Response to: ‘Corresponence on ‘Shared epitope defines distinct associations of cigarette smoking with levels of anticitrullinated protein antibody and rheumatoid factor’ by Ishikawa et al’ by Regueiro and Gonzalez

We are pleased to welcome the correspondence by Regueiro and Gonzalez1 on our work.2 As they wondered if cigarette smoking (CS) introduced a differential association between the two subsets of patients with shared epitope (SE) and high anticitrullinated cyclic peptide/protein antibody (ACPA) described in figure 3B of the original manuscript, we add further explanation as follows; as shown in figure 3B of the original manuscript, smokers at the time of disease onset (SaO) with SE alleles have higher (OR 3.10, 95% CI 1.82 to 5.11, p=2.3×10−5) than never smokers with SE alleles (OR 2.24, 95% CI 1.56 to 3.24, p=1.5×10−5), while SaO without SE alleles does not have significant risk of high ACPA levels (OR 0.49, 95% CI 0.16 to 1.53, p=0.22). This indicates that CS does not independently affect ACPA production, but rather interacts with SE alleles and further increases the risk. Furthermore, we presented the linear association between SaO with SE alleles and ACPA levels (not presence of high ACPA level) in online supplementary …