Table 2 Population studies of RA investigating the association of smoking and anti-CCPs

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].