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 phases 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.

Keywords: Anti-citrullinated protein antibodies (ACPA); Lung; Pre-RA; Pulmonary; Rheumatoid arthritis (RA); Smoking.

Figure

Schematic of proposed biologic mechanisms linking smoking and the lung to preclinical phases in the pathogenesis of anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). An asymptomatic individual with high genetic risk, such as the HLA-DRB1 shared epitope, is exposed to environmental triggers such as cigarette smoking. This induces mucosal inflammation in the airways and alveoli of the lung. Activated enzymes, including peptidylarginine deiminase (PAD), stimulate citrullination of proteins at these sites to form neoantigens. Antigen presenting cells (APCs) in the innate immune system present these neoantigens through the HLA-DRβ1 protein to T cells that results in adaptive immune system dysregulation and leads to systemic inflammation. Stimulated B cells in the respiratory mucosa produce ACPA. Systemic inflammation leads to non-specific symptoms such as fatigue and arthralgias. Autoantibodies exhibit specificity to peripheral joints eventually leading to synovitis and the clinical diagnosis of ACPA-positive RA.