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Subject: Antinuclear Antibody (ANA)
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ANAs refer to a diverse group of antibodies that target nuclear and cytoplasmic antigens. ANAs have been detected in the serum of patients with many rheumatic and nonrheumatic diseases as well as in patients with no definable clinical syndrome. The strong association of ANA with SLE is well established, and this finding satisfies the 1 of 11 criteria available for diagnosis.
These autoantibodies may be useful as an aid in the diagnosis of systemic rheumatic diseases such as SLE, mixed connective tissue disease (MCTD), undifferentiated connective tissue disease, Sjögren syndrome, scleroderma (systemic sclerosis), polymyositis, and others. The diagnosis of a systemic rheumatic disease is based primarily on the presence of compatible clinical signs and symptoms. The results of tests for autoantibodies, including ANA and specific autoantibodies, are ancillary.
Normal range: negative.
Evaluating patients suspected of having a systemic rheumatic disease
Progressive systemic sclerosis
Some patients without clinical evidence of an autoimmune disease or a systemic rheumatic disease may have a detectable level of ANA. This finding is more common in women than in men, and the frequency of a detectable ANA in healthy women >40 years old may approach 15–20%. ANA may also be detectable following viral illnesses, in chronic infections, or in patients treated with many different medications.
The traditional tool used to detect ANAs is IFA, which is a labor-intensive microscopic technique. Test interpretation is operator dependent. This assay is considered the gold standard for ANA testing with greater sensitivity. The IFA testing is currently performed using Hep-2 cells, and they contain approximately 100–150 possible antigens, and most of them are not well defined and/or characterized. When performed with a history and physical examination, it identifies almost all patients with SLE (95% sensitivity), although the specificity of this assay is only 57%. In addition, ANA by IFA has the sensitivity of 85% for systemic sclerosis, 61% for polymyositis/dermatomyositis (PM-DM), 48% for Sjögren syndrome, 57% for juvenile idiopathic arthritis, 100% for drug-induced lupus, 100% for MCTD, and autoimmune hepatitis (60%), as well as being important in monitoring and assessing prognosis in individuals with the Raynaud phenomenon.
Multiplex immunoassay (MIA) tests have been recently developed for use in clinical laboratory. They utilize individually identifiable, fluorescence microspheres (beads), each coupled with a different antigen or antigen mixture to test for multiple antibodies simultaneously in the same tube. This multiplex ANA screen is intended for qualitative screening of specific ANAs, the quantitative detection of dsDNA antibodies, and semiquantitative detection of 10 separate antibody assays (chromatin, ribosomal-P, SSA, SSB, Sm, SmRNP, RNP [ribonucleoprotein], Scl-70 [topoisomerase I], Jo-1, and centromere-B). This ANA by MIA screen detects the presence of clinically relevant circulating autoantibodies in serum. These assays are specific compared to IFA, and they are not as sensitive as IFA, because it is not looking at 100–150 possible antigens in the Hep-2 cells, rather specifically looking at 11 specific targeted antibodies. These assays have typical sensitivities of 66–94% for SLE, 94% for Sjögren, 68% for systemic sclerosis, and 48% for PM-DM. They are specific compared to IFA for detecting specific targeted connective tissue disorders. In persons with no connective disease, the specificity of MIA ranged from 77 to 91%, and in apparently healthy individuals, it is at 93%.
Disorders associated with a positive ANA titer include chronic infectious diseases, such as mononucleosis, hepatitis C infection, subacute bacterial endocarditis, TB, and HIV, and some lymphoproliferative diseases.
The presence of ANAs is rarely associated with malignancy, with the exception of dermatomyositis, in which both may be present. ANAs have also been identified in up to 50% of patients taking certain drugs; however, most of these patients do not develop drug-induced lupus.
Drugs that may cause positive results include carbamazepine, chlorpromazine, ethosuximide, hydralazine, isoniazid, mephenytoin, methyldopa, penicillins, phenytoin, primidone, procainamide, and quinidine.
Antibodies to double-stranded DNA (dsDNA)
Moderate to high titers of antibodies directed against dsDNA are very specific (97%) for SLE, making them very useful for diagnosis. Anti-dsDNA have also been found at low frequency (<5%), and usually in low titer and with low avidity, in patients with RA, Sjögren syndrome, scleroderma, Raynaud phenomenon, MCTD, discoid lupus, myositis, uveitis, juvenile arthritis, antiphospholipid syndrome, Grave disease, Alzheimer disease, and autoimmune hepatitis.
Titers of anti-dsDNA antibodies often fluctuate with disease activity and are, therefore, useful in many patients for following the course of SLE.
There is a well-recognized association of high titers of IgG anti-dsDNA titers, especially for high avidity antibodies, with active GN; there also appear to be highly enriched amounts of anti-dsDNA antibodies in the glomerular deposits of immune complexes found in patients with lupus nephritis. These observations have led many investigators to believe that anti-dsDNA antibodies are of primary importance in the pathogenesis of lupus nephritis.
Anti-dsDNA antibodies have also been reported in patients receiving minocycline, etanercept, infliximab, and penicillamine.
An increased frequency of these antibodies has also been noted in some otherwise normal individuals, particularly first-degree relatives of patients with lupus and some laboratory workers.
Antibodies to chromatin
Chromatin refers to the complex of histones and DNA. Assaying for the presence of antichromatin (antinucleosome) antibodies may be more clinically relevant than testing for individual antihistone antibodies. Antichromatin antibodies are present in 69% of those with SLE but in 10% or less of patients with Sjögren syndrome, scleroderma, or antiphospholipid syndrome. Among those with SLE, the prevalence of antichromatin antibodies is twofold higher in those with renal disease (58% vs. 29%).
Anti-Smith antibodies and anti-RNP antibodies
The anti-Smith (anti-Sm) and anti-ribonucleoprotein (anti-RNP) systems are considered together, since they coexist in many patients with SLE and bind to related but distinct antigens.
Anti-Sm antibodies occur more frequently in African Americans and Asians than in Caucasians with SLE.
Anti-Sm antibodies generally remain positive when titers of anti-DNA antibodies have fallen into the normal range and clinical activity of SLE has waned. Therefore, measurement of anti-Sm titers may be useful diagnostically, particularly at a time when DNA antibodies are undetectable.
Anti-RNP antibodies bind to antigens that are different from but related to Sm antigens. These antibodies bind to proteins containing only U1-RNA. Anti-RNP antibodies are found in 3–69% of patients with SLE but are a defining feature in the related syndrome, MCTD. The antibody is present in lower titers in several other rheumatic diseases, including primary Raynaud phenomenon, RA, and scleroderma.
Ro/SSA and La/SSB antibodies
Anti-Ro/SSA and anti-La/SSB antibodies have been detected with high frequency in patients with Sjögren syndrome. They also have diagnostic usefulness in patients with SLE. They are infrequently seen in other connective tissue diseases such as scleroderma, polymyositis, MCTD, and RA.
Anti-Ro/SSA antibodies have been associated with photosensitivity, a rash known as subacute cutaneous lupus, cutaneous vasculitis (palpable purpura), interstitial lung disease, neonatal lupus, and congenital heart block connective tissue disease. A minority evolve into a well-defined disorder.
Anti-La/SSB antibodies are found in the following circumstances:
It is very unusual to encounter sera that contain anti-La/SSB activity without demonstrable antibodies to Ro/SSA in patients with SLE or Sjögren syndrome.
Isolated anti-La/SSB antibody activity has been seen in some patients with primary biliary cirrhosis and autoimmune hepatitis.
Antibodies to the La/SSB antigen are present in 70–95% of patients with primary Sjögren syndrome, and in 10–35% of patients with SLE, and are occasionally seen in patients with cutaneous LE, scleroderma disorders, and RA.
Antibodies to topoisomerase I (Scl-70)
Antibodies to Scl-70, proteins associated with the centromere (CEN-A, CEN-B), U3-ribonucleoprotein (U-3 RNP), and RNA polymerases I and III. These antibodies are highly specific for systemic sclerosis and are associated with a higher risk of interstitial lung disease. When present in high titers, they are associated with more extensive skin involvement and disease activity.
Antibodies to Ribo-P
The reported incidence of antiribosomal P protein antibodies among patients with SLE is variable. These antibodies were initially detected in 10–20% of patients with SLE; however, several authors (particularly those studying Asian populations and children) have reported higher incidence rates (40–50%). Some clinical data suggest that the presence of antiribosomal P protein antibodies among patients with lupus is associated with lupus cerebritis. The presence of antibodies to ribosomal P protein has an overall sensitivity and specificity for neuropsychiatric lupus of 26% and 80%, respectively. The test characteristics were similar for psychosis, mood disorder, or both (sensitivity 27%, specificity 80%). These antibodies may also be found among patients with lupus hepatitis and/or nephritis.
Antibodies to Jo-1
Antibodies to the Jo-1 antigen (histidyl-tRNA synthetase) are found in approximately 30% of adult patients with myositis (including polymyositis, dermatomyositis, and overlap syndromes) and are particularly common (approximately 60%) in patients with both myositis and interstitial lung disease (cryptogenic fibrosing alveolitis or pulmonary interstitial fibrosis). Jo-1 antibodies are most commonly found in patients with the antisynthetase syndrome, which is characterized by acute onset, steroid-responsive myositis with interstitial lung disease, fever, symmetrical arthritis, Raynaud phenomenon, and mechanic's hands. The presence of Jo-1 antibodies in idiopathic polymyositis patients is usually accompanied by severe disease, tendency to relapse, and poor prognosis.