Seronegative and Seropositive Rheumatoid Arthritis

Blood vials for serology testing.
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Rheumatoid arthritis is a chronic, systemic, autoimmune, inflammatory type of arthritis. There is no single test that confirms the diagnosis of rheumatoid arthritis. That said, the rheumatoid factor blood test is among the criteria used to diagnose the disease. Rheumatoid factor was identified in the 1940s. In recent years, another test known as the anti-CCP test (anti-cyclic citrullinated peptide antibody) was found to be useful early in the course of the disease.

The Autoantibodies Associated With Seropositivity

Rheumatoid factor is an autoantibody, usually IgM, which bind to the Fc region of IgG. Autoantibodies are proteins that are produced by the immune system, but they mistakenly attack the body's own tissues rather than attacking foreign substances. The presence of one or both of the autoantibodies, rheumatoid factor, and anti-CCP, is referred to as seropositivity or seropositive rheumatoid arthritis. The absence of the two autoantibodies in the peripheral blood is known as seronegativity or seronegative rheumatoid arthritis. Approximately 80% of patients with rheumatoid arthritis are seropositive for rheumatoid factor. Approximately 70% of patients with rheumatoid arthritis are seropositive for anti-CCP.

A Difference in Disease Severity

It has been suggested, based on clinical studies, that patients with seropositive rheumatoid arthritis have greater disease severity and disease progression, as well as a worse prognosis than patients with seronegative rheumatoid arthritis.

It would seem then that seropositive patients require more aggressive treatment, but that view appears too simplified. In fact, the classification of seronegativity can be misleading.

A patient classified as seronegative could have autoantibodies that initially were at too low of a level to be detected.

Essentially, a more accurate classification for that would be "unrecognized or undetected seropositivity". There may also be other autoantibodies at play that are not yet tested for routinely. For example, in addition to anti-CCP and rheumatoid factor, autoantibodies known as anti-CarP (anti-carbamylated protein) may be present years before rheumatoid arthritis is diagnosed. Anti-CarP appears to be present in about 45% of rheumatoid arthritis patients, as well as in 16% of rheumatoid arthritis patients who are negative for anti-CCP.  The presence of antiCarP is said to predict a more severe disease course for rheumatoid arthritis. Therefore, seronegative patients may have disease activity or a disease course as severe as seropositive patients and they may respond well to aggressive treatment (e.g., DMARDs or biologic drugs). 

Does Seropositivity Establish Rheumatoid Arthritis Diagnosis?

It's possible to have a negative result for rheumatoid factor and anti-CCP, but still be diagnosed with rheumatoid arthritis. According to the 2010 ACR/EULAR Score-Based Criteria for Rheumatoid Arthritis, a score of at least 6 out of 10 is consistent with a diagnosis of rheumatoid arthritis. Joint involvement, serologic testing, acute phase reactants, and the duration of symptoms are all scored in this classification scheme.

Conversely, a patient could be positive for rheumatoid factor and not be diagnosed with rheumatoid arthritis. Other conditions that may be positive for rheumatoid factor include: 

Anti-CCP antibodies have not been found at a significant frequency in other diseases. Anti-CCP is considered more specific than a rheumatoid factor for detecting rheumatoid arthritis.


Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Shi J. et al. Annals of the Rheumatic Diseases. 2014 April;73(4):780-3.

Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis. Niewold TB et al. QJM. 2007 April;100(4):193-201.

Rheumatoid Arthritis: Seronegative and Seropositive RA: Alike But Different? Ajeganova and Huizinga. Nature Reviews Rheumatology. 11, 8-9(2015).

Kelley's Textbook of Rheumatology. Chapter 69. Etiology and Pathogenesis of Rheumatoid Arthritis. Gary S. Firestein. Ninth edition.