Background and Objective Anti-citrullinated protein antibodies (ACPA) and IgM-rheumatoid factor (IgM-RF) are auto-antibodies that can be detected many years before the clinical diagnosis of rheumatoid arthritis (RA). In recent studies we discovered a novel family of autoantibodies, anti-carbamylated protein (anti-CarP) antibodies. Carbamylation, like citrullination, is a post-translational modification of proteins. We observed that in RA, next to an antibody response against citrullinated proteins, also an immune response against carbamylated proteins exists. These anti-CarP antibodies are of prognostic value in RA as they associate with severe joint destruction in ACPA negative RA. In addition anti-CarP antibodies associate with future development of RA in patients suffering from arthralgia.
Here we analysed whether anti-CarP antibodies are already present prior to symptom onset of RA and which auto-antibody appears first over time.
Materials and Methods Sera of 79 RA patients prior to diagnosis and 141 age and sex matched controls that were regular blood donors of the Amsterdam Bloodbank (Amsterdam, The Netherlands) were tested for the presence of anti-CarP antibodies, anti-CCP2 antibodies and RF-IgM using sequential pre-RA sera, obtained at 1-2 year intervals.
Results Anti-CarP antibodies were present in 39% of the serum samples that were drawn just prior to the diagnosis of RA of blood donors compared to 4% of the matched control samples. Anti-CarP antibodies were present in both ACPA positive and in ACPA negative patients. Of the 79 individuals that developed RA, 42% were positive for anti-CCP2 antibodies and 24% for IgM RF.
Analysis of the longitudinal samples revealed a gradual increase in the number of samples positive for anti-CarP antibodies and in the levels of anti-CarP antibodies towards the diagnosis of RA. We observed that anti-CarP antibodies could be detected many years before the onset of symptoms with a median of 8 years and a maximum of 14 years. Comparing the first appearance of the three autoantibody families revealed that both ACPA and anti-CarP antibodies appear earlier than IgM-RF.
Conclusions Next to ACPA and IgM-RF also the newly identified anti-CarP antibodies appear many years before the onset of clinical symptoms of RA.