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The antinuclear antibody (ANA) test determines whether serum from the child's blood reacts with various types of material in the nuclei of cells. ANA testing used to be very significant in diagnosing children with rheumatic disease.

The main problem with the test was that the results were difficult to compare between different laboratories. Each lab used its own materials for running the test and did its own calibrations. In the early 1980s it was decided that a standardized test would be better. A uniform cultured human cell line, called Hep2, was agreed on for the standard. But there are so many variables in performing ANA testing that it is still not safe to compare results between different laboratories. Furthermore, this cell line gives low-titer positive results (see below) much more frequently than the old method did. As a result, positive tests are now very common in children who do not have a rheumatic disease. Higher-titer positive tests are more meaningful. However, having only a low-titer ANA does not guarantee that your child does not have disease. As a result, the situation has become very confused.

Titer refers to how much the serum used in the test can be diluted and still give a positive reading. Serum is initially screened after being diluted at a ratio of 1:40. If the screen is positive, then further tests are done at dilution ratios of 1:80, 1:160, 1:320, and so on, until there is no detectable fluorescence. The last dilution at which the test is positive is the ANA titer.

Positive tests for ANA are found in a wide variety of conditions. They are certainly found in children with SLE, but they are also found in children with a wide variety of other rheumatic diseases including JA. They may briefly appear after a wide variety of infections (especially viral infections in which the virus has damaged the nuclei of the cells it infects). Positive tests for ANA have been seen in many children with no identifiable disease and in some children with many different diseases. The presence of a positive ANA should prompt consideration of a rheumatic disease, but it may be a false lead.

A positive test for ANA is also important in children with arthritis. In children with any of the various forms of juvenile arthritis, the complication of eye disease occurs more frequently in children who have a positive test for ANA than in children who have a negative test (see Chapters 5 and 6). Despite extensive investigation, the explanation for this association is unknown.

The pattern of ANA test results can be significant. Homogeneous pattern ANA occurs in many different people and is not disease-specific. Speckled pattern ANA is also common at low titer, but at higher titer it may be associated with mixed connective tissue disease or scleroderma. Rim pattern (also called shaggy pattern) is almost always a sign of active lupus.

The antibodies the patient's serum is reacting to during the ANA test can be extracted by a chemical solution. These antibodies are named Ro, La, Sm, and RNP. Different patterns of antibodies correlate with different patterns of disease (see Chapters 9 and 10).

Another early finding was that some of the antibodies detected by the ANA test were directed against DNA and that people with high titers of anti-DNA antibodies were often sicker. These tests used to be separated into tests for single-stranded DNA (ssDNA) and tests for double-stranded DNA (dsDNA). Tests for ssDNA have mostly disappeared, as these antibodies are very nonspecific and occur in a wide variety of situations. Most anti-DNA tests today measure dsDNA. High titers of anti-dsDNA are much more specific for lupus than a positive ANA. However, there are children with anti-dsDNA antibodies who have other diseases. Sometimes a child is very sick with a viral infection and anti-dsDNA antibodies appear as part of the immune response to the virus. These usually go away within a few months.

Many sources of DNA contain DNA in chains with damaged ends, which can cause positive anti-dsDNA test results that are not truly meaningful. A lab may run what's called a Crithidia lucilliae test, which uses as the source of the DNA a microorganism that has circular DNA, with no loose ends to be damaged. A positive test for anti-dsDNA antibodies using Crithidia lucilliae is more meaningful. However, even this test is occasionally positive in children who don't have SLE.

Antineutrophil cytoplasmic antibodies (ANCAs) are relatively newly described. Unlike antinuclear antibodies, which react with materials in the nucleus of the cell, these antibodies are reacting with elements in the cytoplasm of neutrophils (one type of white blood cell). The cytoplasm is the body of the cell surrounding the nucleus. There are two major variations: cANCA reacts with proteinase 3, and pANCA reacts with myeloperoxidase. With continued investigation it has become clear that pANCA may also represent antibodies to lactoferrin (a common protein) and other substances in the blood.

How and why pANCA and cANCA occur is unclear. Their importance lies in their association with Wegener's granulomatosis, pauci-immune glomeru-lonephritis, Churg-Strauss syndrome, other systemic vasculitis syndromes, and inflammatory bowel disease. If a child has unusual symptoms or symptoms that suggest one of these disease, the rheumatologist may test for ANCAs; if the antibodies are present, then more extensive testing is indicated. Unfortunately, the association of the antibodies with these diseases is incomplete. Some patients with the diseases do not have the antibodies, and some people with the antibodies do not have these diseases. As with so many other tests in rheumatic disease, we recognize the association but do not yet fully understand the how and why.

Anti—Saccharomyces cerevisiae antibodies (ASCA) are antibodies to a fungus that commonly occurs in the large intestine. These antibodies occur more often in children with IBD than in normal people. These antibodies are not routinely measured by rheumatologists but are increasingly being used by gastroenterologists in the evaluation of children who may have IBD. Studies have shown ASCA to be common in children with Crohn's disease, which is one type of IBD.

Serum complement levels. These tests are done in children with possible lupus. Although the complement system consists of many separate components, only C3 and C4 are routinely measured. C3 is typically depressed in children with active lupus and may be a warning of more active disease to come. However, the predictive value of a change in C3 level is the subject of much debate. There are few diseases other than lupus that cause a low C3. C4 is also frequently low in children with lupus. However, the significance of a low C4 is less clear. This is discussed in much more detail in Chapter 9. Many laboratories will also report CH50, but this is not a complement component. The test for CH50 measures the function of the entire complement system. If any one of the components of the system is low, then CH50 will be low.

C1q and C2 are two other complement components that can be measured, but these are not tested routinely. Genetic deficiency of C1q is associated with an increased risk of developing lupus. The risk of developing lupus is also increased in children who are deficient in C2 or C4. Deficiency of C4 does not cause any obvious illness, but deficiency of either C2 or C3 is associated with increased infections. Children with complete genetic deficiency of C3 often die of infections. Children genetically deficient in C2 have an increased incidence of infections and of rheumatic diseases but may live a normal life if they are recognized and given antibiotic prophylaxis. Most physicians think that C2 deficiency is extremely rare, but I have several children with C2 deficiency in my practice. You have to look for it to find it.

Anticentromere and anti-Scl-70 antibodies are associated with forms of scleroderma. Anticentromere antibodies are often present in children with CREST syndrome, and anti-Scl-70 antibodies may be present in children with systemic scleroderma. These antibodies are very significant if they are present. Most children who test positive for the antibodies will ultimately turn out to have the disease. However, I have seen false positive results and low-titer positive results that have turned out not to mean anything.

Like all diagnostic tests, tests for anticentromere and anti-Scl-70 antibodies are useful when they are done in children suspected of having the disease, but you must be very careful in interpreting them if they do not fit the clinical picture. Not every laboratory does these tests well. Before you get concerned about a positive test that does not make sense, make sure the test has been repeated in one of the nationally recognized laboratories (see the Resources section). Unfortunately, the absence of these antibodies does not guarantee that you do not have one of these diseases. They are found in less than half of affected patients and less often in children than in adults.

Anti-Jo-1 antibody is one of a variety of antibodies that have been described in adults with muscle disease. Some doctors still look for this antibody in children with muscle disease, but it is very uncommon in childhood. Adults with this antibody tend to have a more difficult disease course. There is a growing belief that patients who test positive for this antibody have a completely different disease from other patients with myositis.

Factor VIII, or Von Willebrand's factor, is one of the blood clotting factors. Someone who has no factor VIII has hemophilia (a serious bleeding disorder). In children with other types of inflammatory disease, the factor VIII level will rise and fall as an acute phase reactant. Some physicians like to follow this level in children with muscle disease or other diseases in which the blood vessels tend to be involved. A rising level suggests more disease activity, while a falling level suggests things are better.

Antigliadin antibodies, antitissue transglutaminase, and antiendomysial antibodies. Testing for these is done to detect children with celiac disease (gluten-sensitive enteropathy). This is an uncommon disease in which patients are sensitive to gluten, a protein in wheat and some other grains. Whenever they eat too much of this protein, they get abdominal pain and diarrhea. Interestingly, people with this disease develop arthritis and other autoimmune diseases more often than would be expected. Antigliadin antibodies can be of the IgG type or the IgA type. IgG-type antigliadin antibodies are very common and probably not meaningful. IgA-type antigliadin antibodies should raise suspicion of celiac disease. Antitissue transglutaminase and antiendomysial antibodies are much more specific indicators of celiac disease. Not everyone who tests positive has the disease, and a negative test does not guarantee the absence of the disease. However, these tests are helpful in deciding which children with abdominal complaints should be evaluated further. The definitive diagnosis of celiac disease depends on a biopsy of the small bowel that demonstrates the classic findings under the microscope.

Rheumatoid factor (RF). This test measures the presence of IgM antibodies directed against IgG in the blood. While the test is very useful in diagnosing adults with rheumatoid arthritis, the test is not often positive in children and should not be used to make the diagnosis of juvenile arthritis. RF is found in some normal people, people with a variety of rheumatic diseases, and in people with various infections, especially subacute bacterial endocarditis (SBE).

Adult-onset rheumatoid arthritis (RA) by definition occurs after sixteen years of age. However, since the disease does not always proceed as described in the literature, it occasionally starts earlier. So there are children with true adult-type RA that starts in the early teenage years, though this is not common. Children with certain infections, including SBE, also may have a positive RF test, as can children with other rheumatic diseases. A child with joint pain, a positive RF, and a positive ANA should be carefully evaluated for the possibility of scleroderma or mixed connective tissue disease.

You may hear about "hidden" rheumatoid factor. This is a very confusing subject. Typical RF is IgM directed against IgG. Because IgM has a unique structure that is very large, it is easy to detect these antibodies. Using special techniques, one can measure IgG and IgA antibodies against IgG, which are smaller and not detected by the normal RF test. These "hidden" rheumatoid factors are found in some children with juvenile arthritis. However, these tests are not commonly done, and their proper interpretation remains unclear.

Lyme titer. Lyme disease testing is a key element of the evaluation of any child with arthritis in areas where the disease is endemic. There are many different laboratories doing Lyme testing, and a variety of techniques are used. The easiest, least expensive test is the ELISA (enzyme linked immunosorbent assay), which identifies antibodies in the blood against spirochetal antigens. Borrelia burgdorferi, the agent that causes Lyme disease, is a spirochete; however, there are many spirochetes, some of which are normally found in saliva. If a child has Lyme disease, he or she will have a positive ELISA for antibodies to spirochetes, but so will many children who have been exposed to spirochetes other than

Lyme. All children with a positive ELISA should then be tested on a Western blot. The Western blot, a more complicated and more expensive test, determines exactly which spirochetal antigens the antibodies in the child's blood are reacting with. The Western blot can distinguish between antibodies found only in people with Lyme disease and antibodies found in people exposed to other spirochetes.

A child with a positive Western blot has definitely been exposed to Borrelia burgdorferi and needs to be treated for Lyme disease. However, that does not prove that Lyme is the cause of the child's symptoms, as Lyme disease and exposure to Borrelia burgdorferi are very common in many parts of the United States. If symptoms continue after treatment for Lyme, there may well be another problem.

Thyroid function tests are often done in children with joint problems because both excessive thyroid hormone (hyperthyroidism) and too little thyroid hormone (hypothyroidism) can be associated with diffuse aches and pains. Both hyperthyroidism and hypothyroidism also may be associated with fatigue and muscle weakness. In addition, autoimmune diseases such as SLE may be associated with antibodies that interfere with thyroid function.

The main thyroid function tests are T3 (triiodothyronine), T4 (thyroxine), and TSH (thyroid-stimulating hormone). T3 and T4 are hormones produced by the thyroid gland that regulate the body's metabolism. TSH is secreted by the pituitary gland and influences the function of the thyroid. In children with rheumatic disease, we occasionally see abnormalities of TSH without T3 or T4 abnormalities. This can be a warning of problems to come.

Some children with autoimmune diseases have high titers of antithyroid antibodies for a long period before they actually have thyroid disease. These may be antithyroid peroxidase antibodies or antithyroglobulin antibodies. Often children with antithyroid peroxidase antibodies have a family history of Hashimoto's thyroiditis. These children should be monitored carefully for the possibility that they too may ultimately develop Hashimoto's thyroiditis. Thyroid antibodies are also seen in some children with SLE and occasionally in children with celiac disease and other autoimmune diseases.

Serum protein electrophoresis (SPEP) is a test that measures the pattern of the proteins in the blood. A specific pattern indicates multiple myeloma, a cancer of the cells that make antibodies, but this virtually never occurs in children. However, the SPEP may detect IgA deficiency or a low level of other immu-noglobulins.

Anticardiolipin and antiphospholipid antibodies were first noted in lupus patients with excessive bleeding, but it was discovered they were also present in lupus patients who had problems with excessive blood clotting (deep vein thrombosis, strokes, etc.). It turns out that these antibodies are present in some adults and children with a variety of rheumatic diseases as well as people who do not have any other identified autoimmune disease.

When these antibodies are found in someone who is not having problems with clotting, no one is sure what to do. It appears that most people with anti-cardiolipin antibodies are at very little risk, and it can be dangerous to give anticoagulants to people because they can bleed excessively if they fall, are cut, or are in an accident. Therefore, if the child has never had trouble with clotting, most doctors either do nothing or just give a baby aspirin daily. However, if a child has had a blood clot, most doctors believe he or she should be treated with anticoagulants.

Anticardiolipin or antiphospholipid antibodies can also affect pregnant women. Women known to have anticardiolipin antibodies should be carefully monitored when they become pregnant. Women who have an excessive number of spontaneous abortions (miscarriages) in mid- or late pregnancy often turn out to be anticardiolipin-antibody-positive.

PT and PTT. Routine clotting studies consist of two tests: the prothrombin time (PT) and the partial thromboplastin time (PTT). The PT measures the ability of blood to clot once it is exposed to thromboplastin (a substance that starts clotting). The PTT measures the ability of blood to clot when left out of the body without being exposed to anything extra to start clotting.

Anticardiolipin antibodies can prolong clotting, as can many drugs. Some children have prolonged clotting times because they either do not make or do not make enough of the clotting factors, which may be a genetic defect or the result of liver disease. Vitamin K is important for making the clotting factors, and someone who has prolonged bleeding should be given an injection of vitamin K. Surgery on children with an unexplained significantly prolonged bleeding time is dangerous.

HLA B27 is an inherited genetic marker. It is most common among people of northern European descent, but also is prevalent among those of Chinese descent and certain North American Indian backgrounds.

Eight percent of the white population is positive for HLA B27, and the vast majority of people are positive for this marker do not have arthritis. However, more than 90 percent of adults with ankylosing spondylitis have the marker. HLA B27 is also associated with Reiter's syndrome, the arthritis of IBD, psoriatic arthritis, and other forms of spondyloarthropathies.

Though we do not fully understand the operation of the gene that HLA B27 serves as an indicator for, we do know that HLA B27 signals a greater risk of developing arthritis given other circumstances. For example, if you have no other genetic predisposition to arthritis, being positive for HLA B27 is not significant. You may also have a genetic predisposition to arthritis that carries a certain likelihood that you will develop the disease. However, if you have the genetic predisposition plus the HLA B27 marker, your likelihood of developing arthritis doubles.

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