Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis

Abstract

Background: The presence of rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and antibodies against citrullinated protein and peptides (ACPA) precedes the onset of symptoms of rheumatoid arthritis (RA) by several years. Relationships between the development of these antibodies are not obvious.

Methods: Three isotypes [immunoglobulin A (IgA), IgG and IgM) of RF were analysed in 321 pre-symptomatic individuals who provided 598 samples collected a median of 6.2 (interquartile range 7.2) years before the onset of symptoms, and in 492 population control subjects. All samples were donated to the Biobank of Northern Sweden. RF isotypes were analysed using the EliA system (Phadia GmbH, Freiburg, Germany) with 96 % specificity according to receiver operating characteristic curves. Ten ACPA specificities were analysed using the ImmunoCAP ISAC system, and anti-CCP2 and anti-CarP antibodies were evaluated using enzyme-linked immunosorbent assays.

Results: The frequencies of RF isotypes in pre-symptomatic individuals were significantly increased compared with control subjects (p < 0.0001). In samples collected ≥15 years before the onset of symptoms, the IgA-RF isotype was significantly more prevalent than the most frequent ACPAs. Combinations of IgM- and IgA-RF isotypes with ACPA specificities [α-enolase (CEP-1/Eno5-21)], fibrinogen (Fib)β36-52, Fibα580-600, filaggrin (CCP-1/Fil307-324) and anti-CCP2 antibodies were associated with a significantly shorter time to onset of symptoms (p < 0.001-0.05). Using conditional inference tree analysis, anti-CCP2 in combination with anti-filaggrin antibodies gave the highest probability, 97.5 %, for disease development.

Conclusions: RF isotypes predicted the development of RA, particularly in combination with ACPA, anti-CCP2 or anti-CarP antibodies. The highest probability for disease development was the presence of anti-CCP2 and anti-filaggrin antibodies.

Fig. 1

Polar chart depicting the frequencies for ever being positive for the combinations of the ten ACPA and anti-CCP2 and anti-CarP antibodies with IgA-, IgG- and IgM-RF isotypes in pre-symptomatic individuals (a) and patients with RA (b). CCP2 anti-CCP2 antibodies, Vim60-75 anti-vimentin 60-75 antibodies, Fib36-52 anti-fibrinogen (Fib)36-52 antibodies, Fib72 anti-Fibβ62-81a antibodies, Fib74 anti-Fibβ62-81b antibodies, Fib591 anti-Fibα580-600 antibodies, CIIC1cit anti-citC1 CII 359-369 antibodies, CEP1 anti-α-enolase antibodies, Fib573 anti-Fibα563-583 antibodies, filaggrin anti-filaggrin antibodies, Vim2-17 anti-vimentin2-17 antibodies, CarP anti-CarP antibodies, RA rheumatoid arthritis, + = positivity, − = negativity

Fig. 2

Proportional Euler diagrams illustrating the relationships between, as an example, one anti-citrullinated protein antibody (ACPA), anti-CEP1 antibody (CEP1), immunoglobulin M rheumatoid factor (IgM-RF)/IgA-RF and anti-carbamylated protein antibodies (CarP). The numbers indicate the number of individuals positive for the antibody/RF of the pre-symptomatic individuals for each factor or combinations

Fig. 3

Cumulative percentage of positivity for rheumatoid factor of immunoglobulin A (IgA), IgG and IgM isotypes and antibodies against fibrinogen (Fib)β_36–52, α-enolase (CEP-1), filaggrin and carbamylated protein (CarP) including all pre-symptomatic samples