Articles on Medical Diseases and Conditions

Category: Bone, Joint, and Collagen-Vascular Disorders

Bone, Joint, and Collagen-Vascular Disorders

  • Radionuclide Bone Scanning

    Certain disorders affecting bone are discussed elsewhere (hyperparathyroidism, metastatic tumor in bone). The commonest diagnostic problems involve fractures, osteomyelitis, and metastatic tumor. The nonradiologic procedures most frequently used in bone disease are serum alkaline phosphatase and bone scanning.

    Strontium 85 was the first agent to be widely used in bone scanning. Its relatively high patient radiation dose and problems with excretion by the colon led to replacement by fluorine 18, which, in turn, has been superseded by the technetium-labeled phosphates. Bone scan abnormality is due to increased osteoblastic activity, whether neoplastic, reactive, reparative, or metabolic. Local hyperemia is also a factor.

    Bone scan provides important information in the evaluation of trauma and unexplained pain in areas where an occult fracture is a possibility. Whereas some fractures are immediately evident on x-ray film, in many cases the fracture line cannot be seen, especially in the spine, ribs, face, and smaller bones of the extremities. The radiologist is then forced to look for secondary changes produced by healing, which will not become evident before 10-14 days and in some cases may never be detectable. On bone scan, many fracture sites become abnormal by 3 days after trauma, and the great majority in 5 days. Once evident, the abnormality persists for a variable length of time, the average being approximately 2 years. A fracture site revealed on x-ray film but not on scan at least 7 days after trauma usually represents an old healed injury. Severe osteoporosis or severe malnutrition retards osseous reaction and may result in an equivocal or false negative scan. As noted previously, various types of joint disease can be visualized on the bone scan and may on occasion present problems in differentiation of the disease from possible fracture in the neighborhood of the joint.

    Osteomyelitis is another disease in which bone scan may be invaluable. X-ray changes do not usually appear before 10-14 days after onset and may be delayed further or be difficult to interpret. Bone scan shows abnormalities days or weeks before x-ray films. Although the exact time after onset necessary for most patients to display abnormality is not as clearly defined in osteomyelitis as in fracture, the literature seems to suggest 5-7 days. If the bone scan is normal and osteomyelitis is strongly suspected, a gallium scan may be helpful, or the bone scan may be repeated after several days. Certain conditions resemble osteomyelitis clinically and to some degree on scan. These include cellulitis, arthritis, and focal bone necrosis or infarct. Patients already receiving steroid or antibiotic therapy before onset of osteomyelitis may display changes in normal bone response. These changes can affect the bone scan latent period or the image characteristics.

    Metastatic tumor detection is the reason for most bone scan requests. All malignancies capable of metastasis may reach bone. Some of these, including prostate, breast, lung, kidney, urinary bladder, thyroid follicular carcinoma and possibly malignant lymphoma, are more likely to do so than other tumors. Formerly, bone scanning was widely used to establish operability of these neoplasms by excluding bone metastases after a primary tumor was discovered. Most reports on breast carcinoma patients in early (potentially operable) stage disclosed a very small incidence of abnormal bone scans (usually <10%) unless there was some other evidence of bone metastases such as bone pain or elevated alkaline phosphatase levels. For example, in stage I and II breast carcinoma, there is an average reported incidence of 6% bone scan abnormality (literature range, 1%-40%). False positive abnormality due to conditions other than metastasis is also a problem (3%-57% of cases, average about 10%). Therefore, bone (and also liver or brain) scans are not being recommended in most institutions as routine preoperative tests in breast carcinoma. Fewer data are available for lung carcinoma, but there may be a better case for preoperative bone scans in potentially resectable patients based on higher rates of detectable occult metastases and the greater magnitude of the operation, which becomes unnecessary if metastases are found.

    Tumor-related bone scanning is indicated in several situations: (1) to investigate bone pain when x-ray films do not show a lesion, (2) to document extent of tumor in nonresectable malignancies known to have a high rate of bone metastasis to follow results of therapy, and (3) in some cases, to help investigate unexplained symptoms that may be due to occult tumor. Until bone scanning became available, skeletal x-ray survey was the mainstay of diagnosis. Numerous comparisons have shown that bone scanning detects 15%-40% more bone metastases (literature range, 7%-57%) than x-ray. This difference is related to osteoblastic reaction induced by the tumor, which may occur even when the lesion is osteolytic on x-ray film. On the other hand, about 5% of metastases are seen on x-ray film but not on scan (literature range, 3%-8%); these are usually pure osteolytic lesions. The implication of these figures is that bone scan is sufficient for routine detection of metastases in the major bone-seeking tumors and that x-ray should be reserved for specific anatomical areas in which the scan is equivocal or the etiology of scan abnormality is in doubt. X-ray is also useful when there is strong suspicion of bone malignancy yet the scan is normal, when the scan is normal in areas of bone pain, and to help differentiate metastasis from focal severe osteoarthritis.

    Bone scanning does have disadvantages, chief of which is nonspecificity. The variety of conditions that may produce abnormal bone scans include fractures (even those of long duration), osteomyelitis, active osteoarthritis, joint synovial inflammation, areas of bone necrosis or infarct, myositis ossificans, renal osteodystrophy, Paget’s disease of bone, certain benign bone tumors such as fibrous dysplasia and osteoid osteoma, and various artifacts such as ossification centers in the sternum or costochondral junction calcification. On the other hand, when tumor produces widespread bone marrow invasion, the spine or other bones may sometimes have a homogeneous appearance on scan that may be misinterpreted as normal unless certain other findings are taken into account. As a general rule, the greater the number of focal asymmetric lesions on bone scan, the more metastatic tumor should be suspected. Healing fractures (which actually may have occurred at different times) and Paget’s disease create the most interpretative difficulty. Some institutions routinely scan only the spine, pelvis, and ribs instead of the total body. A question may arise about the probability of metastases elsewhere. One large study encompassing a wide variety of tumors indicates that the incidence of solitary uptake (other skeletal areas negative) in the skull is about 4%; in the extremities as a unit, about 9%; in the humerus, about 1%; in the femur, 5%; in the tibia or fibula, 2%; and elsewhere in the extremities, quite rare.

  • Radionuclide Joint Scanning

    Besides synovial fluid examination, radionuclide joint scanning is a procedure that may offer useful information. For screening purposes, the scan could be performed with one of the isotope-labeled phosphate compounds used for bone scanning. These scans reveal abnormality in most joints that have a significant degree of inflammation, even when subclinical. Joint scanning permits a reasonably accurate assessment of the number, location, and degree of activity of involved joints and offers an objective (although only semiquantitative) method for evaluating results of therapy. Although fairly sensitive, the phosphate agents are not ideal for joint scanning, since increased concentration denotes increased activity of bone osteoblasts in response to adjacent synovial abnormality rather than a primary synovial reaction. Other etiologies for osteoblastic stimulation, such as osteochondritis dissecans, traumatic joint disease, active osteoarthritis, healing fractures, and the later stages of aseptic necrosis, may all produce abnormal bone scan images, which sometimes are hard to differentiate from arthritis. In such cases other compounds may be employed, including technetium pertechnetate or labeled albumin. These tend to remain in blood vessels, thereby indicating regions of increased vascularity or hyperemia such as the synovial membrane when involved by active arthritis. These compounds are a little less sensitive than the phosphates but are more specific for synovial disease.

  • Synovial Fluid Analysis

    When synovial fluid is aspirated, 1 ml or more should be placed into a sterile tube for possible culture and a similar quantity into a heparinized tube for cell count. The remainder can be used for other procedures. A cell count is performed on anticoagulated fluid using 0.9% saline as the WBC pipette diluent (the usual diluent, Turk’s solution, contains acetic acid, which coagulates synovial fluid mucin and produces clots that interfere with accuracy of the WBC count).

    Synovial fluid tests

    Mucin clot. The Ropes test for mucin clot is performed by adding a few drops of aspirate to 10-20 ml of 5% acetic acid in a small beaker. After 1 minute, the beaker is shaken. A well-formed clot remains compact; a poor clot is friable and shreds apart easily. In general, noninflammatory arthritides form a good clot. In noninfectious inflammation, the clot may be good to poor, whereas the clot of acute bacterial infection is poor.

    Viscosity (string sign). Aspirate is allowed to drip slowly from the end of a needle. The length of the strand formed by each drop before it separates is the end point. In normal fluid and in noninflammatory arthritides the strands string out more than 3 cm. In acute inflammatory conditions fluids drip with little, if any, stringing.

    Synovial fluid glucose. Synovial fluid glucose value is usually within 10 mg/100 ml (0.5 mmol/L) of the serum glucose value and is always within 20 mg/100 ml. A blood specimen for glucose should be obtained as close as possible to the time of joint aspiration. The patient should have fasted at least 6-8 hours to achieve baseline values and to compensate for delay in glucose level equilibration between blood and synovial fluid. In degenerative arthritis, synovial fluid glucose levels are usually normal. In acute inflammatory noninfectious arthritis (SLE, RA, gout, etc.) there may be a mild or even a moderate decrease (up to 40 mg/100 ml below serum levels). In acute bacterial (septic) arthritis there typically is a marked decrease of more than 40 mg/100 ml (2.22 mmol/L) below serum glucose levels, but a decrease of this extent is said to occur in only about 50% of cases.

    Microbiologic studies of synovial fluid. Gram stain is reported to demonstrate organisms in 40%-75% of patients with septic arthritis (literature range, 30%-95%), more often with gram-positive than with gram-negative bacterial infection. However, Gram stain is not always easy to interpret, especially when only a small number of organisms are present, due to debris from the joint that may take up some of the stain. Culture of synovial fluid is the mainstay of diagnosis in septic arthritis. Since gonococci are a major cause of joint infection, provision should be made for the special conditions necessary to culture these organisms. It has been reported that blood cultures may be positive and synovial fluid cultures negative in 15% of patients with septic arthritis. Previous antibiotic therapy considerably decreases the chance of diagnosis by culture.

    Synovial fluid white blood cell count. There is considerable overlap between WBC counts of noninflammatory conditions and noninfectious inflammatory diseases in the area of 500-2,000 WBCs/ mm3 (0.5-2.0 x 109/L) and between infectious disease and noninfectious inflammatory conditions in the area of 10,000-100,000 WBCs/mm3 (10-100 x 109/L). Thus, only very high or very low WBC counts are of great help without other information. A very high percentage of neutrophils (>75%, usually >90%) is said to occur in most cases of untreated acute bacterial infectious arthritis. A neutrophil percentage of more than 90% may therefore be a more reliable indicator of bacterial infection than cell count, synovial glucose level, or Gram stain (unless the cell count is >100,000, the synovial glucose level is >40 mg/ 100 ml below the fasting, simultaneously drawn serum glucose level, or the Gram stain discloses unequivocal organisms).

    Other examinations. Other examinations include a serologic test for RA. The RA tests on synovial fluid occasionally show positive results before serum tests. In SLE, LE cells sometimes form in synovial fluid and can be demonstrated on the same Wright’s-stained smear used for differential cell count. Synovial fluid total complement (CH50, Chapter 22), is said to be decreased in SLE and active RA (more often if the patient with RA has a positive latex tube agglutination test result). Total complement is reported to be increased in Reiter’s syndrome. Most other noninflammatory and inflammatory arthritic diseases are associated with normal synovial fluid complement levels. However, there are sufficient exceptions to these general observations that synovial fluid complement assay has not become popular. For example, in one study, 15% of SLE patients had normal synovial fluid total complement values and only about 40% of patients with Reiter’s syndrome had elevated levels.

    Synovial fluid specimen collection

    An anticoagulated tube is necessary for cell count, WBC differential, and examination for crystals. Heparin is preferred, but liquid ethylenediamine tetraacetic acid can be used. Without anticoagulation, spontaneous small or large clots may form that trap WBCs and alter the cell count. A sterile tube should be used for fluid that is to be cultured; heparin anticoagulant is preferred. This must be sent to the laboratory immediately. A tube without anticoagulant is needed for the mucin test, complement assay, and glucose assay. Some prefer a tube with fluoride anticoagulant for glucose to help preserve the specimen. Fluid for complement assay should be frozen immediately if the assay is not performed within 1-2 hours.

  • Other Conditions Associated with Arthritis

    Arthritis and arthralgia may be present in 4%-23% of patients with primary biliary cirrhosis. One report indicates that many more have radiologic abnormalities of erosive arthritis but have no symptoms. About 50% of patients with hemochromatosis and about 25% of patients with chronic active hepatitis develop arthritis or arthralgias; up to 40% of patients with hepatitis virus hepatitis have arthralgia (usually not true arthritis); and arthritis may occasionally be found in patients with viral infections of various etiology (e.g., rubella). Patients with cancer may develop joint symptoms due to direct extension from or a reaction to a nearby primary site or from joint area metastasis. Joint metastasis usually involves one of the knees and is most often due to carcinoma of the lung or breast. Metastasis to the hand is most often due to lung carcinoma. Childhood acute leukemia rather frequently appears to produce joint pain for a variety of reasons. Neoplasia have been associated with gout, vasculitis, and occasionally, syndromes resembling some of the collagen diseases. Occasionally, there may be arthritic symptoms without neoplastic joint involvement. Sarcoidosis may occasionally produce arthritis.

  • Septic Arthritis

    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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.