By Linda Rath | 27 June 2022
Some researchers believe rheumatoid arthritis (RA) is not a single disease, but rather a collection of diseases. It can also be one disease with many different causes. Regardless of how RA is ultimately defined, there are two main subtypes in adults: seropositive and seronegative. In seropositive RA, blood tests show unusually high levels of antibodies called anti-cyclic citrullinated peptides (anti-CCPs). These are specific markers of RA and can appear as much as a decade before symptoms do. About 60% to 80% of people diagnosed with RA have anti-CCPs. By definition, people with seronegative RA do not have these antibodies in their blood, although this is somewhat disputed.
Doctors once used an antibody called rheumatoid factor (RF) to test for seropositivity. Most people with anti-CCPs also have RF, but so do people with many other conditions, including infections. Therefore, anti-CCP is now the test of choice, although an RF test is often used in conjunction with it for greater accuracy.
The role of blood tests in RA diagnosis
No single blood test can reliably diagnose RA. Some healthy people test positive for anti-CCPs, while others who have RA have negative test results. Blood tests are just one of several factors, including a medical history, physical exam and X-rays, that help doctors diagnose the disease. Still, antibodies are a pretty good indicator of RA if you also have joint pain and swelling and bone and cartilage damage on imaging tests.
Seronegative RA is more challenging and takes longer to diagnose because doctors try to rule out other types of arthritis that are not associated with high levels of anti-CCP, such as rheumatoid arthritis. psoriatic arthritis, gout and spondyloarthritis.
Still, seronegative RA remains an imprecise diagnosis, according to some experts. It is rare for someone who is seronegative to become seropositive, but it is not uncommon for a diagnosis of seronegative RA to be changed to something else later. In a study of nearly 10,000 people diagnosed with seronegative RA, more than 500 were subsequently found to have spondyloarthritis, 275 had psoriatic arthritis, and 245 had axial spondyloarthritis. Since these forms of arthritis mainly affect the lower back and spine, and RA affects the hands and feet, it appears that the original diagnosis was based solely on the absence of anti-CCP.
Another wrinkle: Some studies have found that about a third of people diagnosed with seronegative RA actually have high levels of the same autoantibodies found in seropositive RA patients.
Seropositive vs. Seronegative: What’s the worst?
In the debate about whether seropositive or seronegative patients have more severe disease, study results are mixed. A Dutch study showed that people with seronegative disease had significantly more inflammation and disease activity than those with seropositive RA. And an international group of researchers reported a rare but particularly severe and destructive subtype of seronegative disease. However, another study reported similar disease activity and progression in both types of RA at two years.
A growing body of research has been devoted to seropositive and seronegative RA, but more is needed. For now, if you are diagnosed with seronegative RA, ask why your doctor reached that diagnosis and consider getting a second opinion. If you have severe symptoms, talk to your doctor about using the same treat-to-target approach and medications prescribed for seropositive RA.
