RHEUMATOID FACTOR: normal, high and low values

What is rheumatoid factor

The rheumatoid factor (abbreviation FR) is an antibody, that is a glycoprotein produced by plasma cells, so called because it is often associated with rheumatoid arthritis (frequent autoimmune disease in women).

The antibodies, or immunoglobulins, are small symmetrical glycoproteins, composed of four two-by-two symmetrical peptide chains called light chains (of type kappa or lambda) is heavy chains (A, D, E, G, M, hence the names IgA, IgG, etc.). These chains are placed in specific complexes based on the type of immunoglobulin; in the case of RF, the most typical form is that of immunoglobulins M o IgM, in which the chains are placed in pentamer (five antibodies joined in the shape of a star) and are therefore equipped with a large capacity opsonize (to tie) the antigens towards which they are directed. Another structure in which RF can be present, albeit less frequently, is the a form immunoglobulin G. or IgG, in which the peptide complex is monomeric, i.e. not assembled in superstructures.

It is also good to understand the differentiation of structure which is important from a laboratory point of view: the IgG are divided into a fragment Fc ("crystallizable fragment") and a fragment Fab (antigen-binding) based on the result of their treatment with proteolytic enzymes such as pepsin or papain.

Antigens are, in general, structures that are recognized by the immune system and that may or may not give rise to an immune response against them; the antigens they are very thick proteins, but not only. Furthermore, antigens are distinguished in the organism self, ie produced by the organism itself, e not self, or deriving from the external environment. In the specific case of rheumatoid factor, the recognized antigen is of type self, and in particular it is the portion Fc of IgG antibodies: rheumatoid factor, itself an antibody (almost always of the IgM class), binds antibodies of the IgG class and leads to an immune reaction.

In theory, under normal conditions, the immune system should produce antibodies to antigens only not self, towards which it is necessary to trigger an immune response: in this way, bacteria, viruses and other microorganisms they can be eradicated. Conversely, antibodies directed towards antigens self ("Autoantibodies", involved in autoimmune diseases) they shouldn't be there, thanks to activities of deletion of the autoimmune response present in the body. However, certain small amounts of antibodies directed against antigens are also present in the normal population self, which in most cases do not cause real diseases: an example is the rheumatoid factor which, as will be seen later, is often present in adults and elderly subjects even without any pathology in progress.

Classical rheumatoid factor IgM

Rheumatoid factor, which is an IgM immunoglobulin that binds to the crystallizable fragment of IgG class immunoglobulins.

Indications for carrying out the examination

The dosage of rheumatoid factor it is required when, following an evaluation by a general practitioner or a specialist (rheumatologist), there is a suspicion of certain pathologies. Therefore, this dosage is carried out only when the signs and symptoms, together with the medical history, may be indicative of certain rheumatological diseases (and not) to which the rheumatoid factor is often associated: if this is found in significant values there is a greater suspicion towards specific diseases, but very often it is not possible to make a definitive diagnosis.

THE symptoms that the subject can perceive, and that can induce the physician to request the analysis of the rheumatoid factor, I'm:

  • Symptoms of rheumatoid arthritis, such as joint pain ("rheumatism"), especially if bilateral and symmetrical with an "inflammatory rhythm": pain from inflammation is present a rest, in particular in the night hours, and is improved by movement and physical activity; moreover, the stiffness associated with pain is prolonged over time, exceeding half an hour.
  • Tiredness, malaise, fever (very little indicative as they are associated with many different diseases)
  • Dry eye (feeling of "sand in the eyes"), lack of salivation

Others signs is symptoms visible and investigable by the doctor which may be indicative:

  • Soft swellings, floating of joints
  • Tendon inflammation (tendinitis)
  • Syndrome of the carpal tunnel
  • Presence of cyst of Baker
  • Anemia from chronic disease
  • Serositis
  • Presence of cutaneous purpura

Very often, in addition to the dosage of the rheumatoid factor, other researches of autoantibodies: ACPA (antibodies anti citrulline), antibodies anti core, p-ANCA, c-ANCA, antibodies anti-dsDNA, etc.

Preparation for the examination and method of dosage

To detect the presence of rheumatoid factor in the subject's blood, a simple blood sample is required, in the same way as a sample for the most frequent blood analysis.

No preparation is usually required by the patient for the test: there is no need to fast o follow particular restrictions; of course it is good to follow the instructions of the treating doctor or rheumatology specialist.

As regards the laboratory method of investigation, the blood sample is sent to the analysis laboratory, where a sample preparation and then the analysis of Rheuma test (RA Test) with technique nephelometric (evaluation of concentration through the study of variations in the diffusion of light radiation).

On the other hand, it is almost no longer used in modern laboratories reaction of Waaler Rose, in which erythrocytes (red blood cells) of sheep were used, associated with rabbit immunoglobulin G, and were made to react with the serum taken from the patient: if hemagglutination (formation of solid corpuscles) occurred, the test was considered positive.

Reference values of the rheumatoid factor

For what has been said so far, in theory a normal value of rheumatoid factor (as well as other autoantibodies) should be zero. However, in fact, the presence of various types of autoantibodies is noted even in healthy subjects, usually in very small quantities: this marks the efficacy, but also the imperfection, of the regulatory mechanisms that should prevent the formation of clones self-reactive.

Therefore, from the population analyzes, according to the assay method, we mean normal values of rheumatoid factor when lower than 15-20 IU / ml (International Units per milliliter).

High values: what does a high rheumatoid factor indicate?

Upon finding by high rheumatoid factor, with values higher than 15-20 IU / ml, the doctor is oriented towards a possible diagnosis of autoimmune disease; first of all, however, some important characteristics must be considered, among which first of all the age of the subject in question: about 5% of the healthy population has a positive Rheuma test, a percentage that reaches values between 15 and 20% of subjects with age older than 60-65 years, but who nevertheless do not show any symptoms of disease.

Therefore, first of all, the symptoms in the presence of high rheumatoid factor (joint rheumatism, joint deformations, swellings ...) should be compared with any other autoantibodies required by the clinician, the presence of other indicators (for example if there is high ESR or normal ESR, high C reactive protein ...), and then with the age of the patient and his already known pathologies.

Between causes of elevated rheumatoid factor, in the absence of a purely autoimmune disease, there are:

  • Age > 60 - 65 years
  • Subjects affected by COPD (chronic obstructive pulmonary disease), a disease that unfortunately affects a large percentage of people, especially among the elderly
  • Hepatopathies chronic, such as in individuals infected with HCV (Hepatitis C), cirrhosis, etc.
  • Others lung disease, in particular interstitial ones (also called interstitial diseases), such as UIP, NSIP, etc.
  • Various infections, including bacterial endocarditis and tuberculosis (not so rare, especially in people from poor countries)
  • Leukemia, multiple myeloma

Instead, the rheumatic pathologies Frequently associated with high blood rheumatoid factor are:

  • Cryoglobulinemia mixed (CM, or cryoglobulinemic vasculitis), caused precisely by the presence of a very high level of rheumatoid factor and for which always associated with positivity.
  • Syndrome of Sjögren, in 60-70% of cases; other investigations are used to diagnose this disease, including other more specific antibodies.
  • Rheumatoid arthritis, also present in this case in about 70%. Also for the diagnosis of rheumatoid arthritis many other investigations are needed (despite being widely used, in this case the ESR is not very indicative of disease activity, and it is easy to find high rheumatoid factor and normal ESR), and above all a rather specific clinical picture (bilateral, symmetrical polyarthritis, especially at the level of the hands).
  • Systemic lupus erythematosus o SLE and other autoimmune diseases (rheumatic polymyalgia, connective tissue diseases).
Rheumatoid Arthritis Symptoms

Typical deformation of the interphalangeal joints in rheumatoid arthritis.

Low values, or negative Rheuma test

There is no real presence of low rheumatoid factor; in the case of values within the norm or a “negative Reumatest” report, it is good to understand that this can be completely physiological.

However, as the presence of FR is not necessary due to the presence of autoimmune diseases such as rheumatoid arthritis, negative values cannot exclude the diagnosis of these diseases, especially if a strongly indicative clinical picture is present. Up to 30% of patients with rheumatoid factor negativity is instead affected by autoimmune disease, and it is therefore very important to associate other diagnostic investigations.

Factors affecting the test

As described above, increasing age is itself an important factor that can affect RF levels in healthy subjects; in addition to this, no other factors are known which could significantly modify the dosages of rheumatoid factor.

How is it treated?

At this point in the article it should be clear by now that the rheumatoid factor is not in itself a disease but rather a non-specific indicator of some conditions; it therefore has no meaning to talk about remedies for a very high rheumatoid factor, or to research methods on how to lower the rheumatoid factor.

Cost of the exam

The dosage of the levels of rheumatoid factor can be carried out in the National Health Service or in a private regime; costs vary between € 5.80 in the public regime and around € 10 in the private regime.


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