The major finding in the present report is that alcohol consumption exhibits a dose-dependent inverse association with RA. Furthermore, alcohol consumption is associated with attenuation of the effect of the best established risk factors for RA, smoking and HLA-DRB1 SE with regard to ACPA-positive RA.
It is methodologically demanding to investigate the relationship between two life style factors (alcohol, smoking) and one genetic factor (HLA-DRB1 SE) in two subsets of RA, since these factors may be interrelated to varying degrees in RA patients, and as completeness of information and non-biased recruitment of cases and controls is crucial for the reliability of results. The present two studies both utilised unique features of the Scandinavian health care systems in capturing representative and population-based collections of patients and well matched controls. The alcohol consumption differed between the studies. In the Danish CACORA study, the average alcohol consumption was higher than in the Swedish EIRA study, a well-known country difference which is in accordance with WHO information on alcohol consumption in Denmark and Sweden.[29
] The high response frequencies of cases and controls should minimise the risk for selection bias. As always in case-control studies with retrospective exposure information, recall bias is a concern. Most often recall bias relates to the tendency to over-report previous exposure among cases relative to the controls. In our study, the situation is the opposite, i.e. if our results should be explained by recall bias, cases should have systematically understated their previous alcohol consumption in relation to the statements among controls. In order to highlight if RA cases tend to change their alcohol consumption by time, we studied the association between disease duration and alcohol consumption in EIRA. Reported alcohol consumption in RA cases with disease duration less than 6 months did not differ from that of patients with longer disease duration. On the assumption that recall bias is influenced by disease duration, the lack of such association is reassuring. Another potential bias may stem from RA patients treated with methotrexate or non-steroidal anti inflammatory drugs (NSAID). These patients may have been advised to abstain from alcohol by their physician. However, in EIRA, we did not find any differences regarding reported alcohol consumption between cases taking methotrexate or NSAID and cases not taking these medications. In CACORA, questions were asked specifically for the alcohol consumption 10 years back in time which should minimise the risk of differential recall between cases and controls. Although our findings need replication we consider our ability to use two parallel but completely independent studies performed in two countries with similar socioeconomic and cultural conditions to be a strength of this study. Recently, similar findings as ours with regard to alcohol consumption and risk of RA, was presented from a prospective cohort study conducted in south of Sweden. [15
A further concern is that information on interacting exposures such as smoking must be accurate and detailed, and that replication is needed also in these respects. Also here, we are confident that the Swedish and Danish studies on the interaction between smoking and RA have been so consistent, and that these results have been confirmed also in a Dutch study.[2
] Why these results were not fully replicated in a recent study from North America is not yet clear, but may depend on regional differences in the complex interplay between a variety of genetic and environmental factors besides smoking.[30
] Also from this perspective, our combination of independent studies from culturally and genetically similar environments in Sweden and Denmark is advantageous.
Somewhat unexpectedly, we observed an interaction between lack of alcohol and smoking and between lack of alcohol and presence of HLA-DRB1 SE alleles, respectively, with regard to risk of ACPA positive RA. The method used to calculate this interaction is based on a calculation of deviation from additivity and the existence of such interactions is an indication of at least one pathway towards disease in which both risk factors are required.[24
] Further research into mechanisms behind the interactions between smoking and alcohol may thus be of value in helping to understand molecular aspects of the RA pathology, similarly to what appears to be the case from our recent studies of interactions between smoking and the HLA-DRB1 alleles.[2
Evidence that alcohol intake may protect against development of arthritis has recently been obtained also from studies on experimental arthritis, where administration of alcohol both reduced the incidence and severity of collagen induced arthritis in mice.[12
] Further studies on the mechanisms of this protective effect indicated an effect of alcohol on the NFKB-dependent pro-inflammatory signalling pathways, but limited effects on the anti-collagen immune response, i.e. on adaptive immunity.[8
] These data lend some support to the notion that alcohol intake may be causatively associated with a reduced risk for RA also in humans. The evidence from the larger of the two studies, the EIRA, that alcohol intake is inversely related to both ACPA+ and ACPA− RA is compatible with an effect on general pro-inflammatory mechanisms also in human disease. We do not, however, have any good biological hypothesis to explain neither the interaction between alcohol intake and HLA-DRB1 SE, nor the observed interaction between smoking and alcohol intake. Together this calls for extended studies on biological effects of alcohol and related compounds in relation to arthritis.
Seen in a wider perspective of inflammatory diseases, the now observed association of alcohol on the risk to develop RA shows similarities to what has for long been known for cardiovascular disease. Here, moderate alcohol consumption is dose-dependently associated with a decreased risk to develop cardiovascular disease.[31
] Despite many years of research, no clear-cut mechanism has, however, been identified that can explain these relationships. Our current demonstration of a similar effect in a classic inflammatory disease, RA, may shed some light also on the relationship between alcohol consumption and other inflammatory diseases; these relationships should be subject to more combined studies in the future.
In summary, this study has several potential medical implications. From a public health perspective, we consider the findings of interest as they provide new information on how modifiable life style factor may influence the risk of developing RA. In this context, the main message remains that cessation of smoking is the most effective way to diminish risk for RA, irrespective of genetic constitution, but that this recommendation should not necessarily be combined with a recommendation to stop moderate alcohol consumption. Equally interesting are the potential biological implications. The fact that data from both animal and human studies suggest that arthritis risk can be reduced by alcohol – or with other agents having similar effects – should encourage further studies on how such prevention can be achieved.