Rheumatoid arthritis (RA) has been traditionally broken into two disease groups: seropositive and seronegative. Either status is defined by the presence (or absence) of specific antibodies (a type of protein) that are made by the immune system. In RA, autoantibodies recognize your healthy tissues and joints as foreign and attack them. People with seronegative RA do not have these autoantibodies, giving different characteristics to the disease.

What Is Seronegative RA?

Unlike seropositive RA, seronegative RA means that there are no detectable anti-cyclic citrullinated peptides (anti-CCPs) present in your bloodstream. Anti-CCP antibodies are also known as anti-citrullinated protein antibodies (ACPAs). They recognize proteins that have undergone citrullination, a type of molecular change in structure.

Seronegative RA is less common than seropositive RA, accounting for around 20 percent of cases. In some cases, a person will be diagnosed with seronegative RA if the antibodies are present but the levels are so low that they cannot be detected by a blood test. Seronegativity makes it more difficult to diagnose RA.

How Is It Different From Seropositive RA?

In addition to the lack of antibodies, there are a few other differences between seropositive and seronegative RA.

People with seropositive RA all share a common sequence of amino acids, known as a shared epitope. This sequence is encoded in the human leukocyte antigen (HLA) gene site that is responsible for controlling immune responses. The exact role of this sequence in RA is unknown. However, it is believed that the shared epitope attaches to citrullinated proteins and triggers the production of anti-CCP antibodies, which leads to seropositivity.

Although both seropositive and seronegative RA share many risk factors, evidence suggests that smoking and obesity can increase a person’s risk of developing seronegative RA.

Seronegative individuals may also be less likely to develop rheumatoid nodules and vasculitis than people who are seropositive.

Why Does the Distinction Matter?

The distinction between seropositive and seronegative RA is important because it can help doctors rule out other rheumatic diseases during diagnosis. People who have anti-CCP antibodies and other relevant symptoms can easily be diagnosed with RA.

However, seronegative individuals may have a more difficult time getting an accurate diagnosis. For example, if a seronegative person develops a skin rash, they may be diagnosed with psoriatic arthritis. Osteoarthritis can also be mistaken for seronegative RA because both conditions cause joint pain and other similar symptoms.

How Is Seronegative RA Diagnosed?

Rheumatoid arthritis is diagnosed through laboratory and imaging tests. These tests help your doctor or rheumatologist determine whether you have RA or another autoimmune disease.

Physical Examination

The doctor will generally begin by taking a thorough medical history and performing a physical examination. Common questions include:

• When did the symptoms begin?
• What joints are being affected?
• How would you describe the pain? (For example, sharp, dull, or aching.)
• Have you become more fatigued?
• Do you experience morning stiffness?
• What other symptoms are you experiencing?

The doctor will also typically evaluate the joints to look for signs of inflammation. They may test joint strength, range of motion, and endurance.

Blood Tests

There are a few laboratory tests that can be performed to help diagnose RA.

Two tests can help determine the level of inflammation in the body. Erythrocyte sedimentation rate (ESR) analyses look at the rate at which red blood cells settle in a test tube over one hour. C-reactive protein (CRP) levels can also be measured to determine levels of inflammation or if you are experiencing a flare-up. ESR and CRP tests are not specific to RA but instead can show how active the disease is.

Other blood tests can help your doctor determine if you have seropositive or seronegative RA. These tests look for rheumatoid factor (RF) and anti-CCP antibodies. If there are no anti-CCP antibodies and you show the signs and symptoms of RA, you can be diagnosed with seronegative RA.

However, RF and anti-CCP blood tests may not always be accurate. In early cases of RA, antibodies are produced at a slower rate than in more progressed stages. As a result, the blood tests may not detect the antibodies, giving a false-negative test result. False-positive results are also possible, so your doctor will likely order imaging tests to confirm a diagnosis.

Imaging Tests

If the blood tests show negative or inconclusive results, the next step is to rule out other autoimmune or rheumatic diseases. Ultrasound imaging can be used to look for inflammation in the joints and tendons, called synovitis, which is characteristic of RA. X-ray imaging may also be used, but it can be difficult to detect soft tissue swelling in the early stages of RA. X-ray is typically used to look for bone damage as the disease progresses.

How Does Seronegativity Affect Treatment and Prognosis?

Generally, the available treatments for RA can be used to treat both seronegative and seropositive cases. The types of medication you receive will depend on how long you have had RA and how severe your symptoms are. RA treatments work by targeting the source of inflammation or treating symptoms and may include:

• Disease-modifying antirheumatic drugs (DMARDs)
• Biologics
• Steroids (also known as corticosteroids)
• Nonsteroidal anti-inflammatory drugs (NSAIDs)

People with seronegative RA may respond better to traditional RA medications. People with seronegative RA may also have a milder disease course than those with seropositive RA. However, this may not always be the case and depends on other factors such as underlying conditions and genetics.

Connect With Others Who Understand

On myRAteam, you’ll have access to the social network for people living with RA and their loved ones. Here, more than 146,000 members come together to ask questions, give advice, and share their stories with others who understand life with RA.

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