Patricia A. Thomas
Gout was the first form of arthritis that was recognized to be caused by the deposition of (urate) crystals in the joints and periarticular tissues. It now is known that other crystalline substances—most commonly calcium pyrophosphate dihydrate (CPPD), hydroxyapatite, and basic calcium phosphates—also are implicated in the pathogenesis of certain kinds of arthritic disease. Although disorders associated with these various crystals differ in cause and specific characteristics, they have in common the deposition of crystals in and around joints, the propensity to episodes of acute inflammatory arthritis, and sometimes the development of a chronic destructive arthropathy. Therefore, it is appropriate to consider these varied clinical disorders together under the unifying concept of crystal-induced arthritis.
Mechanisms of Crystal-Induced Arthritis
When crystals such as monosodium urate and CPPD are experimentally injected into joints, they produce an acute inflammatory response. The mechanisms involved in this response are complex but perhaps are as well studied as any of the stimuli that produce arthritis (1). By virtue of the nature of their electrostatic surface characteristics and mechanical properties, crystals bind to various plasma proteins as well as to cell surface receptors. Binding of crystals to macrophagelike synovial cells results in cellular activation with release of cytokines, which are immunoregulatory proteins that play an important role in the ensuing inflammatory response. Neutrophils are the major inflammatory cells in the synovial fluid during an acute episode of gout or pseudogout. Neutrophils phagocytose crystals and release factors that further intensify the inflammatory response (1). The mechanisms of crystal-induced stimulation and release of inflammatory mediators for the most part are similar with both monosodium urate (in gout) and with CPPD crystals (in pseudogout). Dissemination of cytokines into the circulation probably is responsible for the systemic effects of fever, leukocytosis, and acute phase reactants sometimes observed in acute crystal-induced arthritis (1).
Crystals may be identified in synovial fluid and synovial membrane in the absence of an acute inflammatory response and can be helpful in the diagnosis between acute attacks (2). Usually there is a paucity of neutrophils in this circumstance, with low levels of phagocytosis, mostly by mononuclear cells. The events that then trigger acute inflammation are not entirely clear. Crystals may precipitate from the fluid phase as a result of a change in temperature or pH, or they may be released from soft-tissue deposits. The sudden increase of crystals within the joint space may initiate the cycle of increased phagocytosis and inflammation. In patients with gout, there is an association of acute attacks with rapid changes in serum urate concentration, as may occur with initiation of drugs that lower serum urate, or with alcohol ingestion, dietary indiscretion, or rapid weight loss. In CPPD arthritis, a rapid fall in serum calcium (3) and/or magnesium (4) may precipitate an acute arthritis. The frequent development of acute gout or pseudogout after acute infection, trauma, surgery, or myocardial infarction suggests that the arrival of systemically generated cytokines may alter the balance within the joint toward a proinflammatory response (5). In CPPD deposition disease, release of crystals from tissue deposits in cartilage or soft tissues may result from trauma.
The invariable association between phagocytosis of crystals and the acute inflammatory response is important clinically, because demonstration of crystals within leukocytes from synovial fluid (Fig. 76.1A) is a convenient
P.1239
method for making a definitive diagnosis in patients with acute inflammatory crystal-induced arthritis.
|
FIGURE 76.1. A: Urate crystals in synovial fluid examined by polarized light microscopy. Note the needle shape and variable size (arrow), but many have a larger diameter than white blood cells (arrow) (100× oil immersion). B: Urate crystals from tophus examined by polarized light with red plate compensator (100× oil immersion). C: Calcium pyrophosphate dihydrate (CPPD) crystals in white blood cell found on Gram staining (100× oil immersion). Note the shape and size relative to nucleus and cytoplasm. Gram staining is not the usual method of demonstration but occasionally is useful. D: Wet preparation of synovial fluid demonstrating variable size and shape of CPPD crystals phagocytized by white blood cells (100× oil immersion lens, polarized light). Size and shape vary from squat rhomboid to rod shaped. Note several crystals in some cells. |
The acute inflammatory response in crystal-induced arthritis is self-limited. The complex mechanisms that terminate the attack are not well understood but probably involve inactivation of inflammatory mediators by locally elaborated factors. Although gouty arthritis and other crystal-induced diseases usually are characterized by symptoms and signs of acute inflammation, the persistence of crystals in the joint with mild chronic inflammation eventually may contribute to chronic joint damage.
Crystal Identification
The identification of crystals in synovial fluid or periarticular tissue is fundamental to the diagnosis and treatment of patients with crystal-induced arthritis. Crystals of monosodium urate are best identified by placing a drop
P.1240
of aspirated tissue fluid directly on a glass slide and examining the wet preparation through a microscope under polarized light. When one lens is rotated so that the field becomes dark, the negatively birefringent urate crystals (i.e., crystals capable of bending light rays in two planes—the notation of negativity is an arbitrary term used by physicists to describe the direction of bend), dimly seen in ordinary light, stand out brightly and can be identified within the cytoplasm of polymorphonuclear leukocytes. The crystals are even more easily identified with a red plate compensator because the field turns red and crystals parallel to the axis of the compensator appear yellow, whereas those perpendicular to the axis appear blue (6). Monosodium urate crystals usually are needle or rod shaped. The size varies, but some large crystals equal to or larger than the diameter of the leukocyte usually are seen. A wet slide of joint fluid prepared in this manner may be kept for a few hours at room temperature; however, once the cells die and lyse, evaluation is less valid. If the aspirated fluid cannot be examined immediately, urate crystals may be preserved overnight by refrigeration in a plain test tube. However, CPPD crystals may dissolve within a few hours even at refrigerator temperatures (7). Methods useful for later examination include Gram-stained smears (Fig. 76.1C) and cytospin-stained smears (8). These methods function well for preservation of specimens for evaluation by light and polarized light microscopy, with sensitivity approximating that of wet mount preparations.
|
TABLE 76.1 Identification of Crystals in Synovial Fluid |
||
|
Monosodium urate crystals (which usually are present in abundance) are pathognomonic of gout (Table 76.1 and Fig. 76.1). Absence of crystals in an inflamed joint is strong evidence against the diagnosis. In such cases, especially if leukocytosis is significant, infection or another diagnosis should be considered.
Monosodium urate usually is easily distinguished from CPPD based on the morphology and characteristics of the crystals under polarized light (Table 76.1 and Fig. 76.1). CPPD crystals vary much more in size and shape, from rodlike to rhomboid and irregular forms. They usually are much shorter than monosodium urate crystals, and they are never needlelike. They usually are refractile without polarized light and do not increase appreciably in brilliance when the light is polarized. They are weakly positively birefringent and change color in the opposite direction to urate when the red plate compensator is placed between the polarizing lenses (i.e., blue when parallel to the axis and yellow when perpendicular).
P.1241
Because CPPD crystals are small and do not stand out in polarized light, they are overlooked more often by the occasional observer. The need to use ordinary light microscopy as well as polarized light has been emphasized by the observation that the majority of CPPD crystals (80% in one study) are not birefringent and could be missed if only polarized light is used (9). Use of 100× oil immersion (difficult for wet preparations) is useful in identifying small CPPD crystals in stained smears. Routine reports from nonspecialized clinical laboratories often are inaccurate. In one review of five quality-control studies, as few as six of 50 CPPD crystals were correctly identified (10). Therefore, it is important to be familiar with the expertise available and the operating characteristics of the particular laboratory called upon for crystal identification (8,11). The clinician needs to alert the pathology laboratory if microcrystals are suspected in a tissue or biopsy specimen, because tissues for microscopy require alcohol fixative rather than formalin to preserve crystals of monosodium urate.
Other crystalline materials that may be seen include those from previously injected corticosteroids (which appear as crystals of varying and unusual configuration) and occasionally cholesterol crystals, which are easily distinguished from all of the others mentioned (they resemble a folded envelope). Contaminating crystalline or refractile substances, such as ethylenediamine tetra-acetic acid (EDTA) anticoagulant and talc, can be prevented by use of careful technique.
|
TABLE 76.2 Causes of Hyperuricemia |
||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Gout
Pathophysiology
Gout is a word derived from Latin meaning “a drop.” It is applied to this form of arthritis because of the false belief, in ancient times, that the disease was caused by drops of bad humor. Gout is caused by an alteration in purine metabolism, the end product of which is uric acid. This alteration results in hyperuricemia and the deposition of urate crystals in various tissues. Periodic attacks of acute inflammatory arthritis, characteristic of gout, are caused by the deposition of urate crystals in and around joints. Primary gout is caused by an inborn error in the production or excretion of uric acid. Secondary gout is caused by an increased breakdown of nucleic acids in association with one of a variety of acquired diseases or by impaired excretion of urate as a consequence of acquired renal disease (Table 76.2).
Although there is frequently a family history of gout, few specific genetic defects responsible for hyperuricemia
P.1242
have been identified. In a segregation analysis of serum uric acid, the heritability factor was 0.399, supporting the hypothesis that hyperuricemia is a multifactorial trait influenced by complex hereditary and environmental factors (12). Therefore, in patients with primary gout due to overproduction of urate (only approximately 10% of patients), the specific cause usually is not identified. Overproduction of urate in primary gout can occur as a result of an X-linked dominant defect in hypoxanthine-guanine phosphoribosyl transferase, an important enzyme in purine metabolism (13), or from overactivity of 5′-phosphoribosyl-pyrophosphate synthesis (14). An hereditary nephropathy with tubulointerstitial renal damage and early appearance of hyperuricemia and gout is an example of primary gout, with underexcretion of urate caused by an autosomal dominant gene (15,16). A positive family history and onset of gout before age 35 years should suggest the possibility of a primary condition causing overproduction or underexcretion of urate. To assess production and excretion of urate, measurement in a 24-hour sample of urine may be indicated. Normal urinary uric acid excretion is <600 mg/day if the diet for 5 days has been free of purine-rich foods. Because this diet is impractical for most patients, a reasonable estimate can bemadeonaregulardiet.Urinaryexcretion>1,000mg/day is clearly abnormal, and 800 to 1,000 mg/day is borderline. An alternative method to screen for increased urate excretion on a regular diet is to measure urate and creatinine in serum and in midmorning urine after a light, low-purine breakfast, calculating the urate excretion normalized to a glomerular filtration rate of 100 mL/min (17). This can be calculated simply by using the formula (Uu × Sc) ÷ Uc, where Uu is urine urate in milligrams per minute, Sc is serum creatinine in milligrams per minute, and Uc is urine creatinine in deciliters per minute. A value >0.6 mg/dL suggests overexcretion. Because overproduction related to a genetic defect is an uncommon cause of primary gout, measurement of urinary urate is unnecessary for the management of most cases of gout unless a secondary cause of hyperuricemia is suspected or uric acid stones have developed.
Normal concentrations of serum urate vary widely in the population (range 3–8 mg/dL); in addition, spontaneous variation may occur within an individual patient. The upper limit of normal for serum urate measured by the uricase method usually is considered 7.0 mg/dL for adult men and 6.0 mg/dL for adult women. Ranges may be higher by ≥1 mg/dL if automated colorimetric methods are used.
Epidemiology
Gout is estimated to occur at a lifetime frequency of three cases per 1,000 population in the United States. The prevalence of gout in the United States has been estimated to be 8.4 per 1,000 persons of all ages and both sexes, corresponding to a total of 2.1 million persons (1.5 million men and 550,000 women) (18). Because this figure is based on self-reported data, it likely is an overestimate. Several population-based studies have indicated that the prevalence of gout has increased recently. One review noted that the prevalence of gout in the United Kingdom increased from 2.6 per 1,000 to 9.5 per 1,000 from the 1970s to 1993 (19). Obesity and excessive weight gain were important risk factors for the development of gout in a prospective study of white men (20). The incidence of gout in African American men was significantly higher than in white men, and gout was associated with systolic blood pressure at baseline and subsequent development of hypertension (21). Gout in all of its forms is ten times more common in men, and it is rare in premenopausal women. Gout is rare before age 30 years and increases in frequency to a plateau at age approximately 60 years. Age at onset probably is related to the duration and severity of preceding hyperuricemia. In a prospective study of 223 men in Taiwan with asymptomatic hyperuricemia, the 5-year cumulative incidence of gout was 19% (22). The only predictor of development of gout at baseline was the concentration of uric acid. Independent risk factors in followup included further increase of serum urate, persistent alcohol consumption, use of diuretics, and increased body mass index. Excessive alcohol consumption was the most important independent risk factor in this group of hyperuricemic men.
Hyperuricemia due to decreased renal clearance of uric acid (23) is a constant feature of a complex cluster of metabolic and clinical abnormalities associated with insulin resistance, the so-called metabolic syndrome (24). These abnormalities include hyperinsulinemia, impaired glucose tolerance, dyslipidemia with elevated fasting triglyceride levels and lowered high-density lipoprotein cholesterol levels, hypertension, and central obesity. As a result of long-standing hyperuricemia, gout is often seen in middle-aged men with this syndrome and may be one of the initial clinical presentations (25). Management of gout in such patients may be difficult and requires attention to the other features of the syndrome. Although the etiology involves both genetic and environmental factors, increased visceral fat accumulation (20,26) and alcohol consumption (22,27) are risk factors that contribute to the abnormalities observed and to the development of clinical gout. Alcohol increases the risk of gout in a dose-dependent fashion (27).
Use of thiazide diuretics is a risk factor for gout (28) and complicates the observed association of gout with hypertension. Diuretic use is often a factor in the occurrence of gout in elderly women (29). Gout is often a complication in patients who have undergone renal or cardiac transplantation, in part because of the hyperuricemic effect of cyclosporine (30). In a study of 225 patients after cardiac transplantation, 23 patients developed acute gout that
P.1243
complicated therapy within 50 months of followup (31). A possible relationship of gout to hypothyroidism, especially in women, has been reported (32).
|
TABLE 76.3 Clinical Features of Gout |
|
|
Clinical Features
Acute Arthritic Attack
The acute arthritic attack is the hallmark of gout (Table 76.3). It is characterized by pain, swelling, and discomfort that progress rapidly to a peak level of intensity within 24 to 36 hours after onset. The pain is often severe enough to prevent use of the affected joint or even for the patient to bear the weight of bed clothing. The metatarsophalangeal joint of the great toe is the most commonly affected joint, followed by the forefoot, heel, ankle, knee, wrist, fingers, and elbow. The great toe is affected at some time during the course of perhaps 90% of gouty subjects. Usually a single joint is involved early in the course of the disease, but pauciarticular arthritis (two or three joints) may occur; polyarticular (more than three joints) onset is rare. Polyarticular gout is more common in late disease associated with soft-tissue tophi. Recurrent acute arthritis is more common in previously affected joints.
Several events may trigger an acute attack of gout: trauma, an acute illness such as an acute myocardial infarction, dietary indiscretion, overuse of alcohol, fasting, and recent administration of drugs that lower the serum urate concentration (see Pathophysiology).
A family history of gout may be present in patients with primary gout and especially in patients who excrete excessive amounts of uric acid, in whom a specific enzyme defect may be suspected. However, a positive family history is obtained in fewer than half of gouty subjects, so a negative history is not of differential diagnostic value.
Physical examination of the patient with acute gouty arthritis often reveals erythema overlying or adjacent to the affected joints, especially when small joints are involved. The erythema often involves only a localized area rather than the entire joint. The intensity of the inflammatory reaction often results in a mistaken diagnosis of cellulitis, a diagnosis that may appear to be supported by a fever that may reach 101°F (38°C), although temperature in this range or higher is uncommon in acute gout. Joint swelling usually is marked, and joint effusion is common. Tenderness on palpation or motion of the affected part usually is marked.
The intensity and severity of these classic acute signs and symptoms may vary from one attack to another. Early in the disease, milder episodes lasting only a few days may be passed off by the patient as being caused by minor trauma. The outward evidence of inflammation may be less evident when a large joint such as the knee is involved, especially in elderly patients and in patients with polyarticular gout. However, the history almost always indicates rapid progression to a peak intensity within 24 to 36 hours, an important feature in differential diagnosis. A history of episodes of similar events is helpful.
Laboratory findings may include a mild leukocytosis and an elevated erythrocyte sedimentation rate. Serum uric acid almost always is elevated, but this finding is of limited diagnostic value because of the frequency of
P.1244
hyperuricemia in the absence of gout and because the acute attack, which is related principally to the concentration of tissue urate, may occur at a time when the serum urate concentration is normal as a result of previous drug administration or spontaneous variation. Examination of the synovial fluid provides diagnostic findings in almost all instances in which it can be obtained. There is leukocytosis in the joint fluid with polymorphonuclear leukocytes that, when examined under polarized light, can be seen to contain phagocytized urate crystals (see Crystal Identification). Chapter 74 discusses the technique of aspiration of joint fluid. One should be experienced in this technique before attempting it, or the patient should be referred to a rheumatologist. The first metatarsophalangeal joint is a particularly painful joint to tap, especially during an acute attack, and this technique is not recommended without considerable experience. A dorsal approach with the toe in maximally tolerated plantar flexion usually is recommended.
The acute attack is self-limited, and even without treatment it subsides in several days to weeks. Early in the disease, once the acute attack subsides or is treated, there are no residual joint symptoms—another important point in the differential diagnosis.
Recurrent acute attacks are usual. Approximately 75% of patients have a second gouty attack within 2 years after the first attack, in most cases within the first year; occasionally, 10 or more years elapse between attacks (33).
Intercritical Gout
Between acute attacks of gout, patients are totally asymptomatic, with no abnormal physical findings unless tophi are present or unless the disease has progressed to the chronic phase. If the patient is in this stage at the first visit, a presumptive diagnosis can be made on the basis of a history of a typical attack, especially multiple attacks, and hyperuricemia. Aspiration of the great toe during intercritical gout demonstrates urate crystals in approximately 70% of patients with gout, but crystals rarely may be found in patients with asymptomatic hyperuricemia or renal failure (34,35). Knee joint aspiration has yielded urate crystals in patients with intercritical nontophaceous gout. In a study of 101 asymptomatic joints that previously had been inflamed, samples were obtained from 90 (90%) attempts (91% knees, 86% metatarsophalangeal joints). Crystals were found in all joints of patients who were not receiving urate-lowering therapy but in fewer of the patients receiving therapy (2). Therefore, in the patient who has a prior history of acute gout, especially within the past year, and who is not receiving urate-lowering therapy, aspiration of the affected joint where possible with analysis of synovial fluid for crystals is a reasonably sensitive and highly specific test for the diagnosis of intercritical gout.
Chronic Gout
Chronic gout is uncommon, especially since the advent of effective therapy for control of hyperuricemia. Patients with chronic gout often have some persistent symptoms (e.g., morning stiffness) and manifest signs of synovial tissue thickening and some joint deformity. Acute exacerbations are common and often polyarticular. Tophi (soft-tissue deposits of sodium urate) are present in 90% to 95% of patients with chronic gout. The rate of tophi formation seems to be a direct function of the concentration and duration of hyperuricemia. Tophi are chalky or pinkish, gritty, usually superficial deposits that are palpable in joints or over tendons, in pressure points, or in the pinnae of the ears. Tophi in finger pads were found in 30% of a small group of patients with tophaceous gout attending hospital outpatient clinics (36). They usually are painless but may be tender after palpation. Large tophi may look like bulbous swellings of the joints or, when they are located over the extensor surface of the forearm or in the ulnar bursa, they may be mistaken for rheumatoid nodules. The distribution of tophi may be different in women, in whom elbows and feet are less common sites than in men (37). The coincident occurrence of proven gout in distal interphalangeal joints associated with nodal osteoarthritis, especially in elderly patients receiving diuretic therapy for hypertension, has been reported (28,38). In patients with chronic gout who have radiographic changes of bone erosion, deformity of the fingers, and ulnar bursal nodules due to tophi, rheumatoid arthritis may be suspected (39). In these patients, aspiration of joints or biopsy of tophi with demonstration of urate crystals confirms the diagnosis of gout. The actual occurrence of gout and rheumatoid arthritis in the same patient is extremely rare.
Extra-Articular Manifestations
It has long been known that gout may be associated with renal disease in three forms: chronic urate nephropathy, nephrolithiasis, and acute uric acid nephropathy.
Chronic urate nephropathy develops after many years of hyperuricemia. It results from deposition in the interstitial medullary tissue of sodium urate crystals that ultimately cause an interstitial nephritis. In patients with asymptomatic hyperuricemia, regardless of the level, the risk of developing nephropathy does not warrant treatment to lower the serum urate as a prophylactic measure (40). At one time, the frequency of the complication of chronic urate nephropathy in gouty subjects was assumed to be high. However, controlled studies indicate that the incidence of renal insufficiency caused solely by gout and hyperuricemia is low, and renal dysfunction usually is mild. Most often, renal failure in patients with gout can be attributed to other causes, such as vascular disease or primary renal disease. Renal insufficiency from primary gout
P.1245
and hyperuricemia usually is silent and suspected only because of the identification of a mild abnormality of the blood urea nitrogen or serum creatinine concentration. Some patients have slight proteinuria; only a few have peripheral tophi. Chapter 52 discusses the evaluation and management of patients with renal failure.
Uric acid nephrolithiasis accounts for only a small number of patients who have urinary calculi (see Chapter 51). However, approximately 20% of patients with gout develop calculi, although the stones may antedate acute gouty arthritis by years. From a different perspective, approximately 25% of patients with uric acid calculi have an abnormal serum urate concentration. The prevalence of uric acid calculi increases proportionately to the concentration of serum urate or the excretion of uric acid, whether or not gout is present (41). In gouty patients, urinary excretion rates of <300, 301 to 700, 701 to 1,100, and >1,100 mg uric acid per 24 hours were associated with an incidence of renal stones of 11%, 21%, 35%, and 50%, respectively (42). The development of uric acid calculi is related not only to uric acid excretion but also to urinary pH and concentration. Chapter 51 details an effective scheme for ambulatory evaluation of nephrolithiasis.
Acute uric acid nephropathy is associated with a sudden increase in urate production and a marked rise in uric acid excretion, which results in the formation of microcrystals in the renal tubules. This condition most often occurs in patients with lymphoproliferative or myeloproliferative disorders, especially during treatment. It occasionally is a complication of vigorous administration of potent uricosuric drugs such as sulfinpyrazone. Preventive measures to lower urate production are effective, and acute uric acid nephropathy is rarely encountered in ambulatory practice.
Differential Diagnosis
During the acute attack, gout must be differentiated principally from acute infectious arthritis, bursitis related to a bunion (see Chapter 73), and other forms of crystal-induced arthritis. Therefore, it is important to aspirate joint fluid for smear and culture (see Chapter 74) as well as for crystal identification. If inexperienced in the aspiration technique of the joint in question, one should refer the patient to a rheumatologist. Infectious arthritis is associated with a very low synovial fluid glucose concentration, not found in gouty fluids. Rarely, acute gout and infectious arthritis coexist. Fever >101°F (38°C) or lack of prompt defeverescence in response to anti-inflammatory drugs should raise suspicion of infection or an alternative diagnosis.
Radiographic Studies
In the early course of gout, radiographs are normal except for acute soft-tissue swelling. As the disease progresses, lucent areas of urate deposits may be seen in bone adjacent to the joints (Fig. 76.2). These lesions may be mistaken for the erosions seen in rheumatoid or other arthritides, but osteoporosis and bony sclerosis, which are common in other erosive diseases, are not present. Overhanging margins of bone are said to be characteristic of gouty erosions but often are not found. Therefore, only occasionally are radiographic studies indicated as an aid to diagnosis or differential diagnosis of patients with suspected gout. Tophi appearing as capsular or intra-articular opaque masses were identified on computed tomographic scans of the knee in five of 16 patients with advanced crystal-proven gout, sometimes in the absence of subcutaneous tophi (43).
|
FIGURE 76.2. Radiograph of the foot in a patient with gout, showing soft-tissue swelling over the first metatarsophalangeal joint and typical gouty erosion: away from joint margin, punched out with overhanging edge, and no osteoporosis. |
Management
If the diagnosis of gout can be established with certainty by the demonstration of urate crystals, the treatment is generally straightforward (44). Unless there is a complicating illness, hospitalization is not required. Even the most severe case can be effectively managed on an ambulatory
P.1246
basis. The key elements in management are control of the pain of the acute attack and patient education. Patient education ensures compliance with therapy administered to reduce the serum urate concentration, which will prevent recurrent attacks and progression to chronic tophaceous gout. Lack of understanding of the disease and lack of compliance with therapy are major deterrents to effective management. Adapting an analogy of crystals to matches, as described by Wortman (45), is a useful way to explain to patients how drugs are used in treatment: early use of anti-inflammatory drugs, or occasionally colchicine, to “put out the fire” of an acute attack; colchicine prophylaxis between attacks to keep the “matches wet;” and urate-lowering drugs to “get rid of the matches.”
A paucity of randomized controlled trials address the treatment of gout (40). Empiric therapy as addressed here is based on available literature and experience and is effective for most cases of gout. Clinicians should be aware, however, that the treatment of gout in the elderly must be especially cautious. In a prospective study of elderly patients presenting to the emergency room, gout was one of the conditions most frequently associated with medication error (46).
Management of the Acute Attack
If the diagnosis of acute gout is established or if gout has been diagnosed previously by the identification of urate crystals in the affected joints, rapid relief can be obtained in almost all cases by the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) in appropriate dosages. The best studied NSAID in acute gout is indomethacin.
Indomethacin (Indocin) 50 mg (two 25-mg capsules) every 6 hours for six to eight doses is dramatically effective in reducing pain, often within a few hours. In the absence of moderate to severe compromise of renal function, few side effects occur if the dosage is quickly reduced to 25 mg every 6 to 8 hours after the pain and inflammation begin to wane and then maintained at that level until the attack is completely resolved, usually in no more than 5 to 7 days. Alternatively, other NSAIDs can be used (see Chapter 77) and are apparently equally effective although few comparative studies are available. The plasma concentration and therapeutic effect of indomethacin (and of naproxen, but apparently not of other NSAIDs) are potentiated by an unknown mechanism by the simultaneous administration of probenecid (see later discussion). Although the clinical significance of this interaction is unclear, especially with short-course therapy, the manufacturer recommends that the NSAID dosage be reduced in patients who also are taking probenecid. Caution should be used in patients with impaired renal function or reduced renal blood flow caused by cardiovascular disease, because NSAIDs may acutely reduce renal function and precipitate acute renal failure or hyperkalemia. This is especially important in frail elderly patients with low muscle mass, in whom the degree of renal impairment may not be immediately evident from the serum creatinine concentration.
Colchicine is the time-honored drug for treatment of acute gout, but its efficacy is limited by side effects that are almost invariable if an adequate dosage is administered orally (47). The usual regimen is 0.6 mg every 1 to 2 hours for up to a maximum of ten doses in 12 hours, until relief is obtained or until side effects, usually diarrhea, nausea, or vomiting, develop. The total dosage should be reduced in patients with impaired renal or hepatic function. However, it is no longer necessary to subject a patient to severe diarrhea when he or she already has a very painful joint because oral colchicine has largely been replaced by other agents that are as effective and have fewer side effects. The exception is the well-instructed patient who, immediately after recognizing the onset of an acute attack of gout, can institute oral colchicine and in doing so can abort the attack with a few doses and minimal side effects.
Intravenous administration of colchicine was used in the past because it rapidly provides a therapeutic plasma concentration of the drug and does not cause gastrointestinal side effects. Most authors now recommend avoidance of intravenous colchicine because of its risk for complications and availability of other options (40,44).
Production of a therapeutic response to oral colchicine of a typical attack of gout in the great toe has often been advocated to make a presumptive diagnosis of gout in the absence of crystal identification. Such a trial has limited value, however, because acute gout of several days’ duration may not respond rapidly to colchicine and because pseudogout caused by CPPD-induced arthritis or occasionally by other forms of arthritis may affect this joint and response.
Because the patient or the inexperienced clinician may be wary of aspiration of the first metatarsophalangeal joint when it is exquisitely painful with acute inflammation, a presumptive diagnosis of gout is often made on clinical grounds and the patient is treated with nonsteroidal or other agents. A raised serum uric acid concentration would further support the diagnosis of gout but is neither specific nor always present. A strong suspicion of infection would mandate a diagnostic aspiration.
Corticosteroids provide another therapeutic alternative for acute gout in the patient who has a contraindication to therapy with NSAIDs (44,48). Aspiration and intra-articular injection of corticosteroid suspension (e.g., 40 mg triamcinolone in the knee joint) are useful when a single large joint is involved. For patients requiring parenteral therapy, intramuscular or intravenous injections of adrenocorticotropic hormone (ACTH) or a soluble corticosteroid preparation is effective. Intramuscular ACTH, 40 to 80 units every 6 to 12 hours for up to 3 days; intravenous methylprednisolone, 100 to 150 mg repeated as needed; and triamcinolone acetonide, 60 mg intramuscularly per
P.1247
day for 2 to 3 days, are equally effective (49,50). Moderately high initial dosages of oral corticosteroids (30–60 mg/day prednisone tapered slowly over 7–10 days) usually are required for complete resolution without recrudescence (49).
Drugs administered to lower serum urate concentrations have no place in the treatment of the acute gouty attack. In fact, these agents may exacerbate acute attacks by the associated changes in plasma urate concentration (see Mechanisms of Crystal-Induced Arthritis).
Intercritical Gout
The efficacy of colchicine in dosages of 0.6 mg given one, two, or rarely three times daily (dosage frequency depends on control; most patients tolerate two doses per day without side effects) in reducing the frequency of acute attacks of gout has been well established (30,51). Therefore, prophylactic colchicine is indicated for patients who have had more than one episode of acute gout in a single year or when therapy to lower the concentration urate is initiated (see Chronic Gout). Caution is required in patients with impaired renal function. Reversible myopathy and neuropathy have been observed in some patients whose serum creatinine concentration was >1.6 mg/dL even with two tablets per day (52). Patients with renal insufficiency on colchicine prophylaxis should undergo a complete blood cell count and creatine kinase analysis once every 6 months of therapy to monitor for colchicine-related myopathy and myelosuppression (40). In elderly patients without tophi (nontophaceous gout), with infrequent acute attacks, and only mild hyperuricemia (i.e., <8 mg/dL), prophylactic colchicine may be all that is required. Some patients who have nontophaceous gout with infrequent attacks of arthritis (e.g., fewer than one or two per year) and mild hyperuricemia (<8 mg/dL) may elect not to take regular colchicine prophylaxis. In this instance, episodic use of an NSAID such as indomethacin is appropriate to control acute attacks. However, in most patients with gout and persistent hyperuricemia ≥8 mg/dL, the serum urate concentration should be reduced to prevent recurrent gout and to reverse the accumulation of urate in the tissues. In this instance, colchicine prophylaxis should be continued until the patient has been free of attacks for at least 1 year after the serum urate concentration has returned to normal. As an alternative in patients intolerant of colchicine, NSAIDs can be used for prophylaxis, but they may have more serious toxic effects than colchicine. Omitting prophylactic therapy and treating acute attacks early if they occur is an alternative for some patients with infrequent attacks.
Two classes of drugs that lower serum urate concentration are available: uricosuric agents promote urinary excretion of urate by blocking tubular urate resorption, and allopurinol decreases urate production through inhibition of purine metabolism. (Oxypurinol, an active metabolite of allopurinol, is not generally available and has few advantages over the parent compound.) Uricosuric agents are most effective in patients with nontophaceous gout who have good renal function (creatinine clearance at least 60–80 mL/min) and normal uric acid excretion (<750 mg/24 hours). The terms uric acid and urate are sometimes used interchangeably, but the correct terminology uses uric acid where it is the dominant moiety in the uric acid–rate equilibrium. Uric acid is dominant only in very acid situations, as in the distal renal tubule. In blood and at the usual tissue pH, the dominant moiety is urate. In most patients, clinical evidence of impaired urinary excretion rather than overproduction of urate is obvious (Table 76.2). When there is uncertainty, evaluation of urinary uric acid excretion is important not only as a clue to the mechanism of hyperuricemia but also to the choice of therapy (Table 76.2).
Probenecid (Benemid) is the uricosuric agent of choice because of its well-established safety and its long duration of effect. An initial dosage of 250 mg twice daily should be increased to 1.5 g daily or to a maximum of 2 g/day (in two or three divided doses) to achieve a serum urate concentration consistently <6.0 mg/dL, the level required to produce a urate gradient from tissue to plasma and to prevent further deposition of urate. To minimize the chance of precipitating a recurrent arthritic attack, the uricosuric agent should not be initiated until at least 1 week after an acute attack of gout has subsided and only after colchicine prophylaxis (described earlier) has been initiated for 3 or 4 days. The principal side effect of probenecid is gastrointestinal distress (which is uncommon), but there is a risk for formation of uric acid calculi in the renal tubules during the first week of therapy, especially with a large basal uric acid excretion (i.e., 600–800 mg/day). This risk can be minimized by starting at a dosage of 250 mg twice daily and gradually increasing the dosage over 2–3 weeks. The patient may be advised to drink 2 to 3 L of fluid daily and to take an alkalinizing agent such as sodium bicarbonate or citrate salt (polycitrate), 0.5 to 1 mEq/kg of body weight in five or six doses per day, to keep the urine pH (measured occasionally with pH paper) >6.0 or 6.5 for the first few weeks of uricosuric therapy. Small dosages of aspirin (2.4 g/day), but not a single low-dose enteric tablet as used for cardiac prophylaxis (53), block the effect of probenecid on renal excretion of urate and should be avoided. Probenecid may reduce the excretion of other drugs, including NSAIDs and penicillin, and prolong their half-life. Probenecid may cause a false-positive result for glucose in the urine.
Sulfinpyrazone (Anturane) is a more potent uricosuric agent but has more potential for adverse effects, including renal toxicity and nephrolithiasis. It can be given beginning with 50 mg twice daily and increased gradually to 600 mg/day, if required, to achieve the desired serum urate concentration (i.e., <6 mg/dL). Sulfinpyrazone is available in 100- and 200-mg strengths. This agent, which is
P.1248
an analogue of phenylbutazone, can cause gastric ulceration and platelet dysfunction. It can interact with sulfonamides or sulfonylureas to increase their hypoglycemic effect. For these reasons, it should be used principally when probenecid or allopurinol is not tolerated.
Allopurinol (Zyloprim or generic) is a potent agent that reduces the serum urate concentration. Because it blocks urate production by inhibition of xanthine oxidase, it is particularly useful in patients with renal dysfunction or with uric acid calculi and in patients with long-standing gout with tophi or with excessive basal uric acid excretion (>750 mg/24 hours). Serious side effects of rash, fever, leukopenia, hepatitis, and occasionally a generalized vasculitis occur in fewer than 2% of patients. These symptoms are most likely to occur within the first 2 months after initiation of therapy, so patients should be kept under close surveillance during this period. Toxicity is enhanced in patients with severe renal compromise or when the drug is administered concomitantly with ampicillin or thiazide diuretics (54). Allopurinol (available in 100- and 300-mg tablets) should be started at a dosage of 50 to 100 mg/day and increased over 2 or 3 weeks until the serum urate concentration is consistently <6.0 mg/dL; no more than 300 mg should be administered as a single dose. Prolonged use of dosages in excess of 300 mg twice per day increases the risk of toxicity; however, dosages of 400 to 600 mg/day may be required initially for effective control of serum urate concentration and reduction of the tissue urate load. Careful monitoring of the dose in patients with renal insufficiency is mandatory (54). In patients with renal insufficiency and in those who have undergone renal or cardiac transplantation and are receiving cyclosporine, adverse drug reactions are common with allopurinol, as well as with colchicine and NSAIDs (30).
Concomitant use of allopurinol and probenecid has been advocated for patients with chronic tophaceous gout. These agents seem to have an additive effect in lowering the serum uric acid concentration. However, use of a single agent, if possible, is preferred.
Febuxostat, a new nonpurine selective inhibitor of xanthine oxidase, has been submitted for FDA approval. In clinical trials, febuxostat in daily doses of 80 and 120 mg was more effective than allopurinol 300 mg daily in lowering serum urate concentration and similarly reduced the number of gouty flares (55,56).
Compliance is the major factor in the effective treatment of intercritical gout. Patients feel well between attacks. Continued compliance with medications requires reinforcement in patient education and followup visits to ensure maintenance of normal serum urate concentrations (45). The duration of treatment to lower serum urate is uncertain and depends significantly on the severity of the disease, the presence or absence of tophi, the frequency of acute attacks, and compliance with drug dosage. In one study, patients who were able to achieve a serum concentration ≤6 mg/dL had a reduction in gout attacks and in the finding of crystals on knee joint aspiration compared with patients whose serum urate concentration was higher (57). Continued treatment with drugs to lower the serum urate concentration was estimated to be cost-saving if the patient had two attacks per year and cost-effective if the patient had one attack per year (58).
Dietary advice to patients with gout should be offered, especially to patients who are obese and/or use alcohol (40). High-purine foods (organ meats, seafood, all meats, meat gravies and extracts, lentils, peas, asparagus, yeast, and beer) are common in Western diets, and strict avoidance is neither practical nor necessary in the treatment of most patients with gout. Patients should be aware of these high-purine foods and avoid excesses of intake. More important dietary advice is to avoid alcohol (especially beer because it adds to the purine load) and to avoid fasting beyond 24 hours, because both of these situations may be associated with an acute increase in the serum urate concentration, which may precipitate an attack of gout. Obese patients should practice calorie reduction for weight loss, but a severe restriction may precipitate acute attacks. In a pilot study of patients with gout associated with elevated serum triglyceride concentrations and obesity, weight loss with moderate calorie and carbohydrate restriction and a proportionate increase of unsaturated fat and protein intake resulted in an improved lipid profile, a reduction of serum urate concentration, and a decrease in acute attacks of gout (59). Possibly helpful as a nonpharmacologic management strategy, this diet, which addresses both the complicating factor of dyslipidemia and hyperuricemia, deserves further study with a larger number of patients.
Chronic Gout
Compliance with appropriate therapy should eliminate this phase of gout except in a few patients with severe disease who are intolerant of one or more drugs used in treatment. Continuous or intermittent use of NSAIDs may be required in some of these patients for adequate control of inflammation and chronic symptoms. Effective reduction in serum urate concentration for months or years results in dissolution of tophi and general improvement. However, very large tophi may require surgical removal. After prolonged therapy and resolution of tophi, consideration has been given to discontinuation of therapy with urate-lowering drugs. However, acute attacks and tophi are likely to recur (60), so stopping therapy is generally not recommended.
Patients with chronic tophaceous gout and moderate renal insufficiency present a difficult problem in management. Uricosuric drugs usually are not effective. NSAIDs may further impair renal function. Withdrawal of NSAIDs produced a significant improvement in renal function
P.1249
in patients, with an average creatinine clearance of 60 mL/ min after control of hyperuricemia was achieved (61). The incidence of adverse reactions to colchicine and allopurinol is increased in patients with renal disease, requiring lower doses and careful monitoring (54). For patients with tophaceous and polyarticular gout whose renal function makes uricosuric drugs ineffective, there are few alternative agents for lowering uric acid when a cutaneous reaction to allopurinol requires withdrawal of this therapy. Success was reported in desensitizing some patients by administering small, gradually increasing doses of allopurinol on a careful protocol beginning with 50 µg/day. A followup study indicated successful continuation of allopurinol and control of hyperuricemia in 78% of patients. Some developed a pruritic skin eruption that responded to withdrawal of allopurinol and dosage adjustment (62). It is important to note that patients with severe reactions, such as toxic epidermal necrolysis, hepatitis, or acute interstitial nephritis, were excluded from this study. Febuxostat (see Intercritical Gout) may prove to be a reasonable alternative in patients who have an adverse reaction to allopurinol.
Asymptomatic Hyperuricemia
Hyperuricemia (>7 mg/dL in men or 6 mg/dL in women) is a common laboratory finding in asymptomatic patients evaluated in a variety of clinical settings. In most patients, clinical findings point to an obvious cause, and no other therapy is required unless gout or nephrolithiasis develops. If the cause is unclear or the serum urate concentration is near 11 mg/dL, further evaluation to estimate urinary excretion and identify secondary causes of excessive urate production (Table 76.2) should be initiated. Although the serum urate concentration often is markedly elevated in patients with end-stage renal disease, clinical gout is rare.
Hyperuricemia Secondary to Diuretics
The renal tubular handling of urate is complex. Complete glomerular filtration is followed by tubular resorption, tubular secretion, and further tubular resorption. Resorption of urate is partly modulated by the volume of extracellular fluid (expansion increases excretion and contraction decreases excretion). Diuretics modify the renal handling of urate and uric acid by their effect on volume, and some diuretics may directly affect urate transport. Thiazides regularly cause a dosage-related rise in the serum urate concentration that is reversed on withdrawal of the agent. The increase in concentration averages 1 to 2 mg/dL but occasionally may be 4 to 5 mg/dL. Furosemide and bumetanide often are associated with a rise in serum urate concentration; less commonly, ethacrynic acid, acetazolamide, and rarely triamterene are associated with hyperuricemia. Spironolactone is not associated with hyperuricemia.
The incidence of gout after initiation of diuretic therapy is a complex issue. Other factors that affect the incidence of gout, such as hypertension and obesity, often are present in patients treated with diuretics. Approximately 10% of hypertensive patients with hyperuricemia secondary to diuretic therapy develop gout. This risk increases in patients with known gout and in patients with diseases associated with elevated serum urate concentration, such as myeloproliferative disorders or psoriasis. With diuretic therapy, uric acid excretion is diminished, and the incidence of urinary calculi does not increase. The risk of developing urate nephropathy is minimal (seeExtra-Articular Manifestations). For these reasons, expectant management of patients with asymptomatic hyperuricemia secondary to diuretics is appropriate.
Should acute gout develop, the treatment described previously may be initiated. Intercritical gout is managed similarly to primary gout, and prophylactic colchicine and uricosuric therapy with probenecid (if there is no renal failure) or allopurinol to decrease production of urate may be used. Reducing the dosage or stopping the diuretic usually is associated with a slight fall in the plasma urate concentration, but many patients continue to have attacks of gout. Therefore, if a patient develops gout while taking diuretics and the need for the diuretic continues, it is best to treat the gout as described previously and to continue use of the diuretic at the minimally effective dosage. In the management of hypertension, the use of β-blockers, angiotensin-converting enzyme inhibitors, and long-acting calcium channel-blocking agents, which have no effect on urate excretion, may allow discontinuation of diuretics in some patients. The angiotensin receptor blocking agent losartan 50 mg/day has been shown to decrease serum uric acid concentrations (63).
Calcium Pyrophosphate Dihydrate-Induced Arthritis
Pathophysiology
CPPD deposition disease occurs as a result of altered metabolism of inorganic pyrophosphate (iPP), which causes deposition of CPPD crystals in articular cartilage, fibrocartilage, ligaments, tendons, bursae, and synovia. This may occur as an accompaniment or consequence of aging, often in association with osteoarthritis, or as a result of genetic defects or certain systemic metabolic diseases (Table 76.4). The precise mechanisms by which these deposits develop are not clear and likely are multifactorial. Most of the research toward an understanding of this process has involved alterations of iPP metabolism in articular cartilage. With aging and cartilage degeneration, chondrocytes proliferate, become hypertrophic, and undergo apoptosis (programmed cell death), with increased production
P.1250
of iPP and calcification (64). Once formed, calcium crystals may activate processes that enhance degenerative changes in articular cartilage (65). Once released in sufficient quantity into the joint, CPPD crystals induce an acute inflammatory response similar to that of monosodium urate and an acute arthritis, the syndrome of pseudogout.
|
TABLE 76.4 Diseases Associated with Calcium Pyrophosphate Dihydrate Deposition Disease |
||||||||||||
|
Epidemiology
Chondrocalcinosis increases in frequency with age. It is present in approximately 5% of the adult population at the time of autopsy and in 20% to 30% of people older than 80 years, most of whom are asymptomatic. The exact prevalence of CPPD deposit disease is unknown. In one series of consecutive patients with newly diagnosed crystal-induced arthritis, CPPD deposit disease accounted for approximately one third of the cases. Men probably are affected more than women, with a male/female ratio of 1.5:1 (66).
Causes
Familial cases with an autosomal dominant inheritance in which chondrocalcinosis appears at an earlier age have been described (67). These families are uncommon, and many of these patients remain asymptomatic for many years. Although genetic defects in the nucleotide pyrophosphohydrolase enzymes have been suspected, the metabolic defect(s) has not been specifically identified. Most cases of CPPD deposit disease are sporadic and idiopathic; a few are associated with one of a variety of metabolic diseases (68). Many of the diseases associated with deposits of CPPD involve metabolic abnormalities in connective tissues, but the precise mechanisms of CPPD crystallization are unknown. Table 76.4 provides a list of these associated diseases. There is a strong association with osteoarthritis (see Chapter 75).
Clinical Features
Patients usually are middle aged to elderly at the time of onset of arthritic symptoms (Table 76.5). Several patterns of presentation are possible. Approximately one fourth of patients have self-limited, acute, goutlike attacks (pseudogout) predominantly affecting the knees and wrists, but occasionally involving other joints and rarely the first metatarsophalangeal joint. Monarticular attacks are the rule, but involvement of symmetrical joints and polyarthritis may occur rarely. Symptoms often are less intense than they are in gout, but the presentation is variable, and some attacks may be severe. Systemic symptoms, including fever to 101°F (38°C) or more, may occur as in gout, and patients often are misdiagnosed as having infection. In some elderly patients, fever is the dominant symptom, and the joint abnormalities are subtle and may be overlooked. Attacks often are exacerbated by trauma or acute illness. Long intervals (sometimes years) between attacks are common.
|
TABLE 76.5 Clinical Features of Calcium Pyrophosphate Dihydrate Deposition Disease |
|
|
In approximately half of patients, and especially in women, the presentation resembles that of osteoarthritis with bilateral involvement, especially of the knees. The wrists, metacarpophalangeal joints, hips, shoulders, elbows, or ankles also may be affected. Acute exacerbations occur in approximately half of these patients, with features that resemble those of osteoarthritis, except that the disease is more progressive and destructive. Varus or valgus knee deformities are common, and extensive calcification around the patella may be seen on radiography. Flexion contractures may occur. The relationship to ordinary osteoarthritis is unclear, except that the involvement of joints not usually affected in osteoarthritis (metacarpophalangeal joints, wrists, shoulders, elbows) suggests a different pathogenesis. In one study, sensitive techniques demonstrated CPPD or basic calcium phosphate crystals in
P.1251
11 of 12 samples from patients with typical osteoarthritis of the knee when the crystals were too small or too few to be detected by usual methods (see Chapter 75) (69).
In a few patients, persistent subacute inflammation with fatigue, morning stiffness, and synovial swelling in multiple joints lasting weeks or months resembles rheumatoid arthritis.
A few patients with severely destructive arthritis that resembles the Charcot joints of neuropathic arthropathy but is associated with a normal neurologic examination have been reported. CPPD deposit disease may be associated with a true neuropathic arthritis caused by tabes dorsalis.
Laboratory Findings
Patients may have peripheral leukocytosis and an elevated erythrocyte sedimentation rate in association with acute or subacute attacks of arthritis. The synovial fluid shows polymorphonuclear leukocytosis that may be >50,000/mm3 in acute pseudogout but more commonly ranges from 15,000 to 25,000/mm3. Crystal identification is the key to diagnosis (see earlier discussion). In the absence of acute or subacute inflammation, leukocyte counts may be low (<2,000/mm3), and crystals may be largely extracellular.
Because of the occasional association with other potentially treatable disorders (Table 76.4), the patient's serum calcium, phosphorus, magnesium, alkaline phosphatase, and uric acid (actually urate, as discussed earlier) concentrations should be measured, although they usually are normal. Chondrocalcinosis is a frequent manifestation of the Gitelman variant of Bartter syndrome, a rare genetic disorder (70). The findings of hypomagnesemia, mild hypokalemic alkalosis, and hypocalciuria lead to the correct diagnosis. The defect is an abnormality in the sodium chloride transporter in the distal convoluted tubule of the kidney. A striking reduction of chondrocalcinosis over a 10-year period and a good prognosis (71) are seen if hypomagnesemia and hypokalemia can be reversed with potassium and magnesium supplementation, sometimes aided with spironolactone. Because pseudogout may be the presenting manifestation of hemochromatosis and because of the importance of early diagnosis in this disorder, measurement of serum ferritin concentration and/or genetic testing are indicated if there is any suspicion of this diagnosis (66).
|
FIGURE 76.3. Radiograph of the knee in a patient with chondrocalcinosis. Stippled calcification of the medial and lateral menisci is easily identified. |
Radiographic Findings
The typical radiographic findings of CPPD deposit disease are punctate and linear calcifications (chondrocalcinosis), seen most often in the fibrocartilage of the menisci of the knee, usually bilaterally (Fig. 76.3). Other fibrocartilages may show similar changes, including the disc in the distal radioulnar joint, the symphysis pubis, the lip of the acetabulum, the glenoid fossa, and intervertebral discs. Hyaline cartilage may be involved, with similar punctate linear calcifications that may be identified as a dense line parallel to the subchondral bone in the midzone of the articular cartilage. Calcification in the soft tissues of the joint capsule and occasionally in ligaments and
P.1252
tendons may be seen but is less characteristic. In patients with the type of CPPD deposit disease that resembles osteoarthritis, subchondral cyst formation with bony collapse may be prominent. Osteophyte formation is variable and inconsistent.
These radiographic findings may be helpful in suggesting or confirming the diagnosis of CPPD deposit disease (72). However, it may not be possible to visualize the extent of deposits radiographically, and their absence does not exclude the diagnosis if typical crystals can be demonstrated in synovial fluid or in biopsy material.
Management
No therapy influences the deposition or resolution of tissue deposits of CPPD in idiopathic CPPD deposition disease. During the acute attack of pseudogout, diagnostic aspiration of synovial fluid (see Chapter 74) with removal of crystals and leukocytes may provide significant clinical improvement. Local injection of depo corticosteroid (see Chapter 74) often is effective and avoids potential side effects of systemic drug therapy. Efficacy of colchicine has been debated; although it sometimes is effective, use of indomethacin or other NSAIDs as described for acute gout is generally preferred. Because many of these patients are elderly (and therefore may have an impaired glomerular filtration rate), caution regarding renal toxicity of these agents should be exercised (see Chapter 52). As in the treatment of acute gout, a brief course of systemic corticosteroids is an alternative; however, because a single large joint usually is affected, intra-articular steroid administration is preferred. In patients with only recurrent acute attacks, no therapy is indicated between attacks, but early administration of anti-inflammatory agents on exacerbation may minimize or abort attacks. Therapy for patients with more subacute inflammation or for those with osteoarthritislike disease is similar to that described for osteoarthritis (see Chapter 75), except that anti-inflammatory concentrations of drugs may be required for optimal symptomatic control.
Hydroxyapatite-Induced Arthritis
The capacity of hydroxyapatite crystals to induce an inflammatory response was first appreciated in some patients with acute tendinitis (73). More recently, hydroxyapatite crystals were identified in patients with osteoarthritis, especially in association with acute inflammatory episodes (74), and in patients with destructive arthropathy of the shoulder joint (75). The latter, called Milwaukee shoulder, is associated with painful limited shoulder motion, complete disruption of the rotator cuff, and extensive degenerative changes in the bone. In these conditions, crystals of other basic calcium salts, including octacalcium phosphate and tricalcium phosphate in addition to hydroxyapatite, have sometimes been identified. This has prompted the use of the term basic calcium phosphate (BCP) deposit disease to describe these syndromes (75). The capacity of the various crystals to induce inflammation varies according to crystal type, surface area, and calcium/phosphate ratio (76). CPPD crystals may be found in addition to BCP crystals in these syndromes and in some familial cases (77). Alizarin red S dye (available from scientific supply houses) may be used to stain wet preparations of synovial fluid to screen for the presence of hydroxyapatite crystals, which appear under ordinary light microscopy as red-stained clumps of crystalline material (78). Because all other calcium-containing crystals and even noncrystalline calcium salts stain with this dye, specific identification of BCP crystals requires techniques that are not usually available, such as electron microscopy, microprobe analysis, or x-ray diffraction. It now is clear that BCP crystals alone or in combination with CPPD are broadly associated with calcinosis in soft tissue, tendons, and bursae as well as in joints. These deposits may be secondary in some instances to trauma, neurologic injury, collagen disease, or chronic renal failure. In any of these locations, an acute goutlike inflammation or a more chronic and sometimes destructive tissue response may ensue. One need only be aware of the potential inflammatory properties of this crystalline material and consider its implication in these various clinical situations. The patient may be treated with aspiration, from a joint or soft tissue, of the crystalline material and subsequent local injection of a lidocaine/corticosteroid solution (see Chapter 74) or with an NSAID (see Chapter 77). These modalities should provide symptomatic relief in patients with acute inflammatory arthritis or tendinitis associated with BCP crystal deposits. If symptoms become chronic or extensive destructive arthropathy is present, rheumatologic or orthopedic referral is indicated.
Arthritis Associated With Calcium Oxalate
Another crystal-associated arthritis has been demonstrated in patients receiving long-term dialysis therapy (usually hemodialysis, but also seen with peritoneal dialysis) for end-stage renal disease. Extensive deposits of calcium oxalate in soft tissues occur in this setting, and these deposits can cause acute arthritis, destructive arthropathy, tenosynovitis, or bursitis (79,80). These patients are difficult to treat because of the presence of extensive and continuing deposits and incomplete response to colchicine, nonsteroidal agents, and corticosteroids.
P.1253
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
P.1254