Background/Purpose:

Previous studies indicate that anti-citrullinated peptide antibodies (ACPAs) may be detected in individuals who later develop rheumatoid arthritis (RA) years before onset, and that smoking and early menopause (before age 46) are risk factors for RA. Whereas smoking is a predictor of seropositive RA, early menopause has been associated with a milder, predominantly rheumatoid factor negative, phenotype. The objective of this study was to investigate circulating ACPAs and their relation to age at menopause and smoking before the onset of RA.

Methods:

Incident cases of RA were identified among participants (n=30447; 18326 women) in a community based health survey, which was linked to local and national registers, followed by a structured review of the medical records. One control, matched for age, sex and year of inclusion in the health survey, was selected for each validated case. Using a multiplex assay system, sera from 131 female pre-RA cases and 131 controls were investigated for 12 different ACPA fine specificities.  For all investigated antibodies, previous studies had shown good correlations between results obtained using this system and standard ELISAs. Corrected net values for ACPA specificity were calculated by subtracting values for arginine control peptides from the corresponding citrullinated peptides. Cut offs were set at the 98^thpercentile, based on investigation of sera from the matched controls. Analyses were stratified by time from inclusion in the health survey to RA diagnosis (1-4, 5-7 and 8-13 years, respectively), and by age at menopause (≤ 45 years vs > 46 years) or history of ever smoking.

Results:

Serum was available from 131 women, who were diagnosed with RA a median of 5.5 years (IQR 3-8; range 1-13) after inclusion in the health survey. Seventy (53 %) of the pre-RA cases were positive for ≥ 1 ACPA. Significantly greater numbers of positive ACPA specificities were detected among pre-RA cases sampled closer to RA diagnosis (p for trend 0.03). A history of early menopause (p=0.001) and ever smoking (p=0.003) were both associated with subsequent development of RA. Ever smokers were more likely to be positive for most ACPAs and had higher numbers of positive ACPA specificities compared to never smokers (p=0.047). Ever smokers were more likely to be positive for ≥ 1 ACPA compared to never smokers, regardless of the time from inclusion to RA diagnosis. By contrast, women with a history of early menopause were less likely to be positive for ≥ 1 ACPA compared to those with normal or late menopause, in particular among cases included ≥ 8 years before RA diagnosis (29 % vs. 48 %).

Conclusion: The early occurrence of ACPA and the increase in ACPA specificities with a shorter time to diagnosis indicate that epitope spreading may precede disease onset. The immune phenotype in the pre-clinical phase of RA may differ between subsets depending on environmental exposures and associated disease mechanisms. The present results suggest that hormonal changes influence pathways in the pathogenesis of RA that are distinct from those associated with smoking.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/early-menopause-smoking-and-circulating-antibodies-against-citrullinated-peptides-in-the-pre-clinical-phase-of-rheumatoid-arthritis/