Rheumatoid factor

We are familiar with the fact that it is possible to do tests for various types of disease. A well-known example are tests for HIV, often called AIDS tests in everyday language. I asked myself the question to what extent there are also reliable tests for autoimmune diseases. If there is no pathogen such as a virus present then one approach to tests is ruled out. But are there others? One relevant example I found is that of rheumatoid arthritis (RA) and tests based on a substance called rheumatoid factor. I will say more about this below but first I wanted to recall one well-known pitfall of tests in general. This shows that the notion of a reliable test is not completely obvious. It is useful to introduce some terminology. The sensitivity of a test is the proportion of people having the disease for which the test gives a positive result. The specificity is the proportion of people not having the disease for which the test gives a negative result. Consider the example of a disease which affects one person in one million and a test where the probability of a positive result in someone who does not have the disease is one in ten thousand. In this case the specificity is 0.9999, which sounds very good. Suppose now, however, one million people are tested. The expected number of people in the sample having the disease is one but the number of people who will test positive is one hundred. In other words a positive test only really says that the probability of the patient having the disease is at least one per cent, a rather weak statement. The problem here is simply that looking for an effect which is very rare can make reliable testing very hard. The quantity which comes out to be one per cent in this example is called the positive predictive value.

After this digression I now come back to rheumatoid factor. Autoimmune diseases can be divided into those where the immune system attacks a particular tissue (e.g. insulin dependent diabetes mellitus where it is the $\beta$ cells of the pancreas which are attacked) and those which are systemic and affect a variety of tissues. RA is of the latter type although its best-known effects concern the joints. The presence of rheumatoid factor is an indication of RA but it may also be present in people suffering from Sjögren’s syndrome or in healthy individuals. Thus, in the above terminology, the specificity of the test is not very high. It also happens that rheumatoid factor is not detectable in people with RA during extended periods. To sum up, this is test for RA but it does not seem to be a very precise one. What kind of substance is rheumatoid factor? I mention at this point, since it is something that used to confuse me, that the words ‘antibody’ and ‘immunoglobulin’ are synonymous. Rheumatoid factor is an immunoglobulin of type M against immunoglobulins of type G. The antigen it binds to is in the Fc part of the antibody. This is a part which is independent of the antigen for which the antibody is specific and only depends on the isotype. The isotype differs between antibodies with different functional properties and is designated by the letter M, D, G, A or E. There is another test for RA with better specificity using anti-citrullinated protein antibodies. Citrulline is a non-classical amino acid. It is not coded for by DNA but can be produced by modification of existing proteins.

What about other autoimmune diseases? Another important systemic autoimmune disease is systemic lupus erythematosus (SLE). Here a common test involves antinuclear antibodies, i.e. antibodies against parts of the cell nucleus. The test has high sensitivity but low specificity. In the case of multiple sclerosis there seems to be no test comparable to those just mentioned. One diagnostic criterion which is used is that of oligoclonal bands. What this means is the occurrence of proteins in the cerebrospinal fluid (actually immunoglobulins of type G) which show up as bands in electrophoresis. It is important that there are a few of those bands (oligo) in the cerebrospinal fluid which are not present in the blood. This is regarded as evidence of activity of the immune system within the central nervous system. The difference to the tests discussed above is that little seems to be known about what substances the antibodies producing the bands are antibodies against.

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