathy
asymptomatic hyperuricemia is common and usually does not lead to clinical gout

Risk Factors

local factors:
- pH level (e.g., from perioperative ketosis in surgical patients)
- lower body temperature (explains nocturnal attacks)
- articular dehydration (from initiation of diuretic therapy)
systemic factors
- high-purine diet
- alcohol use
- obesity
- diuretic therapy
- red meat and seafood
- protective effect from dairy prodcuts
common triggers
- infection
- IV contrast
- acidosis
- rapid fluctations in serum uric acid - trauma, surgery, psoriasis flares, chemotherapy, diuretic therapy, stopping or starting allopurinol

Clinical Presentation

Acute Gout

single or multiple joints
most commonly lower extremities
most commonly first metatarsophalageal (podagra), midtarsal, ankle, knee joints
pain, erythema, swelling
worse in the morning and increase and peak within 24-48H
severe pain, patients often cannot wear socks or touch bedsheets
typically subsides in five to seven days
may resemble cellulitis
may cause acute bursitis or tenosynovitis of periarticular structures
may cause fever and leukocytosis
if unable to differentiate from septic arthritis, defer corticosteroid injection

Chronic Gout

frequent, recurrent acute attacks cause chronic tophaceous gout
tophi are deposits of monosodium urate crystals in soft tissue
- especially helix of ear, over elecranon processes, interphalangeal joints
- may eventually cause joint erosion and destruction
- occasionally, polyarticular tophaceous gout may cause subcutaneous nodules and resemble rheumatoid arthritis

Diagnosis

Classification criteria to aid in the diagnosis of gout have been proposed by the American College of Rheumatology (Table 1),16 and a consensus panel of experts from the European League Against Rheumatism (EULAR) has reviewed the evidence and made recommendations for diagnosing gout.17 The main differential diagnosis (Table 2) of acute gout is pseudogout (calcium pyrophosphate deposition disease) and septic arthritis.

Table 1. American College of Rheumatology Preliminary Criteria for Gout

Gout may be diagnosed if one of the following criteria is present:

Monosodium urate crystals in synovial fluid

Tophi confirmed with crystal examination

At least six of the following findings:

Asymmetric swelling within a joint on a radiograph

First metatarsophalangeal joint is tender or swollen (i.e., podagra)

Hyperuricemia

Maximal inflammation developed within one day

Monoarthritis attack

More than one acute arthritis attack

Redness observed over joints

Subcortical cysts without erosions on a radiograph

Suspected tophi

Synovial fluid culture negative for organisms during an acute attack

Unilateral first metatarsophalangeal joint attack

Unilateral tarsal joint attack

Adapted with permission from Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yu TF. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 1977;20:896.

Table 2. Differential Diagnosis of Acute Gout
		Synovial fluid findings
Diagnosis	Joint distribution	WBC count*	Gram stain/culture	Synovial fluid crystals†	Radiography findings
Gout	Lower extremities: metatarsophalangeal, midtarsal, or knee joints; initial attacks may be less common in upper extremities	2,000 to 50,000 per mm3 (2 × 109 to 50 × 109 per L)	Negative	Needle shaped, negative birefringence	Acute: asymmetric swelling Chronic: periarticular erosions with overhanging edges
Pseudogout (calcium pyrophosphate deposition disease)	Knee, wrist, or first metatarsophalangeal	2,000 to 50,000 per mm3	Negative	Rhomboid shaped, weak positive birefringence	Soft tissue swelling, chondrocalcinosis (calcification of cartilage)
Septic arthritis	Knee is most commonly involved (may be any joint distribution)	> 50,000 per mm3	Positive	No crystals	Joint effusion; radiography results otherwise normal early in the disease
NOTE: This table applies to immunocompetent patients. WBC = white blood cell. *-The synovial fluid WBC count should not be used alone to exclude infection. †-Septic arthritis may coexist with crystalline arthritis.

Table 3 presents data for the accuracy of key elements in the diagnosis of gout.16-18 The presence of podagra or tophi strongly supports a gout diagnosis. The presence of monosodium urate crystals in synovial fluid is confirmatory, although a synovial fluid analysis is not always feasible. In the appropriate clinical scenario, a patient with hyperuricemia and classic podagra can be diagnosed and treated empirically. However, if a gout diagnosis is in question, synovial fluid analysis should be attempted. Serum uric acid measurements are not sufficient for confirming or ruling out gout because they may be normal during an acute attack.12,17,19

Table 3. Accuracy of Key Findings in the Diagnosis of Acute Gout
Findings	Sensitivity (%)	Specificity (%)	LR+	LR-
Asymmetric swelling shown on a radiograph16,17	42	90	4.2	0.64
Hyperuricemia	92	91	10.2	0.09
Monosodium urate crystals in synovial fluid16,17	84	100	167.0	0.16
Podagra (first metatarsophalangeal joint involvement)16-18	96	97	32.0	0.04
Tophi confirmed16-18	30	99	30.0	0.71
LR+ = positive likelihood ratio; LR- = negative likelihood ratio. Information from references 16 through 18.

A 24-hour urine collection to detect uric acid excretion is not routinely performed. Collection and dietary restrictions are difficult, and most patients receive allopurinol for chronic urate-lowering therapy regardless of the cause of hyperuricemia.

Treatment

The goals of gout treatment are symptom control for acute attacks, risk factor modification, and pharmacotherapy to prevent recurrence and chronic sequelae. Recommendations from the EULAR guideline for the treatment of gout are summarized below.20

Therapy for acute attacks

The most important symptoms of gout are pain and swelling, which may be accompanied by systemic symptoms such as fever and malaise. Table 4 summarizes pharmacotherapy for acute gout.21

Table 4. Pharmacotherapy for Acute Gout
Therapy/dosing	Cautions	Comments
NSAIDs Indomethacin (Indocin), 50 mg three times daily for four to 10 days Naproxen (Naprosyn), 500 mg twice daily for four to 10 days Sulindac (Clinoril), 200 mg twice daily for four to 10 days	Use with caution in older patients and in patients with renal insufficiency, heart failure, peptic ulcer disease, or liver disease and in those receiving anticoagulation therapy	Any NSAID is effective
Corticosteroids Prednisone, 20 to 40 mg daily for two or three days, then taper over 10 to 14 days Intra-articular methylprednisolone (Depo-Medrol), one 20- to 40-mg dose Intramuscular methylprednisolone, one 80- to 120-mg dose	Avoid in patients with joint sepsis and use cautiously in patients with diabetes	Intra-articular therapy may be the treatment of choice if only one or two accessible joints are involved
Colchicine, 0.6 mg orally two or three times daily Suggested renal dosing (based on creatinine clearance): > 50 mL per minute (0.83 mL per second): 0.6 mg twice daily 35 to 50 mL per minute (0.58 to 0.83 mL per second): 0.6 mg daily 10 to 34 mL per minute (0.17 to 0.57 mL per second): 0.6 mg every two or three days < 10 mL per minute (0.17 mL per second): avoid	Avoid in patients with severe renal or hepatic impairment because it can lead to bone marrow suppression and neuromyopathy	Avoid intravenous use; best if used within the first 24 hours of the attack; the most common adverse effects are nausea, vomiting, and diarrhea; reduce the dosage in older patients
NOTE: NSAIDs or corticosteroids are first-line therapies, depending on comorbidities; colchicine is an effective second-line therapy. NSAID = nonsteroidal anti-inflammatory drug. Information from reference 21.

Nonsteroidal anti-inflammatory drugs22,23 or corticosteroids24 are first-line therapies for acute gout, depending on patient comorbidities. Although colchicine is an effective second-line therapy, in higher doses the risks of adverse effects outweigh the benefits.25 Occasionally, these therapies may need to be supplemented by short-acting opioids such as hydrocodone (Hycodan) and oxycodone (Roxicodone). All medications should be used cautiously in older persons, in whom the threshold of toxicity is lower.

Urate-lowering therapy for chronic gout

About 60 percent of persons who experience a gout attack will have another attack within 12 months.26 Therefore, nonpharmacologic treatment of hyperuricemia should begin with the first gout attack and should initially focus on modifiable risk factors such as diet (i.e., less red meat and seafood, more dairy) and alcohol intake. Substitution of diuretic therapy with other antihypertensives reduces hyperuricemia in many patients.13,14,17

Urate-lowering pharmacotherapy (Table 521,27) using a xanthine oxidase inhibitor or uricosuric agent is recommended for patients with more than two gouty attacks per year, in patients with tophi, and in patients with joint damage seen on a radiograph.20 However, this therapy should not commence until the acute phase of gout has completely resolved because fluctuations in serum uric acid levels will exacerbate the inflammatory process. When initiating urate-lowering therapy, concurrent prophylaxis with low-dose colchicine (0.6 to 1.2 mg daily) for three to six months has been shown to reduce the risk of flare-ups.28 The target serum uric acid level is less than 6 mg per dL (355 µmol per L),29 and doses of the urate-lowering therapy should be titrated upward until this target is reached.

Table 5. Pharmacologic Options for Urate-Lowering Therapy in Patients with Chronic Gout
Therapy/dosing	Cautions	Comments	Monthly cost (generic)*
Allopurinol (Zyloprim), 50 to 300 mg daily (maximal daily dosage: 800 mg) Suggested initial daily renal dosing (based on creatinine clearance): >= 90 mL per minute (1.50 mL per second): 300 mg 60 to 89 mL per minute (1.00 to 1.49 mL per second): 200 mg 30 to 59 mL per minute (0.50 to 0.98 mL per second): 100 mg 10 to 29 mL per minute (0.16 to 0.48 mL per second): 50 to 100 mg < 10 mL per minute (0.16 mL per second): use very cautiously	May precipitate acute gout, hypersensitivity syndrome, or mild rash; avoid using with azathioprine (Imuran); interacts with warfarin (Coumadin)	Do not initiate until four to six weeks after an acute attack; concurrent prophylaxis with colchicine (0.6 mg once or twice daily for six months) may prevent flare-ups; titrate dose until the uric acid level is less than 6 mg per dL (355 µmol per L); continue therapy during acute flare-ups	Thirty 300-mg tablets: $34 (6 to 18)
Probenecid, initially 250 mg twice daily, gradually titrated to 500 mg to 2 g per day	May precipitate acute gout, nephrolithiasis, gastrointestinal upset, or rash; modifies renal handling of other drugs; use cautiously with heparin	Maintain hydration (about 2 L per day); avoid using with low-dose aspirin; ineffective if creatinine clearance is less than 50 mL per minute	Sixty 500-mg tablets†: (59 to 131)
Febuxostat, 80 mg daily	Avoid in patients with hepatic impairment	Investigational medication not yet approved by the U.S. Food and Drug Administration	-
note: Urate-lowering therapy should not commence until the acute phase of gout has completely resolved because fluctuations in serum uric acid will exacerbate the inflammatory process. *-Estimated cost to the pharmacist based on average wholesale prices (rounded to the nearest dollar) in Red Book. Montvale, N.J.: Medical Economics Data, 2007. Cost to the patient will be higher, depending on prescription filling fee. †-No brand available for probenecid. Information from references 21 and 27.

Allopurinol is the first-line urate-lowering therapy. In patients with normal renal function, the initial dosage may be 300 mg daily, although many physicians advocate starting with a lower dosage (e.g., 50 to 100 mg) and then titrating upward by 50 to 100 mg every two to four weeks (maximal daily dosage: 800 mg) until the target serum uric acid level is reached.

In patients with renal insufficiency, the allopurinol dosage should be adjusted based on the estimated creatinine clearance. Approximately 2 to 5 percent of patients taking allopurinol have minor rashes and other adverse effects. Rarely, a severe hypersensitivity syndrome occurs with fever, toxic epidermal necrolysis, hepatitis, and eosinophilia; this syndrome has been shown to have a 20 percent mortality rate.27 Those intolerant of allopurinol may undergo desensitization30 or may take oxypurinol (the active metabolite of allopurinol), if available.

Uricosuric agents are second-line therapy for patients who are intolerant of allopurinol, or they may be used in combination with allopurinol in patients with refractory hyperuricemia. Probenecid is the uricosuric agent most often used in the United States. Uricosuric therapy is contraindicated in patients with a history of nephrolithiasis and is ineffective in those with a creatinine clearance of less than 50 mL per minute (0.83 mL per second). Losartan (Cozaar) and fenofibrate (Tricor) have uricosuric properties and may be useful adjunctive therapies for patients with gout, hypertension, and hyperlipidemia.31

Newer therapeutic options

Febuxostat (investigational drug not yet approved by the U.S. Food and Drug Administration) is a novel nonpurine, xanthine oxidase antagonist that was recently shown to be comparable with allopurinol in lowering uric acid levels.32 Compared with patients taking 300 mg of allopurinol daily, more patients taking 80 mg of febuxostat reached target uric acid levels. However, the allopurinol dosage could not be titrated, and the febuxostat group had a high dropout rate because of adverse effects. At 52 weeks, the groups had similar rates of gout flare-ups. Febuxostat is cleared primarily through the liver and may be useful in those with chronic renal insufficiency who have elevated uric acid levels despite renal dosing of allopurinol.

There has been growing interest in reducing total body urate load using a recombinant uricase enzyme (rasburicase [Elitek]) in patients with advanced tophaceous gout. This therapy has been available for the treatment of tumor lysis syndrome and has been used for refractory tophaceous gout.33 Long-term use is limited because of induction of antigenic responses. A pegylated uricase enzyme has been developed and is currently undergoing trials.34

The author thanks Eswar Krishnan, MD, for his assistance in the preparation of the manuscript.

The Author

Aaron T. Eggebeen, MD, is a senior rheumatology fellow at the University of Pittsburgh (Pa.) Arthritis Institute. He received his medical degree from Michigan State University College of Human Medicine, East Lansing, where he also completed an internal medicine/pediatrics residency.

Address correspondence to Aaron T. Eggebeen, MD, University of Pittsburgh Arthritis Institute, S700 Biomedical Science Tower, 3500 Terrace St., Pittsburgh, PA 15261. Reprints are not available from the author.

Author disclosure: Nothing to disclose.

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