Cigarette smoking and silica exposure as determinants for the development of rheumatoid arthritis

Abstract. Author Patrik Stolt.

Rheumatoid Arthritis (RA) is an autoimmune, inflammatory disease with obscure etiology. This thesis is based on the hypothesis, that there is a link between respiratory exposures and the development of RA. Cigarette smoking and silica exposure were selected as the environmental exposures to study, as they have previously emerged as probable, but not fully elucidated, risk factors for RA.

The major part of the analyses was based on a population based case-control study, comprising a population, aged 18-70 years, in Sweden. A case was defined as a person in the study base with newly developed RA, defined according to the American College of Rheumatology criteria. Controls were randomly selected from the study base, considering age, gender and residency. Smoking habits, silica exposure, HLD-DR shared epitope (SE) genes, Rheumatoid factor (RF) and antibodies to cyclic citrullinated peptides (anti-CCP) were analysed. Comparisons were made between smokers and never-smokers, between silica exposed men and unexposed men, between carriers of SE genes and persons without SE genes and between persons with various combinations of smoking habits and SE genes and never-smokers without SE genes. Comparisons included the risk of RA overall, and of RA of different RF status and anti-CCP status, by calculating odds ratio (OR) with 95 % confidence interval (95 % CI).            

Smokers had an increased risk of RF+ and anti-CCP+, but not of RF-, or anti-CCP-, RA. Carriers of SE genes and silica exposed men had an increased risk of anti-CCP+, but not anti-CCP-, RA. The increased risk of RA associated with smoking, required a long duration, but merely a moderate intensity of smoking, increased with increasing cumulative dose of smoking and remained for several years after smoking cessation. Smoking was observed to be linked to occurrence of citrulline in lung cells. Evidence for an interaction between smoking and SE genes, and results compatible with, but not conclusive for, an interaction between smoking and silica exposure, in the development of RA, was seen.

This thesis demonstrates that respiratory exposures may be associated with increased risk of developing RA and that this association may be linked to RA related antibodies and influenced by genotype.