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Elevations of Autoantibody Isotypes in RA Prior to Diagnosis

Differences in patterns of elevations of autoantibody isotypes have implications in understanding the pathophysiology or rheumatology arthritis (RA) development, a new study suggests. Researchers identified 214 patients with RA and 210 matched controls. A mean of 3 pre-RA and 1 post-RA diagnosis serum samples were tested for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) immunoglobulin (Ig) A, IgG, and IgM. The timing and trajectories of autoantibodies were evaluated. Among the findings:

  • Pre-RA autoantibody levels were elevated in RA cases vs controls as follows: ACPA-IgG 17.9 years, RF-IgA 14.2 years, RF-IgM 7.2 years, ACPA-IgA 6.2 years and ACPA-IgA both at 5.0 years.
  • The autoantibodies as positive/negative showed similar relationships, with the median time of first positivity of ACPA-IgG at 1.9 years pre-RA, RF-IgA at 1.7 years, followed by the other isotypes.
  • All autoantibody levels demonstrated an early initial elevation, a period of stability, and then an increase immediately pre-RA diagnosis.


Kelmenson LB, et al. Timing of elevations of autoantibody isotypes in rheumatoid arthritis prior to disease diagnosis. [Published online ahead of print August 29, 2019]. Arthritis Rheumatol. doi: 10.1002/art.41091.


Evidence from the Department of Defense Serum Repository has previously given use evidence that RA-autoantibodies are detectable prior to the onset of disease symptoms. The meaning of rheumatoid factor and ACPA isotypes has not been previously known. Using a case-control design, this study found that IgA-RF increased in RA patients 14 years prior to diagnosis, earlier than IgM and IgG RF. For ACPA, IgG elevation occurred at 18 years prior to diagnosis, preceding both IgA and IgM ACPA. Interestingly, IgA-ACPA increased post-RA diagnosis, while the other ACPA isotypes and all RF isotypes did not. Interestingly, patients whose antibody levels increased earlier on in disease were somewhat more likely to have lung disease and use anti-TNF. Perhaps contrary to expectations, smoking history was not associated with early or late antibody presence. These results don’t clearly define mucosal (IgA) autoimmunity as cause of RA, and the factors that cause the initial elevation in autoantibodies as well as the rise in other antibodies closer to diagnosis should be investigated further. —Arundathi Jayatilleke, MD