Crystal Arthropathies

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Gout and pseudogout are conditions caused by deposition of crystals of urate and calcium pyrophosphate dihydrate, respectively, with a resulting inflammatory response. These conditions can be distinguished from each other and from other causes of an acutely swollen joint or joints by synovial fluid examination, looking for crystals using polarized light microscopy.

• Hyperuricemia is present (usually >8 mg/dL) in patients with gout.

• Gout affects more men than women.

• Negative birefringent crystals are seen on fluid analysis in gout.

Gout primarily affects middle-aged men (40-60 years) and postmenopausal women. It typically manifests as an acutely painful monoarticular arthritis, possibly becoming chronic after years of progressively more severe and frequent episodes, interspersed with variable symptom-free periods. Hyperuricemia is a marker for gout, but each can exist without the other. Asymptomatic hyperuricemia is not a disease. The risk of gout, however, is proportional to the degree and duration of hyperuricemia. Multiple genetic and environmental factors affect uric acid concentration. Uric acid is derived from ingestion of a diet rich in purines (e.g., typical American diet), as well as from endogenous production of purines. Inborn errors of metabolism, either reduced excretion (90% of patients) or increased production (10%) of uric acid, cause primary hyperuricemia. Secondary hyperuri-cemia results from diseases or drug therapies that raise uric acid levels.

In addition to attempting to prevent acute flares, the family physician's goal in treating patients predisposed to gout is to minimize the risk of developing other sequelae. These include interstitial nephropathy with renal function impairment; accumulation of urate crystal deposits in joints, soft tissue, cartilage, and bone, called tophi; and uric acid calculi in the genitourinary (GU) tract.

Clinical Presentation

The first MTP joint (great toe) is involved in 50% of initial acute gouty attacks (podagra) and is eventually affected in 75% to 90% of gout patients. This joint sustains more microtrauma and is relatively cool compared with the rest of the body. The heel, ankle, knee, midtarsal joints, and olecranon bursa can all be initially involved but are so less frequently than the first MTP joint. Gout severity ranges from vague aches and pains to severe pain, swelling, redness, and exquisite tenderness. Acute attacks resolve within several days to weeks, even in untreated gout.

In contrast to the typical middle-aged male presentation, gout in women and in older adult patients tends to be poly-articular. Because gout in these patient subgroups tends to involve more than one joint, it can often be misdiagnosed as RA (tophi are mistaken for rheumatoid nodules) or septic joint cellulitis, especially if low-grade fever, leukocytosis, redness, or desquamation is present. Synovial fluid analysis is necessary for definitive diagnosis.

Synovial Fluid Examination

A presumptive diagnosis of gout can be made by clinical signs and symptoms, a negative joint culture, response to NSAIDs or colchicine, and hyperuricemia. However, definitive diagnosis can be made only by finding needle-shaped, negatively birefringent urate crystals on synovial fluid examination or in tophi.

Clinical Stages of Primary Gout

Hyperuricemia is defined as two standard deviations (2 SD) above the individual laboratory's mean based on gender, usually 8 mg/dL in men and 7 mg/dL in women. Hyperuricemia is present in 5% of men, only 5% to 10% of whom develop acute gout. It normally takes at least 20 years of hyperuricemia before a patient has a first episode of gouty arthritis. Lowering the serum uric acid level does not decrease the risk of gouty nephropathy; chronic renal disease is almost always caused by

Gout

Key Points

Figure 32-11 Advanced gout in the feet. A, Calcified tophi (arrow) of gout seen on x-ray. B, Osteophyte formation in knee (arrow). (From Visual Aids, Subcommittee of the Professional Education Committee of the Arthritis Foundation. Clinical Slide Collection on the Rheumatic Diseases. New York, Arthritis Foundation, 1972, p 82.)

Figure 32-11 Advanced gout in the feet. A, Calcified tophi (arrow) of gout seen on x-ray. B, Osteophyte formation in knee (arrow). (From Visual Aids, Subcommittee of the Professional Education Committee of the Arthritis Foundation. Clinical Slide Collection on the Rheumatic Diseases. New York, Arthritis Foundation, 1972, p 82.)

concurrent diseases such as diabetes or hypertension. Because of expense and potential drug toxicity, treatment of asymptomatic hyperuricemia is therefore generally not recommended.

The two most important factors in the development of acute gouty arthritis are obesity and alcohol (Choi et al., 2005). Ethanol metabolism blocks renal excretion of uric acid, leading to gouty attacks. Studies have shown a 2.5-fold increase in the risk of gout in men who drink 2 or more beers per day. This risk was similar but slightly lower in men who drank the same amount of distilled alcohols. In contrast, two 4-ounce glasses of wine or more per day was not associated with an increased risk of gout (Choi at al., 2004). Other factors include rapid decrease or increase in serum urate level (thus a possible attack at start of allopurinol treatment), emotional stress, infection, and surgery. Dietary excesses of purine-rich foods (e.g., sweetbreads, sardines, anchovies, kidney, liver) have traditionally been mentioned but are in reality rarely responsible for acute gouty attacks. Diuretics, both hydrochlorothiazide and loop, have been associated with increased serum uric acid. Risks, benefits, and cost must be evaluated before deciding to change or stop these medications for hypertension.

After an initial gouty attack, more than half of patients will have a recurrent attack. The timing is highly variable, however, and the recurrent attack can be weeks or years later. As time passes, gouty attacks tend to become more frequent, more severe, and less responsive to therapy and to involve more joints. Between acute attacks, urate crystals can still be aspirated from asymptomatic joints, demonstrating that this so-called intercritical or interval gout represents a progression of disease. Chronic tophaceous gout occurs at least 10 years into the disease and is now seen infrequently because of more aggressive treatment of gout and hyperuricemia. Tophi can occur anywhere but tend to occur in the helix of the ear, on the proximal ulnar surface of the forearm, on the olecra-non, on the Achilles tendon, on the prepatellar bursa, or near active joints. Tophi are not seen on plain radiographs unless they are calcified. The classic radiographic finding of chronic gout is sharply marginated erosions proximal to the joint space, with an overlying rim of cortical bone (Fig. 32-11).

Secondary gout is caused by drugs or disease processes affecting uric acid metabolism or excretion. Myeloprolif-erative and lymphoproliferative diseases, hemolytic anemia, multiple myeloma, and other malignancies result in overproduction. Renal disease, diuretics, salicylates, alcohol, nicotinic acid, and chronic lead intoxication (saturnine gout) all cause underexcretion. Chemotherapy for hematologic or myeloproliferative disorders can result in gouty nephropathy unless adequate hydration and possibly allopurinol prophylaxis are initiated before therapy.

Treatment of Gouty Arthritis

The NSAIDs are generally used first because of their efficacy and relative lack of toxicity. Indomethacin (Indocin) has been used for years for gouty arthritis attacks, but any NSAID can probably be used with similar efficacy, as long as an initial maximal dose is given. After 2 days of therapy at the maximal dose, the NSAID can be tapered over the next several weeks.

Colchicine decreases inflammation associated with lactic acid production and phagocytosis of urate; it terminates most gouty attacks within 6 to 12 hours but is limited by GI side effects (nausea, vomiting, abdominal cramps, diarrhea). Two 0.5- or 0.6-mg tablets are taken initially, then 1 tablet every hour, until clinical response has been achieved, GI side effects cause discontinuation, or a total of 6 mg has been given (Cox, 2004). Colchicine at 0.5 to 1 mg every 6 hours intravenously, up to 4 mg total, can also be given for a single attack, but the parenteral route is associated with increased bone marrow suppression, renal and hepatic toxicity, and myopathy. No additional colchicine should be given for at least 1 week if the patient is given the full 4-mg total dose.

When NSAIDs and colchicine are ineffective or contrain-dicated, corticosteroids might be used. Treatment options include oral corticosteroids using prednisone, 0.5 mg/kg, followed by tapering the dose by 5 mg/day. An intra-articular injection can be given using triamcinolone hexacetonide (Aristospan), triamcinolone acetonide, or methylpredniso-lone (Medrol); typical doses are 10 to 40 mg in large joints and 5 to 20 mg in small joints. Intra-articular injection is preferred for monoarticular episodes. Finally, adrenocortico-tropic hormone (ACTH), 40 to 80 mg intravenously or intramuscularly every 8 to 12 hours, has been successful when all other therapies fail, but it is quite expensive.

Prophylaxis of Recurrent Gout

Asymptomatic hyperuricemia need not be treated, but after one episode of acute gouty arthritis or acute nephrolithiasis, patients should be offered the option of prophylaxis. Some choose not to take a daily drug, particularly if their gouty attacks are not severe or are infrequent. For patients with recurrent gouty attacks, renal damage, nephrolithiasis, or uric acid levels higher than 12 mg/dL, or those undergoing cancer chemotherapy, uric acid-lowering therapy should be initiated. Prophylaxis may be discontinued when uric acid levels are brought down to normal levels for 2 months. Patients should be instructed to avoid alcohol, aspirin, diuretics, prolonged fasting, and high-purine foods. Several days before initiating uric acid-lowering therapy, it is prudent to start colchicine, 0.5 mg twice daily, to avoid precipitating an acute attack. This therapy can continue for up to 6 months after the desired uric acid levels have been obtained.

Allopurinol (Zyloprim) is a xanthine oxidase inhibitor that decreases uric acid production but also produces a more soluble metabolite. Allopurinol is therefore effective regardless of the cause of the hyperuricemia. Allopurinol therapy should never be initiated until an acute attack has subsided. Allopurinol is started at 100 mg/day with food, then increased at weekly intervals by 100 mg/day until the serum uric acid level is lower than 6 mg/dL. The usual effective dose is 200 to 300 mg/day, although some patients require up to 600 mg/day (Perez-Ruiz et al., 1998). Patients should ensure adequate fluid intake to produce more than 2 L of urine output daily. The dose needs to be adjusted for decreased creati-nine clearance. If an acute attack occurs when the patient is taking allopurinol, the dose should be maintained and the attack treated as usual (NSAIDs, colchicine, corticosteroids). Allopurinol can cause rash, liver transaminase level elevations, and renal toxicity if used with thiazide diuretics. It might also potentiate the effect of anticoagulants and cause a rash if used with amoxicillin.

The uricosuric drugs probenecid and sulfinpyrazone (Anturane) block renal tubular reabsorption of uric acid. Probenecid is started at 250 mg twice daily for 1 week, then increased to 500 mg twice daily, and then increased by 500 mg/week, up to 3 g/day, until the urate level is normal. Sulfinpyrazone is started at 100 mg twice daily, increasing to 400 mg twice daily. These drugs should also never be started during an acute attack but should be maintained if the patient is already taking them. Urate stone formation risk can be minimized by a high fluid intake and alkaliniza-tion of the urine. A 24-hour urine sample for determination of creatinine clearance and uric acid level should be obtained before starting these drugs, because GFR must be higher than 50 mL/min and uric acid excretion less than 800 mg/24 hr.

KEY TREATMENT

Patients with gout who are overweight should be instructed on weight loss (Choi et al., 2005) (SOR: B).

Patients with gout should limit intake of beer and distilled alcohol (Choi et al., 2005) (SOR: B).

Colchicine is an effective treatment for acute gout but should be used as second-line therapy when NSAIDs or corticosteroids are ineffective (SOR: C).

Allopurinol should be started for prophylaxis in patients with frequent severe attacks, nephrolithiasis, or gouty tophi (Perez-Ruiz et al., 1998) (SOR: B).

Antihyperuricemic therapy should be titrated to a dose that results in a serum urate level less than 6 mg/dL (slowly, <0.6 mg/dL/mo) (SOR: C).

Before starting allopurinol, colchicine prophylaxis can be used for up to 6 months after desired uric acid level is reached, to prevent acute attacks (SOR: C).

Pseudogout Key Points

• Knees are the most common source of pain in pseudogout (CPDD).

• Genetic factors are present in calcium pyrophosphate deposition disease.

• Positive birefringent crystals are seen on fluid analysis in CPPD disease.

• Radiographic appearance of CPDD is punctate or linear densities in cartilage.

Cppd Birefringence

Figure 32-12 Chondrocalcinosis in calcium pyrophosphate deposition disease. A, Anteroposterior radiograph of knee. B, Lateral radiograph of knee. C, Anteroposterior radiograph of wrist. D, Radiograph of pelvis. (From Reginato AJ, Reginato AM. Diseases associated with deposition of calcium pyrophosphate or hydroxyapatite. in Kelley WN Harris ED, Ruddy S, et al [eds]. Textbook of Rheumatology, 5th ed, vol 2. Philadelphia, Saunders, 1997, pp 1352-1367.)

Figure 32-12 Chondrocalcinosis in calcium pyrophosphate deposition disease. A, Anteroposterior radiograph of knee. B, Lateral radiograph of knee. C, Anteroposterior radiograph of wrist. D, Radiograph of pelvis. (From Reginato AJ, Reginato AM. Diseases associated with deposition of calcium pyrophosphate or hydroxyapatite. in Kelley WN Harris ED, Ruddy S, et al [eds]. Textbook of Rheumatology, 5th ed, vol 2. Philadelphia, Saunders, 1997, pp 1352-1367.)

Calcium pyrophosphate deposition disease (CPDD) is known as pseudogout because of the acute goutlike attacks that CPPD crystals can cause. Chondrocalcinosis refers to radiographically detectable densities in cartilage and joint inflammation caused by these calcium-containing crystals. Calcium pyrophosphate (CP) crystals can be deposited not only on articular cartilage but also in ligaments, tendons, soft tissues, and synovium.

This arthritis is caused by genetic factors (autosomal dominant inheritance pattern) secondary to trauma and various metabolic diseases or is sporadic or idiopathic. CPDD is most often associated with aging, and about 4% of the adult U.S. population has articular CP crystal deposits at death (Agudelo and Wise, 2000). CPPD disease can be associated with hyperparathyroidism, hypothyroidism, hypo-magnesemia, hypophosphatemia, hemochromatosis, and amyloidosis. Therefore, newly diagnosed CPDD should be followed up with serum measurements of calcium, magnesium, phosphorus, thyroid-stimulating hormone (TSH), ferritin, transferrin, serum iron, and alkaline phosphatase (ALP) levels.

The most common site is the knee, although the first MTP joint is also often affected, resulting in difficulty differentiating CPDD from gout. Any joint can be affected, however. Synovial fluid examination for rhomboid or rod-shaped, weakly positively birefringent crystals is diagnostic. Analysis needs to be done promptly after aspiration because identification of crystal diminishes over time. The crystals are also smaller and more difficult to detect, so careful preparation of the slide to avoid false-positive results must be taken. Pseudogout can also cause pseudo-RA. CPDD can be mis-diagnosed as RA because of its often multiple joint involvement with symmetric distribution, morning stiffness, and elevated ESR, and because 10% of CPDD patients have positive RF tests. CPDD might also be confused with OA because of its knee and hip involvement, but it also often affects the wrists, MCP joints, elbows, and shoulders. An acute attack of CPDD can cause low-grade fever, leukocytosis (12,000 15,000/mm3), and elevated ESR. The typical radiographic appearance of CPDD is punctate or linear densities in cartilage (chondrocalcinosis) (Fig. 32-12). Definitive diagnosis relies on either the typical radiographic signs or synovial fluid confirmation.

Treatment of acute pseudogout consists of removal of the crystals through joint aspiration, use of NSAIDs or colchi-cine during the acute inflammatory period, intra-articular joint injection with a glucocorticoid when possible, and a limited period of joint immobilization. No solid data support removal of crystals and prevention of crystal deposition, which are done only for diagnostic purposes and pain relief. If only one or two joints are involved, intra-articular injections may give the most symptomatic relief; if more joints are involved, a NSAID or colchicine is a better option. Because of severe pain associated with acute events, limited weight bearing may be needed for a short period while symptoms improve.

For patients with recurrent episodes of pseudogout, prophylaxis with colchicine, 0.6 mg twice daily, should be considered.

In 10 patients with recurrent attacks, colchicine was associated with a marked decrease in the number of episodes (10) in 1 year compared with the previous year (32 episodes) (Alvarel-los and Spilberg, 1986).

KEY TREATMENT

Aspiration of knee joint for symptomatic relief and diagnosis of pseudogout (CPDD) (SOR: C).

The patient with CPDD receives intra-articular injection of glucocorticoid if septic joint has been ruled out and less than two joints are involved (SOR: C).

A NSAID or colchicine is prescribed for acute pain of pseudogout (SOR: C).

For recurrent pseudogout attacks, colchicine can be used for prophylaxis to decrease number of episodes (Alvarellos and Spilberg, 1986) (SOR: B).

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