Table 2.
Population studies of RA investigating the association of smoking and anti-CCPs
| Study population | Results |
| Incident cases of arthritis (n = 1,305) (undifferentiated arthritis, n = 486; RA, n = 407) | Smoking increases the risk of anti-CCPs only in shared epitope-positive patients [63]. |
| National case–control study (515 RA patients and 769 controls) | Smoking is related to an increased risk of anti-CCP-positive RA [64]. |
| Consecutive sera of RA patients (n = 241) | Higher anti-CCP titers are associated with tobacco exposure. |
| Anti-CCP seropositivity is associated with a higher incidence of erosions. | |
| Moderate correlation between anti-CCP and rheumatoid factor titers [65]. | |
| Case–control study (EIRA, 967 RA patients and 1,357 controls) | Previous smoking is dose-dependently associated with occurrence of anti-CCPs. |
| Presence of double copies of shared epitope alleles confers about 20-fold risk for anti-CCP-positive RA in smokers [66]. | |
| Nationwide case–control study (309 seropositive RA and 136 seronegative RA patients and 533 controls) | There is an increased risk for anti-CCP-positive RA in heavy smokers with homozygote shared epitope alleles [67]. |
| Study of Leiden Early Arthritis Clinic (977 patients with early arthritis) | HLA-DRB1*0401, HLA-DRB1*0404, HLA-DRB1*0405, or HLA-DRB1*0408 shared epitope alleles confer the highest risk of developing anti-CCPs. |
| Smoking-shared epitope interaction is highest in case of HLA-DRB1*0101 or HLA-DRB1*0102 and HLA-DRB1*1001 shared epitope alleles [68]. | |
| Study of Leiden Early Arthritis Clinic (n = 216) | Current or former tobacco smoker anti-CCP-positive RA patients show a more extensive anti-CCP isotype usage, valid for shared epitope-negative RA patients too [69]. |
| French population of RA patients (n = 274, one-half of them multicase families) | Presence of at least one shared epitope allele (especially the DRB1*0401 allele) is related to the presence of anti-CCPs [70]. |
| Case-only analysis of three North American RA cohorts (n = 2,476) (NARAC, n = 1,105; SONORA, n = 618; Inception Cohort, n = 753) | There is an association between smoking and anti-CCP in the NARAC and the Inception Cohort, but not in the SONORA. |
| Only the NARAC cohort supports evidence for the interaction of smoking and shared epitope alleles in anti-CCP-positive RA [71]. | |
| African Americans with recent-onset RA (n = 300) | There is no association between smoking and anti-CCPs [72]. |
| Three case–control studies (1,977 cases and 2,405 controls) (EIRA, NARAC, Dutch Leiden Early Arthritis Clinic) | There is an association of smoking, HLA-DRB1 shared epitope alleles and anti-CCP-positive RA. |
| No interaction between smoking and PTPN22 is found [73]. |
CCP, cyclic citrullinated peptide; EIRA, Epidemiological Investigation of Rheumatoid Arthritis; Inception Cohort, National Inception Cohort of Rheumatoid Arthritis Patients; NARAC, North American Rheumatoid Arthritis Consortium; PTPN22, protein tyrosine phosphatase nonreceptor 22; RA, rheumatoid arthritis; SONORA, Study of New Onset Rheumatoid Arthritis.