Background and Objectives In rheumatoid arthritis (RA), smoking has been described to be specifically associated with the presence of anti-citrullinated protein antibodies (ACPA). However, smoking has also been shown to be associated with the presence of autoantibodies in various other autoimmune diseases, such anti-dsDNA in systemic lupus erythematosus and anti-Jo1 in idiopathic inflammatory myopathy. We therefore investigated whether smoking is specifically associated with ACPA-positive RA, or with autoantibody-positive RA in general. Materials and Methods A meta-analysis was performed using RA patients from 5 countries: Norway, the Netherlands, Japan, Sweden, and the United Kingdom. Complete data on rheumatoid factor (RF)-, ACPA-status and tobacco exposure were available for 6320 RA patients. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the presence of RF, ACPA or both, were calculated by logistic regression comparing ever smokers with never smokers, and using the RF-negative ACPA-negative RA patients as the reference category. Results There was no significant association between smoking and RA in patients who were positive for only one antibody, being either RF (OR 1.04, 0.76 – 1.42) or ACPA (OR 1.00, 0.82 – 1.22). However, smoking was significantly associated with double-positive (RF-positive and ACPA-positive) RA (OR 1.55, 1.20 – 2.00). When ANA-status was also taken into account in the Dutch cohort, the association with smoking was strongest for the triple-positive group (OR = 2.43, 95% CI 1.47 – 4.00), although the difference with the double-positive RA patients (RF- and ACPA-positive, ANA-negative) (OR = 1.73, 95% CI 1.14 – 2.62) was not statistically significant. Conclusions Smoking is not specifically associated with ACPA-positive RA, but rather with the concurrent presence of RF and ACPA in RA patients. These data indicate that smoking predisposes to the development of several autoantibodies, and that current hypotheses about the role of smoking in the pathophysiology of RA may need to be revisited.

Background In rheumatoid arthritis (RA), several genetic risk factors and smoking are strongly associated with the presence of anti-citrullinated protein antibodies (ACPA), while much less is known about risk factors for ACPA-negative RA. Antibodies against carbamylated proteins (anti-CarP) have been described in both ACPA-positive and ACPA-negative RA patients. Objectives In this study we have analysed the relationships between anti-CarP antibodies, ACPA, genetic risk factors (HLA-DRB1 alleles and PTPN22) and smoking in RA. Methods Presence of antibodies to carbamylated fetal calf serum (CarP-FCS) and fibrinogen (CarP-Fib) was determined by in-house ELISAs in the Leiden Early Arthritis Cohort (EAC) and in the Swedish Epidemiological Investigation of RA (EIRA) cohort. Odds ratios for associations with different HLA-DRB1 alleles, PTPN22 genotypes and smoking were calculated separately for each cohort as well as in the combined meta-analysis, in RA subsets defined by anti-CarP and anti-cyclic citrullinated peptide (CCP) antibody status. Results In both cohorts, anti-CarP antibodies were mainly detected in the anti-CCP-positive population, but also in the anti-CCP-negative population. No associations between anti-CarP antibodies and HLA-DRB1 shared epitope alleles could be identified, while a consistent signal for an association between anti-CarP-FCS and HLA-DRB1*03 was observed. Further analyses did not reveal any specific associations of anti-CarP antibodies with other HLA-DRB1 alleles, PTPN22 genotypes or smoking. Conclusions Anti-CarP antibodies were present in both ACPA-positive and ACPA-negative RA. Except for a modest association with HLA-DRB1*03, there were no strong associations between anti-CarP antibodies and HLA-DRB1 alleles, PTPN22 or smoking. These data suggest that different biological mechanisms may underlie anti-CarP versus anti-CCP antibody formation. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4653

Background Smoking is associated with the presence of autoantibodies in various diseases, such as chronic obstructive pulmonary disease (COPD)1, systemic lupus erythematosus (SLE)2 and polymyositis3. In rheumatoid arthritis (RA), smoking is assumed to be specifically associated with the presence of anti-citrullinated protein antibodies (ACPA), with smoking putatively leading to increased pulmonary citrullination. 4 Objectives To investigate whether the association of smoking with RA is limited to ACPA-positive disease, or whether smoking is associated with autoantibody-positive RA in general. Methods A meta-analysis based partly on published data (2 cohorts)4,5, and partly on new data (4 cohorts) was performed using 6 cohorts of RA patients from 5 countries: United Kingdom, Sweden, Norway, Japan, and the Netherlands. Complete data on rheumatoid factor (RF)-, ACPA-status and tobacco exposure were available for 7055 RA patients. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the presence of RF, ACPA or both were calculated by logistic regression comparing previous and current smokers with non-smokers, and using the ACPA-negative RF-negative RA patients as the reference category, since not all cohorts had matched controls. Results There was no significant association between tobacco exposure and seropositive RA in patients who were positive for only one antibody, being either RF (n = 644, OR 1.04, 95% CI 0.75 – 1.44) or ACPA (n = 770, OR 1.00, 95% CI 0.83 – 1.22). However, smoking was significantly associated with double-positive (ACPA-positive and RF-positive) RA (n = 3598, OR 1.61, 95% CI 1.31 – 2.00). When double-positive patients were compared to single-positive patients, the effect of the additional presence of RF or ACPA was comparable; OR for RF: 1.42 (1.20 – 1.67), OR for ACPA: 1.49 (1.25 – 1.87). Conclusions Smoking is not associated with ACPA-positive RA as such, but rather with the concurrent presence of multiple autoantibodies (RF and ACPA) in RA patients. In light of the association between smoking and autoantibodies in other diseases such as SLE and COPD, these data indicate that smoking predisposes to the development of auto-antibodies in general, and not to the development of ACPA per se. References Feghali-Bostwick C. A. et al. 2008 Am J Respir Crit Care Med. 177(2):156-63 Freemer M. M. et al. 2006 Ann Rheum Dis. 65(5): 581-4 Chinoy H. et al. 2012 2012 Ann Rheum Dis. 71(6): 961-5 Klareskog L. et al. 2006 Arthritis Rheum. 54(1): 38-46. Morgan A. W. et al. 2009 Arthritis Rheum. 60(9): 2565-76 Disclosure of Interest None Declared