Published: August 2010
Crystal-induced arthropathies are a group of disorders that involve deposition of crystals into joints and soft tissues, resulting in articular and periarticular inflammation and injury. Examples of such crystals are monosodium urate (MSU), calcium pyrophosphate dehydrate (CPPD), hydroxyapatite, and calcium oxalate. The crystals most commonly involved in joint inflammation and seen in synovial fluid analysis are the MSU crystals involved in gout and the CPPD crystals involved in pseudogout.
Gout is a crystal deposition disease characterized by the supersaturation and precipitation of MSU crystals in tissues resulting in inflammation and, consequently, tissue damage. Gout is characterized by acute or subacute attacks of joint or soft tissue inflammation resulting from MSU crystal deposition. The clinical course of gout can be summarized into the stages of acute intermittent gout and chronic tophaceous gout.
Hyperuricemia is the underlying metabolic aberrancy in gout and is defined as the serum urate level, in body fluids, above which urate precipitates into monosodium urate crystals. A urate level greater than 6.8 mg/dL is considered hyperuricemia.
Gout is a fairly common disease, more common in men than women, and rare in premenopausal women. There have been few studies on the incidence or prevalence of gout and even fewer on CPPD arthropathy. In a population of medical students with a median age of 22 years, the cumulative incidence of gout was reported as 8.6%.1 In this same study, body mass index (relative risk [RR], 1.12), excessive weight gain (RR, 2.07), and hypertension (RR, 3.26) were identified as risk factors for developing gout.1
Overall, the prevalence of gout in the U.S. population increased between 1990 and 1999,2 and factors such as lifestyle habits, obesity, diet, alcohol intake, comorbid diseases such as hypertension, and the use of diuretics were identified as potential contributing factors.3 A study done in the United Kingdom, examining the epidemiology of gout, reported the prevalence of gout to be 1.4% in 1999 and as high as 7% in men older than 65 years.4 Reviews have found that epidemiologic investigations suggest that incidence of gout is on the rise worldwide.5
The annual incidence of gouty arthritis is about 5% at serum urate levels of 9.0 mg/dL or higher and less than 1% at urate levels of 7 mg/dL and lower.6
Gout is an inflammatory crystal arthropathy that results from the pathogenic effect of MSU crystals in the joints and soft tissue. Uric acid in body fluid, at pH 7.4, exists in the urate form. Thus, when referring to uric acid in physiologic fluid it is preferable to use the term urate.
Uric acid comes from the metabolism of purine nucleotides. Purine metabolism leads to inosine then hypoxanthine. Hypoxanthine is metabolized to xanthine and xanthine to uric acid. These two last steps are catalyzed by the enzyme xanthine oxidase, which is the major site for pharmacologic intervention by allopurinol. Uric acid, in humans, is the final product. Human beings lack the ability to degrade urate further.7
Minimal amounts of urate are eliminated through the urinary and intestinal tracts. Therefore, when the human body is unable to eliminate large burdens of urate, hyperuricemia develops. As urate levels increase and saturate the synovial fluid or soft tissues, crystals precipitate, leading to tissue damage and the development of tophi. After urate crystals deposit in soft tissues and joints, monocytes and macrophages are activated in an attempt to clear the crystals by phagocytosis. This then leads to the release of proinflammatory cytokines and chemokines into the surrounding area, triggering a cascade of acute inflammatory reaction and influx of neutrophils into the joint, for example.7,8
The mechanism leading to the self-limited inflammatory process is not fully unveiled. The innate anti-inflammatory processes, mediated by anti-inflammatory cytokines, possibly are called into action and interrupt the inflammatory process.8 Thus, the natural course of gout is one that would resolve spontaneously in 1 to 2 weeks on average.7
An additional proposed mechanism has been elucidated in research work indicating the role of an inflammasome and interleukin 1 (IL-1) in the pathogenesis of inflammation induced by monosodium urate (the crystal in gout) and calcium pyrophosphate dehydrate (the crystal in pseudogout). Cryopyrin inflammasome detects MSU and CPPD crystals, resulting in an inflammatory cascade by activation of IL-1.9 These IL-1–mediated inflammatory effects of MSU crystals could potentially be blocked by IL-1 inhibitors, such as anakinra. This presents opportunities for the management of patients with gouty arthritis who are otherwise intolerant of or inadequate responders to standard anti-inflammatory therapies. Large randomized, controlled trials are required to assess the benefit and safety of blocking IL-1 in the management of polyarticular gouty arthritis.
The cascade of pathologic events leads to acute inflammation of the joint or soft tissue. The clinical manifestations of gout include arthritis, direct soft tissue damage, and accumulation of MSU crystals, known as tophi, in soft tissue and bones. Hyperuricemia can also result in uric acid nephrolithiasis and possible nephropathy if uric acid accumulates in the renal interstitium and tubules.
The arthritis in acute gout usually manifests as asymmetric monoarticular or oligoarticular inflammation, lasts 3 to 10 days, and resolves spontaneously. Eventually the attacks occur more frequently, last longer, and do not resolve completely, leading to chronic gouty arthropathy. Gouty arthropathy can lead to erosions and joint destruction, but it is distinguished from rheumatoid arthritis by the absence of joint space narrowing and absence of periarticular osteopenia.
In general, joints involved in gout include the lower extremity joints as well as those of the upper extremities. Inflammation in joints such as the first metatarsophalangeal (MTP) joints is termed podagra and is highly suggestive of gout. Any joint in the feet, ankles, knees, hands, wrists, or elbows may be involved. Acute gout can occur in bursae, such as the olecranon or prepatellar bursae, causing bursitis.
Occasionally, a gout attack triggers a systemic inflammatory response manifesting with fevers, leukocytosis, elevated sedimentation rates, and elevated C-reactive protein (CRP).
Acute attacks can be precipitated by several factors, such as increased alcohol consumption (especially beer), trauma, use of diuretics, dehydration, cyclosporine, diet (organ meat, shellfish), and any drug that can lead to sudden changes (increase or decrease) in urate levels, such as hypouricemic agents.10,11
When urate accumulates in a supersaturated medium, it can deposit in soft tissue or bones and form a tophus. Tophi can be present over the helices of the ears, extensor areas of the limbs, pressure areas such as the finger pads, and over the Achilles tendons. Occasionally, they are not seen on physical examination but are noted on x-ray films as cystic or masslike lesions. In general, a tophus on radiographic films is radiolucent, but when it occurs over a calcified nodule it may be seen as radioopaque.12
Synovial fluid analysis is the gold standard for diagnosis,and one should attempt a synovial aspiration for microscopic analysis whenever feasible.
Synovial fluid analysis offers a valuable diagnostic tool for evaluating patients with gout or pseudogout. Once the fluid is aspirated, it can be examined grossly for color and turbidity. In general, transparent synovial fluid in the syringe is more suggestive of a noninflammatory condition, whereas fluid that appears turbid or purulent is more suggestive of inflammation or infection (e.g., rheumatoid arthritis, gout, septic arthritis). However, gross appearance alone is by no means diagnostic.
To confirm or rule out infection, the fluid needs to be processed for Gram stain and culture. It is possible to have concomitant gout and septic arthritis at the same time. On microscopic examination, the number of white blood cells (WBCs) per high-power field can be estimated. The WBC count may be a useful adjunct in estimating the degree of inflammation present.13 With gout, synovial fluid analysis reveals leukocytosis, a nonspecific finding of inflammatory arthritis including infectious and crystalline causes.
Crystal analysis is done with compensated polarized light. An accurate diagnosis can be made by a trained observer by detecting and identifying MSU crystals or CPPD crystals.14
MSU crystals are birefringent, with strong negative elongation when viewed under compensated polarized light. CPPD crystals are weakly birefringent and rhomboid or rod shaped. CPPD crystals might not be as evident and thus possibly missed, especially if the analysis is not done by a trained examiner.13-15 In addition to shape and birefringence, MSU and CPPD differ in color depending on the axis of orientation with respect to the polarizer. When the axis of the MSU crystal is parallel to the polarizer it appears yellow, and when it is perpendicular it appears blue. The CPPD crystal is the reverse of that, so when the CPPD crystal is parallel it appears blue and when perpendicular it appears yellow (Table 1).13
|Shape||Needle-like, sharp edges||Rhomboid, rod-like|
|Color parallel to polarizer||Yellow||Blue|
|Color perpendicular to polarizer||Blue||Yellow|
CPPD, calcium pyrophosphate dehydrate; MSU, monosodium urate.
Urate levels are not helpful in the acute gouty attack because they fluctuate and may be normal, low, or elevated. In chronic gout, a urate level is helpful in determining hypouricemic therapy. Once a hypouricemic agent is started, the dose should be adjusted according to urate blood levels (see later).
Other blood tests, such as a complete blood count, a creatinine, and transaminases are useful for assessing contraindications to a drug, to evaluate for other comorbid diseases, and for monitoring drug toxicity after initiating therapy. For example, colchicine is not indicated if the patient has evidence of bone marrow suppression. If there is any evidence of renal insufficiency, therapy with uricosuric medications (such as probenecid or sulfinpyrazone) would not be effective because they require functional renal apparatus to excrete excess urate. In addition, the dose of allopurinol will have to be decreased, and colchicine should be avoided.
A 24-hour urine test for uric acid levels is necessary when considering a uricosuric agent, such as probenecid or sulfinpyrazone. Because results are partly affected by diet, it is best to repeat the test twice on two separate occasions. If the 24-hour urine levels are abnormally elevated, then uricosuric agents should not be used so as to avoid an increased risk of urate stones.
Changes of arthropathy take years to develop, but findings of erosions can appear sooner. Distributions of affected areas include most commonly the feet, ankles, hands, wrists, and elbows. Well-defined erosions with sclerotic margins and overhanging edges are classic in gout. Little or no joint space narrowing and no periarticular osteopenia can differentiate gout from rheumatoid arthritis.12
Once the diagnosis of gout has been made, other associated medical conditions need to be considered, such as alcoholism, the metabolic syndrome, myeloproliferative disorders, and possible medication triggers (diuretics, cyclosporine). Any comorbid disease should be appropriately managed as clinically indicated.
Differential diagnosis of monoarticular arthritis includes infection, pseudogout, atypical rheumatoid arthritis, trauma, and fracture. The differential diagnosis should be considered based on the history and clinical presentation. Thus, the best approach starts with a good history and physical examination. If the history and clinical examination do not indicate a history of trauma or fracture, then a synovial aspiration, as discussed earlier, is performed, rather than an x-ray of the joint.
Erosive gouty arthropathy can mimic rheumatoid arthritis or CPPD arthropathy. Often, patients with advanced gouty arthropathy, especially of the hands, are mistakenly treated for rheumatoid arthritis.
Treatment depends on the clinical presentation and findings. The aim in treating gout is to treat the acute attack, prevent future attacks, and prevent chronic joint and soft tissue mutilation from chronic tophaceous gouty arthropathy. As discussed earlier, gout is characterized by the acute or subacute attacks of joint or soft tissue inflammation resulting from deposit of MSU crystals. Hyperuricemia and gout may be divided into three stages: asymptomatic hyperuricemia, acute intermittent gout, and chronic tophaceous gout.
There are no sufficient data to support treatment of asymptomatic hyperuricemia with hypouricemic agents. In general, initiating such therapy in asymptomatic persons is not recommended, but one should consider investigating the underlying comorbid conditions and treating those conditions as clinically indicated.
The acute attack can be managed with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids (intra-articular injection or systemic). The choice of agent is dictated by the patient's tolerance of those medications and the presence of any comorbid diseases that prevent the use of such drugs. Younger, otherwise healthy patients who can tolerate NSAIDs or colchicine may be treated with either. NSAIDs should be avoided in patients who are intolerant of such drugs or in whom such drugs are contraindicated. NSAIDs are contraindicated in renal disease, insufficiency, or failure; gastrointestinal bleeding, ulcers, or gastritis; high risk of cardiovascular disease; and history of allergy to the drug. Occasionally, in an acute gouty attack, when all of these medications are contraindicated, narcotics may be used to relieve pain until the acute attack has resolved.
Although indomethacin has been traditionally used for acute gout, most other NSAIDs can be used as well. NSAIDs provide rapid symptomatic relief within the first 24 hours. Indomethacin can be given at a dose of 150 mg (in three divided doses) daily for the first 3 days then 100 mg (in two divided doses) for 4 to 7 days.16
NSAIDs should be avoided in patients who are intolerant of such medications or who have other comorbid conditions contraindicating their use. Avoid NSAIDs in patients at risk for gastrointestinal (GI) bleeding, GI intolerance, or gastropathy; renal failure; hepatic failure; congestive heart failure; asthma; or hypersensitivity to NSAIDs. Avoid NSAIDs in the third trimester of pregnancy.
Adverse effects of NSAIDs should be discussed with the patient. These include potential GI intolerance, GI bleeding,17 GI ulceration or perforation, nephrotoxicity, prolonged bleeding, fluid retention, risk of cardiovascular events, Stevens-Johnson syndrome, and others.
Colchicine originates from the autumn crocus plant; it works as an anti-inflammatory agent.18 Early on, colchicine blocks microtubule assembly in neutrophils, which attenuates phagocytosis and the transport of MSU crystals to the lysosome.6 Colchicine impedes the activation of neutrophils in the vicinity of MSU crystals by blocking the release of chemotactic factors, thus diminishing recruitment of polymorphonuclear leukocytes to the inflamed joint.18
Colchicine offers the best response when initiated within the first 48 hours of acute gout. Patients usually notice improvement within 48 hours of therapy. During acute gout, oral colchicine can be started at 0.6 mg three or four times daily (taken preferably every 8 hours or in doses separated by at least 1 hour) for 2 days, then decreased to twice daily. Colchicine should not be prescribed to be taken until diarrhea develops, because this will only add more ailment to the patient already suffering from marked pain. Once symptoms resolve, colchicine may be stopped. However, colchicine may be continued at a dose of 0.6 mg every 12 hours to prevent further attacks.
Intravenous colchicine should be used only by experienced rheumatologists and reserved for hospitalized patients, if absolutely necessary, who are unable to take oral colchicine. Caution must be used with dosing, which must not exceed 3 mg per dose. Intravenous colchicine carries a high risk of myelosuppression, can be caustic, and has been associated with fatalities.
Onset of action (pain relief) is 24 hours after the first oral dose. Colchicine requires dose adjustment with decreased renal function and should not be used in dialysis patients because it is not dialyzable.
Adverse effects of colchicine include diarrhea, abdominal cramping, bone marrow suppression, axon-loss neuropathy, myopathy (especially in renal insufficiency), potential liver toxicity, arrhythmia, shock, and skin rash (uncommon). Use caution in patients with biliary obstruction, hepatic failure, or renal insufficiency or end-stage renal disease and in pregnant women, neutropenic patients, and transplant patients on cyclosporine. Concomitant use of colchicine with cyclosporine can lead to rapid-onset myopathy and increased myelosuppression.16,18
It is best to consider steroids in the absence of concomitant infection. In the case of systemic infections or septic arthritis, steroids should be avoided if possible. Corticosteroids may be used locally as an injection or systemically (orally, intramuscularly, or intravenously). Corticosteroids are usually very effective, and response is noticed within 24 hours of beginning therapy.
Oral corticosteroids can be used in the form of a methylprednisolone pack or prednisone starting at 40 mg or less, with a gradually tapering dose.6,16,18 Systemic steroids are the preferred agents in patients with renal failure in whom NSAIDs and colchicine are contraindicated. Local steroid injections may be the best alternative route of administration in patients who are unable to tolerate systemic therapy with steroids, NSAIDs, or colchicine. Steroids, however, are not usually the first line of therapy because of their potential adverse effects such as hyperglycemia, gastrointestinal diseases, weight gain and fluid retention, muscle weakness, immune suppression, and long-term effects such as those on bone resorption. The potential adverse effects need to be considered when making the decision of treating acute gout.
The main goal of treatment is to decrease urate levels to less than the level of precipitation, which is 6.8 mg/dL. The therapeutic target level should be less than 6 mg/dL, at which level risk of gout attack is decreased and so is the formation of tophi (for which urate levels of <5 mg/dL are preferred).
The decision to start a hypouricemic agent needs to be considered on a patient-by-patient basis, taking into consideration factors such as the absence of definite reversible causes of hyperuricemia, the number of attacks (two or more acute gouty attacks), the degree of hyperuricemia, and the presence of tophi. The decision should be clearly discussed with the patient, because treatment with a hypouricemic agent is usually lifelong and compliance is crucial.16 Hypouricemic therapy should be started only after the acute attack has completely resolved so as to avoid exacerbation of the attack. Prophylactic agents (colchicine, NSAIDs, or systemic steroids) should be initiated concurrently with hypouricemic drugs to decrease the risk of an acute gouty attack. Hypouricemic drugs include xanthine oxidase inhibitors (e.g., allopurinol), uricosuric agents (e.g., probenecid, sulfinpyrazone, benzbromarone), and new agents (febuxostat and PEG-uricase).
Allopurinol inhibits xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine to uric acid. Steady doses of this drug thus result in decreases in the serum urate levels and dissolution of tophi. Before starting allopurinol, a thorough discussion with the patient is necessary regarding potential adverse effects. The patient must be cautioned about early signs and symptoms of hypersensitivity reactions.
Potential adverse effects of allopurinol include rash, nausea, vomiting, renal failure or impairment, and, less commonly, nephrolithiasis, bone marrow suppression, angioedema, bronchospasm, exfoliative dermatitis, pancreatitis, hepatitis, peripheral neuropathy, Stevens-Johnson syndrome, and toxic epidermal necrolysis.19 Allopurinol hypersensitivity syndrome can manifest with erythematous rash, fever, hepatitis, eosinophilia, or acute renal failure. Allopurinol hypersensitivity is a serious and potentially life-threatening reaction to allopurinol. If hypersensitivity is suspected, the drug should be discontinued immediately and the patient should be followed closely for failure of symptoms to resolve and for any progression of symptoms. Hypersensitivity can occur in patients with renal insufficiency; therefore, a low starting dose, 25 to 50 mg, is recommended in this patient population.
Drug interactions occur with oral anticoagulation (such as warfarin), azathioprine, mercaptopurine, cyclophosphamide, cyclsoporine, and iron supplements. Allopurinol, azathioprine, and mercaptopurine share the same enzyme, xanthine oxidase, and could therefore increase the levels of those drugs, leading to exaggerated marrow suppression. Caution is necessary with the use of allopurinol in patients treated with cyclosporine, because this combination can lead to an increase in the serum levels of cyclosporine.
The recommended starting dose is 100 mg a day, increasing gradually every 2 weeks to reach a target serum uric acid level of less than 6 mg/dL. In patients with renal impairment, it is safer to start at 25 to 50 mg a day.
Uricosuric agents available in the United States are probenecid and sulfinpyrazone; benzbromarone is not available in the United States. These agents inhibit the urate-anion exchanger in the proximal tubule that mediates urate reabsorption, leading to increased urate excretion through the kidneys. It is advisable to maintain good urine volume and avoid dehydration in patients taking those agents.
Before starting uricosuric agents, a 24-hour urine excretion of uric acid should be checked. These drugs are avoided in patients who have overproduction of urate. In addition, these drugs should be avoided in patients with a history of urate nephrolithiasis.
For probenecid, as with all hypouricemic drugs, it is advisable to start at a low dose and increase gradually to the target serum urate level. The starting dose is 250 mg twice a day. The maintenance dose varies and on average is 500 to 1000 mg two or three times a day. The maximum effective dose is 3000 mg a day.
For sulfinpyrazone, the starting dose is 50 mg twice a day, and the average dose varies, depending on serum urate levels, from 100 to 200 mg three or four times a day. The maximum effective dose is 800 mg a day.
Adverse effects include rash, precipitation of acute gouty arthritis, GI intolerance, and uric acid stones. Probenecid, in particular, increases urinary calcium excretion in gouty patients and thus is contraindicated in patients with a history of calcium or urate nephrolithiasis.
Drug interactions with probenecid include interference with penicillin and ampicillin excretion and autoimmune hemolytic anemia.
Febuxostat and PEG-uricase (Puricase) might have an advantage with their potential role in patients who are allergic or refractory to treatment with allopurinol. However, this specific indication has not been fully investigated.
Febuxostat is a nonpurine selective inhibitor of xanthine oxidase20 that has undergone phase I, II, and III trials for treating hyperuricemia in patients with gout.21 It earned approval from the U.S. Food and Drug Administration (FDA) in February 2009. Current data indicate that it is a potent inhibitor of the enzyme that leads to significant urate reduction and is comparable with allopurinol.22
In a study comparing febuxostat with allopurinol in patients with gout and urate levels of at least 8 mg/dL, urate levels dropped to less than 6 mg/dL in 53% of patients who received 80 mg of febuxostat, whereas this level was achieved in only 21% in the allopurinol group.22 The response was more impressive in the group taking 120 mg of febuxostat. This response was also consistent with reduction in tophus size in both groups.
This study proves the superiority of febuxostat to 300 mg of allopurinol, and it also emphasizes the importance of titrating the dose to reach target levels instead of using a standard dose of 300 mg in all patients. Furthermore, after cessation of prophylaxis (colchicine or naproxen was used), after week eight of starting febuxostat or allopurinol, the incidence of gout flares doubled in the group taking 120 mg of febuxostat and tripled in the group taking 80 mg of febuxostat and 300 mg of allopurinol.22 This result supports the concept of necessary long-term prophylaxis for acute gout attacks when hypouricemic therapy is initiated.
Febuxostat is well tolerated, even in patients with mild renal impairment, without the need for dosage adjustment.
The most frequently reported adverse effects are diarrhea, back pain, headaches, and arthralgias and patients should monitored for thromboembolic events and increase in hepatic transaminases. Adverse effects were not increased in subjects with moderate renal insufficiency (creatinine 1.6-2.0 mg/dL). The doses used in trials were 40, 80, and 120 mg orally daily; however the dose to be used in clinical practice may be closer to 80 mg.22a
PEG-uricase is the pegylated form of uricase, the enzyme that catalyzes conversion of urate to allantoin. This enzyme is naturally lacking in human beings, and thus we are unable to catabolize urate naturally. The enzyme itself is highly immunogenic.
This drug has been used in the past, as Rasburicase, to treat tumor lysis syndrome. However, serious allergic reactions resulted after repeated infusions of this drug, which has limited its use to a one-time infusion. To make the drug less immunogenic, it was pegylated. Pegylation prevented production of antibodies to the uricase protein.
It has been given intravenously or subcutaneously in the studies and has been shown to be safe so far; larger studies are under way. Puricase is promising, and it is probably the most impressive drug used in decreasing tophi burden. However, more data are needed to assess its long-term safety and tolerability.23
During treatment with a urate-lowering agent, urate levels fluctuate, leading to increased risk of gout attacks. The best prevention is caution using prophylaxis therapy. Colchicine is the most popular prophylaxis. However, in patients who are unable to take colchicine, NSAID therapy or low-dose steroids may be helpful.
Colchicine prophylaxis helps decrease the risk of recurrent flares. Ample data suggest benefit from treating patients with colchicine during initiation of allopurinol therapy. Prophylactic therapy should continue for 6 months to 1 year, if possible.22,24
Foods and beverages have long been known to cause gout and gouty attacks. Diet can have some influence on hyperuricemia and gouty attacks, but dietary factors are not sufficient to explain the majority of gout attacks. Patients are encouraged to follow healthy diets sufficient in dairy products; to avoid excessive consumption of alcohol (especially beer), shellfish, and organ meats; and to consume other protein-rich foods in moderation.10,11 Patients whose diets are poor in dairy products have a higher risk of developing gout attacks than those who consume more dairy products.11,25
Gout or hyperuricemia in an adolescent or child is invariably a manifestation of an underlying metabolic or inherited enzyme deficiency. Therefore, gout in the young, although rare, should trigger a workup for such diseases.
Gout is not uncommon in postmenopausal women. Estrogen has natural uricosuric effects in premenopausal women. However, after menopause the uricosuric effect is lost and risk of developing gout is increased. Therefore gout in postmenopausal women is more common and tends to involve the upper extremities more often.26
Use allopurinol with caution in patients taking azathioprine (in the cases of transplant patients and patients with systemic inflammatory diseases who require azathioprine). The combination of azathioprine and allopurinol increases the levels of azathioprine in the blood, and this increases the risk of bone marrow suppression.27 Moreover, cyclosporine, another agent used commonly in transplant patients, can increase urate levels.
The metabolic syndrome needs to be considered and identified in patients with hyperuricemia. In this case, it is essential to treat the underlying conditions, such as hypertension, overweight, dyslipidemia, and insulin resistance, in addition to treating gout. When an antihypertensive is being considered, losartan offers an advantage because it has mild hypouricemic properties. Prevention of obesity and hypertension might decrease the incidence of gout and morbidity.1
Pseudogout is a clinical syndrome in which calcium pyrophosphate dehydrate (CPPD) crystals deposit in joints and soft tissue, resulting in inflammation and tissue damage. The clinical presentation resembles gout in its acute attacks of crystal synovitis, thus the term pseudogout. When calcification of cartilage is apparent under radiographic examination of joints, the syndrome is called chondrocalcinosis. Although CPPD crystal deposition and chondrocalcinosis are seen in pseudogout, not all patients with chondrocalcinosis or CPPD crystal deposition present with pseudogout.
Limited studies published in the literature have specifically addressed the epidemiology of pseudogout. Epidemiologic studies regarding pseudogout or CPPD arthropathy have not been consistent in using universal investigative methods. Some looked at the prevalence of CPPD arthropathy described radiographically by the finding of chondrocalcinosis in degenerative joint diseases,28 and others looked at synovial fluid analysis.
This discrepancy creates limitations in extrapolating these data to patients with the clinical constellation of symptoms of pseudogout. A study that looked at age distribution of patients with CPPD by radiographic examination reported the prevalence to be 15% between the ages of 65 and 74 years and higher than 40% after the age of 84 years.28
Genetic factors have been investigated and are believed to cause familial autosomal dominant CPPD chondrocalcinosis. Studies are looking at mutations of the chondrocalcinosis ANKH gene, but its functional role is not fully understood.29
This disease is not commonly encountered at a younger age without a previous history of trauma or surgery. The disease is seen more commonly after age 50 years, and it has no definite ethnic or gender predilection.30
Although the pathogenesis of CPPD deposition and pseudogout is not as well understood as the pathogenesis of gout, there is probably excessive pyrophosphate production in cartilage resulting in calcium pyrophosphate supersaturation and the formation of CPPD crystals.31,32
Chondrocalcinosis and pseudogout may be associated with certain underlying diseases such as trauma to the joint, hyperparathyroidism, hypomagnesemia, hypophosphatasia, hypothyroidism, and hemochromatosis.33 This highlights the importance of addressing other possible underlying diseases when evaluating the patient with pseudogout and chondrocalcinosis.
Although CPPD crystal deposition disease encompasses a variety of clinical manifestations ranging from asymptomatic to goutlike (pseudogout), rheumatoid arthritis–like (pseudo-rheumatoid arthritis) or osteoarthritis-like (pseudo-osteoarthritis), pseudogout is distinguished by acute attacks of synovitis mimicking gout. These acute or subacute attacks can involve one or multiple joints, commonly not more than four or five joints at one time.34 Pseudogout, like gout, however, can manifest with more systemic features such as fevers, malaise, leukocytosis, and elevated acute phase reactants (sedimentation rate and CRP). Acute attacks may be indistinguishable from acute gout. In fact, it is often difficult to differentiate both without a synovial fluid analysis. Patients have joint pain, synovitis with joint tenderness, and swelling. Pseudogout and gout can share similar joint predilection, but pseudogout affects larger joints more commonly than gout (knee joints) and less so the smaller joints (first metatarsophalangeal joints). It also affects the elbow, shoulder, wrist, and metacarpophalangeal joints.
Because pseudogout closely resembles gout, the definite diagnosis of pseudogout often necessitates synovial fluid analysis. Synovial fluid should be microscopically analyzed for cell count and crystal analysis under compensated polarizing microscopy. In addition, fluid should be examined for Gram stain and culture, especially if crystals are not found.35 On synovial fluid polarization, CPPD crystals might not be as evident as MSU crystals. They are weakly birefringent under polarized light and have a rhomboid or rod-shaped appearance. They are seen either intracellularly or extracellularly, and detection might not be as accurate if fluid analysis is delayed.15 In addition, because pseudogout and gout can coexist, MSU crystals might also be observed. White cell counts can range from a few thousand cells up to 80,000 to 100,000 per high-power field.
Radiographs can show chondrocalcinosis in the joint involved and other more typical joints even if pseudogout is not clinically active at the time of presentation. They are helpful in confirming the clinical impression (especially the knee joints, wrists, and anteroposterior view of the pelvis) and extent of joint degeneration; however, radiographs are not required to make the diagnosis once CPPD crystals are seen under polarized light. Chondrocalcinosis is seen in the knees (hyaline cartilage and menisci), the wrists (fibrocartilage), and other joints such as intervertebral discs and symphysis pubis. Other radiographic features include joint space narrowing, subchondral new bone formation, normal mineralization, cysts more prominent than in osteoarthritis, bilateral preponderance, and osteophyte formation.12,36 Certain metabolic conditions associated with CPPD disease, such as in hemochromatosis, have characteristic findings such as joint narrowing of the metacarpophalangeal joint spaces, squaring of the bone ends, subchondral cysts, and hook-like osteophytes on the radial aspects of the metacarpal heads, especially the second and third metacarpophalangeal joints.37
Most of the differentials mentioned with gout can be considered here. Infection is always a major differential, especially in the patient presenting with new acute monoarticular arthritis. In addition, septic arthritis can coexist in the joint that has been or is involved in an acute pseudogout attack. Thus, it is important to aspirate the involved joint whenever possible for microscopic examination of the synovial fluid and Gram stain and culture. Other differentials include trauma, bleeding, and other crystal-deposit diseases. Calcium pyrophosphate deposition disease mimics polymyalgia rheumatica.38
The optimal therapy is one that promptly treats an acute attack, prevents further attacks, and prevents or reverses the degenerative joint disease associated with CPPD arthropathy. Unfortunately, there is no proven therapy that fits this description.
The treatment of pseudogout is mostly tailored to the manifesting symptoms. In patients presenting with one or two points of acute synovitis, rapid relief of pain and inflammation is accomplished with joint aspiration and steroid injection, if no infection is present. In fact, patients often find relief from the joint aspiration itself. When more than two joints are involved it is not feasible to inject all the joints, so treatment is directed more toward systemic therapy. The side effects and toxicities of NSAIDs, colchicine, or systemic glucocorticoids are similar to those discussed for gout. Colchicine at a dose of 0.6 mg once or twice daily may be effective as a prophylactic measure to reduce the number of attacks in a year,39 especially in patients who experience three or more attacks a year. Unlike gout, however, there are no hypouricemic equivalents to improve the long-term control of pseudogout and to prevent or reverse CPPD crystal deposit disease.
The outcome of patients with pseudogout is influenced by genetic predisposition, extent of crystal deposition and joint degeneration, and aggravating factors from the underlying associated diseases. A study looked at the outcomes of 104 patients with pyrophosphate arthropathy for a mean of 4.6 years and found that patients presenting with acute attacks have a good prognosis, and some patients might not have a progressive disease.40
Because CPPD deposition disease is associated with variety of underlying conditions,33,41 I recommend screening for hyperparathyroidism, hypothyroidism, hypomagnesemia, hypophosphatasia, and hemochromatosis. Blood should be tested for intact parathyroid hormone, calcium, phosphorous, thyroid-stimulating hormone, magnesium, ferritin, iron transferrin, and alkaline phosphatase. Treatment of associated diseases is recommended. However, it is unclear if treatment of comorbid conditions would decrease the chondrocalcinosis or reverse joint degeneration.
Crystal deposition disease is a fairly common condition. It is encountered by rheumatologists and other physicians. Gout and pseudogout are the most commonly encountered, but one needs to be aware of the presence of other types of crystal arthropathy, such as hydroxyapatite crystal deposition disease. In this case, crystals might not be seen on classic synovial analysis.
Gout and pseudogout can manifest with similar symptoms, and their signs might not be distinguishable; thus, it is essential to aspirate the affected joint or bursa for synovial fluid and crystal analysis whenever possible. Cell count, Gram stain, and culture, in the right clinical setting, should be sought.
Once the diagnosis is made, treatment for acute attack should be commenced using the least-toxic agent. Treatment should be initiated while taking into consideration other comorbid conditions, such as renal disease, gastric disease, organ transplant, drug interactions, and others, because these will dictate the choice of therapy. In the case of gout, once the acute disease has resolved, the patient should be followed to assess for indications and need for hypouricemic therapy.
New drugs are on the horizon for managing chronic tophaceous gout. Febuxostat has been approved by the FDA, and PEG-uricase could soon earn FDA approval. Keeping on the lookout for new research data, indications, contraindications, and criteria for use of these drugs is essential, because these drugs might come with different criteria for initiating therapy.