Risk factors for rheumatoid arthritis : Epidemiological studies of perinatal chracteristics, infections and the inflammatory reflex

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterised by symmetric polyarthritis leading to progressive joint destruction. The aim of this thesis was to contribute to better knowledge of the etiology of RA by investigating the importance of the inflammatory reflex, childhood infections and early life exposures as risk factors for RA, based on four epidemiological studies. In the first study we explored the importance of birth characteristics and infections during the first year of life on the risk of later RA and juvenile idiopathic arthritis (JIA). Using data from the Swedish Hospital Discharge Register, the Swedish Early Rheumatoid Arthritis Register and the Swedish Medical Birth Register, we conducted two parallel case-control studies on 333 cases of early adult onset RA and 3334 cases of JIA, and four matched controls per case. We noted an increased risk for JIA and rheumatoid factor (RF) negative RA following hospitalisation for infection during the first year of life. A somewhat reduced risk for RA was suggested for low birth weight, being small for gestational age and preterm birth. In the second study we aimed to confirm, in a larger study population, the role of infections during early childhood on the risk of developing RA and to extend the assessment of infections to encompass infections throughout childhood. We performed a case-control study using 3038 RA cases, born 1949 or later, identified in the Early Rheumatoid Arthritis Register, and five matched population based controls per case. Exposure information was retrieved from the Swedish Hospital Discharge Register. Overall, hospitalisation for any infection before 16 years of age was associated with anincreased risk of developing RA. No overall difference was noted between RF positive and RF negative RA although RF negative RA was associated with infections during the first year of life and RF positive RA was associated with infections at 8 to15 years. In the third study we aimed at exploring the role of the inflammatory reflex on the risk of RA. In two parallel case-control studies of 63 092 prevalent and 2548 incident RA cases identified in the Swedish Hospital Discharge Register and Swedish Early Rheumatoid Arthritis Register respectively, and matched population based controls, we assessed the association between surgical vagotomy and subsequent risk of developing RA. Vagotomy had no effect on the risk of developing RA. In the fourth study we searched to investigate the role of the inflammatory reflex in humans indirectly, through the effect of nicotine. Using a design where we compared disease risks associated with smoking and with use of moist snuff, we aimed to disentangle the role of nicotine from the effect of other inhaled components of tobacco smoke on the development of chronic inflammation. We conducted a retrospective cohort study on the risk of RA, ulcerative colitis, Crohn s disease, sarcoidosis and multiple sclerosis associated with smoking and use of moist snuff, using a uniquely large cohort of 277 777 Swedish construction workers, who provided prospectively collected information on tobacco using habits between 1978 and 1993. Cross-linkage to the Swedish Hospital Discharge Register provided information on occurrence of disease outcome. Our results confirm and extend previous observations that smoking is a risk factor for (RF positive) rheumatoid arthritis, Crohn s disease and multiple sclerosis, that quitting smoking reduces these risks, that smoking cessation increases the risk of ulcerative colitis and that smoking reduces the risk of sarcoidosis. In sharp contrast, we noted no evidence of any association between use of moist snuff and the risk of either of these chronic inflammatory diseases, with the exception of a borderline increased risk for MS, together indicating no major effect of the inflammatory reflex in the etiology of chronic inflammatory diseases.