This document discusses gout and other crystal-associated arthropathies. It begins by explaining how crystallographic techniques have identified the roles of crystals like monosodium urate and calcium pyrophosphate dihydrate in inducing arthritis. It then focuses on gout, describing it as a metabolic disease caused by hyperuricemia that typically results in acute and chronic arthritis. The document outlines treatments for acute gouty arthritis attacks and long-term hypouricemic therapy to control gout by normalizing uric acid levels.
This document discusses gout and other crystal-associated arthropathies. It begins by explaining how crystallographic techniques have identified the roles of crystals like monosodium urate and calcium pyrophosphate dihydrate in inducing arthritis. It then focuses on gout, describing it as a metabolic disease caused by hyperuricemia that typically results in acute and chronic arthritis. The document outlines treatments for acute gouty arthritis attacks and long-term hypouricemic therapy to control gout by normalizing uric acid levels.
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Gout and Othercrystal-Associated Arthropathies.pptx
This document discusses gout and other crystal-associated arthropathies. It begins by explaining how crystallographic techniques have identified the roles of crystals like monosodium urate and calcium pyrophosphate dihydrate in inducing arthritis. It then focuses on gout, describing it as a metabolic disease caused by hyperuricemia that typically results in acute and chronic arthritis. The document outlines treatments for acute gouty arthritis attacks and long-term hypouricemic therapy to control gout by normalizing uric acid levels.
This document discusses gout and other crystal-associated arthropathies. It begins by explaining how crystallographic techniques have identified the roles of crystals like monosodium urate and calcium pyrophosphate dihydrate in inducing arthritis. It then focuses on gout, describing it as a metabolic disease caused by hyperuricemia that typically results in acute and chronic arthritis. The document outlines treatments for acute gouty arthritis attacks and long-term hypouricemic therapy to control gout by normalizing uric acid levels.
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Dr Budi Enoch
GOUT AND OTHERCRYSTAL-
ASSOCIATED ARTHROPATHIES Crystal-Associated Arthropathies The use of polarizing light microscopy during synovial fluid analysis in 1961 by McCarty and Hollander and the subsequent application of other crystallographic 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 have important differences. Before 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 333-1. Gout is a metabolic disease that most often affects middle-aged to elderly men and postmenopausal women. It results from an increased body pool of urate with hyperuricemia. It typically is characterized by episodic acute and chronic arthritis caused by 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 common 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 often is involved, but tarsal joints, ankles, and knees also are affected commonly. 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 that of 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. 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 that cause mild renal insufficiency, and usually are receiving diuretics. Laboratory Diagnosis Even if the clinical appearance strongly suggests gout, the presumptive diagnosis ideally 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, needle-shaped MSU crystals typically are seen both intracellularly and extracellularly . With compensated polarized light these crystals are brightly birefringent with negative elongation. Synovial fluid leukocyte 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 be cultured Serum uric acid levels can be normal or low at the time of an 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, elucidating overproduction or underexcretion of uric acid, and deciding whether it may be appropriate to use a uricosuric therapy 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 features of advanced chronic tophaceous gout. Ultrasound, CT and MRI are being studied and are likely to become more sensitive for early changes. Treatment Acute Gouty Arthritis The mainstay of treatment during an acute attack is the administration of anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or glucocorticoids. NSAIDs are used most often 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. This was repeated later. 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 an attack. One useful regimen is one 0.6-mg tablet given every 8 h with subsequent tapering The drug must be stopped promptly at the first sign of loose stools, and symptomatic treatment must be given for the diarrhea. Intravenous colchicine has been taken off the market. 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 half-life and include indomethacin, 25–50 mg tid; naproxen, 500 mg bid; ibuprofen, 800 mg tid; and diclofenac, 50 mg tid. Glucocorticoids given IM or orally, for example, 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 a single joint or a few involved joints intraarticular triamcinolone acetonide, 20–40 mg, or methylprednisolone, 25–50 mg, have been effective and well tolerated.. Hypouricemic Therapy Ultimate control of gout requires correction of the basic underlying defect: the hyperuricemia. Attempts to normalize serum uric acid to <300–360 mol/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, decreased use of fructose- containing foods and beverages, and avoidance of diuretics). 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 water every day. Probenecid can be started at a dose of 250 mg twice daily and increased gradually as needed up to 3 g per day to maintain a serum uric acid level <360 mol/L (6 mg/dL). Probenecid is generally not effective in patients with serum creatinine levels >177 mol/L (2 mg/dL). These patients may require allopurinol or benzbromarone (not available in the United States). Benzbromarone is another uricosuric drug that is more effective in patients with renal failure. Some agents used to treat common comorbidities, including 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 dose should be lower and adjusted depending on the serum creatinine concentration; for example, with a creatinine clearance of 10 mL/min, one generally would use 100 mg every other day. Doses can be increased gradually to reach the target urate level of 6 mg/dL; however, more studies are needed to provide exact guidance. Toxicity of allopurinol has been recognized increasingly in patients who use thiazide diuretics and patients allergic to penicillin and ampicillin. The most serious side effects include life-threatening toxic epidermal necrolysis, systemic vasculitis, bone marrow suppression, granulomatous hepatitis, and renal failure CPPD Deposition Disease The deposition of CPPD crystals in articular tissues is most common in the elderly, occurring in 10–15% of persons age 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 favors crystal nucleation. In patients with CPPD arthritis there is increased production of inorganic pyrophosphate and decreased levels of pyrophosphatases in cartilage extracts. Mutations in the ANKH gene, as described in both familial and sporadic cases, can increase elaboration and extracellular transport of pyrophosphate Clinical Manifestations CPPD arthropathy may be asymptomatic, acute, subacute, or chronic or may cause acute synovitis superimposed on chronically involved joints. Acute CPPD arthritis originally was termed pseudogout by McCarty and co-workers because of its striking similarity to gout. Other clinical manifestations of CPPD deposition include (1) induction or enhancement of peculiar forms of osteoarthritis, (2) induction of severe destructive disease that may radiographically mimic neuropathic arthritis, (3) production of symmetric synovitis that is clinically similar to rheumatoid arthritis and sometimes seen in familial forms with early onset, (4) intervertebral disk and ligament calcification with restriction of spine mobility that mimics ankylosing spondylitis (also seen in hereditary forms), (5) spinal stenosis (most commonly seen in the elderly), and (6) rarely periarticular tophus-like nodules. Acute attacks of CPPD arthritis may be precipitated by trauma. Rapid diminution of serum calcium concentration, as may occur in severe medical illness or after surgery (especially parathyroidectomy), can also lead to pseudogout attacks. In as many as 50% of cases, episodes of CPPD-induced inflammation are associated with low-grade fever and, on occasion, temperatures as high as 40°C (104°F). Whether or not radiographic proof of chondrocalcinosis is evident in the involved joint(s), synovial fluid analysis with microbial cultures is essential to rule out the possibility of infection. In fact, infection in a joint with any microcrystalline deposition process can lead to crystal shedding and subsequent synovitis from both crystals and microorganisms. Synovial fluid in acute CPPD disease has inflammatory characteristics. The leukocyte count can range from several thousand cells to 100,000 cells/L, with the mean being about 24,000 cells/L and the predominant cell being the neutrophil. Polarized light microscopy usually reveals rhomboid, square, or rodlike crystals with weak positive birefringence inside tissue fragments and fibrin clots and in neutrophils (Fig. 333-2). CPPD crystals may coexist with MSU and apatite in some cases. Treatment: Cppd Deposition Disease Untreated acute attacks may last a few days to as long as a month. Treatment by joint aspiration and NSAIDs or by intraarticular glucocorticoid injection may result in return to prior status in 10 days. For patients with frequent recurrent attacks of pseudogout, daily prophylactic treatment with low doses of colchicine may be helpful in decreasing the frequency of the attacks. Severe polyarticular attacks usually require short courses of glucocorticoids or, as recently reported, an IL-1 antagonist, anakinra. Unfortunately, there is no effective way to remove CPPD deposits from cartilage and synovium. Uncontrolled studies suggest that the administration of antimalarial agents or even methotrexate may be helpful in controlling persistent synovitis. Patients with progressive destructive large-joint arthropathy may require joint replacement Calcium Apatite Deposition Disease Apatite is the primary mineral of normal bone and teeth. Abnormal accumulation of basic calcium phosphates, largely carbonate substituted apatite, can occur in areas of tissue damage (dystrophic calcification), hypercalcemic or hyperparathyroid states (metastatic calcification), and certain conditions of unknown cause (Table 333-3). In chronic renal failure, hyperphosphatemia can contribute to extensive apatite deposition both in and around joints. Familial aggregation is rarely seen; no association with ANKH mutations has been described thus far. Apatite crystals are deposited primarily on matrix vessels. Incompletely understood alterations in matrix proteoglycans, phosphatases, hormones, and cytokines probably can influence crystal formation. Apatite aggregates are commonly present in synovial fluid in an extremely destructive chronic arthropathy of the elderly that occurs most often in the shoulders (Milwaukee shoulder) and in a similar process in hips, knees, and erosive osteoarthritis of fingers. Joint destruction is associated with damage to cartilage and supporting structures, leading to instability and deformity. Progression tends to be indolent, and synovial fluid leukocyte counts are usually <2000/L. Symptoms range from minimal to severe pain and disability that may lead to joint replacement surgery. Whether severely affected patients merely represent an extreme synovial tissue response to the apatite crystals that are so common in osteoarthritis is uncertain. Synovial lining cell or fibroblast cultures exposed to apatite (or CPPD) crystals can undergo mitosis and markedly increase the release of prostaglandin E2 and cytokines and also collagenases and neutral proteases, underscoring the destructive potential of abnormally stimulated synovial lining cells. Clinical Manifestations Periarticular or articular deposits may occur and may be associated with acute reversible inflammation and/or chronic damage to the joint capsule, tendons, bursa, or articular surfaces. The most common sites of apatite deposition include bursae and tendons in and/or around the knees, shoulders, hips, and fingers. Clinical manifestations include asymptomatic radiographic abnormalities, acute synovitis, bursitis, tendinitis, and chronic destructive arthropathy. Although the true incidence of apatite arthritis is not known, 30– 50% of patients with osteoarthritis have apatite microcrystals in their synovial fluid. Such crystals frequently can be identified in clinically stable osteoarthritic joints, but they are more likely to come to attention in persons experiencing acute or subacute worsening of joint pain and swelling. The synovial fluid leukocyte count in apatite arthritis is usually low (<2000/L) despite dramatic symptoms, with predominance of mononuclear cells. A. Radiograph showing calcification due to apatite crystals surrounding an eroded joint. B. An electron micrograph demonstrates dark needle-shaped apatite crystals within a vacuole of a synovial fluid mononuclear cell (30,000x). Definitive diagnosis of apatite arthropathy, also called basic calcium phosphate disease, depends on identification of crystals from synovial fluid or tissue. Individual crystals are very small and can be seen only by electron microscopy. Clumps of crystals may appear as 1- to 20-m shiny intra- or extracellular nonbirefringent globules or aggregates that stain purplish with Wright's stain and bright red with alizarin red S. Tetracycline binding is under investigation as a labeling alternative. Absolute identification depends on electron microscopy with energy- dispersive elemental analysis, x-ray diffraction, infrared spectroscopy, or Raman microspectroscopy, but they usually are not required in clinical diagnosis. Treatment: Calcium Apatite Deposition Disease Treatment of apatite arthritis or periarthritis is nonspecific. Acute attacks of bursitis or synovitis may be self-limiting, resolving in days to several weeks. Aspiration of effusions and the use of either NSAIDs or oral colchicine for 2 weeks or intra- or periarticular injection of a depot glucocorticoid appear to shorten the duration and intensity of symptoms. Local injection of disodium ethylenediaminetetraacetic acid (EDTA) was effective in one study of calcific tendinitis at the shoulder. Periarticular apatite deposits may be resorbed with resolution of attacks. Agents to lower serum phosphate levels may lead to resorption of deposits in renal failure patients receiving hemodialysis. In patients with underlying severe destructive articular changes, response to medical therapy is usually less rewarding