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What is a positive rheumatoid factor?

October 17, 2017
What is a positive rheumatoid factor?

Introduction

What does it mean to have a positive rheumatoid factor (RF)?  Does this mean that you have rheumatoid arthritis, are you at risk of developing rheumatoid arthritis, is your prognosis worse, or is it completely unrelated to arthritis?

Before answering, what is a positive rheumatoid factor, we need to understand antibodies and how they are made.  We can then better understand autoantibodies, and more specifically rheumatoid factor.

What is an antibody?

The goal of the immune system is to protect yourself from bacteria, viruses, as well as cancers.  The immune system is made up of many different components, however, in broad terms it can be divided into three categories: physical barriers, the innate immune system, as well as the adaptive immune system.  Physical barriers include skin as well as mucous membrane barriers that line your digestive, respiratory, and your reproductive tracts.  The innate immune system is the second line of defense.  This is the part of the immune system that deals with immediate dangers.  For example, the skin reaction you get when you get bitten by a dog or you when you accidently cut your hand with a knife.  The third level of defense is called the adaptive immune system.  This is the part of the immune system responsible for making antibodies.

Antibodies, also called immunoglobulin (Ig), are specialized proteins that defend against specific invaders.  An antigen stimulates your body to make an antibody.  For example, if someone gets the chickenpox (antigen) the body will make antibodies directed against the chickenpox virus.  So the next time that person is exposed to the chickenpox virus, the body will have chickenpox antibodies to prevent the infection.

Antibody structure

Immunoglobulin are made up of light and heavy chains.  They also have two regions, Fab regions and the Fc region.  The Fab region is also called the variable region.  This is the place where specific antigens attach to the antibody.  It is variable, because each antigen has its own antibody.  The Fc region helps the antibody communicate with other parts of the immune system.  The Fc region is also called the constant region.  It’s constant because it doesn’t really vary all that much.[1]

Immunoglobulin structure

 

Are there different types of antibodies?

Yes.  There are 5 different classes of antibodies: IgG (75%), IgA, IgD, IgE, and IgM. Remember how I said the Fc region “doesn’t vary all that much”? The Fc region determines the class of the antibody and in turn, which immune system cells the antibody will interact with.  For example, dust mite particles cause the immune system to make IgE antibodies.  When the body is exposed to dust mites for a second time, IgE antibodies interact with mast cells, which release histamine, which cause an allergic reaction.[2]

Every class of immunoglobulin looks different and as I mentioned interacts with different parts of the immune system. IgM antibodies are made very early on during an infection.  IgG antibodies are made about 2-3 weeks after an infection and you typically find them in blood.  IgA antibodies are made in the gut, nose, lungs, and mammary glands.  IgE antibodies are made to parasites and they trigger allergies.  Currently, we don’t know too much about IgD.

What is a rheumatoid factor?

A rheumatoid factor is created when an IgM antibody binds to the Fc portion of an IgG antibody.  In simple terms, this is a situation where an antibody attacks another antibody.  When you have many antibodies doing this at once, they can form large IgM-IgG antibody complexes, which can stimulate the immune system to make some serious inflammation.

My doctor told me my rheumatoid factor was high.  What does that mean?

The answer to this question is varies depending which lab your doctor sent your blood.  Each lab has their own specific cut off points.  Below you will find the cutoff points for Labcorp and Quest Diagnostics.

Labcorp

Methodology: Latex immunoturbidmetry

Negative: < 14.0 IU/mL

Quest Diagnostics

Methodology: Immunoturbidimetric

Negative: ≤ 14 IU/mL

Note: There are many different ways to measure rheumatoid factor and even specific types of rheumatoid factor: IgM, IgG, IgA.  These will all have their own cutoff points.

Now, what does having a positive rheumatoid factor mean?  The answer to this question depends on your symptoms.

Rheumatoid factor and rheumatoid arthritis

About 70% to 80% of people that have rheumatoid arthritis have a positive rheumatoid factor.  Not having a positive rheumatoid factor doesn’t necessarily rule out the disease, but rather, it makes it less likely.  Having rheumatoid arthritis AND having a positive rheumatoid factor is associated with a more severe form of the disease and having non-joint symptoms like nodules or lung involvement (interstitial lung disease).  Unlike lupus, rheumatoid factor doesn’t really go up or down depending how active rheumatoid arthritis, so we don’t follow it if you have an established diagnosis.[3]

What are some other diseases that cause a positive rheumatoid factor?

Rheumatoid factor has an 86% specificity for rheumatoid arthritis.  That being said, if you test positive for rheumatoid factor, there’s a pretty good chance that you have or will have rheumatoid arthritis in the future, but this is by no means set in stone. It’s very important to realize that someone can test positive for rheumatoid factor, AND NOT have rheumatoid arthritis because many diseases can cause the immune system to form antibodies directed towards the Fc portion of an IgG antibody.  However, in most non-autoimmune conditions the rheumatoid factor tends to be lower than in rheumatoid arthritis.  Moreover, when one finds more than one different type of rheumatoid factor particular in the fluid of a joint (e.g., IgM RF and IgA RF), this indicates that we are dealing with rheumatoid arthritis.

Category Disease
Rheumatic diseases
  • Rheumatoid arthritis
  • Systemic lupus erythematosus (SLE)
  • Scleroderma
  • Mixed connective tissue disease
  • Sjogren’s syndrome
Viral infections
  • HIV/AIDS
  • Mononucleosis (Epstein-Barr virus)
  • Hepatitis
  • Influenza
Parasitic infections
  • Malaria
  • Schistosomiasis
  • Trypanosomiasis
  • Kala-azar
  • Filariasisis
Chronic bacterial infections
  • Subacute bacterial endocarditis
  • Tuberculosis
  • Syphilis
  • Salmonellosis
  • Brucellosis
  • Leprosy
  • Yaws
Cancers
  • Lymphoma
  • Leukemia
  • Multiple myeloma
Hyperglobulinemic diseases
  • Sarcoidosis
  • Chronic liver disease
  • Chronic pulmonary disease
  • Cryoglobulinemia
  • Hypergammaglobulinemic purpura[4]

 

It is also important to mention that approximately 5 – 25% of individuals aged 60 years and older have a positive rheumatoid factor without any underlying causative disease.

I have a positive rheumatoid factor, but I have no symptoms

This is where it gets a little tricky.  Here are the following possible scenarios:

  1. You may develop rheumatoid arthritis in the future.
  2. It may be that you actually have another non-rheumatic disease that is causing you to test positive for rheumatoid factor.
  3. The rheumatoid factor is not clinically significant.

When faced with a positive rheumatoid factor, it’s important to rule out other conditions that cause positivity.  If the workup is negative, care monitoring is recommended.  Knowing the symptoms of autoimmune joint disease is of utmost importance as well.

Can you predict who will develop rheumatoid arthritis?

We cannot predict with 100% certainty, who will and who won’t develop rheumatoid arthritis.  There are a few factors that increase the odds like having both a rheumatoid factor AND anti-citrullinated peptide antibodies (anti-CCP)[5].  This is particularly true for people that have high levels of anti-CCP antibodies.[6]

The time between the formation of autoantibodies and rheumatoid arthritis is called preclinical rheumatoid arthritis.  Other terms include: pre-RA, autoantibody-positive arthralgia, probable RA, very early RA, and early undifferentiated arthritis progressing to RA.

Phases of preclinical rheumatoid arthritis

Preclinical RA goes through many phases.  Not everyone progresses so smoothly and some people can even skip steps.

Phase I

People with certain genetic predispositions are exposed to environmental factors that trigger an immune response.  Smoking is a known trigger.

Phase II

The immune system starts making rheumatoid factor and/or anti-CCP antibodies.

Phase III

People start experiencing some joint pain and stiffness, but no swelling or over autoimmune joint pain.

Phase IV

There is some joint swelling, but it’s limited to 1-2 joints.  We can now call this undifferentiated arthritis but it’s not rheumatoid arthritis yet.  If it happens on and off, we sometimes call it palindromic rheumatism.  We think that 30 – 50% of people with undifferentiated arthritis will go into remission, 30-40% will progress to other diseases, and 30 – 40% will evolve into rheumatoid arthritis.

Phase V

It’s spreading!  Now we can call this rheumatoid arthritis.[7]

Is there anything I can do to prevent rheumatoid arthritis?

The following are some modifiable risk factors that can help prevent rheumatoid arthritis.

  • Avoid/quit smoking
  • Maintain good dental hygiene
  • Eat a balanced diet containing fish oil, antioxidants, and vitamin D
  • Avoid excess coffee and foods with high salt content
  • Keep a healthy body weight
  • Prevent infections[8]

Conclusion

If you’ve tested positive for rheumatoid factor and have more questions, I highly urge you to speak with your physician or local rheumatologist.  And remember, doctors treat people not numbers.

Medical Disclaimer

This information is offered to educate the general public. The information posted on this website does not replace professional medical advice, but for general information purposes only. There is no Doctor – Patient relationship established. We strongly advised you to speak with your medical professional if you have questions concerning your symptoms, diagnosis and treatment.

References

[1] L Sompayrac. How the Immune System Works 4th edition

[2] L Sompayrac. How the Immune System Works 4th edition

[3] Rheumatology Secrets 3rd edition

[4] Adapted from Kelley’s Textbook of Rheumatology, 8th edition

[5] Sun J, Zhang Y, Liu L, Liu G. Diagnostic accuracy of combined tests of anti cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol. 2014 Jan-Feb;32(1):11-21.

[6] Heidari B, Firouzjahi A, Heidari P, Hajian K. The prevalence and diagnostic performance of anti-cyclic citrullinated peptide antibody in rheumatoid arthritis: the predictive and discriminative ability of serum antibody level in recognizing rheumatoid arthritis. Ann Saudi Med. 2009 Nov-Dec;29(6):467-70.

[7] Paul BJ, Kandy HI, Krishnan V. Pre-rheumatoid arthritis and its prevention. Eur J Rheumatol. 2017 Jun; 4(2): 161–165.

[8] Paul BJ, Kandy HI, Krishnan V. Pre-rheumatoid arthritis and its prevention. Eur J Rheumatol. 2017 Jun; 4(2): 161–165.

Immunoglobulin image By Fvasconcellos 19:03, 6 May 2007 (UTC) [Public domain], via Wikimedia Commons

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Diseases and Conditions Featured

What is a positive ANA and what does it mean?

December 12, 2016
What is a positive ANA

What does it mean to have a positive ANA also known as an antinuclear antibody?  This is a loaded question and the answer is complex.  The answer is usually quite personalized to the person and their symptoms.  The answer also usually entails follow-up bloodwork and evaluation by a rheumatologist.  But in simple terms, an ANA is an antibody directed towards the nucleus of a cell.

How is an ANA measured?

The ANA is calculated by taking a standardized cell from the lab and mixing it with a person’s blood.  If a person has antinuclear antibodies, these will stick to the standardized cells’ nuclei.  At this point, there’s no way for us to know whether this has happened, so the lab tech adds fluoresceinated antibodies to the mix.  These antibodies bind to ANAs that stuck to a nucleus.  With the help of a specialized microscope, the lab tech can now visualize the ANA because the fluoresceinated antibodies make them light up.

My doctor told me my ANA was high.  What does that mean?

Unfortunately, the tech cannot count how many ANAs they see.  Instead, they see how much they can dilute the blood and still see the fluoresceinated antibodies.  So when you see and ANA of 1:80, that means the tech really wasn’t able to dilute very much.  This is a low level.  If you see a value of 1:640, that means they were able to dilute a lot more.  This is a higher level.

So how much dilution is enough to consider an ANA as positive?  That answer really depends on the lab.  Every lab has different cut off values, but in general, an ANA of 1:80 is typically considered positive.  Whether it’s clinically significant, is a whole different question.  This is where the art of medicine comes into play.  But before that, let’s talk about patterns because those are important too.

Positive ANA patterns

So let’s take an example.  Your doctor runs an ANA and it comes back as 1:320 speckled pattern.  So what does that mean?  When the lab tech was looking at the fluoresceinated antibodies, it basically literally looked speckled.  There are many other kinds of patterns: homogenous, centromere, nucleolar, speckled, rim etc.  Each of these patterns possibly indicate the presence of specific nuclear antibodies.  For example, the presence of a speckled positive ANA indicates the presence of these specific autoantibodies, SSA, SSB, RNP, Smith, and Ku antibodies.  These specific nuclear antibodies are themselves associated with specific autoimmune diseases.  It’s important to take ANA patterns with a grain of salt because interpretation highly depends on experience.

I’m not going to go more into details about specific nuclear antibodies because first, there’s about 150 of them and second, they’re all associated with different diseases lupus being one of them.  That’s a lot of material to cover in one article.

When is a positive ANA clinically significant?

Now that we understand what an ANA actually is, we can now start to approach the subject of clinical significance AND when you should be tested.

The problem with the ANA is that it can be found in normal healthy people.

  • ANA 1:40 is found in 20 – 30% of healthy people
  • ANA 1:80 is found in 10 – 15% of healthy people
  • ANA 1:160 is found in 5% of healthy people
  • ANA 1:320 is found in 3% of healthy people
  • 5 – 25% of healthy people with a family member suffering from lupus have a positive ANA
  • Up to 70% of people aged above 70 years have a positive ANA

To complicate things even more, someone who is about to have and autoimmune disease can have a positive ANA… UP TO 10 YEARS before they actually develop the disease.  Cancer and infections can also cause someone to have a positive ANA.  It can even be positive when people are taking certain medications.  Not terribly helpful right?

Bad example

So someone runs an ANA just because and it’s positive.

  1. Does it mean anything?
  2. Is the person one of those healthy people that has a positive ANA?
  3. Is the person going to develop an autoimmune disease in the future?

In this scenario, I would say that this test is of low clinical significance because that person did not have any symptoms.  Because so many people who are completely healthy have an ANA, the test should only be run if a person has a symptom or better yet, multiple symptoms that potentially indicate the presence of an autoimmune disease like lupus, Sjögren’s syndrome, systemic sclerosis, mixed connective tissue disease, etc.  In that situation, it is helping rule in or rule out certain diagnoses.

Good example

If you’ve read my earlier post, 8 important warning signs of scleroderma, you’ll remember that Raynaud’s phenomenon is an important red flag for scleroderma.  The majority of people suffering from Raynaud’s have no underlying autoimmune disease but a small proportion does.  This is the perfect scenario, where an ANA would be useful.  If the ANA is negative, the person likely will NOT develop an autoimmune disease.  If the ANA is positive, then the person has a high risk of developing an autoimmune disease like lupus, scleroderma or Sjogren’s syndrome.

Let’s wrap things up

Ultimately it all boils down to this simple fact: doctors treat people not numbers.

As a physician I care about symptoms and signs way more than lab tests.  Don’t get me wrong, these tests are important.  For example, over 99% of people suffering from systemic lupus erythematosus have a positive ANA.  It’s pretty much safe to say that if someone tests negative for ANA, they likely don’t have lupus.  FYI that other less than 1% usually have a positive SSA, they have a problem with their complement system, or they have a lot of protein in their urine (nephrotic syndrome).

I hope I’ve helped you better understand the elusive and mysterious positive ANA.  If you’ve tested positive for an ANA and have more questions, I highly urge you to speak with your physician or local rheumatologist.  And remember, doctors treat people not numbers.

References

Rheumatology Secrets 3rd edition

Medical Disclaimer

This information is offered to educate the general public. The information posted on this website does not replace professional medical advice, but for general information purposes only. There is no Doctor – Patient relationship established. We strongly advised you to speak with your medical professional if you have questions concerning your symptoms, diagnosis and treatment.

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