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  • Syndromes due Primarily to Autoimmune Vasculitis. Polyarteritis Nodosa.

    Polyarteritis nodosa features inflammation of small and medium-sized arteries, most often in middle-aged males. Single organs or multiple systems may be involved, although usually the lungs are spared. The kidney is the organ most frequently involved (about 77% of cases), with hematuria the main sign. Peripheral nerves are affected almost as frequently, either with clinical or subclinical neuropathy. Hypertension is present in 70% of cases. Arthritis involving multiple joints has been reported in about 50% of patients. Laboratory studies usually show moderate leukocytosis with neutrophilic increase and immaturity of the ordinary type seen with infections. Mild anemia is also common. There often is an increase in serum gamma globulin. Diagnosis sometimes can be made by selective angiography of an affected artery. The main diagnostic procedure is biopsy. The most common specimen is muscle, and the usual region is the gastrocnemius because it is easy to reach. However, if biopsy is done, it should be from some muscle with a painful area if any is present; random samples give poor detection rates. The biopsy specimen should be generous, since the lesions of polyarteritis occur in small arteries. The incidence of positive single muscle biopsy specimens in fairly definite cases of polyarteritis ranges from 20%-40%; obviously, it is on the lower side in mild or questionable cases. Another difficulty is that occasionally patients with classic RA may have arteritis nearly identical to polyarteritis. SLE patients also may have arteritis, but the lesions tend to be in arterioles. Other more rare syndromes of the collagen-vascular group may create histologic difficulty. Therefore, the clinical picture has as much importance as the biopsy report. If the muscle biopsy is normal, some investigators obtain nerve conduction studies on the sural nerve; and if results are abnormal, biopsy the sural.

    Patients with polyarteritis may have various autoantibodies. The ANA test result is positive in about 20%-25% of cases. There may be a positive Crithidia anti-DNA test result in about 10% of cases and a positive RA latex test result in about 15% of cases.

  • Sjogren’s Syndrome

    The parotid gland disease formerly known as “Mikulicz’s syndrome” now is usually included with Sjogren’s Syndrome. Some reports indicate that Sjogren’s Syndrome affects 2%-5% of adults over age 55 and is second only to RA in frequency among the rheumatoid-collagen diseases. SSjogren’s Syndrome occurs in primary and secondary forms. Primary Sjogren’s Syndrome, sometimes called the “sicca syndrome,” involves both the major and minor salivary glands, the lacrimal glands, and the labial glands. There is destruction of the salivary gland parenchymal cells with dense lymphoid reaction. Loss of lacrimal gland function makes the patient unable to produce tears and leads to injury of the cornea and conjunctiva (keratoconjunctivitis sicca). There are many other abnormalities that appear in a minority of patients, such as renal tubular acidosis, pericarditis, chronic hepatobiliary disease with antimitochondrial antibodies present, pancreatitis, disturbances of esophageal motility, and an increased tendency for lung infections. About 20% of patients with primary Sjogren’s Syndrome develop multifocal brain and spinal cord dysfunction closely resembling multiple sclerosis, both from clinical and laboratory aspects. Some of these patients develop cerebrospinal fluid oligoclonal bands and elevated IgG production indices.

    Secondary Sjogren’s Syndrome is the coexistence of substantial components of primary Sjogren’s Syndrome with some other disease. The disorders that overlap with Sjogren’s Syndrome include most conditions that have a strong autoimmune component. The diseases most frequently reported to be associated with Sjogren’s Syndrome are RA (10%-25% of RA patients) and SLE (up to 30% of SLE patients). Some investigators report elements of Sjogren’s Syndrome in many patients with PSS and primary biliary cirrhosis.

    Laboratory aspects. Patients with Sjogren’s Syndrome have various detectable autoantibodies. About 50%-80% have a positive ANA test result, about 15%-20% have positive LE prep test results, and about 75%-90% have detectable rheumatoid factor. About 25% have anti-dsDNA antibodies. The most characteristic autoantibodies are SS-A (Ro) and SS-B. The SS-A antibody is reported in about 75% (13%-88%) of patients with primary Sjogren’s Syndrome, about 10% of Sjцgren’s syndrome with RA, and about 50% of patients with SLE. The SS-B antibody is found in about 60% (literature range, 48%-73%) of patients with primary Sj?gren’s syndrome, 75%-85% of SLE Sj?gren’s syndrome, and 2%-8% of SLE without Sj?gren’s syndrome. RAP autoantibodies are reported in 60%-80% of Sjogren’s Syndrome with RA and 5%-30% of Sjogren’s Syndrome without RA. Therefore, elevated SS-A or SS-B antibody levels, especially in high titer, suggest primary Sjogren’s Syndrome or Sj?gren’s syndrome with SLE, with SS-B less sensitive but more specific for primary Sj?gren’s syndrome. RAP autoantibodies are useful markers for the RA-associated secondary form of Sjogren’s syndrome. The data on autoantibodies in primary and secondary Sjogren’s Syndrome are rather contradictory except for larger trends, probably due to differences in antigens used in the research laboratories and differences in diagnostic criteria in the populations tested. Standardized test reagents and diagnostic criteria are needed for final evaluation of these tests.

    Diagnosis of Sjogren’s Syndrome can be made from clinical symptoms, biopsy of salivary or labial glands, or presence of SS-A or SS-B autoantibodies in high titer. The SS-B is more specific for Sjogren’s Syndrome than SS-A but is less sensitive. High titers of SS-B suggest primary Sjogren’s Syndrome or SLE with Sjogren’s Syndrome.

  • Mixed Connective Tissue Disease (MCT)

    As the name implies, MCT disease contains elements of several rheumatoid-collagen entities, including SLE, PSS, and dermatomyositis. Clinically, there is arthralgia or arthritis in 90%-95% of patients, Raynaud’s phenomenon in about 80%-90%, abnormal esophageal motility in about 70%, muscle pain in about 70%, and fever in about 30%. There is a low incidence of renal disease. Various autoantibodies have been found, and there is a positive ANA test result in more than 95% (usually with a speckled pattern), elevated SS-A in up to 50% of cases, and elevated anti-dsDNA antibody in about 25%. The characteristic serologic feature of MCT disease is a high titer of autoantibody against RNP in 95%-100% of patients. Lesser degrees of RNP elevation are found in some patients with SLE and PSS.

  • Progressive Systemic Sclerosis (Scleroderma; PSS)

    PSS leads to progressive dense connective tissue replacement in certain areas that normally contain only small amounts of loose collagen. These include the dermis of the skin, the submucosa of the esophagus or other parts of the GI tract, and the heart. The lungs frequently develop a slowly progressive type of diffuse fibrosis, radiologically most prominent in the lung bases. In addition, the kidneys are often affected by a somewhat different histologic process, similar to malignant hypertension. The disease is most common in middle-aged women. Clinically, the skin changes produce tautness and lack of elasticity; these changes most often occur in the hand and are often accompanied by Raynaud’s phenomenon. Esophageal involvement leads to dysphagia, and small bowel changes may produce localized dilation.

    Laboratory aspects. Laboratory tests usually show normal hemoglobin levels. There may be an increased ESR, and there may be associated hypergammaglobulinemia of a diffuse type, although this is not a consistent feature. Progressive system sclerosis gives a positive ANA test result in about 70% of cases, and the anti-DNA test may be positive in about 15% of cases. Various autoantibodies have been reported in a minority of cases (including Scl-70 in 45% of patients). Antinucleolar antibodies in high titer are very suggestive of PSS. Rheumatoid factor test results are positive in about 15% of cases, and there may be a biologic false positive agglutination test result for syphilis.

    Diagnosis usually can be made clinically but may be suggested by barium swallow esophageal x-ray studies in patients who have esophageal symptoms. Biopsy of an affected skin area is the procedure of choice if the diagnosis cannot be made clinically.

  • Systemic Lupus Erythematosus (SLE)

    SLE features various combinations of facial skin rash, arthritis, nephritis, systemic symptoms such as fever and malaise, and inflammation of serous membranes such as the pericardium. The disease is by far more frequent in women, predominantly young or middle-aged adults. In one large series the mean age at diagnosis was 30 years, with a skewed distribution: the majority between ages 14 and 40 years, a lesser but significant number between ages 40 and 55 years, and a few scattered from infancy to age 14 years and over age 55 years. Hepatomegaly is found in 30% of patients (literature range, 23%-44%), splenomegaly in 20% (9%-41%), adenopathy in 50% (37%-68%), and arthritis in 60% (52%-78%).

    Laboratory findings. Anemia is present in 60%-75% of SLE patients, most often mild or moderate and of the normocytic-normochromic type. About 30% (literature range, 18%-65%) of patients have a positive direct Coombs’ test result, although only 10% or less develop autoimmune hemolytic anemia. Leukopenia is found in about 50% of patients (literature range, 43%-65%) and thrombocytopenia in about 15% (literature range, 5%-26%). There are often one or more manifestations of abnormal plasma proteins; these may include cold-precipitable cryoglobulins, circulating anticoagulants, autoantibodies, elevated gamma-globulin levels, circulating immune complexes, false positive RA and syphilis serologic reactions, and certain even rarer phenomena.

    In SLE with active nephritis, total serum complement (C, Cў, or CH50, Chapter 22), C3, and C4 levels are usually all decreased. This complement pattern is not absolutely specific for lupus nephritis and may be found in serum sickness, SBE, and immune complex disease.

    Lupus erythematosus cell preparation. The first reasonably good test for lupus, and one that could still be used, is the LE preparation (LE prep). This test detects antibody against nuclear deoxyribonucleoprotein (DNP; soluble nucleoprotein[sNP], DNA-histone complex; see the box) that is produced in SLE. The LE prep technique first provides a source of nuclei from laboratory-damaged cells, either tissue cells or WBCs. The nuclei are then incubated with patient serum, during which time the nuclear material is converted by the ANA against sNP into a homogeneous amorphous mass that stains basophilic with Wright’s stain. This mass is then phagocytized by nondamaged polymorphonuclear neutrophils; these neutrophils containing the hematoxylin (blue-staining) bodies in their cytoplasm are the so-called LE cells.

    Some Autoantibodies Found in Systemic Lupus Erythematosus and Other Autoimmune Disorders
    I. Anti-DNA
    A. Double-stranded (“native”) DNA (dsDNA)
    B. Single-stranded DNA (ssDNA)
    II. Antinucleoprotein (soluble nucleoprotein [sNP]; DNA-histone)
    III. Antibasic nuclear proteins (histones)
    IV. Antiacidic nuclear proteins (extractable nuclear antigens[ENAs]: includes Smith[Sm] and ribonucleoprotein [RNP])
    A. Nuclear glycoprotein (Sm)
    B. Ribonucleoprotein (RNP)
    C. Sjцgren’s syndrome A and B (SS-A[Ro] and SS-B)
    V. Antinucleolar (nuclear RNA)
    VI. Anticytoplasmic (ribosomal RNA and others)

    Artifacts may be confused with true LE cells. To be definitive, the basophilic hematoxylin body must be completely amorphous, without any remaining nuclear structure whatever. In many LE preps one finds neutrophils or monocytes with phagocytized nuclear material that still retains some identity as a nucleus, such as a residual chromatin pattern. These are not true LE cells; they are called “Tart cells.” Increased numbers of these may be seen in SLE, but they do not have any diagnostic significance. Neutrophils with ingested RBCs can also be misdiagnosed as LE cells by inexperienced persons. Adrenocorticosteroid therapy often suppresses LE cell production.

    In SLE, positive LE prep results were reported in 70%-80% of cases, with a range in the literature of 40%-100%. The great differences in the literature were due to several factors. First, many of the studies report data based on LE preps obtained at various times during the entire illness rather than the result obtained on the first test at the first admission. Cumulative or repeated studies would result in a higher percentage of patients with positive results. Various modifications of the basic LE prep technique were widely used, and the modifications differ in sensitivity. Finally, patients with active disease were more likely to have a positive LE prep than those with inactive disease. A realistic figure for likelihood of a positive LE prep result in a person with SLE on initial workup is probably 60%-70%.

    Because LE prep methodology is not standardized, preparing and examining the slides is time-consuming, and many laboratory workers lack expertise in interpreting the slides, the LE prep has been mostly replaced by Crithidia anti-DNA assay.

    Antinuclear antibody (ANA) test. The antinuclear factor that causes the LE cell phenomenon is not the only autoantibody or “factor” demonstrable in SLE. A wide variety of such factors has been demonstrated, reactive against either nuclear or cytoplasmic constituents with varying degrees of tissue and cellular constituent specificity. An ANA test usually involves incubating patient serum with nucleated cells. Afterward, a tagged antibody against gamma globulin is added to detect patient ANA coating the cell nuclei. The antibody tag can be fluorescent (FANA test) or can be an enzyme (EANA test). Various types of tissue cells have been used as sources of cell nuclei. Most of these tests yield initial-visit positive results in 95% or more of patients with SLE, compared with positive results on the LE prep of 60%-70%. However, the ANA test is more frequently abnormal than the LE prep in conditions other than SLE. Therefore, current practice is to employ the ANA procedure as a screening test. If the ANA test result is negative, chances that the patient has SLE are very low. If the ANA test result is positive, other studies must be done to obtain a definitive diagnosis.

    Like all laboratory tests, the ANA test is not perfect. Both tissue culture cells (tumor-derived Helen Lake [HeLa] cells, human epithelial cell-derived cells [HEp-2 cells, originally obtained from a laryngeal tumor], and human amniotic cells) and thin tissue sections derived from various sources (most commonly rat liver or mouse kidney) have been used to provide cell nuclei for the procedure; the different nuclear sources do not all have equal sensitivity. Most of the early work was done with rat liver or kidney tissue sections. Tissue culture cells generally are reported to be more sensitive than rat tissue. On the other hand, the more sensitive tissue culture cells detect more low-titer FANA reactions, of which some are produced by disorders other than SLE (if screening for SLE is the only consideration, these would be considered false positive reactions. However, they may be a clue to the other diseases). Also, tissue culture cells demonstrate chromosome centromere staining in patients with scleroderma (progressive systemic sclerosis, or PSS), whereas discrete centromere structures are very difficult to see on rat liver sections and instead tend to have a nonspecific speckled appearance. Similarly, rat liver sections will usually not detect ANA against the Sjцgren’s syndrome. A, (SS-A or Ro) antigen (found most frequently in Sjцgren’s syndrome but also in some patients with SLE and other connective tissue disorders). The anti-human globulin used to detect ANAs can be either a polyclonal type or specific for IgG. Specific anti-IgG eliminates a certain number of false positive reactions due to RF or other IgM antibodies. However, it would fail to detect IgM antibodies against histones due to some causes of drug-induced SLE and some other collagen diseases. In addition, about 4% of SLE patients are reported to produce IgM-type ANA. Results of procedures that use acetone-fixed cell substrates are more likely to be positive with ANA against saline-extractable antigens (extractable nuclear antigens, or ENAs) such as Smith (Sm) and ribonucleoprotein (RNP) than those that omit substrate fixation.

    About 5% of patients with SLE have negative FANA test results using rat liver or mouse kidney tissue sections. About two thirds of these give a speckled nuclear reaction using HEp-2 tissue culture cells; the majority of these were found to be SS-A (Ro) antibodies, which are most often found in Sjцgren’s syndrome but also can be found in SLE. When they are associated with SLE, the predominant clinical symptom seems to be a photosensitive skin rash. In addition, there appears to be a very small subset of SLE patients with anticytoplasmic antibodies rather than ANAs.

    Antinuclear antibody test patterns. The method of reporting ANA results deserves some comment. Both the titer of positive results and the pattern (distribution) of nuclear fluorescence are important. In general, the higher the titer of certain ANA patterns known to be associated with SLE, the more likelihood that the patient has SLE. In addition, the ANA staining pattern can sometimes provide useful information. There are several recognized patterns that appear to be produced by ANAs against certain nuclear proteins. It must be emphasized that none of the fluorescent patterns is specific for only one autoantibody or exclusive for the diseases with which it is traditionally associated. Also, some investigators disagree with the findings of others regarding which pattern is found more often in various diseases.

    Rim (peripheral) pattern. Fluorescence is much more intense on the nuclear border. This was originally thought to be specific for antibody against dsDNA. However, it is now known to be produced by ANA against several additional nucleoproteins, including sNP, single-stranded DNA (ssDNA), and histones. However, a high ANA titer (1:160 or greater) with a rim pattern strongly suggests SLE. Drug-induced SLE usually does not have a rim pattern, nor is a rim pattern common in other rheumatoid-collagen diseases (present in <10% of those patients). However, when the ANA titer is borderline or only mildly elevated, the rim pattern is less helpful because of overlap with the other diseases.

    Solid (homogeneous) pattern. Fluorescence is uniform throughout the nucleus. This is the second most common ANA pattern and, like the rim pattern, can be produced by ANA against dsDNA, ssDNA, sNP, and histones. This is the most frequently seen pattern in SLE, but it is less suggestive of SLE, since it is found more frequently than the rim pattern in other rheumatoid-collagen diseases and is also seen in some patients with drug-induced ANA. The ANA titer is usually less than 1:160 in diseases other than SLE, so that the possibility of SLE is increased in patients with higher titers.

    Speckled pattern. There are many small fluorescent dots throughout the nucleus that do not involve the nucleoli. This is the most commonly encountered ANA pattern. ANAs responsible include those against acidic nuclear proteins, such as ENA (Sm and RNP), Sjцgren’s syndrome A (SS-A; Ro), SS-B (La), Jo-1, histones, and scleroderma 70 (Scl-70). This pattern is the one most frequently associated with the mixed connective tissue (MCT) diseases (discussed later), although the MCT disease does not produce the majority of speckled ANA reactions. It has also been reported in about 25% of patients with SLE (due to anti-Sm) and in some patients with RA, progressive systemic sclerosis, Sjцgren’s syndrome, drug-induced ANAs, and some aged persons. However, if the ANA titer is very high with a speckled pattern, this suggests MCT disease. At least one report indicates that many fluorescence patterns reported as speckled actually consist of small rods or filaments with dots, which is not a true speckled configuration. This pseudospeckled pattern is said to represent most of the conditions other than MCT disease that others include in the speckled category. If the speckled pattern is present in moderately elevated or high titer, specific antibody testing is useful since specific ANA against Sm is strongly suggestive of SLE, ANA against RNP suggests MCT disease, ANA against SS-B suggests Sjцgren’s syndrome, and ANA against Scl-70 suggests scleroderma (PSS).

    Nucleolar pattern. Fluorescence only in the nucleolar areas of the nucleus is seen as several small areas of irregular shape and different sizes. This is due to ANA against nucleolar ribonucleic acid (RNA; 4-6s RNA). It suggests PSS (55%-90% of PSS patients), especially if the titer is high. Lower titers may be found in SLE and occasionally in other collagen diseases.

    Centromere pattern. The centromere pattern is made up of moderate-sized speckles that vary in size and are fewer in number than expected with a speckled pattern. Chromosomes of mitotic cells show the same speckles along the chromosomal spindles. This pattern is due to ANA against centromere antigen and is highly suggestive of the CREST (calcinosis, Raynaud’s phenomenon, esophageal motility dysfunction, sclerodactyly, and telangiectasia) variant of PSS.

    ANA tests can be reported in several ways. The most common are by titer or some descriptive semiquantitation of the reaction strength. In general a test result positive only at the screening titer is considered a weak positive (for HEp-2 cells, this is usually 1:40; for kidney tissue, 1:20). When positive at one dilution above screening titer, it is called moderately positive; when positive two dilutions above screening titer, it is considered a strong positive reaction (3+).

    Assays for specific antinuclear antibodies. At present, with the possible exception of the anti-DNA assay using the Crithidia method, the various assays for specific ANAs are obtained mostly in large reference laboratories or laboratories specializing in autoimmune disease. It should be emphasized that correlation of specific autoantibodies with specific diseases usually depends on the presence of substantial titer elevations of the antibody; low titers are more likely to be less specific.

    Anti-DNA assay. Assays for various specific autoantibodies have been developed. Currently the most popular of these assays detects antibody against dsDNA. This is usually referred to as anti-DNA, although there is a different antibody against ssDNA. There are currently three well-recognized techniques for measurement of anti-DNA antibody. The Farr method is the oldest; it is a radioimmunoassay (RIA) technique using radioactive tritium (3H) or carbon 14 that depends on ammonium sulfate precipitation or Millipore filter filtration to separate the antigen-antibody complex from nonbound antigen. At least two commercial companies have marketed kits using more traditional radioactive iodine reagents. Assays have also been developed that use a protozoan organism named Crithidia luciliae; this has a large intracytoplasmic structure called a “kinetoplast” composed mostly of dsDNA. Various commercial companies have kits with the dead organisms on prepared slides. Patient serum is added, and the anti-DNA antibodies attach to the kinetoplasts of the organisms. A fluorescent anti-human globulin antibody is added that demonstrates fluorescence of the kinetoplast if anti-DNA antibody is attached (the technique is basically similar to that used for the ANA test). In general, reports indicate that the Farr technique is a small but significant percent more sensitive than commercial RIA kits. There is some disagreement in the literature as to whether the sensitivity of the Crithidia procedure is equal to or less than the RIA procedures. Some of the disagreement is attributable to comparison of the Crithidia kits to the Farr technique versus comparison to a commercial RIA method.

    There have been claims in the literature that the anti-DNA test is highly sensitive and specific for SLE. However, review of the published evaluations discloses that overall sensitivity and specificity (as a composite of all anti-DNA methods) is about the same as those of an optimally performed LE prep. Data from the Crithidia assay, which is now the most widely used procedure, suggest that overall sensitivity of Crithidia is about the same as the LE prep, but that specificity for SLE is better than the LE prep, with somewhat fewer positive results in diseases other than SLE. However, positive results do occur in diseases other than SLE. Some data suggest that anti-DNA assay results by any method are more likely (by 20%-40% of cases) to be positive in patients with active SLE than in patients with inactive SLE. Also, SLE is more likely than other conditions to produce a high antibody titer. Test results of drug-induced ANA are usually negative, and if positive are usually not greatly elevated.

    Anti-sNP antibody reacts against a DNP complex with histone. Antibody to the sNP complex is reported in about 50% of SLE patients, fewer than 10% of patients with RA, Sjцgren’s syndrome, or MCT disease, and uncommonly in patients with scleroderma, dermatomyositis, polyarteritis nodosa, or discoid lupus. When anti-sNP antibody is present, the ANA test shows a solid (homogeneous) ANA pattern. Anti-sNP antibody is thought to produce the LE cell phenomenon. Since anti-sNP antibody is not the only autoantibody to evoke a solid ANA pattern, data on the incidence of sNP in various diseases and on the incidence of the solid ANA pattern in the same diseases may not correlate exactly.

    Anti-ENA is not really a specific antibody but instead is a group of antibodies to certain antigens that consist of RNA and protein; of these, the most important are Sm and RNP (discussed separately in the next paragraphs). The ENA antigen is extracted from thymus using phosphate-buffered saline and therefore, as previously mentioned, is sometimes referred to as saline-extractable antigen. An order for anti-ENA antibodies would generate assays for anti-Sm and anti-RNP. These two ANAs both produce a speckled ANA pattern.

    Anti-nuclear glycoprotein Smith (Sm) antibody is present in 30% of patients with SLE (range, 20%-40%) and 8% of patients with MCT disease but not in patients with most of the other rheumatoid-collagen diseases. Therefore, anti-Sm antibody is fairly specific for SLE, but the sensitivity of the test is poor. Anti-Sm antibody is associated with the speckled ANA pattern.

    Anti-RNP antibody is reported in nearly 100% of patients with the mixed connective tissue syndrome and about 25% of patients with SLE, discoid lupus, and progressive systemic sclerosis (scleroderma). Anti-RNP antibody (like anti-Sm antibody) is associated with a speckled ANA pattern. In high titer, anti-RNP antibody is suggestive of MCT disease.

    Antinucleolar antibody is reported in about 55% of patients with PSS, 25% of patients with SLE, and 10% of patients with RA. In high titer it is very suggestive of PSS.

    Anticentromere antibody is directed against the centromere area of chromosomes and is reported to be suggestive of the CREST syndrome. This antigen is seen when FANA is performed on tissue culture cells but not with rat liver or kidney.

    Anti-SS-A (Ro) and Anti-SS-B (La) antibodies react against nuclear antigens extracted from human B lymphocytes (Wi12 cell line) grown in tissue culture. SS-A (Ro) is found in the cytoplasm of some tissue cells (e.g., human spleen) and in the nucleus of others (HEp-2 cells). It is difficult to detect in FANA using rat liver or kidney cells, but is visible using HEp-2 cells. The SS-A is found in about 70% of patients with Sjцgren’s syndrome without RA symptoms, 10% of Sjцgren’s patients with RA, and 25% of patients with SLE (including about two thirds of SLE with rim-reactive ANA tests and over 90% of patients with neonatal SLE) but usually not in patients with RA. The SS-B is found in about 50% of patients with Sjцgren’s syndrome without RA, less than 5% of patients with Sjцgren’s syndrome with RA, but not in patients with SLE or RA. Therefore, high titers of the SS-A or SS-B anti-Sjцgren antibodies are fairly good markers for Sjцgren’s syndrome, although sensitivity is not good.

    Rheumatoid arthritis precipitin (RAP) is an autoantibody against RA nuclear antigen (RANA) derived from reaction of Epstein-Barr virus with human lymphocytes in tissue culture. RA precipitin is present in about 65% of patients with RA, 70% of patients with Sjцgren’s syndrome and RA, but in less than 10% of patients with SLE or other rheumatoid-collagen diseases. High titers of the RAP antibody are useful markers for RA when RA symptoms are present in other collagen diseases. The SS and RAP antibodies may be present in patients who have a negative ANA test result.

    Anti-scleroderma-associated antigen (Scl-70) antibody. Scl-70 autoantibody is found in about 45% of patients with PSS.

    Anti-Jo-1 antibody. This autoantibody is fairly specific for myositis and is found in about 25% of myositis syndromes (polymyositis, dermatomyositis) as a group and 35%-45% of polymyositis cases.

    Anticytoplasmic autoantibodies. These include antimitochondrial antibodies (found in primary biliary cirrhosis), neutrophil anticytoplasmic antibodies (found in certain types of vasculitis, such as Wegener’s), antimicrosomal antibodies (not detected by HEp-2 cells; associated with chronic active hepatitis), and antiribosomal antibodies (may be present in SLE).

    Skin biopsy with immunofluorescence staining. It is possible to obtain a full-thickness biopsy specimen from an uninvolved area of epidermis next to a skin lesion, prepare frozen section from the biopsy tissue, and apply immunofluorescent stains containing antisera against IgG, IgM, and IgA. Several characteristic immunofluorescent patterns have been described in certain diseases. In SLE, there is either a solid or stippled band involving the epidermis basement membrane area using IgG antiserum. This pattern is said to be present in up to 90% of patients with SLE or discoid LE if the disease is active. The incidence is considerably less if the disease is not active. Other diseases associated with characteristic skin immunofluorescent patterns are pemphigus vulgaris (intraepidermal fluorescence of spaces between squamous epithelial cells using IgG), bullous pemphigoid (“tubular” or linear solid staining of the basement membrane using IgG), and dermatitis herpetiformis (short irregular speckled band at the basement membrane confined to the tips of the dermal papillae, using IgA antiserum).

    Slide latex tests for systemic lupus erythematosus. Commercial companies have marketed 2-minute slide latex agglutination tests for SLE based on latex particles coated with DNA (most often, thymus-derived DNA). The tests available so far have substantial differences in sensitivity but in general yield fewer positive results in SLE than the LE preparation or anti-DNA assay by the Crithidia method. Some of the tests do not have adequate clinical evaluations; in some cases, I was not able to obtain any published evaluations.

    Serum complement in systemic lupus erythematosus. Total serum complement (C, Cў, CH50; Chapter 22), as well as the complement fractions C3 and C4, are often reduced in SLE patients with lupus nephritis. In one study, 38% of SLE patients had decreased C3 levels on initial workup and 66% had decreased C3 levels at some time during that illness. One report suggests that the combination of increased anti-dsDNA levels plus decreased C3 levels is highly specific for SLE; this combination was found in 32% of SLE patients on initial workup and 61% at some time during their illness.

    Drug-induced systemic lupus erythematosus. A syndrome very similar to SLE can be produced by certain medications (drug-induced SLE). The three drugs considered proven SLE-inducing agents are procainamide, hydralazine (Apresoline), and isoniazid. Patients on procainamide develop clinical SLE in 20%-35% of cases. 50%-85% of patients on more than 1.5 gm of procainamide/day have positive LE preps; 1%, anti-dsDNA; and 75%, detectable ANAs. Of patients taking hydralazine, 2%-21% develop SLE and about 24%-50% have positive ANA test results. A small number (<1%) of patients taking isoniazid develop the SLE syndrome, and about 20% have detectable ANAs. Certain other drugs (e.g., methyldopa, phenytoin, quinidine, and chlorpromazine) have, on occasion, been reported to induce positive LE prep results or ANA test results, but are usually not associated with the SLE syndrome. Drug-induced SLE produces ANAs that are most often directed against histones, whereas spontaneous SLE produces ANAs most often directed against dsDNA. Although both spontaneous SLE and drug-induced SLE may produce a solid (homogeneous) ANA test pattern, spontaneous SLE often produces a rim (peripheral) pattern not seen with the drug-induced syndrome, whereas drug-induced ANA results frequently show a speckled pattern, which is uncommon in spontaneous SLE. Assay for anti-dsDNA (usually ordered as “anti-DNA”) is helpful to differentiate SLE and drug-induced ANA or SLE symptoms. High titers of anti-DNA are suggestive of SLE, whereas anti-dsDNA in drug-induced positive ANA is either negative or only minimally elevated.

  • Collagen-Vascular Diseases

    Collagen-vascular diseases are an ill-defined collection of syndromes that have certain points of similarity, among which the most striking are fibrinoid necrosis of collagenous tissue and involvement of various subdivisions of arteries by an inflammatory process. Some diseases emphasize one aspect and some the other. Because blood vessel inflammation and other abnormalities found in the collagen diseases may also be found to a certain extent in some patients with RA, some investigators prefer the term “rheumatoid-collagen diseases.” Others do not wish to use the designation collagen disease at all. Some justification to group together these often quite dissimilar syndromes is the overlap in signs, symptoms, and laboratory abnormalities between the different conditions as well as the probability that their basic etiology is a disorder involving immunologic hypersensitivity. Those conditions usually included in the connective tissue (“collagen”) disease group will be discussed first; then other diseases involving joints; and finally, certain conditions primarily due to vasculitis.

  • Acute Rheumatic Fever (ARF)

    ARF is a disease that has a specific etiologic agent yet has some similarities to the rheumatoid-collagen-vascular group. The etiologic agent is the beta-hemolytic Lancefield group A Streptococcus. Apparent hypersensitivity or other effect of this organism causes connective tissue changes manifested by focal necrosis of collagen and the development of peculiar aggregates of histiocytes called “Aschoff bodies.” Symptoms of ARF include fever, a migratory type of polyarthritis, and frequently cardiac damage manifested by symptoms or only by electrocardiogram (ECG) changes. Diagnosis or confirmation of diagnosis often rests on appropriate laboratory tests.

    Culture. Throat culture should be attempted; the finding of beta-hemolytic streptococci, Lancefield group A, is a strong point in favor of the diagnosis if the clinical picture is highly suggestive. However, throat cultures often show negative results by the time ARF symptoms develop, and a positive throat culture is not diagnostic of ARF (since group A streptococci may be present in 15%-20% of clinically normal children). Blood culture findings are almost always negative.

    Streptolysin-O tests. Beta streptococci produce an enzyme known as streptolysin-O. About 7-10 days after infection, antibodies to this material begin to appear. The highest incidence of positive results is during the third week after onset of ARF. At this time, 80%-85% (range, 45%-95%) abnormal results are obtained; thereafter the antibody titer drops steadily. At the end of 2 months only 70%-75% of test results are positive; at 6 months, 35%; and at 12 months, 20%. Therefore, since the Streptococcus most often cannot be isolated, antistreptolysin-O (ASO) titers of more than 200 Todd units may be helpful evidence of a recent infection. However, this does not actually prove that the disease in question is ARF. Group A streptococcal infections are fairly frequent, so that occasionally a group A infection or the serologic effects of such an infection may coexist with some other arthritic disease. Another problem with ASO elevation is that the elevation persists for varying periods of time, raising the question whether the streptococcal infection that produced the antibodies was recent enough to cause the present symptoms. Commercial tests vary somewhat in reliability, and variations of 1 or 2 dilutions in titer on the same specimen tested by different laboratories are not uncommon.

    Antibodies against other streptococcal enzymes. Commercial slide latex agglutination tests that simultaneously detect ASO plus several other streptococcal antibodies, such as antideoxyribonuclease-B (AND-B) are available. The best known of these multiantibody tests is called Streptozyme. Theoretically, these tests ought to be more sensitive for detection of group A beta-hemolytic streptococcal infections than the streptolysin-O test alone, since patients who develop acute glomerulonephritis are more apt to produce antibodies against AND-B than streptolysin-O, and the antibodies against streptococcal enzymes may be stimulated unequally in individual patients. However, there is considerable debate in the literature on the merits of the combination-antibody tests versus the single-antibody tests. The American Heart Association Committee on Rheumatic Fever published their opinion in 1988 that Streptozyme gave more variable results than the ASO method and therefore was not recommended. If both the streptolysin-O test plus the AND-B test are performed, the combined results are better than either test alone and even a little better than the single combination-antibody slide test. However, relatively few laboratories perform the AND-B test, and even fewer routinely set up both the ASO test plus the AND-B test in response to the usual order for an ASO titer.

    Diagnosis. When a patient has an acute-onset sore throat and the question involves etiology (group A Streptococcus vs. some other infectious agent), throat culture is the procedure of choice, because it takes 7-10 days before ASO antibody elevation begins to occur. On the other hand, ARF and acute glomerulonephritis develop some time after the onset of the initiating streptococcal infection. The average latent period for ARF is 19 days, with a reported range of 1-35 days. Therefore, the ASO (or Streptozyme and its equivalents) is more useful than throat culture to demonstrate recent group A streptococcal infection in possible ARF or acute glomerulonephritis.

    Other tests. The ESR is usually elevated during the clinical course of ARF and is a useful indication of current activity of the disease. However, the ESR is very nonspecific and indicates only that there is an active inflammatory process somewhere in the body. In a minority of ARF patients, peculiar subcutaneous nodules develop, most often near the elbows. These consist of focal collagen necrosis surrounded by palisading of histiocytes. In some cases, therefore, biopsy of these nodules may help confirm the diagnosis of ARF. However, biopsy is not usually done if other methods make the diagnosis reasonably certain. Also, the nodules are histologically similar to those of RA. During the acute phase of the disease there usually is moderate leukocytosis, and most often there is mild to moderate anemia.

  • Seronegative Spondyloarthropathies

    In these conditions arthritis is associated with inflammation that affects the spine and lumbosacral joints (ankylosing spondylitis), the urethra (Reiter’s syndrome), the skin (psoriasis), or the intestinal tract. These conditions were (and are) frequently referred to as “rheumatoid arthritis variants.” This name has been discarded by most rheumatologists because the diseases have relatively little in common with classic RA except for involvement of joints and are considered separate entities. As a group they have certain similarities. There frequently is a component of inflammation at the attachment of ligaments to bone (enthesiopathy) rather than only synovial involvement. Except for ankylosing spondylitis, they are found in association with other well-known diseases, and there is a tendency for spine and large joint involvement in a minority of cases. Spondylitis develops in about 5%-10% of patients with inflammatory bowel arthritis, in about 20% of patients with psoriatic arthritis, and in more than 50% of those with the chronic form of Reiter’s syndrome. Iritis is common in patients with spondylitis, and conjunctivitis is a typical feature of Reiter’s syndrome. The RA test results are usually negative. There is a hereditary component and an increased incidence of HLA-B27. Overall, about 10%-20% of persons with HLA-B27 antigen will develop some form of spondyloarthritis; the rate is said to reflect a genetic relationship, with a 25%-50% risk for those with close relatives who are also HLA-B27 positive but only a 2%-10% risk in those without such relatives.

    Ankylosing spondylitis. Ankylosing spondylitis (Marie-Strumpell disease) involves primarily the spine and sacroiliac joints, with peripheral joint arthritis present in about 30% of cases. Iritis may develop in 30%-40% of cases. The incidence in Afro-Americans is much less than in Europeans. Males are predominantly affected. Mild anemia is found in about 25%. The ESR is elevated in 80%-90% of those with active disease. HLA-B27 is present in more than 90% of affected persons. Since HLA-B27 is found in 6%-7% of Europeans and in 3%-4% of Afro-Americans and the incidence of ankylosing spondylitis is about 1 in 1,000 of the general population, most persons who have positive HLA-B27 results do not have ankylosing spondylitis. Since HLA-B27 is found in about 92% of patients (literature range 83%-98%), absence of HLA-B27 in Europeans is some evidence against the diagnosis in clinically borderline cases.

    Psoriatic arthritis. Psoriatic arthritis most commonly involves the distal interphalangeal joints of the hands and feet, although the spine or pelvis is affected in about 20% of cases. HLA-B27 is found in about 35% of cases (literature range, 20%-90%, the higher percentages being found when spondylitis was present). About 10% (range, 5%-20%) of patients with psoriasis develop psoriatic arthritis.

    Reiter’s syndrome. Reiter’s syndrome typically consists of joint, urethral, mucocutaneous, and eye lesions. These are manifested by a (usually) self-limited nongonococcal urethritis found predominantly in males that may be accompanied by conjunctivitis or iritis and by mucocutaneous ulcers or other lesions. The disease may appear spontaneously, may follow a gonococcal infection (possibly due to concurrent Chlamydia or Mycoplasma infection) or may be precipitated by genitourinary or colon infection. Shigella infection is followed by Reiter’s syndrome in 1%-2% of cases. About 85% (range, 63%-100%) of Europeans with Reiter’s syndrome have the HLA-B27 antigen. The arthritic component primarily involves the lower extremities and may be accompanied by tendinitis. However, spondylitis is said to develop in 50% or more patients with the chronic form of Reiter’s syndrome. Behзet’s syndrome (oral and genital ulceration, iritis, and arthritis) may mimic some components of Reiter’s syndrome. Reiter’s syndrome may occur in females, in which case the urethritis component may not be recognized.

    Arthritis associated with inflammatory bowel disease. Inflammatory bowel disease may be accompanied by peripheral arthritis and by spondylitis. The two types of arthritis behave independently of each other, although either type may be present or the two may coexist. Twelve percent to 20% of patients with ulcerative colitis or regional enteritis (Crohn’s disease) develop asymptomatic peripheral joint arthritis. This is not strongly associated with the HLA-B27 antigen. The knee and ankle are most frequently involved. Spondylitis is said to occur in about 5% (range, 1%-6%) of patients with chronic inflammatory bowel disease, and sacroiliitis in about 15%. HLA-B27 is reported in about 60% of those with spondylitis (literature range, 37%-75%). Iritis is also more common in these patients. Therefore, the arthritis of inflammatory bowel disease in some patients has similarities in several respects to Reiter’s syndrome except for lack of urethritis. Whipple’s disease may also be associated with arthritis.

    Reactive arthropathies. This group partially overlaps the “seronegative spondyloarthropathies” (Reiter’s syndrome traditionally being in both categories), but differs in that each has an infectious or inflammatory etiology as well as a secondary arthritic component. This group includes Reiter’s syndrome, ulcerative colitis and Crohn’s disease (“enteropathic arthropathies”), infection by certain gastrointestinal (GI) tract pathogens (with arthritis but without direct joint infection), and acute rheumatic fever. Although the category of reactive arthropathies is most often restricted to infection by the GI tract pathogens, there is sufficient overlap with various aspects of the conditions I have discussed that it seems reasonable to include them here.

    Arthritis associated with enteric pathogens. Arthritis in these patients appears abruptly 1-4 weeks after a GI tract infection subsides (range, 1 week after onset of infection to 6 weeks after end of the infection). Peripheral joints are predominately (but not exclusively) involved. About 60%-80% of patients are positive for HLA-B27 antigen. Infections that risk developing “reactive arthritis” in HLA-B27 patients, in descending order, are Salmonella (1%-2% of patients), Shigella, Campylobacter jejuni, and Yersinia.

    Diagnosis in these diseases involves exclusion of RA (RF screening test) and SLE (ANA test). If these tests are negative, serologic tests for arthritis-related enteric bacteria would be necessary. These would probably have to be sent to a large reference laboratory. Stool culture would usually be negative (except for a few chronic carriers) since arthritis symptoms generally do not begin until after the enteric infection ends. Elevated antibody titers do not differentiate between those with nonarthritic and those with arthritic conditions. For Yersinia, IgM or IgA antibody titers are the most useful, but the reported sensitivity of these tests varies widely (38%-95%). For Campylobacter, IgM and IgA antibodies are also used, with reported sensitivity of about 75%. Flagellar IgM antibody assay was found to be 85% sensitive in one study. Salmonella antibody tests are discussed in the chapter on microbiology; the Widal test is unreliable and current immunoassay tests reported in the literature mostly use homemade reagents. Shigella IgM and IgA immunosassay tests have been reported but also are homemade in research settings.

    Other infections. Infection by Borellia burgdorferi (Lyme disease) has a prominant arthritic component that occurs later in the course of illness. Lyme disease and its serologic tests are discussed in the chapter on spirochetal diseases. Several virus infections may cause arthritis, notably hepatitis virus B and parvovirus. These are discussed in the chapter on virus diseases. I am also including acute rheumatic fever in this group, although traditionally it has usually been loosely associated with the rheumatoid-collagen diseases.

  • Juvenile Rheumatoid Arthritis (JRA)

    Juvenile rheumatoid arthritis (JRA), also known as “juvenile chronic polyarthritis,” or “Still’s disease,” is the most common disorder of childhood involving chronic joint inflammation (synovitis). Since there is a spectrum of signs and symptoms, diagnosis partially depends on exclusion of other recognized arthritis syndromes (some of which are discussed later). There are three subdivisions of JRA. Polyarticular JRA accounts for 40%-50% of all JRA cases and produces inflammation of multiple joints (more than four), typically in a symmetric distribution. There is no eye involvement, and those affected are predominantly girls. There are two subgroups. In one subgroup, accounting for about 10% of JRA cases, the RA test result is positive, and there is a high incidence of positive antinuclear antibody (ANA) test results. This form occurs more often in late childhood and frequently is associated with severe arthritis; it more closely resembles standard adult RA. The other subgroup accounts for about 30% of JRA cases. RA test results are negative, there is a low incidence of positive ANA test results, and severe arthritis is rare. This form of JRA resembles minimal severity adult RA. Polyarticular JRA frequently is associated with a mild normocytic-normochromic anemia. WBC counts are normal or mildly elevated, usually not more than 20,000/mm3 (20 Ч 109/L).

    Pauciarticular JRA accounts for 30%-40% of all JRA cases and affects only a few joints (less than four) in asymmetric distribution. There are also two subgroups (although this is disputed). The early-onset type occurs before age 5 years and accounts for about 30% of JRA cases. There is no hip or spine involvement, but about one half of affected patients develop iridocyclitis. RA test results are negative, but ANA test results are positive in about 50% of patients. The late-onset subgroup overlaps with ankylosing spondylitis and is not included in JRA by some investigators. This form affects predominantly boys. Hip and sacroiliac involvement are frequent but not iridocyclitis. There is a high incidence of the HLA-B27 antigen, and RA or ANA test results are usually negative.

    Systemic-onset JRA accounts for approximately 20% of JRA cases. Slightly more boys are affected than girls, and onset can occur at any age. There are one or two high fever spikes each day, especially in the evening, for several weeks, with the temperature rapidly dropping after each spike to normal or even low values. There may be chills at the same time as the fever spikes. Some 90% or more of patients develop a macular skin rash that often appears and disappears with the fever spikes. There is splenomegaly or lymphadenopathy in 80%-85% of cases, pleuritis or pericarditis in 30%-60%, and abdominal pain in 30%. Anemia is frequent and may sometimes be severe. Leukocytosis is found in 95%, and WBC counts are often in the range of 20,000-30,000/mm3. Eventually a polyarthritis develops. RA and ANA test results are negative.

  • Rheumatoid Arthritis (RA)

    Rheumatoid arthritis (RA) is a chronic systemic disease whose most prominent symptom is inflammation of joints. The small joints of the hands and feet, especially the proximal interphalangeal joints, are most frequently affected; involvement of larger joints of the extremities is somewhat less frequent, and occasionally nonextremity joints may be affected. Polyarticular involvement is much more common than monoarticular disease. Articular disease activity may or may not be preceded or accompanied by systemic symptoms such as low-grade fever, myalgias, malaise, and fatigue. Rheumatoid arthritis tends to be a slow, intermittently active, migratory process that is frequently symmetric. Onset is gradual in 75%-80% of affected adults and more severe and abrupt in 20%-25%. Subcutaneous nodules with distinctive microscopic appearance occur in 15%-20% of patients, most frequently distal to (but not far from) the elbows. Inflammatory involvement of nonarticular organs or tissues such as the heart or lungs may sometimes occur. Patients with RA have increased frequency of the antigen HLA-DR4.

    Laboratory findings. In active adult-onset RA, anemia is present in about 40% of men and 60% of women. The anemia usually appears within 2 months after onset of clinical disease, usually does not become more severe, and is usually of mild or moderate degree, with a hemoglobin value less than 10 gm/100 ml (100 g/L) in fewer than 10% of cases. There is said to be some correlation between the degree of anemia and the initial severity of illness. The anemia of RA is usually included with the anemia of chronic disease, which typically is normocytic and normochromic. However, anemia in RA is more likely to be hypochromic (reported in 50%-100% of cases), although microcytosis is found in less than 10% of cases.

    White blood cell (WBC) counts are most often normal or only minimally elevated. About 25% of RA patients are said to have leukocytosis, usually not exceeding 15,000/mm3 (15 Ч 109/L), which is more apt to be present when onset of disease is severe and abrupt. Leukopenia is found in about 3% of cases, usually as part of Felty’s syndrome (RA plus splenomegaly and leukopenia).

    Anemia and leukocytosis are more common in juvenile-onset RA than adult-onset RA.

    In active RA, nonspecific indicators of acute inflammation, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein level, are elevated in most (but not all) patients. The serum uric acid level is normal in most patients. The serum iron level is generally low-normal or decreased, and iron-binding capacity is also low-normal or decreased.

    Rheumatoid factor. RA and related diseases are associated with production of a group of immunoglobulins called rheumatoid factors (RFs) that include IgG, IgM, and IgA varieties. These immunoglobulins (antibodies) have specificity for IgG that has been altered in certain ways. It is still not certain whether the altered IgG is the cause of the inflammatory abnormalities in RA or is a body response against the inflammatory process. From the laboratory standpoint, the most important of the is the one that is an IgM macroglobulin. RF combines with its altered IgG antigen in vivo, accompanied by complement fixation. IgM RF, like other antibodies, is produced by lymphocytes and plasma cells of B-cell origin. In some persons, especially in infants, IgM antibody production against some infectious organism not associated with rheumatoid disease may result in concurrent production of varying amounts of IgM RF. Outside the body, IgM RF can combine with normal gamma globulin without complement fixation (in fact, some patient serum contains excess C1q component of complement, which may cause a nonspecific RF test reaction that can be avoided by heat inactivation of complement before the test).

    Serologic tests. Serologic tests are the usual method of laboratory diagnosis in adult-onset RA. Various types of serologic tests may be set up utilizing reaction of IgM RF with IgG gamma globulin, differing mainly in the type of indicator system used to visually demonstrate results. The original method was known as the “Rose-Waaler test,” or “sheep cell agglutination test.” Anti-sheep red blood cell (RBC) antibodies were reacted with tannic acid-treated sheep RBCs, then the RF in the patient’s serum was allowed to combine with the antibody gamma globulin coating the sheep cells. Clumping of RBCs indicated a positive test result. It was found subsequently that synthetic particles such as latex could be coated with gamma globulin and the coated particles could be clumped by RF, thus giving a flocculation test. Just as happened with the serologic test for syphilis, many combinations of ingredients have been tried, with resulting variations in sensitivity and specificity. These tests are too numerous to discuss individually, but a distinction must be made between tube tests and rapid slide tests. The slide tests in general have a slightly greater sensitivity than tube tests but also produce more false positive results. Therefore, slide tests should be used mainly for screening purposes. As noted previously, some patient serum contains a nonspecific C1q agglutinator that can be eliminated by inactivating patient serum by heating at 56°C for 30 minutes.

    The latex fixation tube test for RA, known also as the “Plotz-Singer latex test,” currently is considered the standard diagnostic method. The average sensitivity in well-established clinical cases of adult RA is about 76% (range, 50%-95%). Clinically normal controls have about 1%-2% positive results (range, 0.2%-4%). Latex slide tests offer an average sensitivity of approximately 85% (literature range, 78%-98%), with positive results seen in approximately 5%-8% of normal control persons (range, 0.2%-15%). It may take several weeks or months after onset of clinical symptoms, even as long as 6 months, before RA serologic test results become abnormal.

    False positive results. Certain diseases, especially those associated with increased gamma globulin (“hyperglobulinemia”), produce a significantly high number of positive reactions analogous to the “biologic false positive” reactions of syphilis serology. These include collagen diseases, sarcoidosis, syphilis, viral hepatitis and cirrhosis, bacterial infections (especially subacute bacterial endocarditis[SBE]), and even old age (as many as 10%-25% positive over age 70). The incidence of reactive RA tests is higher with the slide than the tube tests. The percentage of positive reactions in the diseases listed ranges from 5%-40%. Sjцgren’s syndrome (75%-96%) and SBE (50%) are most likely to produce false positive results.

    Differential diagnosis. RA is usually part of the differential diagnosis of joint pain. However, other causes must be considered, especially if symptoms, location of joint involvement, laboratory test results, or other features are atypical. Even a positive test result is not conclusive evidence for RA. Other diseases that frequently enter the differential diagnosis are the so-called seronegative spondyloarthropathies, septic (infectious) arthritis, systemic lupus erythematosus (SLE) and other collagen-vascular diseases, crystal-deposition arthritis, and acute rheumatic fever (ARF). These conditions will be discussed later in this chapter.