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.
Tag: Joint
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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.
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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.
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Rheumatoid Diseases
The relationship between the rheumatoid diseases and diseases of the so-called collagen-vascular group is both close and uncertain. Many of the clinical symptoms found classically in one disease or syndrome may be found in another; the difference is on emphasis of certain aspects over others. This similarity extends to laboratory tests and makes it even more difficult to place borderline or problem cases into one group or the other. Until the exact etiology of each disease is known, overlap in laboratory test results is likely to continue. Fortunately, most patients can be assigned to satisfactory diagnostic categories using available clinical and laboratory data.