The Roles of Cigarette Smoking and the Lung in the Transitions Between Phases of Preclinical Rheumatoid Arthritis

Abstract

While the etiology of rheumatoid arthritis (RA) remains to be fully elucidated, recent research has advanced the understanding of RA pathogenesis to the point where clinical trials for RA prevention are underway. The current paradigm for RA pathogenesis is that individuals progress through distinct preclinical stages prior to the onset of clinically apparent RA. These preclinical RA phases consist of genetic risk, local inflammation, presence of RA-related autoantibodies, asymptomatic systemic inflammation, and early non-specific symptoms prior to clinical seropositive RA. Epidemiologic studies have been important in forming hypotheses related to the biology occurring in preclinical RA. Specifically, studies associating cigarette smoking with overall RA risk as well as transitions between phases of preclinical RA were vital in helping to establish the lung as a potential important initiating site in the pathogenesis of seropositive RA. Herein, we review the epidemiology associating smoking with transitions in preclinical phases of RA as well as the recent literature supporting the lung as a critical site in RA pathogenesis.

Complex Relationships of Smoking, HLA–DRB1 Genes, and Serologic Profiles in Patients With Early Rheumatoid Arthritis: Update From a Swedish Population‐Based Case–Control Study

“…This scenario may be further strengthened from the generation of RF due to reactivity of T cells against antigens present in local immune complexes . Taken together, these data suggest that the dramatic interaction between the HLA–DRB1 SE and smoking in conferring a risk of RF‐positive RA and ACPA‐positive RA requires the simultaneous presence of both of these antibodies.…”

2016 update of the EULAR recommendations for the management of early arthritis

“…Prevention is now considered key in the management of chronic inflammatory rheumatic diseases, but comorbidities are still not optimally managed 76. Smoking is the best-established modifiable risk factor in the development of RA and spondyloarthritis 83 84. Furthermore, tobacco use has been associated with the presence of extra-articular manifestations such as rheumatoid nodules and also serum RF and ACPAs.…”

Lung inflammation in the pathogenesis of rheumatoid arthritis

“…Importantly, however, increased citrullination of proteins in the lung is has been observed in non‐smokers . This suggests that other factors that can be introduced into the lung from the environment such as silica, coal dust, air pollution, or microbial factors, may have interactions with genes and other aspects of the immune system to drive the generation of ACPA or other RA‐related immune factors . Specifically, environmental factors may activate innate immune cells through pattern‐recognition molecules, as well as alter the lung microbiome .…”

“…58 This suggests that other factors that can be introduced into the lung from the environment such as silica, coal dust, air pollution, or microbial factors, may have interactions with genes and other aspects of the immune system to drive the generation of ACPA or other RA-related immune factors. 59,60 Specifically, environmental factors may activate innate immune cells through pattern-recognition molecules, as well as alter the lung microbiome. 59 These events may in turn activate additional pro-inflammatory cascades and immune responses and ultimately lead to the tissue damage observed in ILD and other forms of lung disease in RA.…”