Rheumatoid Factor: Diagnostic and Prognostic Performance and Therapeutic Implications in Rheumatoid Arthritis

Abstract

Rheumatoid factor (RF) is the first autoantibody identified in rheumatoid arthritis (RA) which targets the fragment crystallizable (Fc) region of immunoglobulin (Ig) G. Although IgM isotype is predominant, other Ig isotypes, including IgG and IgA, also exist. While RF is not specific to RA, it remains a valuable serological test for diagnosing the disease, as evidenced by its inclusion in the 2010 classification criteria for RA based on elevated serum RF levels. RF is also associated with RA severity, including joint damage and extra-articular manifestations, serving as a poor prognostic factor and aiding in the identification of difficult-to-treat RA. Recent studies have demonstrated that high serum RF levels are associated with a reduced response to tumor necrosis factor (TNF) inhibitors. In contrast, anti-TNF antibodies lacking the Fc portion have shown stable efficacy in RA patients regardless of baseline RF levels. These findings reaffirm the clinical significance of RF measurement, 80 years after its initial discovery. This review explores the diagnostic and prognostic significance of RF and its impact on treatment selection in RA management.

Keywords: anti-citrullinated protein antibodies; rheumatoid arthritis; rheumatoid factor; tumor necrosis factor.

Figure 1

RF implicated in the pathogenesis of RA. The onset of rheumatoid arthritis (RA) is driven by a complex interplay of genetic and environmental factors. These factors lead to the generation of exogenous and endogenous antigens, which are subsequently presented by antigen-presenting cells (primarily dendritic cells) to CD4+ T cells. Upon activation, CD4+ T cells differentiate into self-antigen-specific subsets, including follicular helper T cells (Tfh) and peripheral helper T cells (Tph). These specialized CD4+ T cells facilitate B cell maturation and promote their differentiation into memory B cells and long-lived plasma cells. Plasma cells in inflamed synovial tissue produce significant quantities of rheumatoid factors (RF), predominantly Immunoglobulin M (IgM) type, and anti-citrullinated protein antibodies (ACPA). These autoantibodies form immune complexes with self-IgG in the synovium of RA patients. These immune complexes amplify complement activation, cytokine production by macrophages, and exacerbate joint damage by promoting osteoclast activation. Abbreviations: DC, dendritic cell; PC, plasma cells; Mφ, macrophage; OC, osteoclast; MHC, Major Histocompatibility Complex; TCR, T-cell receptor; BCR, B-cell receptor.

Figure 2

Methods for RF detection. (A) Nephelometry is based on the RF-induced aggregation of IgG-coupled particles. A laser beam is directed at the aggregates, and the intensity of the scattered light is quantified. The titer (IU/mL) is calculated from a standard curve, using serum aligned with the WHO’s reference standard. The specific contribution of the various RF isotypes to the aggregation observed by nephelometry remains undetermined. (B) In the enzyme-linked immunosorbent assay (ELISA), the Fc portion of purified human IgG is immobilized on polystyrene microtiter plates and reacted with test serum. RF bound to the antigen is detected using an enzyme-conjugated secondary antibody specific to the immunoglobulin class, followed by the addition of an enzyme substrate.

Figure 3

Mechanisms of attenuation of TNF antibody efficacy by RF. (A) The RF-IgG immune complex binds to the Fc receptors for IgG (FcγR) on the surface of antigen-presenting cells (APCs), leading to the internalization and subsequent lysosomal transport of the complex. Within the lysosomes, both the FcγR and the internalized antigen undergo proteolytic degradation. Anti-TNF antibodies lacking the Fc portion are hypothesized to evade this degradation pathway. (B) The neonatal Fc receptor for IgG (FcRn) is predominantly expressed on endothelial cells. These cells internalize serum IgG and engage FcRn within acidic endosomal compartments. FcRn subsequently recycles IgG back into circulation, thereby extending its serum half-life. In contrast, IgG that fails to bind FcRn is routed to lysosomes for degradation, bypassing intracellular sorting. Rheumatoid factor (RF) binds to the FcRn-binding sites of TNF antibodies and may interfere with their recycling process.