There are two main types of rheumatoid arthritis (RA) in adults: seropositive and seronegative. Both have the same symptoms — joint pain, morning stiffness, fatigue, fever, low appetite — but the primary difference is in the bloodwork.

In most people diagnosed with RA, blood tests reveal abnormally high levels of antibodies called rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP), which signal that the immune system is in overdrive and may be attacking healthy tissues instead of just foreign invaders like germs.

The majority of rheumatoid arthritis patients are seropositive: 50 percent to 70 percent of RA patients have anti-CCP antibodies and 65 percent to 80 percent have rheumatoid factor antibodies, research shows.

However, this means that a sizeable number of people with RA are considered to be seronegative, which means they don’t have either of these antibodies in their blood.

Keep in mind that blood tests are just one part of the process that doctors use to diagnose RA. Learn more about different tests that diagnose RA here.

How Are Blood Tests Used to Help Diagnose RA?

RF and anti-CCP tests don’t definitively point to RA because some healthy people without RA test positive for these antibodies, while other people who do have autoimmune problems test negative, says Umbreen Hasan, MD, consultant rheumatologist for Allina Health in Minnesota.

That’s why doctors will also consider RA symptoms, inflammation levels, and the amount of joint swelling with the help of X-rays and ultrasounds.

“Although blood tests for inflammatory arthritis can help in the diagnosis of the condition, a good history and physical examination is more important,” says Dr. Hasan. “The diagnosis [of RA] should not be solely based on blood tests.”

However, if you have symptoms that are consistent with rheumatoid arthritis and you do test positive for these antibodies, your doctor will feel pretty confident being able to diagnose you with RA.

How Do Doctors Diagnose Seronegative RA?

People who don’t test positive for the presence of RF and anti-CCP can still be diagnosed with rheumatoid arthritis based on their symptoms, a physical exam of their joints, and imaging tests (X-rays and ultrasounds) that can show patterns of cartilage and bone deterioration.

Interestingly, some people who initially test seronegative develop those RF and anti-CCP antibodies later. Among people with more established RA, the percentage of seropositive patients rises to 80 to 85 percent, says Konstantinos Loupasakis, MD, rheumatologist with MedStar Washington Hospital Center.

But most people with seronegative RA never develop antibodies and become seropositive.

Because doctors feel less confident diagnosing RA without positive blood tests, they’ll need to rule out other conditions like viral infections, gout, or spondyloarthritis (an umbrella term for conditions such as psoriatic arthritis and reactive arthritis that isn’t associated with high levels of RF and anti-CCP), says Dr. Loupasakis.

“We want to be very careful that we are not missing something,” says Dr. Loupasakis. “There are diseases that can camouflage as rheumatoid arthritis, and [your symptoms] might be something else.”

This may help explain why research shows that people with seronegative RA often take longer to get diagnosed and to start treatment than people with seropositive RA, according to study presented at the 2017 annual meeting of the American College of Rheumatology.

Is Seronegative RA Just Another Kind of Arthritis?

But a seronegative test doesn’t automatically point to spondyloarthritis, which is a separate condition, he says. The two types of inflammatory arthritis affect the joints differently, confirms Dr. Hasan. While rheumatoid arthritis generally hits small joints like the hands and feet, spondyloarthritis is more likely to start in the lower back or shoulders.

Getting the wrong diagnosis can keep patients from the best treatment. While spondyloarthritis has its own approved set of treatments, seropositive and seronegative RA are treated the same way. Both use disease-modifying anti-rheumatic drugs (DMARDs), biologics, corticosteroids, and anti-inflammatory NSAID painkillers like aspirin.

The primary difference is that rituximab, an infused medication, is only effective for seropositive patients, though it’s not among the first treatments a doctor will prescribe anyway, says Dr. Loupasakis.

Seronegative vs. Seropositive RA: Are There Other Differences?

Past studies seemed to indicate that seropositive RA patients had a worse prognosis and more severe disease progression than seronegative RA patients, according to MedPage Today. This has created a certain stigma around seronegative RA — that it is a “less severe disease” and perhaps even requires less aggressive treatment.

However, the thinking here is changing based on newer research. For example, a Dutch study found that seronegative RA patients had significantly greater disease activity and worse functional ability than seropositive patients; on the other hand, seropositive patients had greater joint damage.

A Canadian study found that measures of RA disease activity (such as number of swollen/tender joints or X-ray evidence of joint damage) was higher in seronegative patients than in seropositive patients when the study began. Both seronegative and seropositive patients received similar treatment. When measured again after two years, the seronegative RA patients had a significantly greater improvement in several measures of disease activity and less erosion than those with seropositive disease.

Part of the problem may be the delay in diagnosis. Because people with seronegative RA take longer to get diagnosed and start disease-modifying medication, they may be missing a crucial window to prevent progression and enter remission.

Understanding the differences between seropositive and seronegative patients, as well as nuances within each of those groups, is an ongoing area of study. Both seronegative and seropositive RA likely have different subtypes that haven’t yet been teased out. Personalizing treatment and being able to better predict which patients will do better on which kinds of treatment is a hot topic in the field of rheumatology.

Bottom line, according to MedPage: “RA patients classified as seronegative may indeed experience a level of disease activity that is as severe, or more severe, than patients who are seropositive, and thus may benefit from the type of aggressive treatment strategies that are more routinely used to treat seropositive patients.”

When People Say Seronegative RA ‘Isn’t Real’

Kate Mitchell of Boston knows all too well the importance of getting the right diagnosis. Her rheumatologist first thought she had psoriatic arthritis because of a family history of psoriasis. Realizing she’d only ever had two psoriasis flare-ups, her doctor suggested she might have seronegative rheumatoid arthritis instead. Those medications didn’t work as well as they’d hoped, so he put her back on medication to treat psoriatic arthritis, but her symptoms got even worse, and she developed endometriosis. She finally found relief when she went back to RA medications.

“I’m not spending my entire life in bed or on the couch,” she says. “I can leave my house for things other than a rheumatology appointment.”

Mitchell had a good experience with her rheumatologist but says she’s run into other doctors who have tried convincing her seronegative RA isn’t real or that she has a different type of arthritis. She tries to remind herself that she knows her own body, but “other times it’s upsetting and demoralizing,” she says. Mitchell encourages patients to keep up with doctors’ appointments to find a diagnosis — whether it’s seronegative RA or something else.

“There are so many illnesses and forms of arthritis that do not have a definite test to diagnose them,” she says. “Just because one doctor or one rheumatologist says you do not have x form of arthritis doesn’t mean you don’t have any of the other 100 forms.”

Keep Reading