Gout is a metabolic disease that most often affects middle-aged to elderly men and postmenopausal women. It results from an increased body pool of urate with hyperuricemia. It typically is characterized by episodic acute arthritis or chronic arthritis caused by deposition of MSU crystals in joints and connective tissue tophi and the risk for deposition in kidney interstitium or uric acid nephrolithiasis (Chap. 431e).
ACUTE AND CHRONIC ARTHRITIS
Acute arthritis is the most common early clinical manifestation of gout. Usually, only one joint is affected initially, but polyarticular acute gout can occur in subsequent episodes. The metatarsophalangeal joint of the first toe often is involved, but tarsal joints, ankles, and knees also are affected commonly. Especially in elderly patients or in advanced disease, finger joints may be involved. Inflamed Heberden’s or Bouchard’s nodes may be a first manifestation of gouty arthritis. The first episode of acute gouty arthritis frequently begins at night with dramatic joint pain and swelling. Joints rapidly become warm, red, and tender, with a clinical appearance that often mimics that of cellulitis. Early attacks tend to subside spontaneously within 3–10 days, and most patients have intervals of varying length with no residual symptoms until the next episode. Several events may precipitate acute gouty arthritis: dietary excess, trauma, surgery, excessive ethanol ingestion, hypouricemic therapy, and serious medical illnesses such as myocardial infarction and stroke.
After many acute mono- or oligoarticular attacks, a proportion of gouty patients may present with a chronic nonsymmetric synovitis, causing potential confusion with rheumatoid arthritis (Chap. 380). Less commonly, chronic gouty arthritis will be the only manifestation, and, more rarely, the disease will manifest only as periarticular tophaceous deposits in the absence of synovitis. Women represent only 5–20% of all patients with gout. Most women with gouty arthritis are postmenopausal and elderly, have osteoarthritis and arterial hypertension that causes mild renal insufficiency, and usually are receiving diuretics. Premenopausal gout is rare. Kindreds of precocious gout in young females caused by decreased renal urate clearance and renal insufficiency have been described.
Even if the clinical appearance strongly suggests gout, the presumptive diagnosis ideally should be confirmed by needle aspiration of acutely or chronically involved joints or tophaceous deposits. Acute septic arthritis, several of the other crystalline-associated arthropathies, palindromic rheumatism, and psoriatic arthritis may present with similar clinical features. During acute gouty attacks, needle-shaped MSU crystals typically are seen both intracellularly and extracellularly (Fig. 395-1). With compensated polarized light, these crystals are brightly birefringent with negative elongation. Synovial fluid leukocyte counts are elevated from 2000 to 60,000/μL. Effusions appear cloudy due to the increased numbers of leukocytes. Large amounts of crystals occasionally produce a thick pasty or chalky joint fluid. Bacterial infection can coexist with urate crystals in synovial fluid; if there is any suspicion of septic arthritis, joint fluid must be cultured.
Extracellular and intracellular monosodium urate crystals, as seen in a fresh preparation of synovial fluid, illustrate needle- and rod-shaped crystals. These crystals are strongly negative birefringent crystals under compensated polarized light microscopy; 400×.
MSU crystals also can often be demonstrated in the first metatarsophalangeal joint and in knees not acutely involved with gout. Arthrocentesis of these joints is a useful technique to establish the diagnosis of gout between attacks.
Serum uric acid levels can be normal or low at the time of an acute attack, as inflammatory cytokines can be uricosuric and effective initiation of hypouricemic therapy can precipitate attacks. This limits the value of serum uric acid determinations for the diagnosis of gout. Nevertheless, serum urate levels are almost always elevated at some time and are important to use to follow the course of hypouricemic therapy. A 24-h urine collection for uric acid can, in some cases, be useful in assessing the risk of stones, elucidating overproduction or underexcretion of uric acid, and deciding whether it may be appropriate to use a uricosuric therapy (Chap. 431e). Excretion of >800 mg of uric acid per 24 h on a regular diet suggests that causes of overproduction of purine should be considered. Urinalysis, serum creatinine, hemoglobin, white blood cell (WBC) count, liver function tests, and serum lipids should be obtained because of possible pathologic sequelae of gout and other associated diseases requiring treatment and as baselines because of possible adverse effects of gout treatment.
Cystic changes, well-defined erosions with sclerotic margins (often with overhanging bony edges), and soft tissue masses are characteristic radiographic features of advanced chronic tophaceous gout. Ultrasound may aid earlier diagnosis by showing a double contour sign overlying the articular cartilage. Dual-energy computed tomography (CT) can show specific features establishing the presence of urate crystals.
TREATMENT Gout ACUTE GOUTY ARTHRITIS
The mainstay of treatment during an acute attack is the administration of anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or glucocorticoids. NSAIDs are used most often in individuals without complicating comorbid conditions. Both colchicine and NSAIDs may be poorly tolerated and dangerous in the elderly and in the presence of renal insufficiency and gastrointestinal disorders. Ice pack applications and rest of the involved joints can be helpful. Colchicine given orally is a traditional and effective treatment if used early in an attack. Useful regimens are one 0.6-mg tablet given every 8 h with subsequent tapering or 1.2 mg followed by 0.6 mg in 1 h with subsequent day dosing depending on response. This is generally better tolerated than the formerly advised higher dose regimens. The drug must be at least temporarily discontinued promptly at the first sign of loose stools, and symptomatic treatment must be given for the diarrhea. Intravenous colchicine has been taken off the market. NSAIDs given in full anti-inflammatory doses are effective in ∼90% of patients, and the resolution of signs and symptoms usually occurs in 5–8 days. The most effective drugs are any of those with a short half-life and include indomethacin, 25–50 mg tid; naproxen, 500 mg bid; ibuprofen, 800 mg tid; diclofenac, 50 mg tid; and celecoxib 800 mg followed by 400 mg 12 h later, then 400 mg bid.
Glucocorticoids given IM or orally, for example, prednisone, 30–50 mg/d as the initial dose and gradually tapered with the resolution of the attack, can be effective in polyarticular gout. For a single joint or a few involved joints, intraarticular triamcinolone acetonide, 20–40 mg, or methylprednisolone, 25–50 mg, have been effective and well tolerated. Based on recent evidence on the essential role of the inflammasome and interleukin 1β (IL-1β) in acute gout, anakinra has been used, and other inhibitors of IL-1β, including canakinumab and rilonacept, are under investigation. HYPOURICEMIC THERAPY
Ultimate control of gout requires correction of the basic underlying defect: the hyperuricemia. Attempts to normalize serum uric acid to <300–360 μmol/L (5.0–6.0 mg/dL) to prevent recurrent gouty attacks and eliminate tophaceous deposits are critical and entail a commitment to hypouricemic regimens and medications that generally are required for life. Hypouricemic drug therapy should be considered when, as in most patients, the hyperuricemia cannot be corrected by simple means (control of body weight, low-purine diet, increase in liquid intake, limitation of ethanol use, decreased use of fructose-containing foods and beverages, and avoidance of diuretics). The decision to initiate hypouricemic therapy usually is made taking into consideration the number of acute attacks (urate lowering may be cost-effective after two attacks), serum uric acid levels (progression is more rapid in patients with serum uric acid >535 μmol/L [>9.0 mg/dL]), the patient’s willingness to commit to lifelong therapy, or the presence of uric acid stones. Urate-lowering therapy should be initiated in any patient who already has tophi or chronic gouty arthritis. Uricosuric agents such as probenecid can be used in patients with good renal function who underexcrete uric acid, with <600 mg in a 24-h urine sample. Urine volume should be maintained by ingestion of 1500 mL of water every day. Probenecid can be started at a dose of 250 mg twice daily and increased gradually as needed up to 3 g per day to achieve and maintain a serum uric acid level of less than 6 mg/dL. Probenecid is generally not effective in patients with serum creatinine levels >177 μmol/L (2 mg/dL). These patients may require allopurinol or benzbromarone (not available in the United States). Benzbromarone is another uricosuric drug that is more effective in patients with chronic kidney disease. Some agents used to treat common comorbidities, including losartan, fenofibrate, and amlodipine, have some mild uricosuric effects.
The xanthine oxidase inhibitor allopurinol is by far the most commonly used hypouricemic agent and is the best drug to lower serum urate in overproducers, urate stone formers, and patients with renal disease. It can be given in a single morning dose, usually 100 mg initially and increasing up to 800 mg if needed. In patients with chronic renal disease, the initial allopurinol dose should be lower and adjusted depending on the serum creatinine concentration; for example, with a creatinine clearance of 10 mL/min, one generally would use 100 mg every other day. Doses can be increased gradually to reach the target urate level of less than 6 mg/dL. Toxicity of allopurinol has been recognized increasingly in patients who use thiazide diuretics, in patients allergic to penicillin and ampicillin, and in Asians expressing HLA-B*5801. The most serious side effects include life-threatening toxic epidermal necrolysis, systemic vasculitis, bone marrow suppression, granulomatous hepatitis, and renal failure. Patients with mild cutaneous reactions to allopurinol can reconsider the use of a uricosuric agent, undergo an attempt at desensitization to allopurinol, or take febuxostat, a new, chemically unrelated specific xanthine oxidase inhibitor. Febuxostat is approved in the United States at 40 or 80 mg once a day and does not require dose adjustment in mild to moderate renal disease. Pegloticase is a pegylated uricase, now available for patients who do not tolerate or fail full doses of other treatments. It is given intravenously usually at 8 mg every 2 weeks and can dramatically lower serum uric acid in up to 50% of such patients. New uricosurics are also undergoing investigation.
Urate-lowering drugs are generally not initiated during acute attacks but after the patient is stable and low-dose colchicine has been initiated to decrease the risk of the flares that often occur with urate lowering. Colchicine anti-inflammatory prophylaxis in doses of 0.6 mg one to two times daily should be given along with the hypouricemic therapy until the patient is normouricemic and without gouty attacks for 6 months or as long as tophi are present. Colchicine should not be used in dialysis patients and is given in lower doses in patients with renal disease or with P glycoprotein or CYP3A4 inhibitors such as clarithromycin that can increase toxicity of colchicine.