This report describe smoking and risk of RA in a novel way regarding the impact of smoking both concerning its contribution to RA and concerning the dose-dependent addition of risk conferred by smoking in individuals with different numbers of HLA-DRB1 risk alleles. We also provide novel data on effects of cessation of smoking concerning future risk for RA.
The demonstration that approximately one third of cases of ACPA-positive RA, the most severe variant of RA, appear to be attributed to smoking illustrates the impact of smoking as a major cause of RA on the population level. Notable is that this attribution appears to be higher in men than in women. The smoking attribution to RA is however smaller than the smoking attribution to lung cancer which is estimated to be as high as 90 % [15
], but similar to that seen for ischaemic heart disease [16
The data on interactions between smoking and HLA-DR alleles in providing risk for RA in the present report are in accordance with those published from studies in several different countries [4
], including studies from the Nurses Health (NHS) cohort study [5
]. In one other US-based case-only study the effects of smoking was more limited but still statistically significant [18
Other environmental and genetic factors may modify the effects of smoking on the development of RA. There are indications that airborne exposures such as silica and other air pollutants may enhance or possibly dilute the effects of smoking [19
]. There are also other life style factors such as alcohol consumption or hormonal factors influencing risk for RA that may interact with smoking [20
]. Thus, the precise effects of smoking on RA development may vary considerably in various populations, but so far smoking has been shown to be an essential risk factor for RA in a majority of published studies.
We used case-control methodology to generate data regarding risk for RA as a whole as well for ACPA-positive and ACPA-negative RA in the context of various HLA-DR genes and smoking. The fact that more than 50% of RA cases can be attributed to smoking in individuals carrying two copies of the HLA-DRB1 SE genes, illustrates drastically how smoking may affect disease risk differently in different individuals. Although this type of data should not be taken as an argument of genotyping of healthy individuals, they may provide a rationale for specific counselling against smoking for individuals with a family history of RA.
The problem of selection bias always encountered in case-control studies was in the current study minimised by the population-based design and by the observation that smoking habits did not differ between controls with and without blood samples. This, and the fact that identification of controls was made by matching for age, sex and residential area in the same population that generated the cases, makes us confident that the results are reliable from a methodological standpoint.
In conclusion, the data presented in this paper on the impact of smoking on development of RA, warrants more active information on the association between smoking and RA to the general public as well as to relatives of patients with RA.
To which extent cessation of smoking will be able to alleviate an already ongoing RA is yet incompletely known, although it has been demonstrated that smoking contributes to cardiovascular disease, which is the major reason for premature death in RA [22
]. There are many reasons for the medical community to communicate the known facts on smoking and RA, with the aim to diminish smoking and prevent RA and its consequences.