Anti-carbamylated protein antibodies, a recently identified autoantibody system against carbamylated proteins, can be detected years before symptoms develop in rheumatoid arthritis, according to a retrospective study.
The finding suggests "another source of antibodies which can potentially contribute to RA pathogenesis. ... The moment of first appearance of anti-CarP [anti-carbamylated protein] antibodies is comparable with ACPA [anti-citrullinated protein antibodies] and earlier than IgM-RF [IgM-rheumatoid factor]," both now included in American College of Rheumatology/European League Against Rheumatism RA criteria, said senior author Dr. Leendert A. Trouw and lead author Jing Shi, Ph.D., of the department of rheumatology at Leiden (the Netherlands) University Medical Center and their colleagues.
Dr. Leendert Trouw
Identifying people who could benefit most from early RA intervention "is a challenge, but the presence of autoantibodies could be a useful marker," the investigators said (Ann. Rheum. Dis. 2013 Dec. 13 [doi:10.1136/annrheumdis-2013-204154]).
Anti-CarP antibodies presented in both ACPA-positive and ACPA-negative patients; they "appear by and large [to be] two different autoantibody systems," the investigators said.
The authors tested years of blood samples from 79 donors in the Sanquin Blood Bank – the Dutch national blood bank – who were eventually diagnosed with RA, for the presence of anti-carbamylated-fetal calf serum (anti-Ca-FCS), anti-carbamylated-fibrinogen (anti-Ca-Fib), anticyclic citrullinated-peptide 2 (anti-CCP2) antibodies, and IgM-RF, all by enzyme-linked immunosorbent assay. Levels were considered elevated if they were two standard deviations above the mean of 141 age and sex-matched controls who did not develop RA. The subjects were white, with a median of five sequential sera obtained from blood samples 1-6 years apart. The future-RA group included 48 women; the mean age at diagnosis was 51 years.
Six years before diagnosis, more than half of the future-RA patients harbored one autoantibody, and at least 30% had all three autoantibody families within 4 years of diagnosis. Median levels of autoantibodies started to increase around 5-7 years before the diagnosis.
"IgM-RF, anti-Ca-FCS, anti-Ca-Fib and anti-CCP2 antibodies were [first] detectable [at] 10, 14, 14, and 14 years before diagnosis, respectively. These are the time points when the first samples of these donors were collected. The median of time points when anti-CCP2, anti-Ca-FCS, anti-Ca-Fib antibodies and IgM-RF were detectable were 6, 5, 7, and 2 years before the diagnosis," the investigators found.
Anti-Ca-FCS antibodies were present in 27% and anti-Ca-Fib antibodies in 38% of patients at their last blood draw, which came at a mean of 1.4 years before diagnosis.
Although "anti-CCP antibodies or IgM-RF can be found in both patients and their healthy first-degree relatives, the combination of both anti-CCP and RF is predominantly found in the RA patients. This supports the notion that ACPA and anti-CarP antibodies may initiate the primary target recognition but that amplification of IgM-RF is important for progression towards clinical RA, for example, by enhancing complement activation," they wrote.
The study was funded by the Dutch Arthritis Foundation, the Netherlands Organisation for Scientific Research, Masterswitch project FP7, the Innovative Medicines Initiative Joint Undertaking funded project BeTheCure (through a Pfizer contract), and the Netherlands Proteomics Center and the Center for Medical Systems Biology (as part of the Netherlands Genomics Initiative). Dr. Trouw is supported by a Janssen Biologics fellowship.