Background/Purpose

Anti-citrullinated peptide antibodies (ACPA) are associated with smoking in patients with rheumatoid arthritis (RA). Bronchiectasis (BR), which tends to occur in non-smokers, has been recognised as an uncommon, but potent risk factor for RA for 50 years. Here we examine the potential of BR in generating ACPA in patients with BR alone and in patients with BR and RA (BRRA). 

Methods

The multi-centre study included 122 patients with BR alone, 50 BRRA, 50 RA without lung disease, compared with 87 asthma and 79 healthy subjects as controls. All RA patients met the 2010 ACR criteria for RA. ACPA were measured using CCP2 and fine specificities to citrullinated α-enolase (CEP-1: ⁴KIHA-cit-EIFDS-cit-GNPTVE²¹), citrullinated vimentin (cVim: ⁵⁹VYAT-cit-SSAV-cit-L-cit-SSVP⁷⁴) and citrullinated fibrinogen, ß chain (cFib: ³⁶NEEGFFSA-cit-GHRPLDKK⁵²), with their arginine control peptides (REP-1, Vim, and Fib) by ELISA. The cut-off for positivity for CCP2 was 5 U/ml as per manufacturers instructions and for the remaining peptides was calculated using the 95^th percentile of the healthy controls. The Mann-Whitney U test was used to calculate p-values for differences between the results for each assay and Spearman non-parametric correlations between datasets were calculated.

Results

In the BR patients without RA, there was an increased antibody reponse to the uncitrullinated variants of the antigens tested in this study. Anti-CCP2 antibodies were positive in 5% of patients, significantly increased above the healthy (p< 0.001) and asthma (p<0.01) controls. The anti-CCP2 arginine control test (anti-CPArg) was also significantly increased in 19%. Similarly, antibodies to the arginine control peptides from the specific citrullinated antigens were also increased: REP-1 19% (p <0.01), Vim 16% (p<0.01) and Fib 9% (p ns), compared to both healthy and asthma controls. There was a corresponding increase in antibodies to the citrullinated peptides which in each case strongly correlated with their uncitrullinated variants (Spearman ρ values =0.512- 0.798), further supporting the findings of a citrulline-independent autoantibody response in BR.

In contrast to the BR patients, the BRRA patients had a highly citrulline specific ACPA response and the rate of seropositivity in BRRA vs RA was significantly increased for each ACPA tested: anti-CCP, 88% vs 48%; anti-CEP-1, 60% vs 24%; anti-cVim, 56% vs 20% and anti-cFib 74% vs 40% (each p<0.001) despite a lower frequency of smoking (42% vs 58%; p=0.06). The citrulline specificity of the RA ACPA response was confirmed by the lack of correlation with response to the arginine-containing peptides (Spearman ρ values < 0.298). Collectively, these data show that the citrulline specificity of ACPA in BRRA is increased compared to BR alone and its magnitude is increased compared to RA without any lung disease.

Conclusion

These findings provide further evidence linking BR to RA by indicating that BR may generate ACPA in two stages: firstly a citrulline independent B-cell response to host or bacterial antigens in the lungs with a subsequent evolution of citrulline specificity in the cases where BR evolves into BRRA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bronchiectasis-a-model-for-chronic-bacterial-infection-inducing-autoimmunity-in-rheumatoid-arthritis/