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.