The use of polarizing light microscopy during synovial fluid analysis in 1961 by McCarty and Hollander and the subsequent application of other crystallo-graphic techniques, such as electron microscopy, energy-dispersive elemental analysis, and x-ray diffraction, have allowed investigators to identify the roles of different microcrystals, including monosodium urate (MSU), calcium pyrophosphate dihydrate (CPPD), calcium apatite (apatite), and calcium oxalate (CaOx), in inducing acute or chronic arthritis or periarthritis. The clinical events that result from deposition of MSU, CPPD, apatite, and CaOx have many similarities but also important differences. Prior to the use of crystallographic techniques in rheumatology, much of what was considered to be gouty arthritis in fact was not. Because of often similar clinical presentations, the need to perform synovial fluid analysis to distinguish the type of crystal involved must be emphasized. Polarized light microscopy alone can identify most typical crystals; apatite, however, is an exception. Aspiration and analysis of effusions are also important to assess the possibility of infection. Apart from the identification of specific microcrystalline materials or organisms, synovial fluid characteristics in crystal-associated diseases are nonspecific, and synovial fluid can be inflammatory or noninflammatory. A list of possible musculoskeletal manifestations of crystal-associated arthritis is shown in Table 19-1.
TABLE 19-1
|
MUSCULOSKELETAL MANIFESTATIONS OF CRYSTAL-INDUCED ARTHRITIS |
|
|
Acute mono- or polyarthritis |
Destructive arthropathies |
|
Bursitis |
Pseudo-rheumatoid arthritis |
|
Tendinitis |
|
|
Enthesitis |
Pseudo-ankylosing spondylitis |
|
Tophaceous deposits |
|
|
Peculiar type of osteoarthritis |
Spinal stenosis |
|
Synovial osteochondromatosis |
Crown dens syndrome |
|
Carpal tunnel syndrome Tendon rupture |
|
Gout
Gout is a metabolic disease most often affecting middle-aged to elderly men and postmenopausal women. It is the result of an increased body pool of urate with hyperuricemia. It is typically characterized by episodic acute and chronic arthritis, due to deposition of MSU crystals in joints and connective tissue tophi, and the risk for deposition in kidney interstitium or uric acid nephrolithiasis.
Acute and Chronic Arthritis
Acute arthritis is the most frequent early clinical manifestation of gout. Usually, only one joint is affected initially, but polyarticular acute gout can occur in subsequent episodes. The metatarsophalangeal joint of the first toe is often involved, but tarsal joints, ankles, and knees are also commonly affected. Especially in elderly patients or in advanced disease, finger joints may be involved. Inflamed Heberden’s or Bouchard’s nodes may be a first manifestation of gouty arthritis. The first episode of acute gouty arthritis frequently begins at night with dramatic joint pain and swelling. Joints rapidly become warm, red, and tender, with a clinical appearance that often mimics cellulitis. Early attacks tend to subside spontaneously within 3-10 days, and most patients have intervals of varying length with no residual symptoms until the next episode. Several events may precipitate acute gouty arthritis: dietary excess, trauma, surgery, excessive ethanol ingestion, hypouricemic therapy, and serious medical illnesses such as myocardial infarction and stroke.
After many acute mono- or oligoarticular attacks, a proportion of gouty patients may present with a chronic nonsymmetric synovitis, causing potential confusion with rheumatoid arthritis (Chap. 5). Less commonly, chronic gouty arthritis will be the only manifestation and, more rarely, the disease will manifest only as periarticular tophaceous deposits in the absence of synovitis. Women represent only 5-20% of all patients with gout. Premenopausal gout is rare; it is seen mostly in individuals with a strong family history of gout. Kindreds of precocious gout in young females caused by decreased renal urate clearance and renal insufficiency have been described. Most women with gouty arthritis are postmenopausal and elderly, have osteoarthritis and arterial hypertension causing mild renal insufficiency, and are usually receiving diuretics.
Laboratory Diagnosis
Even if the clinical appearance strongly suggests gout, the diagnosis should be confirmed by needle aspiration of acutely or chronically involved joints or tophaceous deposits. Acute septic arthritis, several of the other crystalline-associated arthropathies, palindromic rheumatism, and psoriatic arthritis may present with similar clinical features. During acute gouty attacks, strongly bire-fringent needle-shaped MSU crystals with negative elongation are typically seen both intracellularly and extracellularly (Fig. 19-1). Synovial fluid cell counts are elevated from 2000 to 60,000^L. Effusions appear cloudy due to the increased numbers of leukocytes. Large amounts of crystals occasionally produce a thick pasty or chalky joint fluid. Bacterial infection can coexist with urate crystals in synovial fluid; if there is any suspicion of septic arthritis, joint fluid must also be cultured.
FIGURE 19-1
Extracellular and intracellular monosodium urate crystals, as seen in a fresh preparation of synovial fluid, illustrate needle- and rod-shaped strongly negative birefringent crystals (compensated polarized light microscopy; 400x).
MSU crystals can also often be demonstrated in the first metatarsophalangeal joint and in knees not acutely involved with gout. Arthrocentesis of these joints is a useful technique to establish the diagnosis of gout between attacks.
Serum uric acid levels can be normal or low at the time of the acute attack, as inflammatory cytokines can be uricosuric and effective initiation of hypouricemic therapy can precipitate attacks. This limits the value of serum uric acid determinations for the diagnosis of gout. Nevertheless, serum urate levels are almost always elevated at some time and are important to use to follow the course of hypouricemic therapy. A 24-h urine collection for uric acid can, in some cases, be useful in assessing the risk of stones, in elucidating overproduction or underexcretion of uric acid, and in deciding if it might be appropriate to use a uricosuric therapy. Excretion of >800 mg of uric acid per 24 h on a regular diet suggests that causes of overproduction of purine should be considered. Urinalysis, serum creatinine, hemoglobin, white blood cell (WBC) count, liver function tests, and serum lipids should be obtained because of possible pathologic sequelae of gout and other associated diseases requiring treatment, and as baselines because of possible adverse effects of gout treatment.
Radiographic Features
Early in the disease radiographic studies may only confirm clinically evident swelling. Cystic changes, well-defined erosions with sclerotic margins (often with overhanging bony edges), and soft-tissue masses are characteristic radiographic features of advanced chronic tophaceous gout.
Treatment:
Gout
ACUTE GOUTY ARTHRITIS The mainstay of treatment during an acute attack is the administration of anti-inflammatory drugs such as nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, or glucocorticoids. NSAIDs are most often used in individuals without complicating comorbid conditions. Both colchicine and NSAIDs may be poorly tolerated and dangerous in the elderly and in the presence of renal insufficiency and gastrointestinal disorders. In attacks involving one or two joints, intraarticular glucocorticoid injections may be preferable and effective. Ice pack applications and rest of the involved joints can be helpful. Colchicine given orally is a traditional and effective treatment, if used early in the attack. One to two 0.6-mg tablets can be given every 6-8 h over several days with subsequent tapering.This is generally better tolerated than the formerly advised hourly regimen. The drug must be stopped promptly at the first sign of loose stools, and symptomatic treatment must be given for the diarrhea. Intravenous colchicine is occasionally used, e.g., as preor postoperative prophylaxis in 1- to 2-mg doses when patients cannot take medications orally. Life-threatening colchicine toxicity and sudden death have been described with the administration of >4 mg/d IV. The IV colchicine should be given slowly through an established venous line over 10 min in a soluset.The total dose should never exceed 4 mg.
NSAIDs given in full anti-inflammatory doses are effective in ~90% of patients, and the resolution of signs and symptoms usually occurs in 5-8 days. The most effective drugs are any of those with a short halflife and include indomethacin, 25-50 mg tid; ibuprofen, 800 mg tid; or diclofenac, 50 mg tid. Oral glucocorticoids such as prednisone, 30-50 mg/d as the initial dose and gradually tapered with the resolution of the attack, can be effective in polyarticular gout. For single or few involved joints intraarticular triamcinolone ace-tonide, 20-40 mg, or methylprednisolone, 25-50 mg, have been effective and well tolerated. Adrenocorticotropic hormone (ACTH) as an intramuscular injection of 40-80 IU in a single dose or every 12 h for 1-2 days can be effective in patients with acute polyarticular refractory gout or in those with a contraindication for using colchicine or NSAIDs.
HYPOURICEMIC THERAPY Ultimate control of gout requires correction of the basic underlying defect, the hyperuricemia. Attempts to normalize serum uric acid to <300-360 μmol/L (5.0-6.0 mg/dL) to prevent recurrent gouty attacks and eliminate tophaceous deposits entail a commitment to long-term hypouricemic regimens and medications that generally are required for life. Hypouricemic therapy should be considered when,as in most patients, the hyperuricemia cannot be corrected by simple means (control of body weight, low-purine diet, increase in liquid intake, limitation of ethanol use, and avoidance of diuretics). The decision to initiate hypouricemic therapy is usually made taking into consideration the number of acute attacks (urate lowering may be cost-effective after two attacks), serum uric acid levels [progression is more rapid in patients with serum uric acid >535 μmol/L (>9.0 mg/dL)], patient’s willingness tc commit to lifelong therapy, or presence of uric acid stones. Urate-lowering therapy should be initiated in any patient who already has tophi or chronic gouty arthritis Uricosuric agents, such as probenecid, can be used in patients with good renal function who underexcrete uric acid, with <600 mg in a 24-h urine sample. Urine volume must be maintained by ingestion of 1500 mL of watei every day. Probenecid can be started at a dosage of 250 mg twice daily and increased gradually as needed up to 3 g in order to maintain a serum uric acid level <300 μmol/L (5 mg/dL). Probenecid is generally not effective in patients with serum creatinine levels of >177 μmol/L (2.0 mg/dL) These patients may require allopurinol or benzbromarone (not available in the United States). The latter is anothei uricosuric drug that is more effective in patients with renal failure. Recent reports have identified that losartan, fenofibrate, and amlodipine have some mild uricosuric effects.
The xanthine oxidase inhibitor allopurinol is by far the most commonly used hypouricemic agent and is the best drug to lower serum urate in overproducers, urate stone formers, and patients with renal disease. It can be given in a single morning dose, 100-300 mg initially and increasing up to 800 mg if needed. In patients with chronic renal disease,the initial allopurinol dosage should be lower and adjusted depending on the serum creatinine concentration; for example, with a creatinine clearance of 10 mL/min,one would generally use 100 mg every other day. Doses can gradually be increased to reach the target urate level; however, more studies are needed to provide exact guidance. Patients with frequent acute attacks may also require lower initial doses to prevent exacerbations. Toxicity of allopurinol has been recognized increasingly in patients with renal failure who use thiazide diuretics and in those patients allergic to penicillin and ampicillin. The most serious side effects include skin rash with progression to life-threatening toxic epidermal necrolysis, systemic vasculitis, bone marrow suppression, granulomatous hepatitis, and renal failure. Patients with mild cutaneous reactions to allopurinol can reconsider the use of a uricosuric agent or undergo an attempt at desensitization to allopurinol.A treatment option for allopurinol-sensitive patients is febuxostat, a new specific xanthine oxidase inhibitor,which is approved for the chronic management of hyperuricemia in patients with gout. In contrast to allopurinol, febuxostat does not require dosage adjustment based on level of renal function. The recommended starting dose of febuxostat is 40 mg once a day, and for patients who do not achieve a serum uric acid level of less than 6 mg/dL after 2 weeks, the dose can be increased to 80 mg daily. Similar to allopurinol, febuxostat has important interactions with azathioprine, mercaptopurine, and theophylline in which concomitant administration could increase plasma concentrations of these drugs resulting in severe toxicity. Urate-lowering drugs are generally not initiated during acute attacks, but after the patient is stable and low-dose colchicine has been initiated to decrease the risk of flares that often occur with urate lowering.Colchicine prophylaxis in doses of 0.6 mg one to two times daily is usually continued, along with the hypouricemic therapy, until the patient is normouricemic and without gouty attacks for 6 months or as long as tophi are present. A new urate-lowering drug undergoing investigation is a PEGylated uricase.
CPPD Deposition Disease
Pathogenesis
The deposition of CPPD crystals in articular tissues is most common in the elderly, occurring in 10-15% of persons aged 65-75 years and 30-50% of those >85 years. In most cases this process is asymptomatic, and the cause of CPPD deposition is uncertain. Because >80% of patients are >60 years and 70% have preexisting joint damage from other conditions, it is likely that biochemical changes in aging or diseased cartilage favor crystal nucleation. In patients with CPPD arthritis there is an increased production of inorganic pyrophosphate and decreased levels of pyrophosphatases in cartilage extracts. Mutations in the ANKH gene described in both familial and sporadic cases can increase elaboration and extracellular transport ofpyrophosphate.The increase in pyrophosphate production appears to be related to enhanced activity of adenosine triphosphate (ATP) pyrophospho-hydrolase and 5’-nucleotidase, which catalyze the reaction of ATP to adenosine and pyrophosphate. This pyrophosphate could combine with calcium to form CPPD crystals in matrix vesicles or on collagen fibers. There are decreased levels of cartilage glycosaminogly-cans that normally inhibit and regulate crystal nucle-ation. In vitro studies have demonstrated that transforming growth factor β1 and epidermal growth factor both stimulate the production of pyrophosphate by articular cartilage and thus may contribute to the deposition of CPPD crystals.
Release of CPPD crystals into the joint space is followed by the phagocytosis of these crystals by monocyte-macrophages and neutrophils, which respond by releasing chemotactic and inflammatory substances.
| TABLE 19-2 CONDITIONS ASSOCIATED WITH CALCIUM PYROPHOSPHATE DIHYDRATE DISEASE |
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Aging |
|
Disease-associated |
|
Primary hyperparathyroidism |
|
Hemochromatosis |
|
Hypophosphatasia |
|
Hypomagnesemia |
|
Chronic gout |
|
Postmeniscectomy |
|
Epiphyseal dysplasias |
|
Hereditary: Slovakian-Hungarian, Spanish, Spanish- |
|
American (Argentinian,a Colombian, and Chilean), |
|
French,a Swedish, Dutch, Canadian, Mexican- |
|
American, Italian-American,a German-American, |
|
Japanese, Tunisian, Jewish, Englisha |
aMutations in the ANKH gene.
A minority of patients with CPPD arthropathy have metabolic abnormalities or hereditary CPPD disease (Table 19-2). These associations suggest that a variety of different metabolic products may enhance CPPD deposition either by directly altering cartilage or inhibiting inorganic pyrophosphatases. Included among these conditions are hyperparathyroidism, hemochromatosis, hypophos-phatasia, and hypomagnesemia. The presence of CPPD arthritis in individuals <50 years old should lead to consideration of these metabolic disorders and inherited forms of disease, including those identified in a variety of ethnic groups (Table 19-2). Genomic DNA studies performed on different kindreds have shown a possible location of genetic defects on chromosome 8q or on chromosome 5p in a region that expresses the gene of the membrane pyrophosphate channel (ANKH gene). Mutations as noted above described in the ANKH gene in kindreds with CPPD arthritis can increase extracellular pyrophosphate and induce CPPD crystal formation. Investigation of younger patients with CPPD deposition should include inquiry for evidence of familial aggregation and evaluation of serum calcium, phosphorus, alkaline phosphatase, magnesium, serum iron, and transferrin.
