Timing of Elevations of Autoantibody Isotypes Prior to Diagnosis of Rheumatoid Arthritis

Abstract

Objective To evaluate patterns of elevations of isotypes of rheumatoid factor (RF) and anti–citrullinated protein antibodies (ACPAs) pre–rheumatoid arthritis (RA) diagnosis and post–RA diagnosis. Methods Using the Department of Defense Serum Repository we identified 214 RA cases and 210 matched controls. Up to 3 pre–RA diagnosis and 1 post–RA diagnosis serum samples per subject were tested for RF and for IgA, IgG, and IgM ACPAs. The timing and trajectories of elevations of autoantibodies were evaluated. Results Autoantibody levels were elevated in cases versus controls a mean of 17.9 years before RA diagnosis for IgG ACPA, 14.2 years for IgA‐RF, 7.2 years for IgM‐RF, 6.2 years for IgA ACPA, and 5.0 years for both IgM ACPA and IgG‐RF (P < 0.01 for all comparisons). There were similar relationships for positive or negative autoantibody status, with cases first showing positivity for IgG ACPA 1.9 years pre‐RA and for IgA‐RF 1.7 years pre‐RA, followed by the other isotypes. Only IgA ACPA positivity was significantly increased in post–RA diagnosis samples (19% 0–2 years pre‐RA versus 39% >2 years post–RA diagnosis; P = 0.04). All autoantibody levels demonstrated an early initial elevation, a period of stability, then an increase immediately before RA diagnosis. A pre‐RA endotype of early elevation of autoantibodies was associated with increased use of biologic therapy, and a higher prevalence of sicca symptoms and lung disease post–RA diagnosis. Conclusion Differences in patterns of elevations of autoantibody isotypes have implications for understanding the pathophysiology of RA development. These include understanding what factors drive initial autoantibody elevations compared to what factors (including mucosal) drive later increases in autoantibody levels and a transition to clinically apparent RA, and how pre‐RA endotypes may influence post–RA diagnosis phenotypes.

Autoantibodies to Malondialdehyde–Acetaldehyde Are Detected Prior to Rheumatoid Arthritis Diagnosis and After Other Disease Specific Autoantibodies

“…In the present study, we have shown for the first time that IgG and IgA anti‐MAA autoantibodies are elevated prior to RA diagnosis. Importantly, this work, coupled with prior efforts by our group (7), demonstrates that anti‐MAA antibodies appear later in the preclinical course than ACPA or RF. Moreover, differences in prediagnosis concentrations of IgG and IgA anti‐MAA antibodies were more pronounced in ACPA‐positive patients compared to ACPA‐negative patients.…”

“…Anti‐MAA antibody concentrations were log 2 ‐transformed for further analyses. As was recently reported for ACPA and RF (7), the relative timing of elevations in anti‐MAA antibody concentrations was explored using separate mixed models for each isotype. In these models, the isotype was the dependent variable, RA status was the independent variable, random subject intercepts and slopes were assumed to have multivariate normal distributions, and time was a continuous covariate modeled using cubic B‐splines that were allowed to vary by group with internal knots placed at tertiles and boundary knots placed at extremes (8).…”

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

“…However, we lack support for this interpretation given the cross-sectional nature of our sample collections. In addition, the studies of preclinical RA samples have been discordant in the order of antibody appearance: IgA RF and IgM RF were the first antibodies in a Swedish cohort 55 , whereas ACPA 4 and ACarPA 56 preceded IgM RF in a Dutch cohort, and again IgG ACPA preceded RF (no ACarPA analysis included) in American military 57 . Similarly, the presence of RF in smokers without RA that has been known for more than two decades 49,50 , cannot be taken as evidence of RF preceding the other autoantibodies because recent studies have found also an increased presence of ACPA in smokers without RA 20,58 .…”

Lung inflammation in the pathogenesis of rheumatoid arthritis

“…Arleevskaya et al demonstrated that rates of respiratory tract infections were increased in individuals during an interval prior to their development of RA above that in controls. In addition, Kelmenson et al demonstrated in a cohort of 214 subjects with pre‐ and post‐RA diagnosis serum samples that the IgA isotype of ACPA significantly increased in positivity during a time period immediately prior to and shortly after the clinical diagnosis of RA, while IgG‐ACPA positivity remained stable. While this finding does not directly implicate the lung, it does suggest that IgA‐dominant mucosal processes likely help drive the transition to clinically apparent IA.…”