Reply to Pouwels et al.: Confounding Factors Affecting sRAGE as a Biomarker for Chronic Obstructive Pulmonary Disease

From the Authors:

We welcome the letter from Pouwels and colleagues, who provide recent and historical evidence to amplify the issues related to the role of smoking and exacerbations in the interpretation of sRAGE (soluble receptor for advanced glycation end-products) data (and other biomarker data) in chronic obstructive pulmonary disease (COPD). The main purpose behind our review of biomarkers in COPD (1) was to draw the reader’s attention away from statistical differences and to the complexity of interpreting what appears to be straightforward data. This is central to the potential use of markers for understanding the pathophysiology of a disease, developing disease-specific treatments, and managing patients. As indicated in our review, sRAGE is a measurable serum factor that acts as a decoy for ligand binding, thereby reducing the inflammation pathway activated by cellular RAGE binding within the lung or peripherally.

We noted the overall variability of this marker in COPD, as well as some factors that may influence its measurement in individuals. In our review, we cited the publication by Iwamoto and colleagues, who demonstrated that smoking alone decreased sRAGE in both control subjects and patients with COPD (2). Pouwels and colleagues discuss this important issue in more detail while highlighting the controversy in the literature regarding the effects of smoking (3), together with their own data using two validated assays to demonstrate an acute smoking effect in both healthy control subjects and patients with COPD (4). This effect is rapid after 2 days of abstention and is similar in control subjects and patients with COPD, suggesting that it is mainly a smoking effect (at least in the circulation). In addition, they remind us that exacerbations do not reduce sRAGE except in hospitalized patients with severe disease of both viral and bacterial causes, although with complete overlap of patient data points (except for two outliers in the stable state), indicating that individual patient values are not discriminatory. They also remind us of a further complicating issue of ligand binding (5), including the binding to integrins (6), that may also affect the measurement of circulating sRAGE.

Importantly, the letter reminds readers that in COPD biomarker studies, just the smoking issue alone adds a major degree of complexity for interpretation. It is also worth noting that the sRAGE reduction seen in patients with COPD and smokers is also a feature of idiopathic pulmonary fibrosis (7), a condition with a totally different pathology, and therefore is likely to be a nonspecific feature of inflammation. Whether it can be used as a marker of different clinical types once COPD has been confirmed, or as a marker of effective treatment in some instances remains to be determined.