Clinical manifestations and treatment of gout

HONORABLE MENTION

CLINICAL MANIFESTATIONS AND TREATMENT OF GOUT Jason D. Wright, MD, and Anil B. Pinto, MD

Gout results from the deposition of urate crystals in a variety of soft tissues throughout the body. Currently over half a million American women suffer from the disorder. Disease manifestations include painful attacks of acute arthritis as well as chronic arthritis with deposition of uric acid crystals known as tophi. The disorder is often overlooked and misdiagnosed as another form of arthritis. Multiple drugs are now available to treat the acute pain of gouty arthritis, as well as to help reduce the long-term complications of gout and chronic hyperuricemia. (Prim Care Update Ob/Gyns 2003;10:19 –23. © 2003 Elsevier Science Inc. All rights reserved.)

Gout results from the deposition of monosodium urate crystals in tissues and joints. Recent estimates suggest that gout affects 8.4 per 1,000 persons.1 Gout more commonly occurs in males, and is present in 1.56 million men in the United States. Five hundred fifty thousand American women suffer from gout.2 The incidence of gout rises dramatically with age. Only 17% of women with gout are premenopausal.3 It is hypothesized that estrogen is protective against urate deposition, by promoting renal excretion of uric acid. Physiologic elevations of urate thus predispose postmenopausal females to the development of gout.4

From the Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.

Volume 10, Number 1, 2003

Pathogenesis

Clinical Manifestations

The clinical manifestations of gout result from the formation and deposition of uric acid crystals. Uric acid is a normal byproduct of purine metabolism that is filtered and excreted by the kidney. Gout results from either the overproduction or the underexcretion of uric acid. Elevated serum urate levels lead to the deposition of monosodium urate crystals in a variety of tissues. Crystalline monosodium urate deposits are commonly found in joints, cartilage, tendons, bones and soft tissues. The crystals are phagocytized by polymorphonuclear neutrophils that initiate chemotaxis and an inflammatory response. The inflammatory response is manifested as the clinical signs and symptoms of gout.4,5

The classic manifestation of gout is recurrent episodes of acute arthritis. Episodes of acute gouty arthritis are interspersed with asymptomatic periods. Chronic tophaceous gout results after several years of intermittent attacks of acute gout.

Classification Gout is classified as either primary or secondary. Primary gout results from abnormal uric acid metabolism without any identifiable acquired disorder. Secondary gout is caused by an acquired disorder. Both primary and secondary gout may result from uric acid overproduction or uric acid underexcretion. Ninety percent of patients have underexcretion of urate; only 10% of cases are attributable to increased uric acid production (Table 1). Hypertension and renal insufficiency are common comorbidities in postmenopausal females who develop gout. Additionally, cyclosporine and diuretics are common predisposing factors in women.6

© 2003 Elsevier Science Inc., all rights reserved. 1068-607X/03/$30.00

●

ACUTE GOUT Acute gouty arthritis is the hallmark of gout. Joint inflammation results in acute pain and swelling. The initial attack often occurs at night and may be excruciatingly painful. The metatarsophalangeal (MTP) joint of the first toe is the most commonly involved joint. Three quarters of patients have inflammation of the great toe at some time during the course of their disease.4 Other less commonly involved joints include the ankle, knee, wrist, fingers, and elbows. The arthritis is most commonly monoarticular; however, oligoarticular and polyarticular arthritis also occur. Recurrent attacks are more often polyarticular. Triggers for acute gouty arthritis include acute illnesses or infections, alcohol and drug use, surgical stress, and recent administration of uratelowering medications.5 Physical findings during an acute attack include joint pain, erythema, and swelling. Systemic signs of inflammation such as fever may also occur. Acute attacks of gout are selflimited and resolve in 3 to 10 days.3 Recurrent attacks occur in 75% of patients and usually develop within 2 years.5 PII S1068-607X(02)00140-3

19

WRIGHT AND PINTO Table 1. Classification of Gout Uric Acid Overproduction Primary Secondary

Uric Acid Underexcretion Primary Secondary

Diagnosis Idiopathic Purine metabolism enzyme defects Myeloproliferative disorders Lymphoproliferative disorders Psoriasis Hemolytic anemia Obesity Glycogen storage diseases Exercise Ethanol abuse Excessive dietary intake Idiopathic Renal insufficiency Lead nephropathy Hypertension Hyperparathyroidism Drugs (diuretics, cyclosporine, ethambutol, pyrazinamide, salicylates) Sarcoidosis Hypothyroidism Fasting

CHRONIC GOUT

GOUT DURING PREGNANCY

Chronic gout occurs after several years of acute gouty arthritis. Usually, multiple attacks of acute arthritis precede the development of chronic gout. Tophi, deposits of monosodium urate in soft tissues, are commonly found in chronic gout. Tophi generally are not identified until 10 years after the initial attack of acute gout. Tophi may be deposited in synovial tissue, bone, tendons, extensor surfaces, joints, finger pads, and the helix of the ear.4 Previously damaged joints are at increased risk for deposition of gouty tophi in women.7 Rarely, tophi are deposited in vascular walls or cardiac valves. Care must be taken to distinguish the tophi of gout from rheumatoid nodules of rheumatoid arthritis. The most common extra-articular organ to be affected by gout is the kidney. Urate nephropathy results from interstitial nephritis secondary to chronic hyperuricemia. Uric acid nephrolithiasis, an uncommon cause of renal stone disease, may occur in patients with longstanding gout.5

Gout is uncommon in young women, thus rare in pregnancy. Kelsall and O’Hanlon8 reviewed four cases of gout reported in pregnancy, and added one patient of their own. Overall, three patients had acute episodes of gouty arthritis during pregnancy. The effect of gout and hyperuricemia on pregnancy remain unknown. Those authors did observe that postpartum exacerbations are common, occurring in 80% of the patients described.8

20

Differential Diagnosis The differential diagnosis of gout includes other crystallineassociated arthropathies: calcium pyrophosphate dihydrate-induced arthritis, calcium hydroxyapatite deposition disease, and calcium oxalate deposition disease. Psoriasis and septic arthritis must also be considered in the differential diagnosis of acute gouty arthritis. Chronic gout may resemble other athropathies including rheumatoid arthritis and osteoarthritis.

A presumptive diagnosis of gout is often made based on the classic presentation of the disease. A definitive diagnosis of gout relies on the demonstration of monosodium urate crystals in synovial fluid or tophi.

SYNOVIAL FLUID ANALYSIS Synovial fluid aspiration can be performed during an acute episode of gout or during an asymptomatic period. Monosodium urate crystals appear as rod-shaped structures on microscopy. Examination with polarized light reveals characteristic birefringent rods. A mild leukocytosis is usually present in synovial fluid. If septic arthritis is considered in the differential diagnosis, the joint fluid should be sent for culture.

LABORATORY Serum uric acid levels should be obtained during the evaluation of a patient with gout. A normal level does not exclude the diagnosis, and most patients will have an elevated uric acid level at some point during the course of their disease. Serial uric acid measurements are valuable in following the course of treatment. A 24-hour urine collection may be performed to assess uric acid excretion. A value of more than 800 mg of urate per 24 hours suggests overproduction of uric acid.3

IMAGING STUDIES During an acute attack of gout, radiographs are often nonspecific, but may reveal soft tissue swelling. Joints affected by chronic gout often display bony erosions, cystic changes, and overhanging bone edges. Prim Care Update Ob/Gyns

GOUT Table 2. Pharmacotherapy of Gout and Hyperuricemia ACUTE GOUTY ARTHRITIS Nonsteroidal Antiinflammatory Drugs Ibuprofen (B)* Indomethacin (B)* Diclofenac (B)* Colchicine Oral (C) Parenteral (D)

Prophylaxis Corticosteroids Intraarticular Methylprednisolone (C) Oral Prednisone (C) Triamcinolone acetonide (C) Parenteral Methylprednisolone (C) CHRONIC HYPERURICEMIA Uricosuric Agents Probenecid (B) Xanthine Oxidase Inhibitors Allopurinol (C)

800 mg tid 25–50 mg tid 50 mg tid

Dyspepsia Peptic ulcer disease Caution with renal insufficiency

1 mg initial dose then 0.5 mg q2 (8 mg max) 2 mg initial dose then 1 mg q6 ⫻ 2

Diarrhea Abdominal discomfort Renal toxicity Hepatotoxicity Bone marrow suppression CNS toxicity Dose reduction if hepatic or renal disease Use lowest effective dose

0.5 mg bid 5–10 mg ⫻ 1 (small joint) 20–60 mg (large joint) 30–50 mg qd taper 7–10 d 60 mg qd 50–150 mg IV taper 5 d 250 mg bid increase up to 2 g

Initiate slowly

300 mg qd

Renal toxicity Rash Bone marrow suppression Dose reduction if renal insufficiency

Little effect if GFR ⬍60 mL/min

Parentheses indicate FDA safety classification in pregnancy. * Agents classified as Category B during first and second trimester and as Category D during the third trimester.

Management A variety of drug treatments are now available for the management of gout (Table 2). The goals of pharmacotherapy include the treatment of pain during acute attacks as well as long-term control of hyperuricemia.

ACUTE GOUT NONSTEROIDAL ANTI-INFLAMMATORY D RUGS . Nonsteroidal antiinflammatory drugs (NSAIDS) are now considered first-line therapy for the treatment of pain associated with acute gouty arthritis. NSAIDS provide effective pain relief in 90% of patients, and result in resolution of symptoms in 5 to 7 days.3 The drugs are most effective when begun Volume 10, Number 1, 2003

early in the course of an attack. Ibuprofen, indomethacin, and diclofenac are the most commonly employed agents. NSAIDS must be used with caution in patients with renal insufficiency. Common side effects include gastrointestinal upset and peptic ulcers. NSAIDS, especially indomethacin, are associated with closure of the ductus arteriosus and must be used with caution, particularly in the third trimester. Other reported side effects of indomethacin include oligohydramnios and intraventricular hemorrhage. Selective cyclooxygenase-2 inhibitors are likely as efficacious as nonselective NSAIDS, with fewer gastrointestinal side effects.

C OLCHICINE . Colchicine inhibits microtubule assembly, thereby inhibiting neutrophil mediated phagocytosis. Colchicine provides effective pain relief in 85% of patients with acute gouty arthritis.3 Colchicine may be given intravenously or orally. Oral colchicine is administered as a 1-mg initial dose, followed by 0.5 mg every 2 hours until symptomatic relief or the development of diarrhea or abdominal pain. The maximum oral dose is 8 mg. Most patients will experience pain relief in the first 18 hours.9 Parenteral colchicine is useful in pre- and postoperative patients, as well as in patients who are unable to tolerate oral colchicines because of gastrointestinal side effects. The 21

WRIGHT AND PINTO

usual initial dose is 2 mg, followed by 1 mg every 6 hours, with a maximum total dose of 4 mg. Side effects with parenteral colchicine include renal, hepatic, and central nervous system toxicity as well as bone marrow suppression and myopathy.9 Severe toxicity may result if the 4-mg total dose of colchicine is exceeded. Dose reduction is mandatory in patients with underlying liver or kidney disease. Reproductive toxicities including oligospermia, azoospermia, and disorders of motility have been reported in men.10 Studies have shown that colchicine is teratogenic in animals, but a paucity of human data exists.11 CORTICOSTEROIDS. Oral, parenteral, and intraarticular glucocorticoids are a third option for patients with acute gouty arthritis. Intraarticular steroids are particularly effective if one or two large joints are involved. Intraarticular steroid administration may allow dose reduction for NSAIDS and colchicine for elderly patients with medical comorbidities. Oral and parenteral corticosteroids are most commonly used for refractory gout, or if NSAIDS and colchicine are contraindicated. Common regimens include oral prednisone and triamcinolone acetonide or parenteral methylprednisolone.9

PROPHYLAXIS Prophylactic therapy may be considered in patients with multiple recurrent episodes of gout. Commonly used medications include colchicine and NSAIDS. The lowest effective dose should be prescribed to minimize toxicity.4

CHRONIC HYPERURICEMIA Treatment of hyperuricemia often requires a long-term commitment on the part of the patient. Lifestyle factors such as obesity, high alcohol intake, and a diet high in purines all contribute to hyperuricemia. Thus 22

before initiating hypouricemic drug therapy, lifestyle modifications should be instituted. Two classes of drugs are used for the chronic management of gout and hyperuricemia. Uricosuric agents increase urinary excretion of urate and are best prescribed for patients with underexcretion of urate (uric acid ⬍600 mg in 24-hour urine collection).3,9 Xanthine oxidase inhibitors act by decreasing uric acid production. Urate-lowering therapy should not be initiated while a patient is suffering from an acute episode of gouty arthritis. U RICOSURIC A GENTS . Uricosuric drugs are best used by patients who underexcrete uric acid. Uricosuric agents increase renal excretion of urate and occasionally lead to deposition of urate in the renal collecting system. To prevent renal complications, drug therapy should be started at a low dose and increased gradually. Adequate fluid intake with good urine output also decrease potential nephrotoxicity.9 Probenecid is the most frequently used agent. The starting dose is 250 mg bid. The dose is increased incrementally up to 2 g. The goal of therapy is to maintain the serum uric acid concentration at ⬍5 mg/ dl.3 Probenecid is ineffective for patients with a creatinine clearance of ⬍50 – 60 ml/min. Probenecid is the preferred agent for the treatment of hyperuricemia in elderly patients who are being treated with thiazide diuretics. Probenecid has not been associated with any congenital anomalies to date.11 XANTHINE OXIDASE INHIBITORS. Xanthine oxidase catalyzes urate production. Thus, xanthine oxidase inhibitors are best employed in patients with overproduction of uric acid. Patients with renal insufficiency, secondary gout, and urolithiasis are also best treated with xanthine oxidase inhibitors. The most common drug employed is allopurinol. The usual dose is 300

mg qd, but dose reduction is required for patients with reduced renal function. Side effects include rash, renal failure, bone marrow suppression, and liver dysfunction. No adverse fetal outcomes have been reported in humans.

Conclusion Gout is an often underdiagnosed disorder that continues to affect females, particularly postmenopausal patients. The efficient evaluation and diagnosis of gout is imperative to prevent long-term complications of hyperuricemia such as chronic gouty arthritis and nephropathy. Effective pharmacotherapy is now available for gout. Acute gouty arthritis is best treated with NSAIDS, and chronic hyperuricemia may be treated with probenecid or allopurinol. References 1. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41: 778 –9. 2. Agudelo CA, Wise C. Gout: diagnosis, pathogenesis, and clinical manifestations. Curr Opin Rheum 2001; 13:234 –9. 3. Wortman RL. Gout and other disorders of purine metabolism. In: Fauci AS, Braunwald E, Isselbacher KJ, et al. Harrison’s principles of internal medicine. 14th ed. New York: McGraw Hill, 1998:2158 – 66. 4. Terkeltaub R, Tate GA, Schumacher HR, et al. Gout. In: Schumacher HR, ed. Primer on rheumatic disease. 10th ed. Atlanta, GA: Arthritis Foundation, 1993:209 –18. 5. Townes AS. Crystal-induced arthritis. In: Barker LR, Burton JR, Zieve PD, eds. Principels of ambulatory medicine. 5th ed. Baltimore, MD: Williams and Wilkins, 1999:974 – 88. 6. Park YB, Park YS, Song J, et al. Clinical manifestations of Korean female gouty patients. Clin Rheumatol 2000;19:142–6. 7. Lally EV, Ho G, Kaplan SR. The clinical spectrum of gouty arthritis in women. Arch Int Med 1986;146: 2221–5. Prim Care Update Ob/Gyns

GOUT 8. Kelsall JT, O’Hanlon DP. Gout during pregnancy. J Rheum 1994;21:1365–6. 9. Emmerson BT. Drug therapy: the management of gout. N Engl J Med 1996;334:445–51. 10. Haimov-Kochman R, Ben-Chetrit E. The effect of colchicines treatment

Volume 10, Number 1, 2003

on sperm production and function: a review. Hum Reprod 1998;13: 360 –2. 11. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 5th ed. Baltimore, MD: Williams and Wilkins, 1998.

Address correspondence and reprint requests to Jason D. Wright, MD, Department of Obstetrics and Gynecology, Washington University School of Medicine, 4911 Barnes Hospital Plaza, Box 8064, St. Louis, MO 63110-1094.

23