The present study provides strong support to recent proposals that RA may not be a single disease entity [28
] but rather a clinical syndrome consisting of at least two distinct diseases with different etiologies. Recent observations suggest that smoking may be selectively associated with RF-positive RA [21
] or anti-CCP-positive RA [22
], notably in genetically predisposed individuals [22
]. We confirm these previous findings that link tobacco smoking to an increased risk of anti-CCP-positive RA, but we also show that a range of other environmental risk factors differ between anti-CCP-positive and anti-CCP-negative RA.
Although unrelated to anti-CCP-negative RA, alcohol consumption 10 years before the interview was significantly inversely linked to risk of anti-CCP-positive RA, suggesting that alcohol may somehow protect against this RA subtype. Other observations are compatible with such a protective effect of alcohol. In one study, alcohol intake at the time of first visit to a rheumatology department was lower among women with RA than among women with soft tissue rheumatism or osteoarthritis [11
], and other researchers have suggested a protective effect of alcohol that may be more pronounced in RF-positive than in RF-negative RA [12
]. Possibly, the unspecific immune suppression exerted by alcohol [30
] might somehow be beneficial in relation to risk of anti-CCP-positive RA if immune mechanisms involved in the pathogenesis of this RA subtype are affected.
Associations with coffee intake or use of oral contraceptive pills were not significantly different for the two subtypes of RA. However, after adjustment for tobacco smoking and a large number of other potential confounders, coffee and oral contraceptives appeared to be more strongly associated with risk of anti-CCP-positive RA than with anti-CCP-negative RA. Prior studies that did not make a clear distinction between anti-CCP-positive and anti-CCP-negative RA have yielded conflicting results for these exposures [8
]. Additional studies are needed to determine whether coffee intake and use of oral contraceptives are subtype-specific risk factors associated with anti-CCP-positive RA only.
Although the test for difference between anti-CCP-positive and anti-CCP-negative RA was not significant, a strong positive association with having a first-degree relative with schizophrenia was present for anti-CCP-positive RA only. An association between schizophrenia and RA is potentially interesting because the prevalence of RA was recently found to be significantly higher in parents of schizophrenia patients compared with parents of non-psychiatric comparison subjects [32
]. Furthermore, a genetic link between schizophrenia and RA has been suggested [33
]. In apparent contrast, however, studies of intra-individual disease correlations have shown a deficit
of RA diagnoses in patients with schizophrenia. If true, such an inverse association might suggest that predisposition to schizophrenia may somehow reduce the likelihood that the same individual will also develop RA. Of note, however, underdiagnosis of non-psychiatric health conditions in patients with schizophrenia may make intra-individual disease associations in schizophrenics hard to interpret [34
]. The strength of the association observed here between anti-CCP-positive RA and schizophrenia in first-degree relatives is unlikely to be the result of spurious recall problems among study participants, but speculations about possible etiological implications should await confirmatory findings in other settings.
A high body mass index was strongly and selectively associated with increased risk of anti-CCP-negative RA, a finding that has not been reported previously. A chance finding appears unlikely given the highly significant trend with increasing body mass index and its specificity to anti-CCP-negative RA. Theoretically, however, although we included only patients who fulfilled ACR 1987 diagnostic criteria for RA as cases in our study, we cannot exclude the possibility that some anti-CCP-negative patients actually had inflammatory osteoarthritis, which is positively associated with body mass index. Consequently, confirmatory findings in other settings are needed. Possibly, the lacking identification of other etiological candidates for anti-CCP-negative RA might reflect that this RA subtype comprises a heterogeneous group of etiologically distinct inflammatory arthritides.
The female predominance in RA has prompted suggestions that sex hormones and reproductive factors may be etiologically involved [16
]. However, in the present study, the only interesting reproductive factor was age at menarche, a finding that accords well with prior findings that women with early menarche are at comparatively low RA risk [35
]. We also searched for clues to a possible venereal etiology, but associations with all examined sexual behaviors and sexually transmitted diseases were consistently non-significant. There was also no indication that infection with parvovirus B19 or Epstein-Barr virus, two previously suggested etiological candidates [37
], would have any bearing on the risk of either anti-CCP-positive or anti-CCP-negative RA.
The patients in our study, identified at hospital departments of rheumatology and internal medicine throughout Denmark over a 5-year diagnostic period, are likely to be representative of patients with RA in need of hospital care. Our findings may not necessarily apply to milder cases of RA managed in outpatient settings, although we have little reason to believe that associations would differ in other RA populations. Although the participation rate was high (83%) among RA cases, invited population controls were slightly more reluctant to participate (64%). Theoretically, such a difference might lead to biased associations for some of the studied risk factors, to the extent these factors were also associated with the decision to accept or decline our invitation to participate. If invited subjects who did not want to participate comprised more tobacco smokers than those who actually participated, such non-random self-selection might have contributed to the observed positive dose-response association with tobacco consumption. However, the supporting evidence for a genuine RA subtype-specific effect of tobacco smoking in anti-CCP-positive RA which has been described by other researchers [22
] and the lack of a spurious positive association between smoking and anti-CCP-negative RA in our study, suggest that the hypothetical impact, if any, of a relative deficit of tobacco-smoking controls would be small. Additionally, because tobacco and alcohol consumption are positively correlated behaviors, the observed inverse association between alcohol intake and risk of anti-CCP-positive RA cannot plausibly be explained by the lower participation rate among controls. If influenced at all, the inverse and RA subtype-specific association with alcohol consumption reported here is likely to be conservative.
We assessed risk factors retrospectively by means of telephone interviews, so the possible influence of recall problems among study participants needs consideration. Because patients with RA are unlikely to be aware of their anti-CCP antibody status and because exposures covered by our questionnaire are not broadly recognised as RA risk factors, we believe that misclassification arising from recall problems would most likely have been non-differential and tended to produce conservative ORs and blur risk factor differences between the two RA subtypes. The RA subtype-specific risk factor associations we observed are therefore unlikely to be the result of recall problems among our study participants.