Anti-Nuclear Antibody (ANA)

There’s a very good chance, at some point in your life, you’ve had your ANA checked with a blood test. Especially, if you are a woman.

My hope is to let you know a little bit about this test. In particular, if you are reading this, chances are you (or someone you know) just tested positive. I’m hoping I can talk you off the ledge so you don’t feel so worried.

As many of you know, the ANA test is in the purview of the specialty Rheumatology. We rightly associate this test with Lupus, Scleroderma, Sjogren’s, Hashimoto’s and even Rheumatoid Arthritis along with other scary sounding diseases. Many primary care doctors, once they get a positive ANA test on a patient, make the automatic referral. But I’d like to think after reading below that you may feel you don’t even need to go. Or, if you do see a rheumatologist, you will be armed with more information so you can understand what is happening a little better.

ANA (Anti-Nuclear Antibody)
What Is It?

ANA are fighting immune proteins that attack the nuclei of our own cells. And, we all have them!

They can become a problem, however, when there are too many of them. But…most of the time…it never becomes a problem. Which is why the test is confusing and controversial. Since we all have them, then technically, the test is always positive. But, they use a dilutional method to separate those who have a ‘normal’ amount and those who have a ‘high’ amount. In order not to miss people who MIGHT have a disease, they set the threshold very low.

At 1:40 dilution, 30% of all people are positive
At 1:160 dilution, 5% of all people are positive.

Which means, there are a LOT of false positives as only 1% of those with a positive ANA have something wrong. i.e. 29 out of every 30 people with a positive ANA at 1:40 have absolutely nothing wrong with them.

By the way, a dilutional method is as follows: You have a test that can find the antibodies. If positive, then you dump out half the blood and add water to the top. If still positive, you are at 1:2. Then, after mixing, you dump out half and add water again. If still positive, you are at 1:4. You keep repeating. If you were following up above, everyone is positive at 1:1. But, by the time you get to 1:40, 70% are negative. The test can no longer find the antibodies as there are too few of them to trigger it as positive.

This is why we don’t test or screen everyone. We’d have all these positives and most of them would be inconsequential. It is thus recommended to only screen those who have symptoms that might be expected from someone with an autoimmune disorder.

I'll start with when NOT to test an ANA as this is easier.

When NOT to Test ANA

Isolated fatigue without other features. e.g. "I just feel tired all the time"
Joint pain that is clearly mechanical—related to excess movement or injury
Symptoms better explained by common conditions such as viral illness or depression

Who SHOULD Get Tested

Constitutional Symptoms

persistent, low-grade fevers
unexplained fatigue
unintentional weight loss

Musculoskeletal

Symmetric (left and right) joint pain or swelling especially the small joints like hands and wrists
Morning stiffness lasting more than 30 minutes
Muscle aches not related to exercise

Skin Findings

butterfly rash
photosensitivity (changes related to sun exposure)
Raynaud's phenomenon (fingers turning white or blue with cold or stress)

Mucosal Symptoms

dry eyes and/or dry mouth
mouth or nasal ulcers

Other things such as unexplained chest pain, anemia or seizures can be reasons to test as well.

AND, the more of these above symptoms, then the more likely we expect a positive titer.

Women vs. Men

Women are two to three times as likely to have a positive ANA. For Lupus, women outnumber men 9 to 1.

So, if a woman has a titer of 1:80 without symptoms, it likely means little. If a man with some symptoms has a 1:80 titer, it would carry much more weight.

Okay, that was a lot of confusing information. Let's step back to discuss why it is felt we have Autoimmune Antibodies in the first place.

Why Do We Have Autoimmune Antibodies?

No one knows.

And, I’m serious. We just don’t know. But, the theories include:

CLEAN UP – When cells die, their nuclear material is leaked into the circulation. The immune system produced nuclear antibodies to help bind and clear these nuclear remnants.

CONFUSION – Viral and bacterial proteins that are similar to our own nuclear material. Our immune system gets ‘mixed up’ and would have attacked a virus but instead attacks our own cells.

ADVANTAGE FOR WOMEN – Women not only have more antibodies to their own nucleus, but they have stronger reactions to infections and vaccines. This is theorized to be a compromise for better early life survival from infections, especially during pregnancy and child-rearing years. In other words, women are more likely to be able to survive infections, but they then become vulnerable to these autoimmune diseases as a trade-off.

CANCER – When you think about it, cancer is our own cells dividing abnormally. Perhaps these antibodies can detect and clear out these rogue cells.

How Do They Work?

In the most simplistic terms, a previously healthy person (though with genetic predisposition) has cells that get injured. Perhaps a virus (Epstein-Barr virus is a common trigger) or radiation or some other way to cause cell death. The already elevated titers of antibodies against our cells get activated to clear away all the cellular debris. This causes surrounding inflammation and typically more cell damage. Which in turn leads to a ramping up of the immune response to clear out more dead cells created by all this inflammation. This becomes a cycle. If there is enough inflammation, it can lead to organ damage.

Treatment

This tends to be medicines that slow down the immune system. Common medicines include:

Prednisone
Cellcept
Cyclophosphomide

Other Helpful Lab Tests

Complement (C3 and C4) – These proteins are necessary and very helpful for a normal immune system. They get activated to help with the ‘attack.’ When these proteins are LOW, it implies active disease. Conversely, rising levels indicate improvement.

Erythrocyte Sedimentation Rate (ESR)—This is one of the simplest tests of all time. You put blood in a tube and watch the red blood cells fall for an hour. Well, this is a little like waiting for water to boil. In this case, I’m sure they do something else, come back in an hour and see how far the red blood cells have settled toward the bottom of the tube. The farther they have dropped, the higher the ESR and the more inflammation you have.

C-Reactive Protein (CRP)—This is a protein that is produced by the liver in response to inflammation. The difference between this and the ESR is that this rises quickly, within hours. So it is known more as an ‘acute phase reactant’.

As expected, both CRP and ESR can be used as markers to determine how well treatment is working. In addition to helping determine if there is a significant disease process in the first place.

ANCA vs. ANA

I only want to mention this test as it SOUNDS a lot like ANA but really has nothing to do with it. The ANCA stands for Anti Neutrophil Cytoplasmic Antibody. This test is ordered when one suspects a problem with vasculitis. I tend to think of this as someone who gets kidney disease (protein or blood in the urine) that is suddenly worsening and you can’t explain. Sometimes lung disease, especially if they are coughing up blood. Again, it’s just very different than ANA and I wanted to mention it as they seem so similar.

Positive ANA – Now What?

ARE THERE OTHER PARTS OF THE BLOOD TEST THAT CAN HELP ME FIND OUT WHAT DISEASE I HAVE?

So glad you asked. And YES.

The ANA with reflex titer. Meaning, under the umbrella of elevated ANA, there are a host of very different diseases. Which one might you have? Of course, symptoms help. Like whether you have a rash. Whether you are having kidney problems, etc.

So we order the reflex titer test and we try to find out what specific disease is causing your symptoms.
What are the choices? There are many and I will just list them now: SSA, SSB antibodies, Smith, RNP, SmRNP, Scl-73, Jo-1, Centromere, dsDNA, Chromatin and Ribosomal P.

This test will typically list one of these more specific types of ANA antibodies as the one triggering your positive ANA. The specific kind might say, “this is what is typically elevated in Lupus.” Or “this is what is typically elevated in Sjogren’s syndrome.”

The ANA Pattern

The ANA test uses immunofluorescence. Think of those black light posters from the 70’s (ok, if you’re not as old as I am, think of those CSI crime shows where they use black light to look for blood). When you do the test you see patterns of bright yellow/ green dots on a black background. They have listed the patterns as the following: Homogeneous, Speckled, Nucleolar, Centromere, Cytoplasmic and Peripheral (Rim). Like the reflex antibodies above, some are more specific for certain diseases such as the Peripheral pattern is common in Lupus.

Final Thoughts

O.k. those last few tests are starting to make your eyes glaze over. I’ll stop now. The bottom line, ANA is very complicated. So, if you feel a little lost at this point, you aren’t alone. In fact, nobody wants to talk about this stuff. Which is why so many times you just get sent to a rheumatologist. The rheumatologist, with almost no explanation says, ‘You’re fine, get out of my office.” This ALWAYS happens when someone suspects their fatigue is related to an autoimmune process. And in fairness to the rheumatologist, fatigue alone almost never is. Which is why they don’t want to waste their time. Yet… a ‘positive’ test makes one presume there is something wrong. And, as we typically expect the worst, we get fearful. I’m hoping what I have written above helps you understand why the test is run. And, let’s you realize, that very likely…29 out of 30 times we see a positive…nothing wrong is ever found.