Low sRAGE Level is Associated with Increased Future Exacerbation Risk in Mild-to-Moderate COPD and Patients with Chronic Bronchitis Symptoms.

Background: Early identification of patients at high-risk for exacerbation in mild-to-moderate chronic obstructive pulmonary disease (COPD), particularly those with chronic bronchitis (CB) phenotype exhibiting worse outcomes, is critical for slowing lung function decline and reducing the subsequent healthcare burden. While the soluble receptor for advanced glycation end products (sRAGE) correlates with emphysema severity in COPD, in mild-to-moderate COPD or patients with CB symptoms, no prospective investigation has evaluated the association between sRAGE and exacerbation risk. Methods: Sub-cohort data from the COMPASS study, a prospective study in China, were analyzed. Associations between sRAGE levels and exacerbations were assessed treating sRAGE as a continuous variable and categorized into tertile. Negative binomial regression and cox regression were used to assess exacerbation rate and onset time. Subsequent analyses of lung function, COPD Assessment Tool (CAT) score and high-resolution computed tomography (HRCT) parameters were evaluated using linear mixed-effects models based on a cutoff determined by Akaike information criteria (AIC). Results: In the COMPASS sub-cohort, 201 patients had mild-to-moderate COPD and 230 individuals reported CB symptoms. Continuous sRAGE level was not associated with exacerbation risks, but with earlier onset time. In addition, participants in the lowest sRAGE tertile exhibited significant shorter time to first exacerbation in both populations. The lowest tertile was also associated with increased exacerbation risks in patients with CB and showed a borderline significant association in patients with mild-to-moderate COPD. No significant differences in lung function decline, HRCT changes, or CAT score progression were observed between the low- and high-sRAGE groups. Conclusion: Lower sRAGE level may be associated with an increased exacerbation risk in mild-to-moderate COPD and in patients with CB symptoms. Blood sRAGE is a candidate biomarker for identifying subgroups at higher exacerbation risk in populations at high risk of disease progression. Clinical Trial Registration: Clinicaltrials.gov identifier NCT04853225; GSK study code 208630.