Key Clinical Questions
Why do patients have acute flares of crystal arthropathies?
How is gout distinguished from other monoarthropathies?
What are the appropriate therapies for acute and chronic gout and pseudogout?
What are the pathophysiologic features of osteoarthritis (OA), and how do these relate to clinical manifestations?
How is OA differentiated from other types of arthritis?
What are the nonpharmacologic, pharmacologic, and surgical treatment options for OA?
Gout, pseudogout, and osteoarthritis make up the largest portion of the rheumatic diseases that affect primarily joints. Although these three disease entities are quite distinct, they share a number of features in common: all tend to be diseases seen at older ages; all three are often seen in overlap with each other; and all three are characterized primarily by inflammatory and/or mechanical abnormalities, rather than autoimmune ones. Whereas gout and pseudogout are diseases of abnormal crystal formation and resultant inflammation, osteoarthritis is primarily a disease of mechanically driven, biochemically propagated cartilage loss and autodestruction. In the following sections, we discuss these three important diseases, their pathogenesis, and management.
Gout currently affects more than 8 million Americans, usually presenting with severe acute episodic arthritis that may evolve over time into chronic destructive tophaceous disease. Gout is more common in men (6.1 million US males vs 2.2 million US females), and is slightly more common among African Americans (5% of the African American population vs 4% of the US white population). The prevalence of gout rises with age, from 3.3% among individuals 40 to 49 years old, to 8.0% among individuals 60 to 69, to as high as 12.6% in those 80 years and older. The annual incidence of gout rose from 4.5 per 10,000 in 1977 to 1978 to 6.4 per 10,000 in 1995 to 1996, and to 12.4 per 10,000 from 1994 to 2007. Overall, the prevalence of gout has more than quadrupled over the past half-century. Despite being the most common inflammatory arthropathy, gout is frequently misdiagnosed and mismanaged.
The most important risk factor for gout is hyperuricemia, or an excess of serum urate, the end product of purine metabolism. Serum urate concentrations are determined by the balance between urate production and elimination; hyperuricemia may be caused by either overproduction or underexcretion of urate, or a combination of both. Consumption of meat or seafood promotes hyperuricemia and gout as a result of the high-purine content of these foods. In contrast, alcohol consumption increases urate production through multiple mechanisms, including generation and turnover of ATP (a purine base), diuresis and dehydration, production of lactic and ketoacids (which block renal urate excretion), and the consumption of purines in alcoholic beverages. Beer and ale ingestion are most strongly correlated with hyperuricemia and gout (presumably because of their higher-purine content), while hard liquor increases serum urate and gout risk to an intermediate degree. Moderate wine consumption has a lesser effect on serum urate and the risk of gout, possibly because of other compounds present in wine. In history, the high prevalence of gout in affluent drinkers of wine and port may have been related to the use of lead acetate by wine merchants as a preservative and sweetener; chronic lead poisoning causes tubulointerstitial kidney disease that promotes hyperuricemia (saturnine gout) (Table 247-1).
TABLE 247-1Substances That Affect Urate Levels
More than 100 years ago Osler suggested that sugar intake might increase the risk of gout; recent studies prove Osler to have been correct. Gout prevalence has increased over the last 50 years, concomitant with the introduction and rising consumption of high-fructose corn syrup as a sweetener in prepared foods. Human metabolism and degradation of fructose generates urate to a greater degree than occurs with other sugars. In addition, fructose may have other hyperuricemia-inducing effects, by virtue of its ability to modulate urate transport in the kidney. In contrast, dairy consumption appears to be protective against hyperuricemia, perhaps because of the uricosuric effect of milk proteins such as casein.
Uric acid is eliminated from the body by both gastrointestinal and renal routes. Approximately one-third of urate elimination occurs through the gastrointestinal system, in saliva, gastric juices, pancreatic secretions, and direct loss from the bowel. The remaining two-thirds of urate excretion is via glomerular filtration and a complex balance of tubular secretion and reabsorption in the kidneys. Urate is freely filtered by the glomerulus, but 90% or more is reabsorbed. Tubular handling of urate is carried out via several organic anion transporters (OATs). Genomewide association studies have expanded our understanding of urate metabolism, and have identified genes that encode urate transporters in the kidney as well as the gut. Important genes involved in renal reabsorption of urate include SLC22A12 (encodes URAT1, a reabsorbing transporter) and SLC2A9 (encodes GLUT9 transporter). A number of agents that lower serum urate, such as probenecid, act by inhibiting URAT1 to promote renal urate excretion. In contrast, the ABCG2 gene has been found to encode the BRCP transporter, which promotes the renal tubular excretion of urate. Patients with genetic defects in BRCP tend to have reduced renal urate excretion, and increased serum levels of urate.
Hyperuricemia is considered either primary (related to intrinsic qualities of the individual) or secondary (acquired). The vast majority of gout patients have primary hyperuricemia, which may be compounded by secondary disease. About 90% of gout patients are primary underexcreters, with genetic molecular defects in renal urate excretion. Most of these patients have otherwise normal renal function. Primary overproduction accounts for the remaining 10% of primary hyperuricemia. Some patients who are primary overproducers have complete (Lesch-Nyhan syndrome) or partial (Kelly-Seegmiller syndrome) deficiency in hypoxanthine phosphoribosyltransferase (HPRT), the rate-limiting enzyme responsible for the salvage of degraded purines for reuse. All patients with Lesch-Nyhan syndrome, and some with Kelly-Seegmiller syndrome, also have neurocognitive deficits that are independent of their serum urate levels.
Secondary hyperuricemia occurs in acquired conditions that result in decreased urate excretion or increased urate generation. Acute or chronic renal insufficiency may impair urate excretion. Diseases of increased cell turnover, such as malignancies and hemolytic anemia, result in high urate production. Hyperuricemia can rarely manifest in the early teens due to a group of autosomal dominant diseases, which include familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney type II disease. These diseases feature a mutant gene that interrupts the tertiary structure of uromodulin, also known as Tamm-Horsfall protein. The clinical presentation of these diseases not only includes early-onset gout, but also progressive renal failure and polyuria.
Gout has traditionally been considered to occur in four progressive stages. In asymptomatic hyperuricemia, the risk of an acute gout attack increases as the level of uric acid rises past its solubility point (> 6.8 mg/dL). Once solubility is exceeded, monosodium urate crystals may precipitate in joint spaces and lead to acute gouty arthritis. During this stage, the innate immune system initiates a cascade of events in response to the crystals, including activation of complement and resident joint tissue macrophages, and recruitment of neutrophils from the bloodstream. The inflammasome, an intracellular assembly in macrophages that activates interleukin-1β (IL-1β), has recently been implicated in the inflammatory response to uric acid crystals. IL-1β in turn stimulates the production of other inflammatory mediators, including tumor necrosis factor (TNF)-α, IL-6, IL-8, and prostaglandin E2. The result is severe local inflammation as well as a systemic response to cytokine release, including low-grade fever and elevated acute phase reactants. Acute gout attacks are exquisitely painful but typically self-limited, even without therapy, apparently because of inflammatory autoregulation.
The asymptomatic interval between acute gouty attacks is known as intercritical gout. Over time attacks tend to come more frequently, the intercritical period dwindles, and chronic tophaceous gout may develop. Tophi are aggregates of urate crystals, typically accompanied by a low-level chronic inflammatory state. They are actually complex structures, consisting of a mix of monosodium urate crystals and cellular debris surrounded by activated macrophages and other immune cells. Although tophi are most obvious when they occur in the periarticular soft tissues, they may also develop in cartilage and bone. Crystal deposition may result in a number of chronic syndromes of pain and disability (Table 247-2). Radiographic images of tophi in periarticular bone reveal the pathognomonic finding of punched-out erosions with sclerotic margins and overhanging edges (Figure 247-1). Recently, more sensitive imaging using ultrasound, magnetic resonance imaging (MRI) or dual-energy computed tomography (CT) have suggested that occult tophi are much more common that previously appreciated, and often form even before the onset of the initial acute gout attack, providing a readily available source of crystals for future acute attacks.
Tophaceous gout causing an erosive arthropathy. Note the large tophi (stars) and “rat-bite” erosions with overhanging edges (arrows).
TABLE 247-2Musculoskeletal Manifestations of Crystal-Induced Arthropathy ||Download (.pdf) TABLE 247-2 Musculoskeletal Manifestations of Crystal-Induced Arthropathy
Acute monoarthritis or polyarthritis
Tophaceous deposits (including vertebrae)
Carpal tunnel syndrome
Crown dens syndrome
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
The gold standard for the diagnosis of gout is needle aspiration of acutely or chronically inflamed joints or tophi, followed by polarized light microscopy to identify negatively birefringent, needle-shaped crystals (uric acid crystals). The presence of such crystals, particularly when seen intracellularly within infiltrating neutrophils, confirms the diagnosis of an acute attack and helps to distinguish gout from septic arthritis, pseudogout, and other causes of inflammatory joint disease. Extracellular crystals alone are diagnostic of gout, but not necessarily an acute gouty attack; in patients with established gout, previously formed crystals may persist even after inflammation has resolved, residing as innocent bystanders in the setting of other joint pathologies. The sensitivity of synovial fluid analysis for demonstrating negatively birefringent crystals in patients with acute gouty arthritis is at least 85%, with a specificity approaching 100%. In contrast, the specificity of a clinical diagnosis of gout is significantly lower, and septic arthritis and pseudogout are often misdiagnosed as gout. Therefore, in almost all circumstances, diagnostic arthrocentesis should be performed if possible, especially in the hospital setting.
As acute gout may coexist with other joint pathology, a wider evaluation is almost always warranted, even in the presence of intracellular, negatively birefringent crystals. In addition to crystal analysis, synovial fluid should always be sent for cell count with differential, Gram stain, and culture. Grossly, synovial fluid is typically straw colored and varies from translucent to opaque. Synovial fluid cell counts in gout may range from 2000 to >100,000 per mm3, with greater than 50% neutrophils (often approaching 90%). Serum uric acid should also be obtained during an acute attack, and a high serum urate supports the possibility of a diagnosis of gout. However, patients may be hyperuricemic without having gout, and serum urate levels in gout patients may be transiently normal or low during an acute attack due to an increase in renal excretion (an effect of the cytokine IL-6 on the kidney). Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are typically elevated during a gout attack, but this finding is nonspecific. Urinary uric acid collections should not be obtained during gout attacks; they are neither useful nor reliable in the acute period.
Radiographs in the acute setting typically show only nondescript soft tissue swelling, but radiographic evidence of erosions can confirm chronic disease. Musculoskeletal ultrasound (MSUS) may visualize intraarticular crystal deposits, with a characteristic hyperechoic enhancement of the outer surface of the hyaline cartilage, known as the double contour sign. MSUS may prove to be an alternative method for the diagnosis of the crystal arthropathies, but limitations include the inability to distinguish the presence or absence of infection. Advanced imaging technologies such as dual energy computed tomography (DECT) and improved magnetic resonance imaging can also play a role in the diagnosis and differentiation of gout from other inflammatory arthropathies, but availability and cost limit their current clinical utility.
The differential diagnosis for acute gout includes conditions generally associated with acute monoarthritis, such as pseudogout and septic arthritis, as well as conditions leading to oligoarthritis and polyarthritis, such as reactive arthritis, psoriatic arthritis, and even rheumatoid arthritis. Ideally, a crystal diagnosis of gout should be the goal; if this is not possible, the diagnosis of acute gouty arthropathy should be made by a combination of historical and clinical criteria. A thorough history will help distinguish an acute gout attack from other causes of acute arthritis. Some of the previously proposed clinical, radiographic, and laboratory criteria include (1) a history of one or more episodes of monoarticular arthritis, followed by intercritical periods completely free of symptoms (may not be applicable in the acute hospital setting); (2) maximum inflammation within 24 hours of onset of the attack; (3) rapid resolution after initiation of colchicine or a nonsteroidal anti-inflammatory drug (NSAID); (4) unilateral first metatarsophalangeal joint involvement (podagra), especially during a first event; (5) hyperuricemia; and (6) bony erosions (punched out lesions with overhanging edges) on plain radiograph or (7) tophi.
Acute attacks most often affect the first metatarsophalangeal joint (up to 50% of first attacks). The tarsal joints, ankles, knees, elbows, and interphalangeal (IP) joints are also commonly affected. In elderly patients with osteoarthritis (OA), Heberden and Bouchard nodes (seen in hand OA) are potential targets for inflammation, and red, swollen proximal and distal IP joints may be the first manifestation of gout. Episodes of acute gouty arthritis frequently come on rapidly at night or in the early morning with dramatic pain and swelling. The joint becomes warm, red, and tender, often mimicking cellulitis. Without treatment, most acute attacks resolve in 2 to 14 days.
While acute gout attacks can often be managed in the outpatient setting, patients may need to be admitted to the hospital to facilitate workup or to rapidly and definitively rule out the possibility of infection. Patients with severe disability from their acute attack and inadequate home support may need to be admitted until they are able to ambulate or otherwise function. Often, patients at risk may develop acute gouty attacks while hospitalized for other problems. In the hospital setting, attacks may be precipitated by metabolic acidosis, fasting, diuretics, or disruptions in volume status or renal function that may cause acute swings (both elevations and depressions) in serum urate levels. Discontinuation of urate lowering therapy in hospitalized gout patients is a common error that can lead to acute serum urate changes that provoke gouty attacks; this practice is not recommended according to the American College of Rheumatology (ACR) 2012 treatment guidelines. Gout flares occurring during hospitalization for other causes are generally avoidable, and increase the length of stay by approximately 3 days.
Colchicine is effective in the acute setting, and, if initiated sufficiently early, may abrogate an acute attack. It is typically less effective after the attack is established (≥36 hours). The traditional dosing of colchicine for acute attacks (0.6 mg by mouth every 1-2 hours until onset of relief or a maximum of 6 mg) frequently led to undesirable side effects. A more limited regimen—colchicine 1.2 mg, followed by 0.6 mg 1 hour later—is equally effective, with toxicity similar to placebo. It has now been adopted as standard of care. Patients with renal insufficiency may receive this regimen, but should subsequently discontinue any use of low-dose daily colchicine for several weeks; patients without renal disease may continue their prophylaxis unabated.
Treatments for acute gout, such as NSAIDs, glucocorticoids and particularly colchicine, work best when administered within hours of the onset of the attack.
For many patients, NSAIDs are preferred agents for acute gout. Indomethacin is the traditional choice at 50 to 75 mg initially, then 50 mg every 6 hours, not exceeding 200 mg in a 24-hour period. However, clinical studies have shown that many other NSAIDs, including COX-2 selective agents, are as effective as indomethacin when used at their maximum doses and may be better tolerated. NSAIDs have the advantage of both analgesic and anti-inflammatory effects, but may be relatively contraindicated in patients with gastritis, renal insufficiency, hypertension, and heart failure. In order to maximize response time while minimizing side effects, a combination of more than one class of medications, such as NSAID plus colchicine, is sometimes used in treating acute attacks.
Glucocorticoids are potent anti-inflammatory agents that can be highly effective at abrogating acute gouty attacks. Intraarticular glucocorticoids may be particularly useful in treating acute gout in a single joint or bursa when systemic glucocorticoid use is undesirable. Care must be taken to establish the diagnosis and to rule out infection prior to injecting glucocorticoids directly into the joint. As a practical matter, this often means performing joint aspiration and injection as separate procedures, which may unfortunately add to the patient’s discomfort. Oral and intravenous glucocorticoids are both very effective, especially in patients with polyarticular attacks, and may be the agents of choice in patients with contraindications to colchicine and NSAIDs, such as renal insufficiency. ACR guidelines recommend a starting dose of approximately 0.5 mg/kg/d of oral prednisone. Although treatment periods with oral steroids are typically brief (about a week), relative contraindications such as diabetes, hypertension, and heart failure must be considered.
A single intramuscular injection of depot adrenocorticotropic hormone, or ACTH gel (25-80 IU, repeated 24-72 hours later if needed) can also terminate attacks effectively and may be particularly useful in patients who cannot take oral medication. In addition to stimulating the adrenal cortex to produce corticosteroids, ACTH reduces the acute inflammatory response by activating melanocortin receptor-3. Follow-up treatment using low-dose (one to two times daily) colchicine is typically recommended to prevent rebound attacks as the ACTH wears off. However, ACTH gel is currently not Food and Drug Administration (FDA) approved for use in gout, and its high cost in the United States limits its use.
Given the role of IL-1β in acute gouty inflammation, several studies have addressed the use of anti-IL-1β biological therapy in acute gout flares. Both anakinra, an IL-1β receptor antagonist, and canakinumab, an anti-IL-1β antibody, have shown efficacy. Although expensive and off-label, these agents may be considered when established therapies have failed and/or are contraindicated.
CHRONIC MANAGEMENT OF GOUT
The goal of chronic gout management is to prevent acute attacks and to decrease the total body urate burden, including both visible tophi and occult deposits. This is achieved by lowering serum urate to less than 6 mg/dL, and requires a multipronged approach. Lifestyle changes such as weight loss, avoidance of fructose-rich foods and high-purine foods such as organ meats and shellfish, and eliminating or reducing alcohol consumption should be the first step, with the addition of one or more urate-lowering agents being necessary for most patients with chronic gout. Medication review may identify agents that are contributing to hyperuricemia. For example, thiazides and loop diuretics reduce uric acid excretion and raise serum urate. Therefore, these should be used at the lowest effective dose, or stopped if appropriate alternatives are available. Both losartan (for hypertension) and fenofibrate (for hyperlipidemia) have uricosuric properties and may be useful options for treatment of these conditions in patients who also have gout.
Current ACR guidelines address the management of gout patients, including the initiation of urate-lowering therapy. Urate-lowering therapy should be started on any gout patient with 2 or more attacks in a 12-month period. Patients with tophi should also undergo urate lowering, as should patients with stage 2 or worse chronic kidney disease or a history of urolithiasis, even after only a single attack. Urate-lowering agents commonly used to treat chronic gout include inhibitors of xanthine oxidase (allopurinol and febuxostat) and uricosuric agents (probenecid, sulfinpyrazone, and benzbromarone).
Long considered a first-line agent for chronic gout management, allopurinol is a purine analog of hypoxanthine. Along with its active metabolite oxypurinol, allopurinol competitively inhibits xanthine oxidase, decreasing urate production and serum uric acid levels. Appropriate allopurinol use requires dose titration to achieve a prespecified serum urate target, most commonly <6 mg/dL (lower if necessary to reduce tophi or control attacks). The most common dose required to achieve target is 400 mg/d. Lower doses may be sufficient in some patients, but doses as high as 800 mg/d may be required in others (and are FDA approved). Side effects are uncommon but may be serious and include rash, cytopenias, and hypersensitivity syndromes, such as toxic epidermal necrolysis and Steven-Johnson syndrome. Although most serious side effects occur within the first 6 to 8 weeks of use, long-term monitoring is required. Dosing should be initiated at 100 mg/d, and increased every 2 to 5 weeks until the target dose is achieved. For patients with stage 4 or greater chronic kidney disease, the ACR recommends initiating a dose of 50 mg/d, but still titrating to serum urate target. Since azathioprine is metabolized by xanthine oxidase, allopurinol use may raise azathioprine levels and result in bone marrow toxicity. Concomitant use of allopurinol and azathioprine should therefore be avoided or relegated to experts.
Febuxostat is a nonpurine, selective inhibitor of xanthine oxidase. Dosing is limited to 40 to 80 mg daily (up to 120 mg daily in Europe), and dose adjustment is not needed in patients with mild to moderate kidney impairment. Febuxostat does not chemically resemble allopurinol and appears to be safe for patients with allopurinol sensitivity. In several clinical trials, febuxostat 40 mg has been shown to be roughly equivalent to allopurinol 300 mg for urate lowering.
Uricosuric medications such as probenecid, sulfinpyrazone, and benzbromarone (the latter two not available in the United States) increase renal urate excretion by inhibiting URAT1 transporters in the proximal tubule. To prevent uric acid kidney stones, patients should drink generous amounts of fluids and avoid high doses of vitamin C and other drugs that may acidify the urine. Urine alkalinization may occasionally be necessary. For most patients these agents are considered second-line therapy, or may be added to a xanthine oxidase inhibitor for added benefit. Most current uricosuric agents work poorly in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rate <50 mL/h). The recently approved uricosuric lesinurad is effective even in patients with kidney disease as low as 45 ml/min, but is indicated for use only in conjunction with allopurinol or febuxostat.
A novel therapeutic approach to urate lowering is to provide uricase, a urate-degrading enzyme that humans lost the ability to synthesize millions of years ago. Pegloticase is a pegylated recombinant mammalian (porcine/bovine) uricase. It is given by intravenous infusion and can rapidly and dramatically decrease serum urate levels. Pegloticase has been approved by the Food and Drug Administration for patients with gout who have failed or are intolerant of other therapy, and is significantly more effective than other agents at resolving tophi.
Since pharmacologic lowering of uric acid paradoxically increases the risk of gout for a period of at least 6 months, patients starting any of these drugs should be prophylaxed against acute attacks. Patients typically should be started with colchicine 0.6 mg once or twice daily beginning several days before the initiation of urate-lowering therapy, and continuing for at least several months after the target urate level has been achieved. Low-dose NSAIDs or prednisone are options for patients who cannot tolerate colchicine.
Rheumatology consultation should be obtained when the diagnosis is unclear or the presentation seems atypical for a patient with known gout. Consultation should also be obtained when synovial fluid cannot be obtained easily, when expertise is required in fluid analysis or interpretation, or when contraindications to traditional therapies complicate patient management.
PSEUDOGOUT AND CHONDROCALCINOSIS: CALCIUM PYROPHOSPHATE DEPOSITION (CPPD) DISEASE
Although pseudogout is frequently considered a poor cousin of gout, it is a common condition that can be acutely incapacitating and chronically destructive, and presents as a cause or consequence of hospital admission. Like gout, pseudogout is a disease in which crystal formation leads to inflammation and mechanical damage. Unlike gout, in which a systemic metabolic derangement promotes crystal deposition, pseudogout usually appears to derive from metabolic abnormalities intrinsic to chondrocytes, resulting in crystal deposition in cartilage. However, the result is similar: innate immune responses to crystals leads to local hyperemia, joint effusion, and neutrophil influx, and the four cardinal signs of inflammation: heat, redness, pain, and swelling.
Although pseudogout may occur in familial, early-onset forms, most cases are sporadic and acquired. Acquired pseudogout is a disease of aging, rarely presenting before the age of 50. Exceptions include patients with cartilage derangement from prior injury and patients in whom pseudogout is secondary to other medical conditions (see below). Both men and women may contract pseudogout, with women affected somewhat more commonly than men.
In pseudogout, the offending crystal is calcium pyrophosphate, and the perpetrating cell appears to be the articular cartilage chondrocyte itself. Chondrocytes in healthy articular cartilage prevent calcification and maintain the elastic cartilage matrix. In pseudogout, chondrocytes go awry and promote calcium pyrophosphate deposition (Figure 247-2). That chondrocytes are able to lay down calcium crystals should not be surprising, as growth plate chondrocytes direct bone formation during fetal development.
Severe pseudogout, with linear deposition of calcium pyrophosphate throughout the meniscus (arrows).
Chondrocyte dysregulation in pseudogout appears to result in a local oversupply of inorganic pyrophosphate (PPi). Abnormalities in several enzymes have been implicated, including nucleotide pyrophosphatase phosphodiesterase 1 (NPP1), which liberates extracellular PPi from adenosine triphosphate (ATP) and other nucleotide triphosphates, and the ankylosis human protein (ANKH), a transmembrane protein that transports PPi from inside to outside the chondrocyte. Mutations increasing ANKH activity have been detected in some cases of familial pseudogout; in sporadic pseudogout, ANKH may be normal in structure, but upregulated in activity. The rise in extracellular PPi concentrations shifts the equilibrium for encounter with extracellular inorganic calcium ions, resulting in precipitation.
Extracellular precipitation of calcium pyrophosphate results in crystal deposition within cartilage (chondrocalcinosis), which can often be detected on plain radiographs or using musculoskeletal ultrasound. The typical appearance of chondrocalcinosis is a linear or stippled radiodense deposit, below but parallel to the surface of the cartilage. Chondrocalcinosis alone is usually insufficient to promote acute inflammation, presumably because crystals in cartilage are sequestered from the immune system. Indeed, chondrocalcinosis is frequently diagnosed as an incidental, asymptomatic finding on radiographs taken for other reasons. However, when crystals appear in joint fluid, either from shedding from cartilage or precipitation in the joint space, they promote the same sorts of inflammatory processes seen in gout. Like uric acid crystals, calcium pyrophosphate crystals may activate complement, promoting neutrophil chemotaxis, and interact with synovial macrophages to induce production of IL-1β and other cytokines. The clinical presentation of pseudogout can therefore mimic gout, with a rapid onset of joint inflammation sometimes precipitated by trauma or metabolic derangements, and is typically self-limiting after days of inflammation. However, the presence of CPP crystals may sometimes promote chronic smoldering inflammation, rather than acute inflammation.
Chondrocalcinosis (radiologic evidence of calcium pyrophosphate deposition in cartilage) indicates overproduction of calcium pyrophosphate. However, chondrocalcinosis frequently exists without the clinical inflammation of acute pseudogout, and pseudogout can conversely occur in the absence of visible chondrocalcinosis.
Calcium pyrophosphate deposition (CPPD) disease may also be associated with chronic noninflammatory joint damage. In such cases, CPPD disease may strongly resemble OA, in that progression is slow, and radiographs are characterized by joint space narrowing (ie, cartilage loss) and osteophyte formation. It is often difficult to distinguish this condition from OA itself. When chondrocalcinosis and arthritis co-occur in joints not usually associated with OA, it is usually presumed that CPPD is the driving process, with cartilage damage from crystal deposition promoting an OA picture.
A number of medical conditions have been associated with chondrocalcinosis or pseudogout. While the exact relationship between these conditions and calcium crystal deposition is not always clear, they tend to fall into several overlapping groups, which include features of cartilage destruction, metabolic abnormalities, and abnormal calcium or phosphate homeostasis. Among these are hemochromatosis, in which iron deposition in cartilage can induce OA; gout; hyperparathyroidism, with its attendant disruptions of calcium and phosphate metabolism; hypophosphatasia (in which PPi degradation by the nonspecific tissue enzyme alkaline phosphatase is diminished); and hypomagnesemia, which may alter pyrophosphatase activity.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
The typical presentation of pseudogout is acute monoarticular arthritis, most often in a large joint such as the knee, sometimes with a violent onset indistinguishable from gout. Although some clinicians aver that pseudogout is typically slower of onset and less severe than gout, these distinctions are not sufficiently rigorous to permit any speculation on whether a specific acute monoarthritis is gout or pseudogout. Compared with gout, pseudogout less commonly affects the big toe and is unrelated to dietary or bibulous indiscretion. Moreover, pseudogout is less likely than gout to be polyarticular, and since pseudogout appears to depend upon the actions of chondrocytes, it is unusual to see pseudogout in a cartilage-free structure such as a bursa. As in gout, the most important consideration in the differential diagnosis of pseudogout is septic arthritis, which may induce rapid joint damage if not promptly managed. Other crystal diseases, including hydroxyapatite and calcium oxalate deposition (the latter most common in dialysis patients), also deserve consideration. Although osteoarthritis is less inflammatory than pseudogout, patients with severe osteoarthritis occasionally have flares that may be confused with acute pseudogout. Reactive arthritis and other forms of inflammatory arthritis may appear in joints typically associated with acute pseudogout and may be clinically indistinguishable from it, though these will more often present in a chronic and polyarticular fashion.
In addition to history and physical examination, initial workup of an acute pseudogout attack should include serum white blood cell count, electrolytes, creatinine, uric acid, and ESR and/or CRP. Chondrocalcinosis on plain radiographs supports the possibility of pseudogout, but many patients with chondrocalcinosis never develop pseudogout, and some patients with pseudogout have no radiologic chondrocalcinosis. Accordingly, the diagnosis of acute pseudogout is best made by inspecting fluid from a joint aspiration using a compensated polarizing microscope. As in gout, in almost all acute circumstances, arthrocentesis should be performed; in the hands of an experienced physician, the procedure is quick, relatively painless, and of high yield. The presence of positively birefringent crystals, either needle-like, rhomboid, or both, is pathognomonic of calcium pyrophosphate deposition. The presence of these crystals within neutrophils confirms that inflammation is directed at CPP crystals. As in gout, the physician should obtain a cell count, Gram stain, and culture, and also examine the fluid for negatively birefringent, needle-like urate crystals. Both pseudogout and gout can coexist with infection, and also with each other, so that the presence of one does not rule out the possibility of the other. Indeed, a patient with a synovial fluid white count of >50,000/mm3 should generally be presumed to have an infection pending Gram stain and culture results, even if evidence of acute pseudogout or gout is also seen.
As noted above, patients with CPPD disease may, either instead of or in addition to acute pseudogout, experience progressive cartilage degeneration as in osteoarthritis. When this occurs in joints not typical for osteoarthritis, a crystal-based etiology may be presumed (Table 247-2). In these individuals, plain radiographs may reveal a combination of osteoarthritis-like joint narrowing and chondrocalcinosis. Patients with pseudogout as well as osteoarthritis in the second and third metacarpophalangeal joints should also be assessed for hemochromatosis, as these joints are atypical for primary osteoarthritis, but typical for CPPD due to hemochromatosis. In addition, patients may experience CPPD as a low-level inflammatory arthritis in almost any joint. When this occurs in the small joints of the hands, it may mimic rheumatoid arthritis (pseudorheumatoid arthritis).
Patients with clinically atypical, crystal-proven pseudogout, or those who develop CPPD before the age of 50, should be assessed for an underlying etiology. The workup may include levels of calcium, phosphate, magnesium; iron studies, including serum ferritin; testing for the hemochromatosis (HFE) gene; levels of parathyroid- and thyroid-stimulating hormone; and levels of insulin-like growth factor in patients with features of acromegaly. In most cases, however, these evaluations are not fruitful.
In an effort to simplify and regularize the nomenclature applied to CPPD disease, the European League Against Rheumatism has proposed that CPPD conditions be considered as four different characteristic conditions, using a naming system that is more accurate if less picturesque than that typically used in current practice. According to the EULAR system, CPPD conditions should be considered to include cartilage calcification, replacing the term chondrocalcinosis; acute calcium pyrophosphate arthritis, roughly the equivalent of the current term pseudogout; and pyrophosphate arthropathy, further subdivided into chronic CPP crystal inflammatory arthritis and osteoarthritis with CPPD, to distinguish between chronic conditions characterized by smoldering inflammation, and osteoarthritic cartilage degeneration presumed to be driven by CPPD, respectively. Of course, these conditions may coexist and overlap.
As with gout, acute pseudogout should be treated with whatever anti-inflammatory is most likely to be both effective and benign for the particular patient. Most patients with acute pseudogout respond well to NSAIDs, with selective COX-2 inhibitors a reasonable option. Oral, intramuscular or intraarticular corticosteroids are also effective. Care must be taken to confirm that the joint is not infected before directly injecting steroids. Conventional wisdom suggests that oral colchicine may be less efficacious for acute pseudogout than it is for gout, but studies are not available to support such a distinction, and colchicine remains a treatment option. Intramuscular ACTH is also an option for acute pseudogout, although availability may be limited. Recent studies implicating IL-1β production in crystal-induced inflammation suggest that brief anti-IL-1β therapy, for example, the IL-1β receptor antagonist anakinra, may be considered for individuals without other viable treatment options. Nonpharmacologic therapy should include topical cooling and resting the affected joint.
Long-term management of pseudogout includes anti-inflammatory prophylaxis for individuals with recurrent attacks, preferentially using daily low-dose colchicine (more effective than in the acute setting, and generally well tolerated), or NSAIDs or low-dose steroids in some cases. For patients with chronic smoldering inflammation, the aforementioned agents remain the first choice, but recent studies have suggested that some immunosuppressives, such as hydroxychloroquine or methotrexate, may also be of value. When underlying etiologies for pseudogout are identified, these should be treated, although data are limited as to whether such treatment affects the outcome of the CPPD disease. In contrast to gout, there is no proven approach to prevent or reverse crystal formation.
Osteoarthritis is the most common of the arthritic conditions, affecting approximately 30 million people in the United States alone. Although typically a disease of the elderly, osteoarthritis may affect individuals of almost any age, particularly when specific risk factors lead to early onset. OA can affect any joint, but most frequently involves the hands, hips, and knees. The current management of OA is largely palliative or surgical, although recent advances raise the possibility that pharmacologic management may be possible in the future.
The hallmark of OA is loss of articular cartilage, often in joints that are subject to stress. This feature of OA led to the long-standing conclusion, still held in some circles, that OA is entirely a disease of wear and tear. The situation is more complex however, and it is increasingly clear that OA represents the intersection of cartilage tissue stress, intrinsic structural qualities, and aberrant cellular and tissue responses that result in a potentially progressive condition. Changes in subchondral bone and synovium occur concurrently, such that OA is a disease that ultimately involves all joint tissues.
Old age is the most robust risk factor for OA. Long life may result in cumulative wear, but intrinsic aging of the cartilage may also contribute; OA cartilage in the nonelderly has features of prematurely aged tissue. Female sex increases the risk for OA, by mechanisms that remain unclear but may be partly related to hormones or genetics. Individuals with obesity are 5 to 10 times more likely to develop knee OA; obesity’s impact may be partly due to mechanical stress, but adipose tissue is also metabolically active, and secretes inflammatory cytokines that may play a role. Indeed, obese individuals are two to three times more likely to develop hand OA, despite the fact that hands are nonweight bearing. Improper joint alignment—whether hereditary or as a result of injury—also appears to increase the risk for OA, as does direct trauma, as in sports injuries. Rarely, genetic abnormalities in cartilage or bone biochemistry may result in premature, familial OA. However, genetic factors have also been associated with ordinary OA development, based upon twin and nontwin sibling, modern molecular, and population studies.
The earliest pathologic features in OA are microscopic fissures on cartilage surfaces where mechanical stress is greatest. Mechanical loading can induce beneficial chondrocyte responses, including cell hypertrophy and the production of structural elements such as type II collagen and aggrecan. However, chondrocytes are sometimes driven to catabolic activities that contribute to cartilage degradation, especially in the context of genetic abnormalities or prior injury. Overall, OA represents an imbalance between anabolic and catabolic processes in cartilage. As the disease progresses, chondrocytes cluster, secreting metalloproteinases and aggrecanases that disassemble the joint cartilage. Over time, this results in loss of articular cartilage thickness, increased susceptibility to mechanical destruction, and progressive deterioration of the cartilage surface.
Bone, bone marrow, and synovium are all involved in OA pathogenesis. Plain radiographs frequently demonstrate subchondral sclerosis and osteophytes, bony ridges that extend the joint surface and may progress to bony hypertrophy (Figure 247-3). It is unclear whether these are compensatory or pathologic features; however, surgical removal of osteophytes generally does not relieve the symptoms of OA. MRI studies have identified bone marrow lesions under the affected joints as a hallmark of OA. On pathology, these represent fibrotic and necrotic tissue, and possibly microfractures. Although OA has long (and incorrectly) been called a noninflammatory disease, imaging with MRI and ultrasound have now confirmed that many OA patients have synovitis, though to a milder degree than is seen in rheumatoid or psoriatic arthritis. Other studies have confirmed that in OA both synovial cells and chondrocytes produce a wide range of inflammatory cytokines.
Knee joint osteoarthritis, showing osteophyte (broad arrow) and medial joint space loss (narrow arrow), as well as medial subchondral sclerosis.
CLINICAL FEATURES AND DIAGNOSIS
Symptoms of OA may come on insidiously or intermittently over a number of years. The most common feature of OA is pain in weight-bearing joints, such as the knees and hips. Involvement of the shoulders, elbows, and hands is not uncommon. Any joint that has suffered stress or injury is more susceptible. Unlike rheumatoid arthritis, joint involvement in OA may be monoarticular or oligoarticular, but is not typically polyarticular, and need not be symmetrical.
Pain from OA is most likely to occur during joint use. For example, knee pain tends to be exacerbated with walking, and some patients can characterize their use limitations with a high degree of accuracy. Many patients report that OA pain is worse during cold or rainy weather, a phenomenon that remains incompletely understood. OA pain may also be nocturnal. Morning stiffness may be present in OA patients but tends to be of short duration, typically lasting 15 to 30 minutes, in contrast to rheumatoid arthritis, where morning stiffness may persist for hours. As OA progresses, the patient may notice limitation in the range of motion of the joint, owing to cartilage defects, joint effusions, and osteophytes. The joint may become swollen and slightly warm. Over a long period of time, joint mobility may become profoundly limited and disability may ensue. For the patient with knee or hip OA, this may mean an inability to walk more than short distances. Patients with shoulder OA may be unable to reach into kitchen cabinets or perform basic dressing, washing, and toileting functions. Pain in one joint not infrequently results in pain in another joint of the same or the opposite limb, possibly relating to the additional stress resulting from compensation for the OA joint. Spinal involvement may lead to spinal stenosis and nerve root impingement by osteophytes.
Physical examination of the osteoarthritic joint typically reveals crepitus—palpable grinding during joint motion that reflects the fraying and roughening of the cartilage surface. The presence of crepitus, in the setting of characteristic joint pain, may be sufficient to diagnose OA, even in the absence of radiographic findings. As OA progresses, joint examination may reveal not only crepitus, but other evidence of OA, including limited range of motion, pain with motion, effusions, and bony hypertrophy. In the knee, OA is frequently accompanied by deterioration and tearing of the menisci and other adjacent structures.
Radiographic studies in OA have characteristic features. In weight-bearing joints, the first and most obvious finding is narrowing of the joint space, reflecting loss of radiolucent cartilage. In the knee, this loss of joint space typically favors a single compartment, such as the medial or lateral tibiofemoral compartment or the patellofemoral compartment, although eventually all compartments may be affected. Meniscal extrusion may also manifest as joint space narrowing. In the hip, the superior, weight-bearing surface of the joint is most often affected. With disease progression, other characteristic findings may appear. Subchondral sclerosis may be seen as a linear increase in bone density just below the joint surface. Although osteophytes are actually circumferential ridges, on the two-dimensional views presented by plain radiographs they will appear as bone spicules off the margins of the joints. Bone cysts—discrete, circular, or ovoid regions of decreased bone density located just below the joint surface—are common, though their importance remains unclear. In the spine, OA findings may include those described above, but the different anatomic nature of the spine may also result in disk-space narrowing, foraminal narrowing, and other unique features. MRI and ultrasound are seldom if ever needed to diagnose an OA joint, but if obtained may demonstrate bone marrow edema, synovitis, and cartilage and meniscal degradation.
Laboratory studies are mainly useful to rule in or out alternative diagnoses. For example, a normal ESR or CRP makes inflammatory arthritis less likely. In patients with features suggestive of rheumatoid arthritis, a serum rheumatoid factor and anticyclic citrullinated peptide antibody (anti-CCP) titer may be useful. Serum urate levels may help stratify the patient’s risk for gout. When a joint effusion is present, synovial fluid analysis may be the most useful laboratory investigation. In OA, synovial fluid should contain only a limited number of leukocytes (<2000/mm3). Higher counts suggest a different or additional condition. Urate or calcium pyrophosphate crystals indicate gout or pseudogout, respectively. Although acute joint swelling only occasionally occurs in OA, aspiration of the joint fluid is needed in this setting to rule out the presence of infection or concomitant crystal-induced inflammation. Serum and joint fluid markers of cartilage turnover, such as N-telopeptide and C-telopeptide, may have some utility in determining the rate of cartilage damage, but they are currently used mainly in the research setting.
Associated conditions. As discussed elsewhere, calcium pyrophosphate deposition and OA often coexist in the same patient. It is unclear whether CPPD predisposes to OA, the cartilage damage of OA predisposes to calcium pyrophosphate deposition, or both. The finding of both diseases in several joints not normally expressing OA, such as the second and third metacarpophalangeal joints, suggests at least an element of the former. Patients with hemochromatosis are predisposed to both calcium pyrophosphate deposition and OA; once again, metacarpophalangeal OA may be a clue. Patients with gout also have a high incidence of OA, though this could be merely coexpression in an older population predisposed to both conditions. Rarely, ochronosis, with cartilaginous deposition of homogentisic acid, predisposes to severe OA. Patients with acromegaly frequently have OA, presumably owing to abnormal forces across the enlarged bone. Diabetics appear to have a higher incidence of OA because of the buildup of advanced glycation end products (AGEs) in cartilage matrix, which may make cartilage more brittle and stiff, impair normal turnover and repair, and have local pro-inflammatory effects.
Current OA management is palliative and conservative. Clinicians should educate their patients and provide them with a greater understanding and sense of control over their condition. Physical therapy helps to preserve muscle strength and proprioception and improve joint stress. Muscle weakness and capsular and ligamentous damage may hinder joint proprioception in OA patients, increasing their fall risk. For the knee, evidence suggests that regular adherence to a quadriceps-strengthening exercise regimen helps reduce pain and maintain function. Small studies also suggest that tai chi may improve pain and physical function in knee OA. Bracing is another underutilized option; even simple bracing with a neoprene sleeve may assist with joint proprioception and reduce pain with ambulation, with essentially no adverse effects. More sophisticated braces and taping techniques may better stabilize the joint, or reduce the load across the cartilage surface. The use of a cane in the contralateral hand also reduces joint stress and contributes to a sense of well-being. Other therapeutic modalities, such as heat, cold, and ultrasound, may have analgesic benefits in individual patients.
For analgesia, the American College of Rheumatology recommends the initial use of acetaminophen for all patients who can tolerate it. This recommendation may be in evolution, as recent studies have questioned the extent of acetaminophen’s effectiveness. While many patients have failed acetaminophen prior to presenting to a physician, in most cases they have not used it at the maximum dose of 3 g daily. Long-acting formulations reduce the dosing frequency and may improve compliance. Care should be taken to avoid the use of acetaminophen with combination agents that also include acetaminophen, thus pushing the dose beyond acceptable limits. Acetaminophen is well tolerated but has a narrow therapeutic window, with an LD50 for a single dose of approximately 10 g. Patients should be warned to avoid exceeding the maximal daily dose and to also avoid excess alcohol use.
NSAIDs may be effective in patients for whom acetaminophen is inadequate. Because NSAIDs are both analgesic and anti-inflammatory, they may be particularly useful for OA patients with a more inflammatory clinical phenotype, such as patients with significant joint effusions. For OA, NSAIDs should be used at the lowest efficacious dose, on either an as-needed or standing basis. While all NSAIDs work by cyclooxygenase inhibition, they differ in potency, half-life, and side effects. Most physicians should have expertise in three or four NSAIDs, and be able to tailor their use to a particular patient. All NSAIDs should be considered to have potential for renal toxicity, hypertension, heart failure, gastritis, ulcers, and cardiovascular disease. A thorough risk/benefit analysis should be made before prescribing regular NSAIDs in patients with these conditions. Selective COX-2 inhibitors reduce gastrointestinal toxicity; there is little evidence that the sole COX-2 inhibitor currently remaining on the market in the United States, celecoxib, has any increased cardiovascular risk relative to other NSAIDs. Patients on chronic NSAIDs other than selective COX-2 inhibitors should receive GI protection, specifically a proton pump inhibitor or misoprostol. H2 blockers do not provide equivalent protection. Extra care should be taken in the elderly, those with renal dysfunction, and patients already on low-dose aspirin for cardiovascular purposes.
Another option for OA is the use of oral opiates. Most rheumatologists approach the use of opiates with great caution. As OA is a chronic disease, the use of opiates is likely to become long-term, with a potential for dependency. There is also evidence that all-cause mortality is increased in older patients taking opiates for arthritis. One alternative is tramadol, with mixed opiate and antidepressant properties, and a somewhat lower abuse potential. Most recently the antidepressant duloxetine has been approved for the management of chronic OA pain. Duloxetine is not an analgesic, and its effects may take days to weeks.
Topical agents are used for OA treatment, with variable degrees of supportive evidence. Capsaicin, the active ingredient in chili peppers, may be applied topically to deplete presynaptic supplies of substance P, a pain-mediating neurotransmitter. It must be applied regularly several times a day, or an initial period of discomfort will occur when it is restarted. Topical diclofenac has been approved by the FDA, in both a gel and solution form. It appears to be about as effective as oral diclofenac for OA, with reduced serum levels. Topical NSAIDs may be considered in some populations such as the elderly, owing to their lower incidence of systemic effects, particularly gastrointestinal side effects. Older preparations such as topical salicylates and counterirritants are available over the counter and may provide some relief.
If oral and topical therapies are ineffective or poorly tolerated, intra-articular treatment may be considered. Aspiration of the joint alone frequently relieves pressure and provides some pain relief. Glucocorticoid injection, such as methylprednisolone 40 to 80 mg, is frequently effective, providing relief that may last for several months. Studies suggest that treatment with glucocorticoid injections every 3 months has no adverse effect on cartilage, at least over the first few years. In hospitalized patients, injection of a painful, osteoarthritic knee may facilitate mobilization and timely discharge.
When glucocorticoids are ineffective, it is reasonable to consider injection of a hyaluronic acid preparation. Although marketed as a lubricant, hyaluronic acid is biologically active and may provide benefit for many months, long after its presence in the joint has dissipated. The efficacy of hyaluronic acid is disputed by some rheumatologists, however. Various hyaluronic acid preparations are available; the superiority of any one preparation over the others has not been established. Given the small but definite risk of infection resulting from joint injection, these procedures should be performed by experienced operators.
Many complementary and alternative therapies have been proposed. Small studies suggest that oral ingestion of the cartilage components glucosamine and chondroitin sulfate may provide analgesia and joint protection. However, a large, well-blinded US study found ambiguous benefit at best. Until further data are available, these agents are probably best used by enthusiastic patients on a trial-and-error basis. They appear to pose little if any risk. Several studies suggest a benefit for acupuncture in the treatment of OA, although like all acupuncture studies, they are plagued by issues of blinding. Surgical options include arthroscopy, total joint replacement, partial joint replacement, and other surgical techniques. In most cases, the goal of arthroscopy is to remove debris and to smooth roughened cartilage and menisci. Although still a very common procedure, a well-blinded study showed no benefit over sham surgery. Another well-conducted study showed no benefit for OA symptoms of arthroscopic knee surgery over standardized physical therapy. Accordingly, arthroscopy for OA should be reserved for those with specific and unequivocal indications, such as joint locking in the presence of loose bodies. By contrast, the benefits of total joint replacement are well established in the treatment of OA. The indications for total joint replacement are failure to manage pain by medical means and loss of mobility. As radiographic studies do not correlate well with pain or disability, their role in surgical decision making is supportive only. Total joint replacement is highly effective at relieving pain and maintaining or restoring function; it is probably underutilized, owing to cost and patient reluctance to undergo surgery. At the present time, replacement of the hip and knee are the best-established procedures. Techniques for replacement of other joints, such as the shoulder, elbow, ankle, and wrist, are improving steadily. In some cases, surgeons may recommend partial joint replacements. Partial approaches may reduce operating time, but at present are mainly recommended for specialized indications.
Arthritis of various forms is the cause of significant morbidity and mortality, and its personal and economic costs are high. Among the arthritides, osteoarthritis, gout, and pseudogout are the most common. Of the three, gout is currently the most treatable, yet patients with gout frequently experience inadequate management. Treatment of osteoarthritis and pseudogout is directed primarily at symptoms rather than at underlying causes, but research is likely to yield new and potentially effective therapies. In the meantime, optimal management of gout, pseudogout, and osteoarthritis, employing both pharmacologic and non-pharmacologic management, can reduce pain and suffering, and help patients live unimpeded, productive lives.
Management of osteoarthritis is currently palliative. Treatment options include analgesics, anti-inflammatories and intra-articular hyaluronan. Weight loss, physical therapy, and bracing are important adjuncts to pharmacologic treatment, and may sometimes be sufficient on their own. For knees and hips, total joint replacement is indicated when medical management fails or the patient’s ambulation is inappropriately limited; total joint replacement is an effective means to relieve pain and restore motion.
Have medications, drink, and diet of gouty patients been reviewed for possible contributors to hyperuricemia?
For patients being discharged on NSAIDs, has gastric protection been prescribed, and arrangements made to check serum creatinine after discharge?
For patients being discharged on colchicine, have arrangements been made to check complete blood count, liver transaminases, creatinine, and creatine phosphokinase as an outpatient? Colchicine side effects may include cytopenias, gastrointestinal upset, hepatitis, and myoneuropathy.
For patients being discharged on allopurinol, have arrangements been made to check complete blood count, liver transaminases, and creatinine as an outpatient? Patients should be cautioned about the possibility of allopurinol-induced rash, which may occasionally include Steven-Johnson syndrome. Consider checking for the HLA-B*5801 allele in persons of Asian descent being started on allopurinol, given the association of this allele with severe cutaneous adverse drug reactions to allopurinol.
Has a workup for underlying disorders, such as hemochromatosis, thyroid disease, and perturbations of calcium, phosphate, and magnesium metabolism, been considered in patients with atypical or early-onset pseudogout?
Have patients with arthritis been assessed by physical therapy, and considered for off-loading and assistive devices such as canes and bracing?
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