NOTE: Other associations: RNP: MCTD; Ro: SCLE, biliary cirrhosis, vasculitis, CHB.

ANTI-SMITH ANTIBODIES AND ANTI-RIBONUCLEOPROTEIN ANTIBODIES

Anti-Smith (Anti-Sm) antibodies are found in only 10% to 40% of patients with SLE, but infrequently in patients with other conditions; in other words, they are not sensitive but are highly specific (tables 28.2 and 28.3). Measurement of anti-Sm titers may be useful diagnostically, particularly at a time when anti-DNA antibodies are undetectable. Given their relatively low sensitivity, however, a negative value in no way excludes the diagnosis.

    Anti-ribonucleoprotein (anti-RNP) antibodies are found in about 40–60% of patients with SLE but are not specific for SLE, being a defining feature of mixed connective tissue disease (MCTD) and in low titers and low frequencies in other rheumatic diseases including RA and scleroderma (tables 28.2 and 28.3).

    The titers (levels) of anti-Sm or anti-RNP antibodies do not correlate with any clinical activity.

ANTI-Ro/SSA and Anti-LA/SSB Antibodies

Anti-Ro/SSA antibodies are found in approximately 50% of patients with SLE (table 28.2). They have been associated with photosensitivity, subacute cutaneous lupus, cutaneous vasculitis (palpable purpura), interstitial lung disease, neonatal lupus, and congenital heart block (table 28.3).

    Anti-Ro/SSA antibodies are found in approximately 75% of patients with primary Sjögren syndrome (table 28.2), and high titers of these antibodies are associated with a greater incidence of extraglandular features, especially purpura and vasculitis. By contrast, Ro/SSA antibodies are present in only 10–15% of patients with secondary Sjögren syndrome associated with rheumatoid arthritis. Therefore, the presence of anti-Ro/SSA or anti-La/SSB antibodies in patients with suspected primary Sjögren syndrome strongly supports the diagnosis.

    Approximately 50% of patients with SLE who have anti-Ro antibody also have anti-La antibody, a closely related RNA-protein antigen. Similarly, most patients with Sjögren syndrome also have anti-La/SSB antibodies. It is exceedingly rare to find patients with anti-La antibodies without anti-Ro antibodies.

    Anti-Ro/SSA and anti-La/SSB have also been detected in patients with photosensitive dermatitis and in 0.1% to 0.5% of healthy adults.

    However, they have limited usefulness for the diagnosis of SLE or other rheumatic diseases, and because they do not correlate well with disease activity, they are not useful for disease management.

    In our opinion, the indications for ordering anti-Ro/SSA and anti-La/SSB antibody tests are as follows:

•  Women with SLE who are pregnant or may become pregnant in the future

•  Women who have a history of giving birth to a child with heart block or myocarditis

•  Patients with a history of unexplained photosensitive skin eruptions

•  Patients strongly suspected of having SLE but who have a negative ANA test

ANTICENTROMERE ANTIBODIES

Anticentromere antibodies (ACA) are found almost exclusively in patients with limited cutaneous systemic sclerosis, especially in those with CREST. ACA has been observed in 57% of patients with CREST but has also been seen in patients with other conditions, including in some patients with Raynaud’s phenomenon alone. ACA are typically detected by the characteristic immunofluorescent pattern on Hep-2 cells.

ANTI-SCL-70 (TOPOISOMERASE-1) ANTIBODIES

Approximately 15% to 20% of patients with scleroderma have antibodies to a 70-kDa protein (topoisomerase-1), subsequently named Scl-70. The usual method for detection is by ELISA. The presence of these antibodies appears to increase the risk for pulmonary fibrosis among patients with scleroderma and is quite specific for the disease.

ANTIRIBOSOMAL P PROTEIN ANTIBODIES

Antiribosomal P protein antibodies have been detected in 10–20% of US patients with SLE, 40–50% of Asian SLE patients, but rarely in other rheumatic diseases. Testing for these antibodies may be useful when the diagnosis of SLE is uncertain because of the high specificity of this antibody for SLE, albeit with low sensitivity (table 28.3).

    Antiribosomal P protein antibodies has limited diagnostic value for central nervous system SLE and is not helpful in differentiating clinical subtypes of SLE (table 28.3).

ANTIHISTONE ANTIBODIES

Antihistone antibodies are present in more than 95% of cases of drug-induced lupus (tables 28.2 and 28.3), particularly those taking procainamide, hydralazine, chlorpromazine, and quinidine—but not in those patients with drug-induced lupus from taking other medications (e.g., anti-TNF, minocycline, etc.); other autoantibodies are uncommon in this disorder. Antihistone antibodies are also seen in up to 80% of patients with idiopathic lupus (table 28.3); however, patients with SLE also form a variety of other autoantibodies, including those directed against DNA and small ribonucleoproteins.

    It is important to note that although up to 80% of patients taking procainamide for 1–2 years will develop a positive ANA, most do not develop drug-induced lupus. Thus, screening for these antibodies in the absence of symptoms and stopping the drug if antibodies develop are not recommended.

RHEUMATOID FACTORS

Rheumatoid factors are antibodies directed against the Fc portion of IgG. The rheumatoid factor (RF) as currently measured in clinical practice is an IgM RF, although other immunoglobulin types, including IgG and IgA, have been described.

    The presence of RF is generally detected by ELISA or nephelometry. Testing for RF is primarily used for the diagnosis of rheumatoid arthritis; however, RF may also be present in other rheumatic diseases and chronic infections.

CLINICAL DISORDERS ASSOCIATED WITH RF POSITIVITY

Patients with a variety of rheumatic disorders, many of which share similar features such as symmetric polyarthritis and constitutional symptoms, may have detectable serum RF. These are shown in table 28.4.

Table 28.4 RF AND ANTI-CCP IN RHEUMATIC AND OTHER DISEASES

    Nonrheumatic disorders characterized by chronic antigenic stimulation (especially with circulating immune complexes or polyclonal B-lymphocyte activation) commonly induce RF production (table 28.4). Patients with indolent or chronic infection or chronic inflammation may also demonstrate RF positivity; examples include subacute bacterial endocarditis or hepatitis B or C virus infection, inflammatory or fibrosing pulmonary disorders including sarcoidosis, malignancy, and primary biliary cirrhosis.

    Rheumatoid factor positivity has also been detected in up to 5% of young, otherwise healthy individuals.

RF Titer

The higher the titer the greater the likelihood that the patient has rheumatic disease. There are, however, frequent exceptions to this rule, particularly among patients with one of the chronic inflammatory disorders noted above. Furthermore, the use of a higher titer for diagnosis decreases the sensitivity of the test at the same time as it increases the specificity.

Prognostic Value

RF-positive patients with RA may experience more aggressive and erosive joint disease and extra-articular manifestations than those who are RF-negative. Similar findings have been observed in juvenile rheumatoid arthritis. These general observations, however, are of limited utility in an individual patient because of wide interpatient variability. In this setting, accurate prediction of the disease course is not possible from the RF alone.

ANTIBODIES TO CITRULLINATED PROTEINS (CCP)

There has been considerable interest in developing a better test for the diagnosis of RA that has greater sensitivity and specificity than the tests that detect RFs. Within the last decade, as an outgrowth of determining the molecular specificity of antifilaggrin, antikeratin, and antiperinuclear antibodies, it was recognized that many patients with RA have antibodies to citrullinated proteins. Proteins that are citrullinated have had an arginine replaced by citrulline, a minor amino acid. A number of peptides containing citrulline were created, and a cyclic peptide was used to develop an assay to detect antibodies thereto. This test (anti-CCP) has now been studied extensively, and it has better sensitivity and specificity than tests that detect RF for the diagnosis of RA. This is summarized in table 28.4.

    In addition, antibodies to CCP were rarely found in patients with other rheumatic conditions and infectious diseases where RF is more frequently found. Anti-CCP is even found frequently before the diagnosis of RA. These observations suggest that the anti-CCP test may be more useful for the diagnosis of RA than are RF tests, or at least should be part of the diagnostic algorithm.

ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCA)

Two different immunofluorescence patterns can be seen when the patient’s serum is incubated with ethanol-fixed normal human neutrophils:

•  Cytoplasmic ANCA (cANCA) stain the cytoplasm diffusely; these antibodies are almost always directed against proteinase 3 (PR3). cANCA with anti-PR3 specificity is found primarily in patients with polyangiitis (Wegener granulomatosis; abbreviated currently as GPA), microscopic polyarteritis, and occasionally in other diseases (table 28.5).

•  Perinuclear ANCAs (pANCA) are usually directed against myeloperoxidase (MPO). The pANCA fluorescence pattern represents an artifact of ethanol fixation, with ethanol and positively charged granule constituents rearranging around and on the negatively charged nuclear membrane. pANCA directed primarily against MPO has been described in patients with a variety of rheumatic autoimmune diseases (table 28.6), whereas non-MPO pANCAs have been associated with several rheumatic and nonrheumatic diseases (table 28.7).

    Although patients with rheumatic diseases have an increased frequency of vasculitis, data suggesting that ANCA positivity enhances the risk of vasculitis are contradictory. Nonvasculitic aspects of rheumatic disease activity, severity, and chronicity also fail to correlate consistently with ANCA status. As a result, there is little clinical utility for ANCA testing for patients in whom the presence of an ANCA-associated systemic vasculitis is not suspected on clinical grounds.

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