Reply: Occupational Exposures in Rheumatoid Arthritis-related Airway Disease: A Missing Link?

From the Authors:

We thank Drs. Lee and Strek for their thoughtful reading of our review highlighting the current knowledge of airway disease manifestations in patients with rheumatoid arthritis (RA) (1). In their response to our review, Drs. Lee and Strek aptly highlight an unexplored part of this discussion: the association between occupational and inhalational exposures beyond cigarette smoking and the development of RA. In fact, this paradigm of exposure to concentrated inhalational exposure such as seen in World Trade Center disaster site workers, followed by the development of RA, fittingly supports one of the conceptual models we presented in our review article. In our proposed model of RA autoimmunity development, bronchus-associated lymphoid tissue responds to local inflammatory pressures that can be triggered by a variety of inhaled factors with the production of RA autoantibodies such as antibodies to citrullinated peptide antigens. In this review, we highlighted the potential role of neutrophil extracellular trap formation (NETosis) in connecting chronic lung inflammation to development of antibodies to citrullinated peptide antigens, and although cigarette smoking has been shown to induce NETosis in models, there is a paucity of data regarding the role of other inhalational injuries on NETosis (2).

We read the recent publication from Drs. Lee and Strek regarding the spectrum of occupational and inhalational exposures found in a large interstitial lung disease registry with great interest (3). We believe their data highlight the underexplored role of inhalational exposures in chronic lung disease regardless of etiology, including RA lung manifestations such as interstitial lung disease (3). The themes in Drs. Lee and Strek’s response highlight the need to understand the role of inhalational injury in NET formation and subsequent development of autoimmunity across chronic lung disease states. Importantly, NET cargo release varies based on the antigenic trigger (4); therefore, it would follow that unique inhalational risks may confer specific autoimmune risk based on the nature of the NET response induced.

We believe, as Dr. Lee and Strek point out, that ongoing clinical exploration of lung disease in patients with RA, including inhalational exposure assessment, remains paramount when approaching the many questions remaining in this realm. Airway disease in RA represents a broad set of manifestations with several potential pathways of development and many unanswered questions for screening, diagnosis, and treatment.