Studies on aetiology of inflammatory diseases such as rheumatoid arthritis (RA) need to investigate the potential environmental triggers that are active before onset of disease, the genetic context in which these triggers act, and whether the presence of such triggers in an arthritis prone genetic context will give rise to the immune reactions associated with/preceding RA. Such knowledge would help not only to address much better the issue of causality of these potential triggers and the immune reactions, but also to carry out various interventions aimed at influencing the disease provoking immune events before development of clinical signs of disease. This short report summarises recent data demonstrating (a) the presence of anticitrullin antibodies or rheumatoid factors in between a third and half of patients with RA before development of clinical signs; (b) long term smoking is associated with a high risk of future development of seropositive but not seronegative RA; and (c) a strong gene-environment interaction between smoking and SE genes in the development of seropositive RA. We conclude that, in a certain genetic context, smoking is a potential trigger of RA, and a combination of the two factors is associated with the occurrence of immune reactions long before the onset of RA.