Background Rheumatoid arthritis (RA) is a systemic, inflammatory disease with an estimated global prevalence of 0.3–1.0%. Evidence suggests that RA is initiated in the lungs. Cigarette smoking and various occupations associated with vapour, gas, dust, and fume (VGDF) inhalation can increase the risk of RA development. The association of VGDF, smoking, development of rheumatoid autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) and their relationship to RA disease development is poorly understood. Structure There are seven chapters in the dissertation. Chapter 1 introduces the dissertation reasoning and hypothesis. Chapter 2 is a published review of literature on RA and inhaled occupational exposures. Chapters 3 and 4 are published empirical studies analysing the clustering pattern of RF and ACPA, suggesting a potential common autoantigen in RA. Chapter 5 is a published empirical study analysing the pattern of autoantibody development with inhalational exposures to smoking and VGDF in male RA. Chapter 6 analyses the role of cadmium (as a common factor in smoking and VGDF), in relation to autoantibody development in nodular and non-nodular RA. Chapter 7 discusses further the strengths, limitations, unanswered questions and future direction of research. Conclusions Overall, this research provides evidence that RA, particularly in males, is precipitated by inhaled environmental exposures and RA patients with multiple inhalational insults are likely to have higher RF and ACPA levels. Empirical and laboratory evidence suggests a common autoantigen in RA to explain autoantibody clustering. Nodular RA patients demonstrate higher rheumatoid autoantibody levels, and significantly higher cadmium levels were found in female nodular RA patients. A model of heavy metal adsorption onto VGDF particles in vitro is proposed, stimulating pulmonary nodule formation and generating autoantibodies in response to a common autoantigen: post-translationally modified heavy chain fragments of immunoglobulin G
