VICTORIA, B.C. – Autoantibodies directed against homocitrullinated fibrinogen may help identify patients with rheumatoid arthritis who would currently be missed, a study has shown.
A team led by Dr. Lillian Barra and Dr. Ewa Cairns of the University of Western Ontario, London, tested 84 patients with rheumatoid arthritis (RA) and found that nearly half had antihomocitrullinated fibrinogen antibodies (AHFAs) in their serum.
Dr. Lillian Barra: "This is an exploratory study, and we are going to do a lot of future work looking at these antibodies in a larger cohort, hopefully the CATCH [Canadian Arthritis Cohort]."
Perhaps most importantly, these antibodies were present in almost a fifth of patients who did not have anticitrullinated fibrinogen antibodies (ACFAs) and would thus have otherwise been considered to be seronegative.
The results also indicated that AHFAs were specific for RA: They were seldom found in 37 patients with systemic lupus erythematosus and 37 patients with psoriatic arthritis. And they were not found at all in any of 27 healthy volunteers.
These findings add to similar results seen in a cohort of patients from Leiden, the Netherlands (Proc. Natl. Acad. Sci. USA 2011;108:17372-7), noted Dr. Barra, who presented the findings at the annual meeting of the Canadian Rheumatology Association "This is an exploratory study, and we are going to do a lot of future work looking at these antibodies in a larger cohort, hopefully the CATCH [Canadian Arthritis Cohort]," she said.
The large collective group of anticitrullinated protein antibodies (ACPAs) target citrullinated proteins, such as the collagen, fibrinogen, and vimentin found in joint synovial fluid. "They are highly specific for rheumatoid arthritis and have been included in the new [American College of Rheumatology]-EULAR criteria" for diagnosing early disease, Dr. Barra pointed out.
ACPAs associate with the shared epitope, the strongest genetic risk factor for RA, and have been found to be pathogenic in mice, she further noted. "However, nearly 50% of patients with early rheumatoid arthritis do not have ACPAs, which begs the question of whether these patients have a different type of antibody that we don’t know about."
The investigators recruited patients meeting diagnostic criteria for various rheumatologic diseases from St. Joseph’s Health Care in Southwestern Ontario, nearly all of whom were white. They also recruited age- and sex-matched healthy volunteers.
Descriptive data indicated that, on average, the patients with rheumatoid arthritis had had their disease for about 9 years and had 4.3 swollen joints, Dr. Barra reported. Fifty-six percent were in remission.
The main study results showed that 49% of patients with rheumatoid arthritis overall had AHFAs. This compared with just 5% of patients with SLE, 3% of patients with psoriatic arthritis, and none of the healthy volunteers.
A full 31% of the patients with RA were negative for ACFAs, but 19% of this subgroup were found to have AHFAs. Viewed another way, 6% of the patients with RA overall were negative for ACFAs but positive for AHFAs. "These patients were previously considered seronegative, but they do have an antibody," Dr. Barra commented.
The investigators also used a computer algorithm to assess whether the proteins and peptides that are homocitrullinated would bind to the shared epitope. The results indicated that 35 of them, only 5 of which could also be citrullinated, would bind with high affinity. "This suggests that there are unique homocitrullinated peptides, but there is also the possibility of cross-reactivity" between AHFAs and ACFAs, she explained.
"We are going to investigate cross-reactivity further, and we would like to look at the immune responses [to these proteins] in vivo in future work," Dr. Barra concluded.
Dr. Barra said she had no relevant financial disclosures.