Septic arthritis is most often monoarticular but may affect more than one joint. Bacteria responsible for joint infection vary with age group, similar to the organisms producing meningitis. Haemophilus influenzae, Staphylococcus aureus, and gram-negative bacteria predominate in early childhood; S. aureus, pneumococci, and streptococci in later childhood; and S. aureus, pneumococci, streptococci, and gonococci in adults. Conditions that predispose to gram-negative bacilli include neoplasia, immunosuppression or decreased immunologic defenses, intravenous drug addiction, and urinary tract infections. Septic arthritis is diagnosed by direct aspiration and culture of the synovial fluid. Gram stain is reported to be positive in 40%-75% (range, 30%-95%) of infected joint aspirates, with detection of gram-positive aerobic organisms accomplished more readily than gram-negative organisms.
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Pseudogout
Pseudogout is caused by calcium pyrophosphate crystal deposition. It clinically resembles gout to some degree but tends to affect large joints such as the knee rather than small peripheral joints. Joint x-ray films indicate some differences from classic gout but are frequently not a sufficient basis for diagnosis. Synovial fluid examination discloses calcium pyrophosphate crystals, either within neutrophil cytoplasm or extracellularly. These appear as short small rectangular structures or short rods, but sometimes color-compensated polarized light (imparting a positive birefringence, blue on red background) is necessary for reliable differentiation from uric acid.
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Arthritis due to Crystal Deposition (Crystalline Arthropathies)
Gout usually involves single specific joints, usually including some of the small joints of the extremities. The most typical location is the metatarsal-phalangeal joint of the great toe, which is affected in about 75% of patients. The knee and ankle are involved in about 50% of patients. One third or more of patients have more than one joint involved during their first attack. The disease is 7 times more common in males than females. Acute attacks are frequently accompanied by fever and leukocytosis. Attacks of gout typically respond to colchicine as specific therapy.
Laboratory tests useful in diagnosis of gout
Serum uric acid. Patients with gout usually have elevated serum uric acid levels. However, 7%-8% have uric acid levels within reference limits at the time of the first attack. Some studies have shown elevated serum uric acid levels in about 10% of patients with RA, 15% of patients with pseudogout, and about 15% of patients with septic arthritis. Therefore, elevated serum uric acid levels are not diagnostic for gout, and normal serum uric acid levels do not conclusively rule out gout. On the other hand, positive latex test results for rheumatoid factor have been reported in 7%-11% of patients with primary gout. Serum uric acid reference values are sex related, with values in males about 1mg/100 ml higher than values in females. One report indicates considerable week-to-week variation (about 30%-40%) in serum uric acid values in the same individual. Stress has been reported to raise uric acid levels. One investigator found that serum uric acid levels increased after exposure to sunlight.
Although elevation of serum uric acid is traditionally associated with gout, the majority of serum uric acid elevations are not due to gout. By far the most frequent cause of hyperuricemia, especially in hospitalized patients, in renal disease with azotemia.
Disorders of hyperuricemia can be divided into those due to increased intake, those due to decreased excretion, and those due to increased production.
Increased intake. Increased intake of purine-rich food usually does not produce hyperuricemia by itself, although it may affect the clinical symptoms of gout or add to the effect of other hyperuricemic agents.
Decreased excretion. Uric acid is excreted predominantly through the kidneys, with about 25% excreted by the GI tract. There is good correlation between severely decreased renal function, as indicated by elevated blood urea nitrogen (BUN) or serum creatinine levels (Chapter 13) and increase in the serum level of uric acid, although the correlation is not linear. According to the literature, more than 90% of patients with elevated BUN and serum creatinine levels also have elevated serum uric acid values. However, when I examined the laboratory work of 156 newly admitted patients with elevated BUN levels, serum creatinine levels, or both, 31% of the patients had uric acid values within the reference range (even in those patients with BUN and creatinine levels both elevated, 31% still had normal uric acid levels). On the other hand, of a total of 222 patients, 30% had normal BUN and creatinine levels but elevated uric acid levels. Besides chronic renal disease, acute renal failure, and severely decreased renal blood flow, other conditions associated with hyperuricemia due to decreased renal excretion include treatment with certain drugs (including most diuretics, but especially the thiazides), ketoacidosis of diabetes or starvation, lactic acidosis, toxemia of pregnancy, lead poisoning, alcoholism, and hypothyroidism. In some of these conditions increased renal tubular reabsorption of urate is a major factor, with or without decreased renal function.
Increased production. Increased uric acid production can be demonstrated by increased uric acid excretion, if renal function is adequate. The standard method of evaluation is a 24-hour urine collection. Most investigators place the patient on a severely restricted (or “purine-free”) purine diet before collecting the urine specimen (e.g., 4 days of diet, with the specimen collected on the fourth day and collection completed before the diet is terminated). The test is more accurate when the patient is asymptomatic, since acute inflammation may increase urine excretion of urate. Under these controlled conditions, the most commonly accepted upper limit of the reference range is 600 mg/24 hours (3,570 mmol/day). About 15%-25% of patients with primary gout have increased excretion of uric acid. The other 75%-85% have normal production and urine excretion levels. Conditions in which a substantial number of patients have increased uric acid production, increased excretion of uric acid, and hyperuricemia, include myeloproliferative syndromes (chronic myelocytic leukemia, polycythemia vera, etc.), chronic lymphocytic leukemia, myeloma, various malignancies (including the aforementioned leukemias and lymphomas), tumor or tissue cell destruction from chemotherapy or radiation therapy (including the tumor lysis syndrome), sickle cell anemia and severe hemolytic anemias, extensive psoriasis (30%-50% cases), sarcoidosis (30%-50% cases), and a congenital enzymatic defect in uric acid metabolism known as the “Lesch-Nyhan syndrome.”
There is also an association of hyperuricemia with hypertension (22%-27% without renal disease), diabetes mellitus, obesity, and atherosclerotic heart disease. In some of these associated conditions there is a demonstrable etiology for hyperuricemia and in some there is not. One report indicates that up to 20% of males on long-term coumarin therapy develop elevated serum uric acid.
Measurement of urine uric acid to creatinine clearance ratio on a midmorning urine specimen has been proposed as a means to circumvent the problems involved with 24-hour urine collection. However, there is rather poor correlation between results obtained by the two methods in the same patients. One reason may be a reported diurnal variation in uric acid excretion, with about 40%-45% of daily quantity found in the 8 hours between 8 A.M. and 4 P.M.
The two most common laboratory assay methods for uric acid assay are colorimetric (based on uric acid reduction of phosphotungstic acid reagent) and enzymatic (using the specific enzyme uricase). Various reducing substances, such as levodopa and large quantities of glucose, ascorbic acid, acetaminophen, caffeine, and theophylline, can falsely elevate the colorimetric method.
Joint fluid aspiration. The most accurate readily available laboratory test for gout is demonstration of uric acid crystals in synovial fluid aspirated from an acutely inflammed joint. The needlelike crystals of sodium monophosphate may be seen within neutrophils or lying free. These may be seen with the ordinary microscope but are best visualized using compensated polarized light. With the color compensator, urate crystals exhibit negative birefringence (yellow against a red background, with the axis of the crystal parallel to the axis of the compensator). When injected into a joint, some steroids form needlelike crystals that may mimic nonpolarized uric acid crystals. It has been reported that uric acid crystals cannot be demonstrated in joint aspirates from about 15% of patients with acute gout.
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Tests for Increase or Decrease in Bone Mass
Increased bone turnover occurs during normal preadult growth; destruction of bone from accidental, metabolic, or neoplastic causes; and as an effect of certain medications. For many years skeletal x-ray was the only clinical method used to detect bone change. Unfortunately, significant change could not be seen until about 50% of bone density was lost. Later, radionuclide bone scans supplemented x-ray, but bone scans were best suited to detect focal rather than generalized abnormality and were better able to detect an osteoblastic than an osteolytic process.
About the same time bone scans became important, it was found that a substance called hydroxyproline (part of the collagen and elastin component of skin, cartilage, and bone) could be used as an index of bone turnover since bone contains a large amount of metabolically active collagenous matrix. Hydroxyproline is a by-product of collagen metabolism, during which it is released into the blood and either catabolized in the liver or excreted in urine. There were a variety of problems associated with hydroxyproline assay. Either a collagen-free diet or an overnight fast and substitution of a hydroxyproline/creatinine ratio were required. There was a diurnal variation with maximum excretion between midnight and 8 A.M. and minimum between noon and 8 P.M. Assay methods were not standardized or completely satisfactory. Hydroxyproline excretion was used mainly to detect the presence of bone metastases (sensitivity, about 75%-80%; range, 36%-95%) and to monitor therapy; it never became popular.
More recently, proteins were found that specifically cross-link and stabilize collagen fibers in cartilage and bone; pyridinoline (PYD) is present in cartilage and bone while deoxypyridinoline (DPD) is present only in bone. Neither is influenced by diet. Both are released when bone matrix is dissolved as part of a resorptive process (either local or generalized; either an osteolytic or metabolic process; or active bone turnover). Therefore, PYD or DPD excretion increases in Paget’s disease, primary hyperparathyroidism, bone metastases, RA, osteomalacia, and osteoarthritis. PYD and DPD are excreted in urine without alteration by the liver. Analytic methods include high performance liquid chromatography and immunoassay. Both are currently being used in research centers primarily to detect bone loss in metabolic bone disease, especially osteoporosis.
In addition to metabolic turnover studies, bone mineral density is being measured by conventional x-ray methods, computed tomography, and radionuclide techniques; in each case, one or two small bone areas are evaluated and the results extrapolated to the skeleton as a whole. This has mainly been applied to evaluation of osteoporosis. Laboratory involvement in osteoporosis at present mainly is directed at excluding “secondary” etiologies. These are corticosteroid excess (Cushing’s syndrome or cortisol therapy), hyperthyroidism, myeloma, and possibly the uncommon cases of estrogen deficiency due to gonadal hormone deficiency. Screening tests for each are discussed in different chapters. In addition, serum calcium, phosphorus, and alkaline phosphatase are useful as a baseline and to (occasionally) detect diseases affecting bone (ALP elevated in 94% of osteomalacia).
Another marker for bone turnover is Gla protein (osteocalcin), the largest (20%) noncollagen protein of bone matrix. This substance is produced only by osteoblasts (and tooth-forming odontoblasts) and is excreted by the kidneys; there appears to be some breakdown in the kidneys. Serum bone Gla measured by radioimmunoassay was found to be increased in conditions associated with increased osteoblastic activity (e.g., Paget’s disease, osteomalacia, renal osteodystrophy, and osteoblastic bone metastases). However, there were some problems. Renal failure results in retention and increase of Gla in serum; there is relatively mediocre sensitivity in detection of skeletal metastases; and there were inconsistant results in conditions such as osteoporosis where the degree of bone turnover was relatively small. There is contradictory data on effects of age and female hormone changes. Bone Gla protein is vitamin K-dependent and is affected by thyroid hormone, parathyroid hormone, and growth hormone through their activity on bone metabolism. Estrogen and corticosteroids decrease bone Gla levels. To date, bone Gla protein assay has not become popular except in research centers. There is also a matrix Gla protein secreted by osteoblasts and found in bone and cartilage.
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Idiopathic Inflammatory Myopathies
The category of idiopathic inflammatory myopathies includes several entities involving progressive muscle weakness due to muscle inflammation of known etiology, primarily involving proximal muscles with a typically symmetrical distribution. There are elevated levels of various muscle-associated enzymes such as creatine kinase (CK), certain electromyographic abnormalities, and microscopic chronic inflammatory infiltrate in the affected muscle. Because of some degree of serological crossover with the rheumatoid-collagen diseases and also more recent finding of other autoantibodies, these myopathies are thought to be autoimmune disorders with as yet unknown etiology. The best-known entities in this group are dermatomyositis, polymyositis, and an uncommon entity called inclusion-body myositis. Also included are less well-defined conditions called myositis overlap and cancer-related myositis.
Diagnosis of the three major entities depends on muscle biopsy; each entity has a different pattern of inflammatory cell infiltration or other findings if the biopsy has a classic picture (if the classic picture is not present, interpretation is much more difficult). In addition, some of these entities have varying incidence of certain autoantibodies. One of these is Jo-1, an antibody directed against synthetase antigen. Jo-1 antibodies are found in about 33% of polymyositis, 33% of dermatomyositis, and 8% of myositis overlap patients. Other antibodies with even less frequency are anti-SRP (against signal recognition proteins) and anti-MAS. Although these antibodies are of little help in diagnosing muscle diseases as presently defined entities, the antibodies do help define patients with certain patterns of symptoms that possibly some day may be used to redefine autoimmune muscle diseases. For example, in patients who demonstrate synthetase (Jo-1) autoantibodies, there is an 87% incidence of fever, 62% of Raynaud’s phenomenon, 84% of myalgias, 94% of arthritis, 4% of distal weakness, 89% of interstitial lung disease, and 49% of carpal tunnel syndrome. In those with anti-SRP, there is no fever, 29% with Raynaud’s; 100% myalgias, no arthritis; 43% distal weakness; no interstitial lung disease; and 20% carpal tunnel syndrome. Anti-MAS is nearly always seen in alcohol-associated rhabdomyolysis, and not present in patients with Jo-1 or anti-SRP. Other than Jo-1, these autoantibodies are currently used more in research than clinical diagnosis; even Jo-1 has limited usefulness due to its poor sensitivity in currently defined muscle diseases.
Of some interest is significant incidence of ANA in most of the inflammatory myopathies (40% in polymyositis; 62% in dermatomyositis; 77% in myositis-collagen disease overlap; 31% in cancer-associated myositis; and 23% in inclusion-body myositis). There is a small incidence (less than 20%) of various ANA subgroups such as SS-A (Ro) in the myositis syndromes and an increased incidence of HLA DRw52 as well as specific DR antigens. However, the DR antigen incidence is not high enough for any one DR antigen to be either specific or diagnostic.
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Circulating Immune Complexes
Immune complexes involve the binding of antigen to specific antibody and form part of the normal host response to foreign antigens. In some cases, immune complexes apparently can be deposited in tissues or organs and produce tissue injury. Blood vessels are most frequently involved. Although immune complexes may involve IgG, IgA, or IgM antibody, immunoglobulin G is the most common type. Immune complexes bind C1q and C3 components of complement. Cryoglobulins are immune complexes consisting either of monoclonal immunoglobulin complexes or, much more commonly, rheumatoid factor complexed with immunoglobulins (“mixed cryoglobulins”). Immune-complexes may be fixed to tissue, circulating in the blood, or both. Diseases associated with circulating immune complexes include certain parasitic (schistosomiasis), protozoal (malaria), viral (hepatitis virus and cytomegalovirus), and bacterial (SBE and meningococcemia) infections; various malignancies; and various inflammatory diseases with an autoimmune component such as the rheumatoid-collagen diseases and the vasculitides. However, circulating immune complexes have been detected in some way by some investigators in a great number of diseases.
Immune complexes can be detected in various ways. Immunofluorescent stains can be applied to tissue sections and visually demonstrate immunoglobulin binding to specific tissue locations. Circulating immune complexes (CICs) can be detected and assayed. The two most common methods include assays that detect C1q binding and methods that detect C3 activation such as the Raji cell assay. The C1q methods detect only CIC that activate complement by the classic pathway. The Raji cell assay uses tissue cultured cells derived from Burkitt’s lymphoma that have high-affinity binding capability for the C3b component of complement. This detects complement activation by either the classic or the alternate pathways. Currently, the Raji cell assay method seems to be used most frequently. An EIA method has also become available. Unfortunately, assay of CIC has not achieved clinical usefulness in any way comparable to their immunologic and basic science interest. Most diseases associated with CIC average at least 10% or more false negative results with current assay methods, so that a negative result does not exclude the disease or presence of the complexes. The frequent presence of detectable CIC in many conditions hinders interpretation of a positive result. Also, use of CIC levels as a parameter of therapeutic response has yielded contradictory and inconstant results in the literature. CIC assay seems to have been most useful in diagnosis and therapy of SBE, especially when related to prosthetic valves. In a patient with a prosthetic valve, absence of detectable CICs is some evidence against SBE. Serial measurement of CICs in SBE apparently has been more helpful in assessing effectiveness of therapy than in most other diseases.
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Polymyalgia Rheumatica
This condition overlaps with temporal arteritis in many respects. Both occur in the same age group and both have the same general systemic symptoms and laboratory abnormalities, including elevated ESR, in about the same frequency. The major difference is that the principal symptom of polymyalgia is aching and stiffness in proximal joints such as the shoulders or hips; this condition is more noticeable after a period of inactivity, especially after sleep. Besides overlap in systemic symptoms and laboratory results with temporal arteritis, about 50% (range, 40%-60%) of patients with giant cell arteritis have symptoms compatible with polymyalgia rheumatica, and about 15% of patients (range, 10%-40%) with typical symptoms of polymyalgia (and normal-appearing temporal arteries on physical examination) have temporal artery biopsy findings of giant cell arteritis. It is controversial, however, whether to biopsy a temporal artery if the patient does not have any symptoms suggesting temporal arteritis.
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Temporal Arteritis (Giant Cell Arteritis)
Actually, temporal arteritis is a subdivision of giant cell arteritis. The disorder involves medium-sized and large arteries, including the aorta. There is a granulomatous inflammation with varying numbers of multinucleated giant cells that involves the vessel wall in a discontinuous, or “skip,” fashion and disrupts the artery internal elastic membrane. In temporal arteritis, most (but not all) patients are Europeans over age 50 and about 70% are female. More than one half of the patients experience headache and have physical abnormality in one or both temporal arteries (tender or nodular to palpation). Important symptoms occurring in less than one half of the patients include visual disturbances and often systemic symptoms such as fever, weight loss, jaw claudication, and myalgias or arthralgias. However, the number of symptoms varies greatly. Occasionally patients have fever of unknown origin.
Laboratory abnormalities include anemia in more than 50% of patients with the characteristics of the anemia of chronic disease, and sometimes a leukocytosis. Liver function tests are mildly abnormal in about 30% of patients, with the alkaline phosphatase level being most frequently elevated. Liver biopsy findings are most often normal. The most characteristic laboratory abnormality is ESR elevation, most often more than 50 mm/hour (Westergren method). This test has been used both for screening, as a part of diagnostic criteria, and to follow therapy effects. However, sometimes the ESR is within reference range when the patient first presents and becomes elevated later; and a small number of patients (exact number unknown but estimated at 2%-9%) never develop an elevated ESR. Definitive diagnosis requires temporal artery biopsy. The detection rate of biopsy is said to be about 90% (range, 65%-97%). About one third of patients have temporal arteries that are not painful and feel normal. It has been emphasized that a 3- to 5-cm temporal artery segment should be obtained, since the lesions are scattered. If this biopsy result is normal on serial section, biopsy of the other artery increases detection rate about 5%-10%.
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Wegener’s Granulomatosis (Granulomatous Vasculitis)
Wegener’s granulomatosis is characterized by granulomatous inflammation containing foci of vasculitis involving the nasopharynx plus crescentic glomerulonephritis (proliferative vascular lesions obliterating a focal area of Bowman’s capsule space). Laboratory test abnormalities include substantial hematuria and proteinuria, and reflect a culture-negative ongoing inflammatory process. The WBC count and ESR are usually elevated when the disease is active.
Limited forms of this syndrome also occur, most often confined to the nasopharynx or less often, the lower respiratory tract. Diagnosis is made when possible by biopsy of clinically affected areas. In addition, a serologic test called the anti-neutrophil cytoplasmic (ANCA) test is now available in larger reference laboratories and medical school centers. This uses a fluorescent antibody method that demonstrates fluorescent antibody localization in the cytoplasm of neutrophils having a granular appearance throughout the cytoplasm (C-ANCA; although there is a minor tendency toward perinuclear accumulation), C-ANCA has been reported in about 90%-95% (range, 84%-100%) of active classic Wegener’s cases, in about 30% (range, 13%-41%) when the disease is inactive, and in about 65% (range, 60%-85%) when the disease is limited to the respiratory tract. Most, but not all, of patients with Wegener’s granulomatosis localized only to the kidneys have negative C-ANCA results.
Even more recently, it was found that using a different fixative for the cells used for antigen in the fluorescent antibody technique produced reaction with a different ANCA, one that predominantly localized next to the cell nucleus (perinuclear; p-ANCA). Perinuclear ANCA has been reported to react with myeloperoxidase, and is detected in 50%-80% of localized Wegener’s centered in the kidneys as crescentic glomerulonephritis or a similar condition known as idiopathic crescentic glomerulonephritis. p-ANCA is also found in other conditions associated with inflammation; in one study it could be detected in about 75% of patients with ulcerative colitis, 75% of patients with primary sclerosing cholangitis, 50% of patients with autoimmune hepatitis, 50% of patients with Churg-Strauss vasculitis, 5%-7% of patients with hepatitis virus B or C active infection, and 8% of patients with Crohn’s disease.
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Allergic (Hypersensitivity) Vasculitis
The most common and well-known entity in this category is Henoch-Schonlein (H-S) purpura. The primary abnormality is necrotizing inflammation of small venules, characterized by infiltration of the vessel wall by segmented neutrophils accompanied by destruction of some neutrophils with release of nuclear fragments (“leukocytoclastic vasculitis”). Immunohistologic methods can demonstrate IgA deposition in the vessel wall due to presence of IgA immune complexes. Overall, H-S purpura demonstrates purpura in over 90% of cases, arthralgias or arthritis in multiple joints in 80%-90% of cases, and gastrointestinal symptoms in about 70% of cases. Schonlein’s purpura features flat or nodular purpuric skin lesions, usually small but of varying size, most often on the lower extremities but which may occur elsewhere. There is no GI involvement. Henoch’s purpura features involvement of and bleeding into the GI tract without emphasis on skin manifestations. Renal involvement with hematuria may occur in either entity in 10%-40% of cases. The syndrome may follow an upper respiratory tract infection or may be due to a drug hypersensitivity reaction and may include systemic symptoms such as malaise, myalgia, and arthralgias. Platelet counts and other coagulation tests usually are normal, except for the tourniquet test, results of which are frequently abnormal. Diagnosis is usually made through biopsy of an area that is abnormal visually or clinically.