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| Issue 4 1999 |  |
| The start of a new year has
seen the arrival of two new information reference services to assist you
with contacting PaLMS and familiarisation with our range of services and
personnel.
The new PaLMS Service Directory is currently being distributed to all users of the service. If you have not received a copy or wish to order extra copies, please call PaLMS Administration on 9926 8086. The PaLMS Internet Website has been launched and is filled with helpful information. Both the Service Directory and the Website hold a comprehensive test directory with information on each test, contact laboratory information, frequency of runs etc. Please note that the Web-based directory has the most current data as it is updated weekly. Visit PaLMS at www.palmslab.com.au New user-friendly request forms are now available to assist clinicians in the never-ending form-filling business. Private practitioners will have pre-printed, bar-coded forms for their rooms. Please contact PaLMS Administration if you would like to order pre-printed forms. Our Autologous Collection Service is rapidly expanding to meet demand. All collections are performed in our medical suite at North Shore Private Hospital to ensure patient comfort and easy accessibility. In this issue, we have included a short survey requesting your input into topics we present in our future InfoLink issues. We would appreciate you taking a couple of minutes to complete it and returning it by fax or mail. For those of you who have not visited RNSH in the past month, the parking arrangements for patients have been greatly improved. There are now many 3 hour parking bays that attract a fine if the limit is exceeded which is a major disincentive for staff to park in them! If your patients are visiting either of our two collection centres on the RNSH campus, they will now find parking very easy. If they visit for less than half an hour, the parking is free. For patients dropping off specimens e.g. 24 hour urine collection, they may find it more convenient to drop it in to the PaLMS Medical Suite, Ground Floor, North Shore Private Hospital. It is well signposted hence easy to locate. We hope this issue is of value, as always we welcome your feedback on any aspect of our service or the articles we present. |
| Kerry
Heintze PaLMS Marketing Manager |
| AUTO-ANTIBODIES IN CONNECTIVE TISSUE DISEASES |
 |
Rodger
Laurent Rheumatology Laboratory PaLMS, Royal North Shore Hospital Tel: +61 2 9926 7351 email: rlaurent@med.usyd.edu.au |
| The connective tissue diseases
include systemic lupus erythematosus, scleroderma and mixed connective tissue
disease. They often present with non-diagnostic symptoms. These include
lethargy, arthralgia, myalgia, rash and fever. Diagnostic tests can be of
value in making the diagnosis but correct interpretation is important. The
connective tissue diseases are associated with a wide variety of auto-antibodies,
most of which are of value in assisting with the diagnosis, but usually
are not a marker of disease activity. 1. Anti-nuclear Antibody The anti-nuclear antibody (ANA) is a useful screening test and may give information about other auto-antibodies that need to be specifically measured. It indicates whether the patient's serum has an antibody against a nuclear component. Interpretation of a positive anti-nuclear antibody is not always simple and it needs to be correlated with the clinical findings, the age of the patient and the antibody titre. About 5 % of the normal population have a positive anti-nuclear antibody at a titre of greater than or equal to 1:160. This group usually has only a slight increase in titre with a speckled pattern. The percent with positive ANA increases with age and in people, 70 - 80 years, up to 15% will have a positive low titre anti-nuclear antibody. In the over 70 age group, the ANA’s are usually antibodies to histone proteins, and there is no increase in antibodies to the significant antigens, for example, DNA, RNP, Scl-70. It is important to remember that a positive anti-nuclear antibody is not diagnostic of systemic lupus erythematosus and can occur with other illnesses, e.g. infection, both bacterial and viral, drug therapy and other inflammatory disorders. The ANA is a good screening test for SLE but it is not specific for SLE. More then 95% of patients with SLE have a positive ANA. ANA negative SLE may have anti-cytoplasmic antibodies, the commonest being SSA/Ro. The titre is not a good guide as to the activity of the disease. Active SLE can have a low titre ANA. Different staining patterns are reported, which may give clues as to the significance of the ANA, and any further tests required. The staining patterns are homogenous, rim, speckled, nucleolar and centromere. There can be variation in reporting of staining patterns between laboratories. They are not diagnostic but are a useful guide as how to proceed with investigations. If the clinical findings and the ANA result do not agree, believe the clinical findings. |
| 1.1 ANA Staining Patterns |
| The different staining patterns are:
1.1.1 Speckled Pattern This is the most frequent staining pattern and the pattern that usually occurs in other illnesses and normal people with low titres of anti-nuclear antibody. 1.1.2 Homogenous Pattern This pattern is most common in systemic lupus erythematosus, drug induced lupus erythematosus and chronic active hepatitis. 1.1.3 Rim Pattern This pattern is also associated predominantly with systemic lupus erythematosus. 1.1.4 Nucleolar Pattern This pattern is suggestive of systemic sclerosis (scleroderma). 1.1.5 Anti-centromere Antibody Anti-centromere antibody is also detected on anti-nuclear antibody testing and has its own clinical significance. Anti-centromere antibodies are associated with the CREST syndrome, a limited variant of scleroderma. Anti-centromere antibody is uncommon in the more diffuse form of systemic sclerosis and is only rarely found in other connective tissue disorders. 1.1.6 Anti-Ro Antibody There is a cell line used for testing ANA that has been transfected with Ro antigen. If the antibody to Ro is present it may be detected on ANA testing, and will be reported as being present. However, it does not detect all Ro antibodies, and if clinically indicated they should be specifically requested or confirmed by asking for extractable nuclear antigens. |
Specimen information
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| 2. Specific Antibodies The clinical findings and ANA result will be a useful guide as to more specific antibody testing. The most important antibody is to double stranded DNA. There is also a group of specific autoantibodies that are usually associated with a particular autoimmune disease or group of diseases. They usually produce a speckled ANA. These include the extractable nuclear antigens, RNP, Sm, SSA/Ro, or SSB/La, Scl-70, Jo-1 and ribosomal-P. They are of diagnostic value and are reported as being present or absent. Levels are not a guide to disease activity. |
| 2.1
Antibodies to dsDNA This is the antibody that is of diagnostic value for systemic lupus erythematosus. Antibodies to dsDNA are specific for systemic lupus erythematosus, being present in 60%-70% of patients. Elevated levels are usually associated with active disease, but patients can have elevated DNA antibodies and be clinically quiescent. Patients who are clinically well with high DNA antibody levels, require more frequent review, but there is no need to change treatment. Rapid rises or falls in DNA antibody levels with doubling or halving time of four weeks or less, may precede flares in the disease. Levels may fall with successful treatment by corticosteroids and immunosuppressive drugs. Serum complement levels of C3 and C4 are useful in monitoring disease activity in conjunction with DNA levels. A rapid rise or fall of DNA levels in association with a fall in complement C3 and/or C4, is more likely to be significant than when the complement levels remain normal. There are two major types of assays used to measure antibodies to DNA, a radio-immunoassay or Farr assay and an enzyme linked immunoassay (ELISA). The Farr assay measures antibodies that are clinically relevant, and is more reliable. ELISA assays have a higher rate of false positive results, so that if there is doubt about the result it should be checked using a Farr assay. The PaLMS Rheumatology Laboratory measures DNA antibodies using a Farr assay. |
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2.2
Extractable Nuclear Antigens The extractable nuclear antigens consist of four antigens which include RNP, Sm, SSA/Ro and SSB/La. |
| 2.2.1 Anti-RNP Antibodies to RNP are present in about one third of patients with SLE and are the only auto-antibody present in patients with mixed connective tissue disease. 2.2.1 Anti-RNP Anti-Sm antibody is specific for SLE but is present in only about 10% of patients. Therefore, it is not particularly sensitive. 2.2.1 Anti-RNP Anti-SSA/Ro is a relatively common antibody found in about 30% of people with SLE and 75% of patients with primary Sjogren’s syndrome. People with SLE who have anti-Ro are more likely to have cutaneous involvement and women with this antibody when pregnant are more likely to have children with congenital heart block. This applies particularly if they also the have antibody to SSB/La. 2.2.1 Anti-RNP Antibody to SSB/La is less common and usually occurs in conjunction with anti-SSA/Ro It is present in only about 10% of people with SLE and in about 50% of primary Sjogren’s syndrome. It may indicate a milder course of disease in SLE. The presence of both SSA/Ro and SSB/La is more commonly associated with primary Sjogren's syndrome. |
| 2.3 Antibodies to Scl-70/Topoisomerase 1 Antibodies to Scl-70 are highly specific for diffuse scleroderma. They occur in about 50% of patients with diffuse scleroderma. They are present in 20% of patients with the limited form of scleroderma which includes the CREST syndrome. 2.4 Antibodies to Jo-1 Antibodies to Jo-1 are present in 30% of people with polymyositis, particularly in those who also have pulmonary fibrosis. 2.5 Antibodies to Ribosomal-P These antibodies are present in about 15% SLE, and may be associated with psychiatric manifestation of SLE. However, the association is strong enough to make them of diagnostic value. Autoantibodies can be useful in helping with the diagnosis of connective tissue disorders. (Table 1). The clinical findings are the most important factors in determining what autoantibody to measure. Their interpretation should always be made in association with the clinical findings. |
| DNA antibodies | Systemic lupus erythematosis |
| RNP | SLE or mixed connective tissue disease |
| Sm | SLE |
| SSA/Ro with SSB/La | Primary Sjogren’s syndrome |
| SSA/Ro without SSB/La | SLE or Sjogren’s syndrome |
| Jo-1 | Polymyositis or dermatomyositis |
| Scl-70/Topoisomerase 1 | Systemic sclerosis, diffuse scleroderma |
| Centromere | CREST syndrome - limited scleroderma |
Total plasma homocysteine is available from PaLMS using the “gold standard” HPLC method. An elevated concentration of this analyte is associated with various clinical conditions including:
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