Testing for rheumatoid factor (RF) is primarily used for the diagnosis and establishing the prognosis of RA. In this article, Dr. Vineeta Shobha explains why the RF test should not be used as a confirmative diagnostic or even a screening test for rheumatoid arthritis.

Historical background

RF was first described by Waaler and Rose in 1940 and it was later found to be immunoglobulin IgM directed to the Fc region of IgG. It was the first autoantibody to be discovered in people with RA. RF should be interpreted in the clinical context: Roughly, about 20% of those with confirmed RA will not have an abnormal RF test, while 5-10% of people who do not have RA will have an abnormal RF test. Negative levels do not exclude the disease, and positive levels do not guarantee the diagnosis.

Furthermore, it’s important to note that once the RF level is elevated, it will often remain so, even if the disease goes into remission. RF is produced in many chronic inflammatory conditions such as long-standing infec­tions like bacterial endocarditis, hepatitis B and C, tuberculosis, chronic bronchitis, silicosis and many others. Some procedures can also contribute to elevated RF levels such as vaccinations and repeated blood transfusions. Thus, RF is not specific for any particular rheumatic disease such as RA. It can also be seen in 5 to 6% of the elderly in the normal healthy population.

Origins and physiologic functions of RF

Why should rheumatoid factor occur in normal healthy individuals or in those with chronic infections?

The origin of RF is incompletely understood. In response to chronic antigenic stimulation, an abnormal immune response appears to select high-affinity RF from the host's natural antibody repertoire which possibly represents antibodies that have reacted with microbes. Its physiologic functions include binding and processing of antigens embedded in immune complexes, amplification of the humoral response to bacterial or parasitic infection and Immune complex clearance.

When do I order for RF?

In my clinical practice, the main indications for RF testing are suspicion of RA or Sjogren's syndrome. The overall sensitivity of RF in RA is 69 per cent (95% CI 65-73 per cent) with a specificity of 85%. In primary Sjogren’s syndrome, RF is positive in more than half, while in secondary Sjogren’s it's prevalent in >90%, usually in high titres. However, it is also commonly elevated in other rheumatology diseases such as mixed connective tissue disease, systemic lupus erythematosus, cryoglobulinemia, pulmonary fibrosis and the polyarticular-onset form of juvenile inflammatory arthritis. It is thus apparent that the specificity of RF in differentiating RA from some other rheumatologic conditions is poor. However, with higher titres of RF, the specificity increases, and RF testing becomes a more useful laboratory tool. Higher titres are also associated with more aggressive and erosive RA disease. Of note, the 20% of RA who are negative for RF and yet have the clinical picture, may potentially have poor outcome when not treated. Furthermore, RF may appear up to several years before the onset of clinical RA and its mere presence should not be considered as an indication to start treatment with immunomodulators.

Laboratory methods and interpretation

In most laboratories, the normal range of RF is from 0-20 IU/ml. Initially, it was performed as an agglutination reaction, using sheep RBC coated with rabbit IgG. More recently, bentonite or latex particles coated with human IgG are used for detection for RF as a semi-quantitative assay. Enzyme-linked immunosorbent assay (ELISA) and nephelometric assays have now become the most common methods for quantifying RF.

In clinical practice, laboratories test only for IgM RF, but RF can belong to all other major immunoglobulin classes as well (IgG, IgA). The titres or absolute value of RF should be considered when analysing its utility. As mentioned earlier, the higher the absolute value, the greater the likelihood that the patient has a rheumatic disease. However, the use of a higher cutoff for diagnosis decreases the sensitivity of RF but increases its specificity. With effective treatment for RA, there may be fluctuations in RF titres but they do not reflect disease activity. Furthermore, RF titres cannot be used to prognosticate or assess response to treatment. Overall, there is no indication for serial testing of RF.

Other autoantibodies in RA

A number of other autoantigens are also targeted in RA, which includes, a wide spectrum of cartilage components, stress proteins, enzymes, nuclear proteins and citrullinated proteins. In 1993, Serre et al. identified filaggrin, a protein present in epithelial cells, as the target antigen of RA-specific anti-keratin antibodies (AKAs). Subsequently, it has been demonstrated that AKAs and other RA-specific autoantibodies known as anti-perinuclear factors (APFs) and anti-Sa antibodies all recognise citrulline-containing peptides/proteins as a common antigenic entity, and they are collectively termed as anti-citrullinated protein antibodies (ACPAs).

ACPAs

Currently, only RF and ACPA are utilised in clinical practice because of their diagnostic and prognostic values; the latter, in particular, is highly specific for RA. ACPAs can be detected by ELISA and immunoblotting methods using citrullinated proteins or peptides. The sensitivity of the ACPA test is around 50 to 60% at the onset of RA and can rise as high as 85% later in the course of the disease. When found in patients with early undifferenti­ated arthritis, ACPAs predicts the later development of classic erosive RA. They are especially prevalent in RF-positive patients but can be found in around 25% of RF-negative RA patients as well. Additionally, ACPA is helpful in discriminating between RA and psoriasis with erosive arthritis and also between RA-associated and hepatitis C associated polyarthritis.

To sum up, RF should not be considered as diagnostic of RA and it should not be used as a screening test. And vice versa, the absence of RF should not be construed as the absence of RA.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. Vineeta Shobha is the Professor & Head of the Department of Clinical Immunology & Rheumatology from Bangalore.