There are two types of blood tests that determine whether a person has rheumatoid arthritis. The first checks for the presence of rheumatoid factor (RF): antibodies produced by the immune system that can attack healthy joints and tissues. The other looks for an antibody called the anticyclic citrullinated protein antibodies (ACPA), which is also considered a marker. When RF and ACPA tests do not reveal abnormally high levels of either antibody, but a person has symptoms similar to those of rheumatoid arthritis, they may be diagnosed with seronegative arthritis. People who have either RF or ACPA antibodies have seropositive RA.

Here are 10 things you should know about seronegative rheumatoid arthritis.

1. Doctors Rely on Symptoms to Diagnose Seronegative RA, Not Just the Results From Blood Tests

Since blood work doesn’t tell the whole story, your doctor will want to find out if you’re experiencing these key symptoms:

Inflammatory joint pain
Morning stiffness for more than an hour in your hands, knees, elbows, hips, feet, or ankles
Joint swelling, tenderness or pain, and sometimes redness. Typically, RA affects distal joints symmetrically
Symptoms that appear symmetrically across the body and in multiple joints
Fatigue

X-rays can also help your doctor make a diagnosis by showing signs of erosions or other changes in your bones.

2. The Presence or Absence of RF or ACPA Doesn’t Make or Break an RA Diagnosis

Testing for rheumatoid factor in people suspected of having RA was popularized in the 1960s, and experts still don’t fully understand the exact link between these factors and the development of the disease. RF can be positive in multiple diseases, such as hepatitis C, endocarditis, and multiple myeloma.

“Rheumatoid factor clearly plays a role in how serious rheumatoid arthritis can be,” says John J. Cush, MD, a professor of internal medicine and rheumatology at UT Southwestern Medical Center in Dallas. A different blood test checks for ACPA, which may be more closely linked to the development of the disease than RF. A study published in the journal Autoimmunity Reviews in July 2016 found that ACPA antibodies represent an independent risk factor for developing RA. Having ACPA suggests there’s a genetic risk factor for the disease, but it’s not necessary for either antibody to be present in the blood for a diagnosis of seronegative RA.

3. Seronegative RA Has Become More Common in Recent Years

According to CreakyJoints, a support, education, advocacy, and research organization for people living with arthritis and rheumatic disease, the majority of rheumatoid arthritis patients are seropositive. But while you’re far less likely to be diagnosed with the seronegative type of the disease, those numbers are on the rise, according to a study published in the March 2020 issue of Annals of the Rheumatic Diseases. Between 1985 and 1994, only 12 out of 10,000 people with RA were seronegative. Between 2005 and 2014, that number crept up to 20 out of 10,000.

4. People With Seronegative RA Often Have Different Symptoms

The conventional wisdom is that seropositive patients have more severe symptoms, but recent studies suggest that the difference between the two forms of the disease may have more to do with the joints affected than with the severity of the RA symptoms. And a report published in June 2016 in BMC Musculoskeletal Disorders found that further research is needed to better understand the long-term outcomes of patients with seronegative RA. “My experience has been that while the symptoms are similar, seronegative patients are more difficult to treat,” says Vinicius Domingues, MD, a rheumatologist in Daytona Beach, Florida, and a medical adviser to CreakyJoints.

5. Seronegative RA Could Become Seropositive Down the Road

Your rheumatoid arthritis markers may change over time from negative to positive, since many people with seronegative rheumatoid arthritis begin to develop RF or ACPA antibodies. “It happens, but it’s not that common,” says Dr. Domingues. Dr. Cush says people with seronegative rheumatoid arthritis may start to develop RF or ACPA within the first two years of diagnosis.

6. Seronegative Rheumatoid Arthritis Doesn’t Need to Be Treated Differently From Seropositive

The treatment options available don’t really differ regardless of what form of the disease you have. “Whether you are diagnosed with negative or positive, be aggressive in treatment and stay ahead of the disease,” advises Cush. The purpose of treatment in either case is to lessen pain and slow or prevent progression. “Remission as early as possible is the goal,” he says.

Standard drug therapy in early disease includes nonsteroidal anti-inflammatory drugs, such as ibuprofen (Advil or Motrin) or Celebrex (celecoxib) to help relieve symptoms, and a class of drugs known as disease-modifying antirheumatic drugs (DMARDs) that can help alter the course of the disease, says Domingues. DMARDs include methotrexate (Trexall, Rheumatrex, Otreup, Resuvo) and hydroxychloroquine (Plaquenil). More powerful drugs known as biologics can be prescribed for more severe cases.

7. Seronegative RA May Not Be the Correct Diagnosis

According to Cush and Domingues, a small percentage of people with the seronegative form of RA will do very well on therapy and go into remission, and others will experience severe disease and require medication. And still others will not respond to conventional treatment, which may be because they don’t have RA at all. Spondyloarthritis conditions, which often affect the spine, are sometimes mistaken for seronegative rheumatoid arthritis.

8. New Symptoms May Change the Diagnosis

Eventually, people with seronegative disease may be diagnosed with a different disease altogether, according to the Arthritis Foundation. If, say, a person diagnosed with seronegative RA develops a skin rash, her diagnosis might change to psoriatic arthritis. Other changes or new test results could lead to a new diagnosis of chronic gout or osteoarthritis. “The most important thing at the time you see a rheumatologist is determining whether you have inflammatory arthritis or mechanical arthritis, where there is less that can be done to treat it,” says Domingues.

9. There Is No Way to Predict the Future Severity of Seronegative RA

Forecasting how any disease may progress is extremely difficult. Whether you’re diagnosed with seronegative or seropositive, there are no set expectations of how either form of the disease will play out in an individual. “Which type you have isn’t all that important, since you treat them both the same way,” says Domingues.

10. Seronegative RA Is Sometimes Linked to Having Higher Levels of Inflammation Than Seropositive

In a European study of 234 people who had both types of rheumatoid arthritis and had experienced symptoms for less than two years, those with seronegative RA showed higher levels of inflammation and more affected joints, according to research published in January 2017 in Annals of the Rheumatic Diseases.

10 Essential Facts About Seronegative Rheumatoid Arthritis