Laboratory Tests in Lupus
Dr. Gavin Spickett, Consultant Clinical Immunologist, Regional Immunology Laboratory, Royal Victoria Infirmary, Newcastle upon Tyne
This article is based on my talk at the 2005 LUPUS UK AGM. One of the key activities undertaken when a lupus patient attends their clinic is the extraction of blood samples, which then disappear off to the laboratory. This is a crucial activity, but many patients are incurious about their results. Hopefully this article will encourage a little more curiosity, based on a better understanding of what is happening to the samples, other than providing material for the local black pudding factory!
What is the purpose of the blood tests?
The purpose of the blood tests can be summarized as four-fold: diagnosis, monitoring of disease activity, monitoring the drug therapy used in treatment and looking for complications of lupus.
Tests to help with diagnosis
The diagnosis of lupus is complex and the process starts with the information provided by the patient to the doctor and the findings on examination. The blood tests are then used to confirm or refute the clinical suspicion of lupus, but they do not make the diagnosis by themselves. Clear criteria have been laid down to diagnose lupus, based on symptoms, signs and the results of blood tests, but all of these can change over time and in many cases, while the doctor may suspect lupus, the strict criteria may not be met. Normally four of the eleven criteria must be positive to make a diagnosis of lupus, but not necessarily simultaneously.
Key features of the laboratory tests contained in the diagnostic criteria are the presence of protein in the urine and 'casts' which are microscopic aggregates of the protein, reduced white blood cell numbers, breakdown of the red blood cells and low platelets (small cells responsible for sealing up leaky blood vessels), and the presence of antibodies in the blood against the nuclear material of cells (anti-nuclear antibodies, antibodies against Sm and antibodies to double-stranded DNA) and that interfere with clotting (anti-phospholipid antibodies).
The doctor will usually do the following tests at the first visit, to help him come to a diagnosis:
- 'Full Blood Count' (Fbc): this detects anaemia, low platelets, low white blood cells (leucopenia, lymphopenia, neutropenia).
- 'Creatinine and electrolytes': this measures the salts (sodium, potassium) in the blood and gives an idea of kidney function (creatinine and urea - waste products passed out through the kidney).
- 'Liver function tests': these include measurement of liver enzymes (indicator of liver cell damage), albumin (marker of kidney problem with leakage of the proteins) and bilirubin, a waste product of the liver that causes jaundice when there is liver damage, or blockage of the drainage of the bile.
- ESR ('sedimentation rate'): this is a marker of non-specific inflammation, tends to be raised in lupus.
- CRP (C-reactive protein): this is another inflammatory marker, but this does NOT usually go up in lupus, unless there is infection.
- Urine sample: the urine tests measure protein and blood cells in urine (should be none!) and identify the presence of 'casts'.
- Blood clotting tests: these will tell how 'sticky' the blood is and will include the 'lupus anti-coagulant' and anti-cardiolipin antibodies.
- Immunological tests: these will look for the presence of the antibodies which identify the different types of lupus and also look at levels of 'complement', blood proteins, normally involved in fighting infection, which drop when there is active lupus. Measurement of the breakdown of complement is helpful in determining how active the disease is. Deficiency of certain types of complement proteins, particularly C2 and C4, increases the risk of developing lupus. The doctor will often measure the total amount of antibody, as lupus can cause both high and low levels, and the treatment may reduce the levels.
What are antibodies?
Antibodies are proteins produced by white blood cells (B lymphocytes), whose normal function is to glue up bacteria and make them easy for the white blood cells to capture and destroy. When the immune system goes wrong, antibodies can be formed that bind to tissues of the body (an 'auto-antibody'). Sometimes infection can cause auto-antibodies to be produced and this may be one of the causes of lupus. Typical autoantibodies found in lupus are:
- Anti-nuclear antibodies: this is a blanket term for lots of different antibodies that bind to the nuclei of cells. Not all types of anti-nuclear antibody are associated with lupus.
- 'LE' cells: this is an old-fashioned test which detected antibodies to histones (proteins that support the DNA in the cell nucleus). Anti-histone antibodies are often found when the lupus is triggered by drugs.
- Antibodies to double stranded-DNA: these antibodies are very important in the diagnosis of lupus; they bind to the DNA in the nucleus of cells.
- Anti-phospholipid (cardiolipin) antibodies: these are found in SLE and in Hughes' syndrome, and were the cause of the original finding of 'false positive' tests for syphilis in lupus.
- Anti-Sm antibodies: this is another antibody that binds to proteins in the nucleus of cells. It is rare in the UK and is mainly found in West Indians with SLE, but it is unique to lupus.
- Antibodies to ENA (extractable nuclear antigens): these are other antibodies to proteins in the nuclei, including anti-Sm. Other important antibodies include anti-Ro (especially associated with lupus skin disease, heart block in new born babies and Sjögrens syndrome), anti-La (SLE, Sjögrens syndrome), anti-RNP (if present with antibodies to DNA, then the diagnosis is SLE, if present alone, then diagnosis is mixed connective tissue disease, MCTD); Anti-Scl70 (found in systemic sclerosis) and anti-Jo1 (found in polymyositis).
- Commonly, patients with lupus will have autoantibodies to other organs, such as the thyroid gland.
Tests related to drug treatment and monitoring
Azathioprine is a drug commonly used to treat severe lupus but it may cause serious side effects. The risk of side effects can be predicted by measurement of the enzyme thiopurine methyltransferase (TPMT) in the blood. The doctor will often do this test early in the course of the disease so that if azathioprine is needed it can be used in safe doses. Deficiency of the enzyme means that serious side effects will occur if the drug is given in the normal doses.
Regular blood tests are essential to monitor how active the disease is and whether treatment is working. The tests will include many of those done at the beginning, as part of the diagnostic process, to monitor for any change in the state of the disease. These tests will usually include:
- Full blood count
- Sedimentation rate
- Kidney and liver tests (creatinine, liver enzymes)
- Tests for protein in urine
- Antibodies to double stranded DNA, as rising levels often predict a relapse
- Complement proteins, as low levels of C3 indicate active disease
Monitoring for side effects of drugs
All drugs have side effects and many of the drugs used in lupus have significant side effects. Laboratory tests help to identify some of the side effects.
- Prednisolone and other steroids: blood glucose (may go up); fats in the blood (may go up) and full blood count (toxic to lymphocytes)
- Azathioprine, methotrexate: both drugs can damage the liver - so regular checks of liver enzymes are needed. Both are toxic to the bone marrow - so regular full blood counts are needed to look at white blood cells and platelets. Total antibodies can become very low, and this may increase the risk of infection: monitoring of total antibody levels is important.
- Cyclophosphamide: this drug is very toxic to white cells - so regular full blood counts are essential. Total antibodies can become very low. It is important to check the urine regularly as it can cause bleeding from the bladder.
- Ciclosporin & Tacrolimus: these are both very powerful immunosuppressive drugs which can damage kidneys and liver - checks on kidney and liver function are essential. Blood levels can be measured in the laboratory to help adjust dose correctly.
Monitoring for the complications of lupus
Kidney disease can develop very suddenly in lupus and is very serious. Regular checks of kidney function are necessary, including urine tests, to enable any deterioration to be picked up early at a point when it may be reversible with treatment.
Because lupus is strongly associated with other autoimmune diseases, doctors will have a high index of suspicion and will often do blood tests to check for these. Tests may include tests for thyroid hormones and autoantibodies to the thyroid gland. Myasthenia gravis is a disease in which auto-antibodies interfere with muscles and prevent the signals from the motor nerves reaching the muscle. This causes weakness of the muscles. The autoantibody can often be found in the blood.
Lupus is strongly associated with blood problems such as haemolytic anaemia (breakdown of red blood cells causing anaemia) and thrombocytopenia (reduced numbers of the platelets required to prevent bleeding). Low white blood cells may also be seen. These are part of the diagnostic criteria, but in treated patients it may be very difficult to distinguish between these problems occurring because of the lupus or because of side effects of the drugs being used to treat it. A bone marrow examination may help to distinguish the two. Similarly liver disease in lupus may be due to the lupus or may be due to the drugs: a biopsy of the liver may be needed.
Summary
Although it may be a trial, particularly in people with difficult veins, all the blood samples are necessary, because they do help the doctors understand and control the lupus. When you are in the clinic, be 'nosey' and ask what the test results show - then you will understand a little more about what is happening too. You need to be aware that some of the tests take longer to do than others and remember - there are lots of technical and scientific staff whom you never see who are deeply involved in your disease through the analysis of your blood samples. You don't see them, but your doctor cannot manage your lupus without them.
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