Background/Purpose:  The aim of the current study was to investigate the influence of genetic and environmental factors in developing anti citrullianted-proteins antibodies (ACPA) and ACPA positive rheumatoid arthritis (RA), using a twin study approach.

Methods: We used a subset of the Swedish population based twin registry, which includes 12 590 monozygotic (MZ) and dizygotic (DZ) twins born 1958 or earlier, who had donated blood and provided information about smoking. RA was verified by data from national public care registers (1964-2009). All sera were analyzed for ACPA occurrence using a CCP2 ELISA  with a cut off set to 25 U/ml. High titer of ACPA was defined as titers >75 U/ml. Twin concordance for ACPA occurrence was estimated by casewise concordance, tetrachoric correlation and odds ratios (OR). Odd ratios (OR) to develop ACPA and high titers of ACPA were calculated according to self-reported smoking status, cumulative dose of smoking and presence of any HLA_DRB1 shared epitope according to GWAS analysis. Twins were defined as smokers if they were or had been smoking regularly or occasionally. Cumulative dose of smoking was estimated by pack years.

Results: 350 out of 12590 tested individuals (2.8%) were positive for ACPA with 202 out of 12590 tested individuals (1.6%) having high titers of ACPA (>75 U/ml). 192 out of 12590 tested individuals  were identified as having RA  in the Swedish patient register during 1964-2009. The median age of the RA patients was 70 (range 53-94) and 73% were females. Monozygotic twins had an OR of 3.1 (95% CI 0.9-10) for developing ACPA, 7.9 (95% CI 1.7-37) for developing high titers of ACPA and 11.6 (95% CI 1.27-98.6) for developing ACPA+ RA if they had a co-twin with corresponding phenotype. Dizygotic twins had lower OR for developing ACPA (OR 1.8, 95% CI 0.5-5.8), high titers of ACPA (OR 3.6, 95% CI 0.8-16) and ACPA+ RA (OR 4.0, 95% CI 0.5-31.1) if they had a co-twin with corresponding phenotype. Smokers had an increased risk of developing ACPA (OR 1.33, 95% CI 1.08-1.63), high titer of ACPA (OR 1.63, 95% CI 1.22-2.18) and high titer ACPA+ without RA (OR 1.99, 95% CI 1.27-3.12) but not significantly increased OR for ACPA+ RA (OR 1.42, 95% CI 0.98-2.06). An increased cumulative dose of smoking was associated with ACPA, with the highest risk of developing ACPA among those smoking more than 10 pack years (OR 1.49, 95% 1.18-1.88). Presence of shared epitope conferred an increased risk of developing ACPA (OR 1.98, 95% 1.53-2.56), high titer ACPA (OR 3.12, 95% 2.15-4.54) and especially high titer ACPA+ RA (OR 7.09, 95% 3.69-13.65) with no significantly increased OR to develop high titer ACPA+ without RA (OR 1.17, 95% 0.81-1.69).

Conclusion: Results from this large population-based cohort of middle-aged twins and measurements of ACPA at one time point indicate that environment, life style and stochastic factors (such as smoking) may be more important than genetics in determining which individuals that develop ACPA, whereas genetic factors (and in particular shared epitope) may have a larger impact in determining which persisting ACPA-positive individuals that will ultimately develop arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evidence-for-distinct-roles-of-environmental-and-genetic-factors-in-the-emergence-of-anti-citrullinated-protein-antibodies-positive-rheumatoid-arthritis-an-epidemiological-investigation-in-twins/