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One subtype of arthritis known as rheumatoid arthritis is characterized by the presence of different antibodies that can serve as biomarkers to help diagnose the condition. This article outlines these antibodies: rheumatoid factor and anti-CCP.

Inflammation of joints is the characteristic feature of arthritis. There are several subtypes of arthritis which are differentiated by clinical features of the disease such as the joints that are involved and severity of symptoms. Over the last decade, researchers have discovered new data which indicates that patients with one subtype can be further differentiated by the presence of specific antibodies in their blood. This type of arthritis is known as rheumatoid arthritis, and it can develop in 0.5 to 1 percent of the general population.

Rheumatoid arthritis is associated with pain and disability, as well as a reduction in life expectancy. Fortunately, research in this area has significantly improved in the past few decades and new innovation has led to the discovery of drugs such as methotrexate and tumor necrosis factor inhibitors that have significantly improved disease outcomes.

With the presence of new drugs that are able to prevent disease progression, it is becoming more and more vital to diagnose the condition early on so that aggressive treatment can be started as quickly as possible. Therefore, there is a need for biomarkers that are present early on in the disease course that can indicate with sensitivity and specificity whether a patient has rheumatoid arthritis. As antibodies are often present in the blood of patients before they present with any symptoms, antibodies can serve as reliable biomarkers for early detection of the disease.

Antibodies are proteins that are produced by cells of the immune system. Their primary goal is to recognize and protect us from foreign pathogens in our body. Unfortunately, in the case of patients with autoimmune disease, their antibodies start to attack to their own body instead. Arthritis is an autoimmune disease. However, not all patients with arthritis will have these antibodies. This has led to establishment of two types of arthritis: seropositive and seronegative arthritis.

What is seropositive arthritis?

Patients with seropositive arthritis have antibodies in their blood called anti-cyclic citrullinated peptides (anti-CCPs). These can also be called anti-citrullinated protein antibodies (ACPAs). These antibodies are found in about 60 to 80 percent of people that are diagnosed with rheumatoid arthritis.

These antibodies can be very specific to a diagnosis of arthritis as their presence actually precedes the development of arthritis by about five to 10 years. In fact, if your doctor suspects that you have rheumatoid arthritis and you test positive for anti-CCPs, then you more than likely have a definite diagnosis of rheumatoid arthritis.

In the past, seropositive arthritis used to be characterized by levels of another type of antibody, known as rheumatoid factor. While it is known that patients with anti-CCPs are more than likely also going to have rheumatoid factor in their blood, the reason why rheumatoid factor is no longer used in the criteria for diagnosing arthritis is because rheumatoid factor is also present in several other autoimmune diseases and infectious diseases. Therefore, it is not specific to arthritis. In fact, it is present at high levels in elderly patients. Hence, nowadays, physicians preferentially choose to test for anti-CCP antibodies compared to rheumatoid factor. However, the current guidelines place as much emphasis on anti-CCP testing as they do on rheumatoid factor testing and therefore, will have to be changed in the future.

Several studies have shown that anti-CCPs are much more specific for a diagnosis of arthritis. In fact, one meta-analysis, which reviewed 37 independent studies, found that while the diagnostic sensitivity (true positive rate) of both anti-CCP and rheumatoid factor were similar, at a rate of 67 percent for anti-CCP and 69 percent for rheumatoid factor, the specificity (true negative rate) of testing for anti-CCP was far more robust at a rate of 95 percent compared to 85 percent for rheumatoid factor.

What is seronegative arthritis?

Testing negative for anti-CCPs means that if you have arthritis, it will be classified as seronegative arthritis. Just because you don’t test positive for these antibodies does not mean that you don’t have arthritis. Likely, it just means you have a different subtype.

You can also have rheumatoid arthritis without being positive for anti-CCPs or rheumatoid factor. About 20 to 40 percent of patients with rheumatoid arthritis are seronegative. Patients with seronegative arthritis could eventually become diagnosed with a different arthritic subtype, such as psoriatic arthritis.

Differences between seropositive and seronegative patients

Clinically, patients that are either seropositive or seronegative tend to present with similar symptoms. However, there are some differences between the two sets of patients. Patients that are seropositive are more likely to have a gene called HLA-B27. This is a genetic marker that physicians often test for before they diagnose patients with arthritis. Furthermore, some studies indicate that patients with HLA-B27 that smoke are more likely to develop arthritis.


Many physicians believe that while seropositive and seronegative rheumatoid arthritis have different etiologies or causes, they generally have a common endpoint, which is a diagnosis of arthritis. Therefore, they are treated similarly. As time has gone on, more and more physicians are starting to recognize the utility of treating patient separately based on their antibody profile. Over the course of the next decade, researchers hope to discover new targets for drugs that are specific to patients that are either seropositive or seronegative.

  • Forslind, Kristina, et al. "Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP)." Annals of the rheumatic diseases 63.9 (2004): 1090-1095.
  • Linn-Rasker, Suzanne P., et al. "Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles." Annals of the rheumatic diseases 65.3 (2006): 366-371.
  • Photo courtesy of SteadyHealth

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