When the anti-CCP antibody is negative

Coming to a diagnosis of Rheumatoid Arthritis (RA) can be easy. We are spared months of bouncing between doctors and tests if we have the “right” symptoms and the “right” labs. Unfortunately, for many, the road to a RA diagnosis isn’t quite so quick. This is most commonly seen when the Rheumatoid Factor (RF) is positive but the anti-cyclic citrullinated peptide antibody (anti-CCP) is negative. 

As we’ve spoken about before, the RF antibody blood test is far from perfect. Despite its name, the Rheumatoid Factor is not specific for RA. In fact, it is seen in many other medical conditions (including the condition of “getting older”). Usually ordered with a RF (and if not with, then usually immediately afterwards) is the anti-CCP antibody. This antibody is MUCH more specific for RA and is seen in individuals years before developing RA symptoms. After 20+ years of practice, it is now standard of care to order an anti-CCP when concerned about RA. And our dependence on it can lead many to be confused when it returns negative.

An opportunity

What do we do when the RF is positive but the anti-CCP antibody result is negative. Frustrating, yes, but also an opportunity. Swollen and inflamed joints is certainly seen in Rheumatoid Arthritis, but it is also be found in a number of other conditions. To further confuse matters, a person can have swollen joints AND a positive Rheumatoid Factor but not have RA. There is an opportunity to make sure all other possible diagnoses have been considered, when the CCP blood test is negative,

So how does the doctor think about this? First, your doc considers the main categories of conditions possible. In this scenario, these are most likely Autoimmune, Infectious and Cancer. Considering these main categories is not sufficient, however. Your doctor has been trained and is continuously practicing, how to RANK these possibilities. For example, in any given individual, the risk of lupus will not be equal to the risk of tuberculosis. In another person, the risk of having lymphoma will not be equal to the risk having Sjogren’s syndrome. Although, technically, all these diagnostic possibilities are, well, possible, your doctor is constantly ranking these possibilities from most likely to least.

But in this scenario, a +RF and a negative CCP, how do docs create that list? The ranking is based on a number of factors, but generally speaking, the main issues considered are:

• RF level (high positive or low positive)
• Severity of arthritis (multiple joints inflamed or just a few)
• Any other symptoms

Examples with negative anti-CCP antibodies:

Mary is a 45 year old accountant who comes in with hand pain. She had assumed the pain was from her computer work. The pain has been steadily increasing however and upon the suggestion from her husband, she is seeking care. Her doc notes some mild swelling of her knuckles. Her blood tests, however, show a markedly elevated Rheumatoid Factor but a negative anti-CCP antibody. Well, surely this must be Rheumatoid Arthritis with a RF that high!? Not so fast, something doesn’t quite fit. RA patients can certainly have very high RF. Usually, however, this correlates with severe arthritis, which Mary doesn’t have. Thankfully, her doc asks the right questions and discovers Mary suffers from multiple cavities and dry eyes. Upon hearing this, her doc’s mental diagnosis list adjusts and she now focuses her attention on a possible diagnosis of Sjgoren’s Syndrome. 

Let’s consider the case of Jake. Jake is a 37 year old musician with wrist, shoulder and ankle pain. It’s been getting worse over the last few weeks and can get so bad that he can’t walk. He has definite swelling of his wrist, right shoulder and right ankle on his examination and he has a very low positive RF and a negative CCP. Well this has got to be Rheumatoid Arthritis! He has multiple, severe, swollen joints and a +RF! But, let’s take a closer look. First of all, the affected joints aren’t the usual joints, in that his hands aren’t too bad. Thankfully, his doc was also sufficiently confused and decided to dig a little deeper. Further discussion with Jake led his doc to move infections up on his possible diagnosis list. He was ultimately diagnosed with gonococcal arthritis, an infectious arthritis.

How you can help

These, of course, are just examples used to highlight the power a negative CCP has to lease to a different diagnosis. Sometimes, however, further investigations just confirms that, in fact, it IS Rheumatoid Arthritis. It is certainly possible for someone to have RA with only a +RF. But, be wary of jumping to conclusions!

So what are some questions you can ask your doc if you find yourself in this position?

1. What other possible diagnoses are you considering?
2. What tests will you need to order to look for those possibilities?
3. Is there any other information you need from me to better hone your list?

There is a method to madness! Many times the doc is doing their due diligence, but fails to communicate this to us. We are left assuming no one knows what to do next and we feel helpless and hopeless. Ask your doc what they are thinking and how you can help move things forward!