Rheumatoid Factor Revisited: An Old Method but Still Reliable

Rheumatoid factor (RF) is one of the best known serological markers in rheumatology – development of the test dates back into the 1940ies. Since this time the toolkit of serological diagnostic tests for rheumatoid arthritis (RA) has been complemented by the more specific anti-citrullinated protein antibody (ACPA) tests. However, none of the various ACPA tests has completly replaced RF until now.

In contrast, the significance of RF has been further substantiated with the definition of the 2010 ACR criteria for classification of RA. Moreover, recent studies have shown the potential of RF as a contributor to disease pathogenesis.

Why do we still measure RF?

Serology is important for RA classification and supports clinical diagnosis. According to the 2010 criteria ACPA and RF analysis represent a major jigsaw piece for RA classification. The criteria define a scoring system attributed to the relative weight of the following parameters: joint involvement, serology, acute-phase reactants and symptom duration. A final score of six out of a maximum score of ten classifies RA [1].

ACPA and RF are considered as equivalent diagnostic markers; low titers of either ACPA or RF add two, high titers three points to the total score, – that is already half of the required six points for definite RA classification.

(For a short summary of the 2010 criteria read our post on   The 2010 ACR criteria for RA classification in brief  or see the scoring table published by the ACR.)

More than 70 years after its invention RF is still regarded as a valuable diagnostic marker for RA. Researchers are now addressing the challenging question whether RF and other autoantibodies in RA are only an epiphenomenon or real pathophysiological effectors that may interact synergistically to drive disease development.

RF and ACPA together upregulate the production of TNF-alpha

Jeremy Sokolove and his coworkers investigated the interaction of ACPA and RF, and its association with disease activity and inflammation [2]. They analyzed sera of 1488 US veterans with RA and compared measures of disease activity and serum levels of cytokines in ACPA+/RF+, ACPA+/RF-, ACPA-/RF+ and ACPA-/RF- individuals.

In addition, they stimulated macrophages with ACPA immune complexes in the presence or absence of IgM-RF, and analyzed the production of tumor necrosis factor alpha (TNF-alpha) as an indicator for macrophage activation.
Compared to the double negative subgroup, as well as to each single negative subgroup, the double positive subgroup of patients had higher disease activity and higher levels of C-reactive protein and inflammatory cytokines.
In vitro stimulation of macrophages with ACPA immune complexes increased cytokine synthesis in these cells. Addition of RF in the stimulation experiments further enhanced TNF-alpha production.

Taken together, these data suggest that ACPAs and IgM-RF act together in the pathogenic process of RA and induce cytokine production in macrophages. IgM-RF may boost the effect of ACPA immune complexes, indicating a mechanistic link by which RF enhances the pathogenicity of ACPA in RA.

This blog first appeared here: http://autoimmunityblog.com/2015/04/15/rheumatoid-factor-revisited/

To read more about the Rheumatoid Factor and autoimmune issues you can also visit: http://autoimmunegal.blogspot.com

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