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Rheumatoid Factor: High Levels + Effects

Written by Mathew Eng, PharmD | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:
Jonathan Ritter
Puya Yazdi
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Mathew Eng, PharmD | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Rheumatoid factor is an antibody that usually signals an autoimmune attack in the body. Although useful in diagnosing rheumatoid arthritis and monitoring disease activity, this marker may also be produced in other inflammatory diseases and certain infections. We break down all the possible causes and effects of high levels.

What Is Rheumatoid Factor?

Rheumatoid factor (RF) is an autoantibody produced by the immune system. Autoantibodies trigger autoimmunity and inflammation responses by mistakenly mounting an attack against the body’s own tissues.

This marker got its name from its initial discovery in people with rheumatoid arthritis. Since then, it became evident that other conditions can also trigger its production. Detectable levels of the rheumatoid factor were uncovered in people with other autoimmune diseases, chronic infections, cancer, liver disease, and parasites [1, 2].

The rheumatoid factor is a curious autoantibody that attacks other antibodies. It mostly takes the form of an IgM antibody (the largest antibody type) and specifically targets a region on IgG antibodies. It can alternatively exist as other antibody types (IgG, IgA, IgE, or IgD), but the IgM form is usually the first to appear in the blood and is most closely linked to disease activity [1, 3].

Healthy people may produce beneficial forms of rheumatoid factors, which are part of the body’s normal defense against bacterial toxins (lipopolysaccharides) and viruses such as the Epstein Barr Virus (EBV). These don’t attack the body’s own tissues but instead help fight infections and clear away immune cells that are no longer needed. Once the threat is over, their levels may naturally drop [1, 2, 4].

In contrast, the rheumatoid factor produced in people with rheumatoid arthritis remains high for longer and attaches to the target (IgG) more strongly. It likely does not directly cause the disease, but it can worsen the symptoms by increasing inflammation and destroying the joints [4, 2].

The rheumatoid factor is mainly used to help diagnose rheumatoid arthritis and determine how the disease will progress. Levels often rise many years before the first symptoms appear and may stay high shortly after, in the early course of the disease. However, the rheumatoid factor is not an exclusive marker – some people with rheumatoid arthritis never test positive for rheumatoid factor [1, 5, 6].

Rheumatoid Factor Testing

Your doctor will typically order a rheumatoid factor test if you show symptoms of rheumatoid arthritis, such as [7, 8]:

  • Joint pain, tenderness, redness, and swelling
  • Joint stiffness
  • Fatigue and weakness
  • Slight fever
  • Eye or mouth dryness

Other types of tests are sometimes performed alongside a rheumatoid factor test to help diagnose rheumatoid arthritis. These other tests can include [7]:

  • C-reactive protein (CRP)
  • Erythrocyte sedimentation rate (ESR)
  • Antinuclear antibody (ANA)
  • Anti-cyclic citrullinated peptide (anti-CCP)

Normal Rheumatoid Factor Levels

Normal ranges can vary between laboratories due to differences in equipment, techniques, and chemicals used. If your results are outside of the normal range, it may not necessarily mean there is something wrong. However, a normal result also doesn’t mean a particular medical condition is absent. Always talk with your doctor to learn more about your test results.

The normal range of rheumatoid factor levels is usually between < 14 and < 20 IU/mL. A level above these values is considered a positive result and may indicate rheumatoid arthritis or other disorders [9, 10, 11].

However, the diagnosis of rheumatoid arthritis also requires evaluating signs and symptoms as well as the results of other tests [7].

Interference With Other Tests

If you’re positive for the rheumatoid factor, your other lab tests may show false values. The rheumatoid factor can interfere with the following lab tests:

  • Malaria (false positive) [12]
  • HIV (false positive) [13]
  • Hepatitis C (false positive) [14]
  • Cardiolipin (a mitochondrial phospholipid) antibodies (false positive) [14]
  • TSH (falsely elevated) [15, 16, 17]
  • Cytokines, including IL-1 beta, IL-4, IL-6, and IL-8 (falsely elevated) [18]

Causes of High Rheumatoid Factor Levels

A number of factors may cause high rheumatoid factor levels. Test results should be interpreted by a doctor who can take into account your medical history and other test results.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases, marked by joint inflammation and destruction.

Between 70 – 90% of people with RA produce rheumatoid factors, which can further drive inflammation and tissue damage. This subset of rheumatoid factor-positive patients typically experience a more intense inflammatory response and can have worse outcomes than those who are negative for it [2, 4, 19, 20].

Higher rheumatoid factor levels (> 50 IU/mL) early on in people with the disease are also associated with worse outcomes and more severe arthritis, according to research [21, 22].

Other Types of Arthritis

Levels of the rheumatoid factor may rise in other forms of arthritis, although less consistently so.

Psoriatic arthritis occurs in people with psoriasis and rheumatoid factor is found in 15% of the patients [1].

Juvenile idiopathic arthritis (JIA) is a form of autoimmune arthritis that affects children under 16 years of age. The cause is still unknown, while rheumatoid factor is found in 5% of children with this disease [1].

Other Diseases and Conditions

Elevated levels of rheumatoid factor are also found across a diverse array of diseases and conditions, including [1]:

  • Sjogren’s syndrome, an autoimmune disease that causes dry mouth and eyes (75 – 95% of the cases)
  • Primary biliary cirrhosis, an autoimmune disease that destroys the bile ducts (45 – 70%)
  • Mixed connective tissue disease, an autoimmune disease similar to lupus (50 – 60%)
  • Viral infections including hepatitis, HIV, Epstein-Barr, cytomegalovirus (10 – 76%)
  • Breast cancer (13 – 47%) [23]
  • Liver cirrhosis, scarring of the liver (25%)
  • Lupus erythematosus, an autoimmune disease that damages the connective tissue (15 – 35%)
  • Sarcoidosis, an inflammatory disease that damages the lungs and lymph glands (5 – 30%)
  • Parasitic infections such as malaria and toxoplasmosis (10 – 18%)
  • Bacterial infections including chlamydia, syphilis, and tuberculosis (8 – 15%)

Lifestyle Factors

Smoking

Smoking is one of the strongest environmental risk factors for developing rheumatoid arthritis (RA) [24, 25].

An observational study of 296 people found that 88% of smokers tested positive for rheumatoid factor over a period of 10 years. Also, the rheumatoid factor-positive group of people contained more smokers than the rheumatoid factor-negative group [26].

The risk of high rheumatoid factor levels was 4 times higher in current smokers than in people who never smoked, according to an observational study of 7,124 people. In another study of 100 people with rheumatoid arthritis (RA), rheumatoid factors were more than twice as high in current and former smokers than in people who never smoked [27, 28].

Smoking the equivalent of 1 pack (20 cigarettes) a day for 25 years was linked to a 3-fold increase in the risk of elevated rheumatoid factor in a study of 336 RA patients. What’s more, rheumatoid factor levels were directly linked to the number of years smoked in two studies of 673 people with RA [29, 30, 25].

Coffee

An observational study of 18,981 people suggests that people who drink four or more cups of coffee each day may have double the risk of developing rheumatoid factor-positive RA compared to those that drank less coffee [31].

A meta-analysis also suggests there may be an association between total coffee intake and the incidence of RA, but only for rheumatoid factor-positive RA. There was no association found with decaffeinated coffee [32].

Aging

Research has found that rheumatoid factor levels tend to be higher in the elderly (10 – 25%) compared to younger adults (5%), even in those that are otherwise healthy [33, 1, 34].

Health Effects of High Rheumatoid Factor Levels

The section below details some potential effects of elevated rheumatoid factor levels, according to clinical research. However, high levels can be found in those that are otherwise healthy. A doctor will evaluate test results based on several other factors, including symptoms, other health conditions, and other test results.

1) Rheumatoid Arthritis

One observational study that followed 9,712 healthy people for 30 years suggests that rheumatoid factor levels of 25 – 50 IU/mL are associated with a nearly 4-fold increase in the risk of developing rheumatoid arthritis (RA). Very high levels (> 100 IU/mL) were linked to a 26-fold increased risk, compared to those with normal levels (< 25 IU/mL) [35].

2) Deep Vein Thrombosis

An observational study of 54,628 people who were followed for over 10 years found that increased rheumatoid factor levels may be associated with up to a 3-fold increase in long-term risk of deep vein thrombosis (a type of blood clot that commonly forms in the thigh or leg) [36].

3) Hardening of the Arteries

In an observational study of 6,532 people who were followed for over 10 years, rheumatoid factor levels above 15 IU/mL were linked to an increased risk of hardening of the arteries (atherosclerosis) in African American women [37].

4) Heart Disease

Men who had rheumatoid factor levels above 6 IU/mL may have a 2.9-fold increased risk of developing heart disease compared to men with levels below 6 IU/mL, according to an observational study of 1,156 people. This link was not found in women [38].

5) Death From Heart Disease, Cancer, or Any Cause

An observational study of nearly 300,000 people suggests that levels above 100 IU/mL are linked to higher rates of death from any cause and deaths from cancer. However, they did not find an association between elevated rheumatoid factor levels and death from heart disease [39].

Rheumatoid Factor Genetics

The SNPs rs2476601 (of the PTPN22 gene) and rs1980422 (of the CD28 gene) may be associated with an increased risk of developing rheumatoid factor-positive rheumatoid arthritis (RA) [40, 41, 42, 43, 44, 45].

Other SNPs associated with rheumatoid arthritis (independent of rheumatoid factors) include [46]:

  • rs2476604
  • rs2476600
  • rs2797416
  • rs974404
  • rs1310182
  • rs1217420
  • rs1217406

SNPs that may be associated with a lower incidence of rheumatoid arthritis include [46]:

Takeaway

Rheumatoid factor is an antibody that mounts an autoimmune attack against your own antibodies (IgG). Rheumatoid factor levels are tested to help diagnose rheumatoid arthritis. However, not everyone with rheumatoid arthritis will test positive for rheumatoid factor. On the other hand, healthy people may also test positive.

About the Author

Mathew Eng

Mathew Eng

PharmD
Mathew received his PharmD from the University of Hawaii and an undergraduate degree in Biology from the University of Washington.
Mathew is a licensed pharmacist with clinical experience in oncology, infectious disease, and diabetes management. He has a passion for personalized patient care and believes that education is essential to living a healthy life. His goal is to motivate individuals to find ways to manage their chronic conditions.

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