What Is Seronegative Rheumatoid Arthritis?

Reviewed by: HU Medical Review Board | Last reviewed: February 2021

There are 2 main types of rheumatoid arthritis (RA) in adults. They are called seropositive and seronegative RA. People with both types of RA will experience symptoms like joint pain, morning stiffness, fatigue, fever, and low appetite. However, their blood work will be different, and they may respond differently to treatments.1,2

Blood tests used to diagnose RA

For people with RA symptoms, doctors often use blood tests as a first step in diagnosing RA. Doctors use the tests to look for high levels of the antibodies rheumatoid factor (RF) and anti-cyclic citrullinated peptides (anti-CCP).3

In seropositive RA, the immune system overproduces RF and/or anti-CCP, which attack healthy tissue.3

In people who have blood tests with high levels of RF or anti-CCP, their doctor may diagnose them with RA. This is called seropositive RA. Seropositive RA diagnoses are more common than seronegative. About 50 to 70 percent of people with RA have high anti-CCP, and about 65 to 80 percent have high RF. False-positive rheumatoid factors are quite common. However, it is rare to have positive CCP levels without RA.1

However, negative blood work results do not rule out the chance of RA. Even if your blood work does not show high levels of these antibodies, you might have seronegative RA. This is why blood work is only one part of diagnosing RA.4

How is seronegative RA diagnosed?

RA that does not cause high levels of anti-CCP or RF is called seronegative RA. Seronegative RA can be difficult to diagnose because doctors cannot rely on a blood test. Symptoms can be an important part of the diagnosing process. Symptoms that may be a sign of seronegative RA include:3

If a person has these symptoms but their blood test did not show high antibody levels, a doctor may recommend imaging tests. X-rays, MRIs, and ultrasounds may show inflamed or damaged joints, which is a sign of RA.4

Without positive blood tests, it may be difficult for your doctor to diagnose you with RA. Other inflammatory conditions, such as viral infections or gout, can cause similar symptoms. Also, other types of arthritis, like spondyloarthritis, do not cause high levels of RF and anti-CCP, and would show a seronegative test. This can cause people with seronegative RA to wait longer for a diagnosis, as compared to those with seropositive RA.1

Differences in outcomes

Currently, the approach to treating seronegative RA is the same as the approach to seropositive RA. However, some researchers now believe seronegative RA may be a separate disease.4

More research is needed to understand seronegative RA. In the past, some studies showed that seronegative was a less serious RA diagnosis than seropositive. More recent research indicates this may not be true. Some studies have shown that people with seronegative RA have more severe symptoms and joint damage. This may be because it takes longer to get a seronegative RA diagnosis and the disease has more time to progress.1

Can seronegative RA turn into seropositive RA?

Previously, researchers thought it was likely that seronegative RA could turn into seropositive RA over time. However, a recent study that followed people with seronegative RA over 10 years found that only about 3 percent developed seropositive RA. Since the long-term outcomes were so varied, the researchers have suggested that seronegative RA may not even be considered a single disease.5

Response to treatment

Other researchers have shown that seronegative and seropositive RA respond differently to treatment. One study looked at the progression of both types of RA over many years. They found that both types responded to treatment in helping with short-term symptoms.6

However, only the seropositive RA cases had long-term improvement from treatment. The long-term improvements included a lower chance of death or disability and a higher chance of being able to stop taking medicine. These findings may be important because currently both types of RA are treated using the same approach.6

While these findings are helpful, more research is needed on seronegative RA. Hopefully, this research can help doctors understand more about seronegative RA and lead to specific treatments.

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