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Abstract Number: 1917

Sputum TGF-β1 Is Elevated in Subclinical and Clinically Significant Rheumatoid Arthritis-Associated Interstitial Lung Disease and Correlates with Soluble IL-6R Levels

Timothy Wilson1, Kevin Deane2, Joyce Lee1, Christopher Collora3, Marie Feser3, Mariana Kaplan4, Joshua Solomon5 and Kristen Demoruelle6, 1University of Colorado, Denver, CO, 2University of Colorado Denver, Denver, CO, 3University of Colorado Denver, Aurora, CO, 4National Institutes of Health, Bethesda, MD, 5National Jewish Health, Denver, CO, 6University of Colorado Anschutz Medical Campus, Aurora, CO

Meeting: ACR Convergence 2021

Keywords: Fibroblasts, Other, interstitial lung disease, rheumatoid arthritis, Transforming Growth Factor (TGF)

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Session Information

Date: Tuesday, November 9, 2021

Session Title: Abstracts: RA – Diagnosis, Manifestations, & Outcomes II: Heart & Lung (1915–1918)

Session Type: Abstract Session

Session Time: 2:30PM-2:45PM

Background/Purpose: Increased levels of transforming growth factor β1 (TGF-β1) in the lung have been implicated in the pathogenesis of several fibrotic lung diseases, but their role in the lung in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) has not been well studied. Evidence suggests that increased TGF-β1 production in the lung can be driven by IL-6 trans-signaling, which requires soluble IL-6 receptor (sIL-6R) complexed with IL-6 binding to membrane-bound gp130; this is in contrast to IL-6 classical-signaling that requires IL-6 binding to membrane-bound IL-6R (mIL-6R). Importantly, gp130, and not mIL-6R, is present on lung fibroblasts which play a key role in lung fibrosis. Also, mIL-6R is present on neutrophils and can be released to form sIL-6R during neutrophil extracellular trap (NET) formation. In this study, we sought to evaluate the relationships between TGF-β1, sIL-6R, NETs and the presence of ILD across a spectrum of patients with RA.

Methods: We included 16 RA patients with clinically significant ILD (RA-ILD), 22 RA patients with subclinical ILD defined as having parenchymal changes on lung high resolution computed tomography (HRCT) (i.e. fibrosis, traction bronchiectasis, reticulation and/or ground glass opacities) but no clinical diagnosis of ILD and normal pulmonary physiology (RA-sub-ILD), and 24 RA patients without ILD on HRCT (RA-no-ILD). All subjects underwent pulmonary function testing (PFT) and induced sputum was collected using hypertonic saline. Sputum was tested for TGF-β1 (Meso Scale Diagnostics) and sIL-6R (R&D Systems). Sputum IL-6 was measured in a subset of 8 RA-ILD, 4 RA-sub-ILD and 3 RA-no-ILD (Luminex) and sputum NET remnants in a subset of 11 RA-ILD and 3 RA-sub-ILD patients (sandwich ELISA for DNA-neutrophil elastase (NE) and DNA-citrullinated histone H3 (DNA-citH3)).

Results: Patient demographics are summarized in Table 1. Sputum TGF-β1 and sIL-6R levels were significantly higher in RA-sub-ILD and RA-ILD compared to RA-no-ILD (Figure 1A and 1B). In regression analyses adjusting for age and smoking, TGF-β1 and sIL-6R levels remained significantly associated with RA-sub-ILD and RA-ILD. Sputum TGF-β1 correlated with sIL-6R levels (Figure 1C) while there was no correlation between TGF-β1 and IL-6. In a subset of RA-sub-ILD and RA-ILD subjects, sputum NET remnants positively correlated with sputum sIL-6R levels (Figure 2A and 2B) but not TGF-β1 levels (p >0.20).

Conclusion: We found for the first time that sputum TGF-β1 and sIL-6R levels are increased in subclinical and clinically significant RA-ILD. The strong correlation between sputum TGF-β1 and sIL-6R along with the correlation between sputum sIL-6R and NET remnants suggest that increased TGF-β1 in the lung may be due to NET-associated increases in sIL-6R and subsequent IL-6 trans-signaling of lung fibroblasts. Future studies are needed to better understand the use of sputum TGF-β1 and sIL-6R as prognostic biomarkers in RA-ILD as well as mechanisms by which TGF-β1 production and IL-6 trans-signaling in the lung may contribute to RA-ILD.


Disclosures: T. Wilson, None; K. Deane, Inova Diagnostics, Inc, 5, Bristol Meyers Squibb, 1, 5, Janssen Research and Development, LLC, 5, imaware, 2, ThermoFisher, 2, 5, Medscape, 6; J. Lee, None; C. Collora, None; M. Feser, None; M. Kaplan, None; J. Solomon, None; K. Demoruelle, Pfizer, 5.

To cite this abstract in AMA style:

Wilson T, Deane K, Lee J, Collora C, Feser M, Kaplan M, Solomon J, Demoruelle K. Sputum TGF-β1 Is Elevated in Subclinical and Clinically Significant Rheumatoid Arthritis-Associated Interstitial Lung Disease and Correlates with Soluble IL-6R Levels [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/sputum-tgf-%ce%b21-is-elevated-in-subclinical-and-clinically-significant-rheumatoid-arthritis-associated-interstitial-lung-disease-and-correlates-with-soluble-il-6r-levels/. Accessed January 28, 2023.
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