Smoking & Autoantibodies in Rheumatoid Arthritis Save

Investigators from the Netherlands have published their findings that smoking is a risk factor in rheumatoid arthritis (RA), led by the induction of local autoimmune responses at mucosal sites (in the lungs) and exemplified by RA-specific autoantibodies. 

RA is characterized by the presence of autoantibodies against modified proteins, known as anti-modified protein autoantibodies (AMPAs), including ACPA (CCP) and others, particularly of the IgA isotype.

They assessed AMPAs in 618 RA patients [including anti-citrullinated protein antibodies (ACPA-) and anti-acetylated protein antibodies (AAPA-) IgA, -IgG and -IgM and RF-IgA and -IgM measured by ELISA] and correlated findings with genetic risk factors, smoking and autoantibodies. A replication analysis assess the same in 3309 RA patients.

Smoking was primarily associated with IgA AMPAs: 

• ACPA-IgA OR 1.89 [1.14–3.12], 
• AAPA-IgA 2.30 [1.35–3.94]). 

These results were substantiated in a meta-analysis of 3309 RA patients, showing that smoking was predominantly associated with the combined presence of ACPA-IgA in addition to ACPA-IgG (OR 2.05 [1.69–2.49], p < 0.001) versus the single presence of ACPA-IgG (OR 1.18 [0.97–1.44], p = 0.11). 

The shared epitope HLA alleles interacted with smoking as a risk factor, but only in patients that were both ACPA-IgG and ACPA-IgA positive, but not in patients who were only positive for ACPA-IgG.

These findings lend credence to the mucosal hypothesis underlying RA pathogenesis and that local (auto)immunity at mucosal sites is pivotal.