Bischoff, Rainer

Klont, Frank

Pouwels, Simon D

Ten Hacken, Nick H T

ARTS repository - University of Groningen

   University of GroningenConfounding Factors Affecting sRAGE as Biomarker for COPDPouwels, Simon D; Klont, Frank; Bischoff, Rainer; Ten Hacken, Nick H TPublished in:American Journal of Respiratory and Critical Care MedicineDOI:10.1164/rccm.201902-0356LEIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Pouwels, S. D., Klont, F., Bischoff, R., & Ten Hacken, N. H. T. (2019). Confounding Factors AffectingsRAGE as Biomarker for COPD. American Journal of Respiratory and Critical Care Medicine, 200(1), 114.https://doi.org/10.1164/rccm.201902-0356LECopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 11-09-202320. Health Effects Institute. Traffic-related air pollution: a critical review ofthe literature on emissions, exposure, and health effects. Boston,MA: Health Effects Institute; 2010. Special Report 17.Copyright © 2019 by the American Thoracic SocietyConfounding Factors Affecting sRAGE as a Biomarkerfor Chronic Obstructive Pulmonary DiseaseTo the Editor:In a review paper recently published in the Journal, Stockley andcolleagues provide an excellent overview of the current literature and thenecessity and limitations of currently available and future chronicobstructive pulmonary disease (COPD) biomarkers (1). In their review,Stockley and colleagues state that the circulating level of sRAGE (solublereceptor for advanced glycation end-products) is the best knownbiomarker for the COPD phenotype emphysema, yet some limitationsprohibit the current use of sRAGE in the clinic, including largeinterindividual variation with overlap between healthy controls andpatients with COPD and limited knowledge on confounding factorssuch as smoking behavior. Although Stockley and colleagues provide athorough overview of the currently available data on sRAGE as abiomarker for COPD, they overlooked key publications by our groupon the role of sRAGE as a COPD biomarker. Stockley and colleaguesspeculate about the potential effects of smoking on circulating sRAGElevels, and state that this needs to be investigated further. In fact, wehave recently addressed these issues, as we have shown that smokingacutely and severely decreases serum sRAGE levels by up to 50% within2 hours after smoking three cigarettes (2). We validated these resultsusing two distinct quantitative sRAGE assays to exclude the possibilityof a technical artifact. Furthermore, in a second study, we showed thatthis difference is not caused by chronic smoke exposure, as we did notfind significant differences in serum sRAGE levels among age-, sex-,and body mass index–matched, young and old smokers and neversmokers (3, 4). These data indicate that smoking acutely andtemporarily decreases serum sRAGE levels, which may cause largeinterindividual variations in serum sRAGE levels, as reviewed byStockley and colleagues. Therefore, we proposed that smoking cessationin the hours before blood sampling may decrease the variation in serumsRAGE levels and increase the discriminative value of sRAGE as abiomarker for COPD. Furthermore, Stockley and colleagues state thatmore studies are needed investigating the effect of COPD exacerbationson serum sRAGE levels. Indeed, we investigated this using serumsamples of 14 patients with COPD that were in stable disease,and serum samples from the same patients when they wereexperiencing an exacerbation (5). Here, we showed that serum sRAGElevels are significantly decreased during an exacerbation, althoughthere is no difference in the expression of the gene encoding RAGE ingranulocytes. In summary, our results are in line with Stockley andcolleagues, that more research on confounding factors is needed beforesRAGE can be implemented as a clinically usable COPD biomarker.nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Simon D. Pouwels, Ph.D.*Frank Klont, Ph.D.Rainer Bischoff, Ph.D.Nick H. T. ten Hacken, M.D., Ph.D.University Medical Center Groningen (UMCG)Groningen, the NetherlandsORCID ID: 0000-0001-7345-8061 (S.D.P.).*Corresponding author (e-mail: s.d.pouwels@umcg.nl).References1. Stockley RA, Halpin DMG, Celli BR, Singh D. Chronic obstructivepulmonary disease biomarkers and their interpretation. Am J RespirCrit Care Med 2019;199:1195–1204.2. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Cigarette smoking acutely decreases serum levels ofthe chronic obstructive pulmonary disease biomarker sRAGE. Am JRespir Crit Care Med 2018;198: 1456–1458.3. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Reply to Biswas: acute and chronic effects of cigarettesmoking on sRAGE. Am J Respir Crit Care Med 2019;199:806–807.4. Biswas SK. Acute and chronic effects of cigarette smoking on sRAGE.Am J Respir Crit Care Med 2019;199:805.5. Pouwels SD, van Geffen WH, Jonker MR, Kerstjens HAM,Nawijn MC, Heijink IH. Increased neutrophil expression ofpattern recognition receptors during COPD exacerbations.Respirology 2017;22:401–404.Copyright © 2019 by the American Thoracic SocietyReply to Pouwels et al.From the Authors:We welcome the letter from Pouwels and colleagues, who providerecent and historical evidence to amplify the issues related to the roleof smoking and exacerbations in the interpretation of sRAGE(soluble receptor for advanced glycation end-products) data (andThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Supported by the Netherlands Organization for Scientific Research NWO(Domain Applied and Engineering Sciences; Perspectief program P12-04;projects: 13541 and 13544) and the Lung Foundation Netherlands (project:6.2.15.044JO).Author Contributions: S.D.P., F.K., R.B., and N.H.T.t.H. providedthe conception and design of the study; S.D.P. provided the drafting of themanuscript; and S.D.P., F.K., R.B., and N.H.T.t.H. provided revision of themanuscript.Originally Published in Press as DOI: 10.1164/rccm.201902-0356LE onMarch 19, 2019This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contributions: R.A.S. wrote the initial response. D.H., B.R.C., andD.S. critically appraised and added to the content, and approved the finalsubmission.Originally Published in Press as DOI: 10.1164/rccm.201903-0573LE onMarch 19, 2019CORRESPONDENCE114 American Journal of Respiratory and Critical Care Medicine Volume 200 Number 1 | July 1 2019

English

Confounding Factors Affecting sRAGE as Biomarker for COPD

NARCIS 

Dissertations of the University of Groningen

   University of GroningenConfounding Factors Affecting sRAGE as Biomarker for COPDPouwels, Simon D; Klont, Frank; Bischoff, Rainer; Ten Hacken, Nick H TPublished in:American Journal of Respiratory and Critical Care MedicineDOI:10.1164/rccm.201902-0356LEIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Pouwels, S. D., Klont, F., Bischoff, R., & Ten Hacken, N. H. T. (2019). Confounding Factors AffectingsRAGE as Biomarker for COPD. American Journal of Respiratory and Critical Care Medicine, 200(1), 114.https://doi.org/10.1164/rccm.201902-0356LECopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 21-06-202220. Health Effects Institute. Traffic-related air pollution: a critical review ofthe literature on emissions, exposure, and health effects. Boston,MA: Health Effects Institute; 2010. Special Report 17.Copyright © 2019 by the American Thoracic SocietyConfounding Factors Affecting sRAGE as a Biomarkerfor Chronic Obstructive Pulmonary DiseaseTo the Editor:In a review paper recently published in the Journal, Stockley andcolleagues provide an excellent overview of the current literature and thenecessity and limitations of currently available and future chronicobstructive pulmonary disease (COPD) biomarkers (1). In their review,Stockley and colleagues state that the circulating level of sRAGE (solublereceptor for advanced glycation end-products) is the best knownbiomarker for the COPD phenotype emphysema, yet some limitationsprohibit the current use of sRAGE in the clinic, including largeinterindividual variation with overlap between healthy controls andpatients with COPD and limited knowledge on confounding factorssuch as smoking behavior. Although Stockley and colleagues provide athorough overview of the currently available data on sRAGE as abiomarker for COPD, they overlooked key publications by our groupon the role of sRAGE as a COPD biomarker. Stockley and colleaguesspeculate about the potential effects of smoking on circulating sRAGElevels, and state that this needs to be investigated further. In fact, wehave recently addressed these issues, as we have shown that smokingacutely and severely decreases serum sRAGE levels by up to 50% within2 hours after smoking three cigarettes (2). We validated these resultsusing two distinct quantitative sRAGE assays to exclude the possibilityof a technical artifact. Furthermore, in a second study, we showed thatthis difference is not caused by chronic smoke exposure, as we did notfind significant differences in serum sRAGE levels among age-, sex-,and body mass index–matched, young and old smokers and neversmokers (3, 4). These data indicate that smoking acutely andtemporarily decreases serum sRAGE levels, which may cause largeinterindividual variations in serum sRAGE levels, as reviewed byStockley and colleagues. Therefore, we proposed that smoking cessationin the hours before blood sampling may decrease the variation in serumsRAGE levels and increase the discriminative value of sRAGE as abiomarker for COPD. Furthermore, Stockley and colleagues state thatmore studies are needed investigating the effect of COPD exacerbationson serum sRAGE levels. Indeed, we investigated this using serumsamples of 14 patients with COPD that were in stable disease,and serum samples from the same patients when they wereexperiencing an exacerbation (5). Here, we showed that serum sRAGElevels are significantly decreased during an exacerbation, althoughthere is no difference in the expression of the gene encoding RAGE ingranulocytes. In summary, our results are in line with Stockley andcolleagues, that more research on confounding factors is needed beforesRAGE can be implemented as a clinically usable COPD biomarker.nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Simon D. Pouwels, Ph.D.*Frank Klont, Ph.D.Rainer Bischoff, Ph.D.Nick H. T. ten Hacken, M.D., Ph.D.University Medical Center Groningen (UMCG)Groningen, the NetherlandsORCID ID: 0000-0001-7345-8061 (S.D.P.).*Corresponding author (e-mail: s.d.pouwels@umcg.nl).References1. Stockley RA, Halpin DMG, Celli BR, Singh D. Chronic obstructivepulmonary disease biomarkers and their interpretation. Am J RespirCrit Care Med 2019;199:1195–1204.2. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Cigarette smoking acutely decreases serum levels ofthe chronic obstructive pulmonary disease biomarker sRAGE. Am JRespir Crit Care Med 2018;198: 1456–1458.3. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Reply to Biswas: acute and chronic effects of cigarettesmoking on sRAGE. Am J Respir Crit Care Med 2019;199:806–807.4. Biswas SK. Acute and chronic effects of cigarette smoking on sRAGE.Am J Respir Crit Care Med 2019;199:805.5. Pouwels SD, van Geffen WH, Jonker MR, Kerstjens HAM,Nawijn MC, Heijink IH. Increased neutrophil expression ofpattern recognition receptors during COPD exacerbations.Respirology 2017;22:401–404.Copyright © 2019 by the American Thoracic SocietyReply to Pouwels et al.From the Authors:We welcome the letter from Pouwels and colleagues, who providerecent and historical evidence to amplify the issues related to the roleof smoking and exacerbations in the interpretation of sRAGE(soluble receptor for advanced glycation end-products) data (andThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Supported by the Netherlands Organization for Scientific Research NWO(Domain Applied and Engineering Sciences; Perspectief program P12-04;projects: 13541 and 13544) and the Lung Foundation Netherlands (project:6.2.15.044JO).Author Contributions: S.D.P., F.K., R.B., and N.H.T.t.H. providedthe conception and design of the study; S.D.P. provided the drafting of themanuscript; and S.D.P., F.K., R.B., and N.H.T.t.H. provided revision of themanuscript.Originally Published in Press as DOI: 10.1164/rccm.201902-0356LE onMarch 19, 2019This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contributions: R.A.S. wrote the initial response. D.H., B.R.C., andD.S. critically appraised and added to the content, and approved the finalsubmission.Originally Published in Press as DOI: 10.1164/rccm.201903-0573LE onMarch 19, 2019CORRESPONDENCE114 American Journal of Respiratory and Critical Care Medicine Volume 200 Number 1 | July 1 2019

Proceedings - University of Groningen

   University of GroningenConfounding Factors Affecting sRAGE as Biomarker for COPDPouwels, Simon D; Klont, Frank; Bischoff, Rainer; Ten Hacken, Nick H TPublished in:American Journal of Respiratory and Critical Care MedicineDOI:10.1164/rccm.201902-0356LEIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Pouwels, S. D., Klont, F., Bischoff, R., & Ten Hacken, N. H. T. (2019). Confounding Factors AffectingsRAGE as Biomarker for COPD. American Journal of Respiratory and Critical Care Medicine, 200(1), 114.https://doi.org/10.1164/rccm.201902-0356LECopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-10-202220. Health Effects Institute. Traffic-related air pollution: a critical review ofthe literature on emissions, exposure, and health effects. Boston,MA: Health Effects Institute; 2010. Special Report 17.Copyright © 2019 by the American Thoracic SocietyConfounding Factors Affecting sRAGE as a Biomarkerfor Chronic Obstructive Pulmonary DiseaseTo the Editor:In a review paper recently published in the Journal, Stockley andcolleagues provide an excellent overview of the current literature and thenecessity and limitations of currently available and future chronicobstructive pulmonary disease (COPD) biomarkers (1). In their review,Stockley and colleagues state that the circulating level of sRAGE (solublereceptor for advanced glycation end-products) is the best knownbiomarker for the COPD phenotype emphysema, yet some limitationsprohibit the current use of sRAGE in the clinic, including largeinterindividual variation with overlap between healthy controls andpatients with COPD and limited knowledge on confounding factorssuch as smoking behavior. Although Stockley and colleagues provide athorough overview of the currently available data on sRAGE as abiomarker for COPD, they overlooked key publications by our groupon the role of sRAGE as a COPD biomarker. Stockley and colleaguesspeculate about the potential effects of smoking on circulating sRAGElevels, and state that this needs to be investigated further. In fact, wehave recently addressed these issues, as we have shown that smokingacutely and severely decreases serum sRAGE levels by up to 50% within2 hours after smoking three cigarettes (2). We validated these resultsusing two distinct quantitative sRAGE assays to exclude the possibilityof a technical artifact. Furthermore, in a second study, we showed thatthis difference is not caused by chronic smoke exposure, as we did notfind significant differences in serum sRAGE levels among age-, sex-,and body mass index–matched, young and old smokers and neversmokers (3, 4). These data indicate that smoking acutely andtemporarily decreases serum sRAGE levels, which may cause largeinterindividual variations in serum sRAGE levels, as reviewed byStockley and colleagues. Therefore, we proposed that smoking cessationin the hours before blood sampling may decrease the variation in serumsRAGE levels and increase the discriminative value of sRAGE as abiomarker for COPD. Furthermore, Stockley and colleagues state thatmore studies are needed investigating the effect of COPD exacerbationson serum sRAGE levels. Indeed, we investigated this using serumsamples of 14 patients with COPD that were in stable disease,and serum samples from the same patients when they wereexperiencing an exacerbation (5). Here, we showed that serum sRAGElevels are significantly decreased during an exacerbation, althoughthere is no difference in the expression of the gene encoding RAGE ingranulocytes. In summary, our results are in line with Stockley andcolleagues, that more research on confounding factors is needed beforesRAGE can be implemented as a clinically usable COPD biomarker.nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Simon D. Pouwels, Ph.D.*Frank Klont, Ph.D.Rainer Bischoff, Ph.D.Nick H. T. ten Hacken, M.D., Ph.D.University Medical Center Groningen (UMCG)Groningen, the NetherlandsORCID ID: 0000-0001-7345-8061 (S.D.P.).*Corresponding author (e-mail: s.d.pouwels@umcg.nl).References1. Stockley RA, Halpin DMG, Celli BR, Singh D. Chronic obstructivepulmonary disease biomarkers and their interpretation. Am J RespirCrit Care Med 2019;199:1195–1204.2. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Cigarette smoking acutely decreases serum levels ofthe chronic obstructive pulmonary disease biomarker sRAGE. Am JRespir Crit Care Med 2018;198: 1456–1458.3. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Reply to Biswas: acute and chronic effects of cigarettesmoking on sRAGE. Am J Respir Crit Care Med 2019;199:806–807.4. Biswas SK. Acute and chronic effects of cigarette smoking on sRAGE.Am J Respir Crit Care Med 2019;199:805.5. Pouwels SD, van Geffen WH, Jonker MR, Kerstjens HAM,Nawijn MC, Heijink IH. Increased neutrophil expression ofpattern recognition receptors during COPD exacerbations.Respirology 2017;22:401–404.Copyright © 2019 by the American Thoracic SocietyReply to Pouwels et al.From the Authors:We welcome the letter from Pouwels and colleagues, who providerecent and historical evidence to amplify the issues related to the roleof smoking and exacerbations in the interpretation of sRAGE(soluble receptor for advanced glycation end-products) data (andThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Supported by the Netherlands Organization for Scientific Research NWO(Domain Applied and Engineering Sciences; Perspectief program P12-04;projects: 13541 and 13544) and the Lung Foundation Netherlands (project:6.2.15.044JO).Author Contributions: S.D.P., F.K., R.B., and N.H.T.t.H. providedthe conception and design of the study; S.D.P. provided the drafting of themanuscript; and S.D.P., F.K., R.B., and N.H.T.t.H. provided revision of themanuscript.Originally Published in Press as DOI: 10.1164/rccm.201902-0356LE onMarch 19, 2019This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contributions: R.A.S. wrote the initial response. D.H., B.R.C., andD.S. critically appraised and added to the content, and approved the finalsubmission.Originally Published in Press as DOI: 10.1164/rccm.201903-0573LE onMarch 19, 2019CORRESPONDENCE114 American Journal of Respiratory and Critical Care Medicine Volume 200 Number 1 | July 1 2019

University of Groningen

   University of GroningenConfounding Factors Affecting sRAGE as Biomarker for COPDPouwels, Simon D; Klont, Frank; Bischoff, Rainer; Ten Hacken, Nick H TPublished in:American Journal of Respiratory and Critical Care MedicineDOI:10.1164/rccm.201902-0356LEIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Pouwels, S. D., Klont, F., Bischoff, R., & Ten Hacken, N. H. T. (2019). Confounding Factors AffectingsRAGE as Biomarker for COPD. American Journal of Respiratory and Critical Care Medicine, 200(1), 114.https://doi.org/10.1164/rccm.201902-0356LECopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 29-04-202320. Health Effects Institute. Traffic-related air pollution: a critical review ofthe literature on emissions, exposure, and health effects. Boston,MA: Health Effects Institute; 2010. Special Report 17.Copyright © 2019 by the American Thoracic SocietyConfounding Factors Affecting sRAGE as a Biomarkerfor Chronic Obstructive Pulmonary DiseaseTo the Editor:In a review paper recently published in the Journal, Stockley andcolleagues provide an excellent overview of the current literature and thenecessity and limitations of currently available and future chronicobstructive pulmonary disease (COPD) biomarkers (1). In their review,Stockley and colleagues state that the circulating level of sRAGE (solublereceptor for advanced glycation end-products) is the best knownbiomarker for the COPD phenotype emphysema, yet some limitationsprohibit the current use of sRAGE in the clinic, including largeinterindividual variation with overlap between healthy controls andpatients with COPD and limited knowledge on confounding factorssuch as smoking behavior. Although Stockley and colleagues provide athorough overview of the currently available data on sRAGE as abiomarker for COPD, they overlooked key publications by our groupon the role of sRAGE as a COPD biomarker. Stockley and colleaguesspeculate about the potential effects of smoking on circulating sRAGElevels, and state that this needs to be investigated further. In fact, wehave recently addressed these issues, as we have shown that smokingacutely and severely decreases serum sRAGE levels by up to 50% within2 hours after smoking three cigarettes (2). We validated these resultsusing two distinct quantitative sRAGE assays to exclude the possibilityof a technical artifact. Furthermore, in a second study, we showed thatthis difference is not caused by chronic smoke exposure, as we did notfind significant differences in serum sRAGE levels among age-, sex-,and body mass index–matched, young and old smokers and neversmokers (3, 4). These data indicate that smoking acutely andtemporarily decreases serum sRAGE levels, which may cause largeinterindividual variations in serum sRAGE levels, as reviewed byStockley and colleagues. Therefore, we proposed that smoking cessationin the hours before blood sampling may decrease the variation in serumsRAGE levels and increase the discriminative value of sRAGE as abiomarker for COPD. Furthermore, Stockley and colleagues state thatmore studies are needed investigating the effect of COPD exacerbationson serum sRAGE levels. Indeed, we investigated this using serumsamples of 14 patients with COPD that were in stable disease,and serum samples from the same patients when they wereexperiencing an exacerbation (5). Here, we showed that serum sRAGElevels are significantly decreased during an exacerbation, althoughthere is no difference in the expression of the gene encoding RAGE ingranulocytes. In summary, our results are in line with Stockley andcolleagues, that more research on confounding factors is needed beforesRAGE can be implemented as a clinically usable COPD biomarker.nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Simon D. Pouwels, Ph.D.*Frank Klont, Ph.D.Rainer Bischoff, Ph.D.Nick H. T. ten Hacken, M.D., Ph.D.University Medical Center Groningen (UMCG)Groningen, the NetherlandsORCID ID: 0000-0001-7345-8061 (S.D.P.).*Corresponding author (e-mail: s.d.pouwels@umcg.nl).References1. Stockley RA, Halpin DMG, Celli BR, Singh D. Chronic obstructivepulmonary disease biomarkers and their interpretation. Am J RespirCrit Care Med 2019;199:1195–1204.2. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Cigarette smoking acutely decreases serum levels ofthe chronic obstructive pulmonary disease biomarker sRAGE. Am JRespir Crit Care Med 2018;198: 1456–1458.3. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Reply to Biswas: acute and chronic effects of cigarettesmoking on sRAGE. Am J Respir Crit Care Med 2019;199:806–807.4. Biswas SK. Acute and chronic effects of cigarette smoking on sRAGE.Am J Respir Crit Care Med 2019;199:805.5. Pouwels SD, van Geffen WH, Jonker MR, Kerstjens HAM,Nawijn MC, Heijink IH. Increased neutrophil expression ofpattern recognition receptors during COPD exacerbations.Respirology 2017;22:401–404.Copyright © 2019 by the American Thoracic SocietyReply to Pouwels et al.From the Authors:We welcome the letter from Pouwels and colleagues, who providerecent and historical evidence to amplify the issues related to the roleof smoking and exacerbations in the interpretation of sRAGE(soluble receptor for advanced glycation end-products) data (andThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Supported by the Netherlands Organization for Scientific Research NWO(Domain Applied and Engineering Sciences; Perspectief program P12-04;projects: 13541 and 13544) and the Lung Foundation Netherlands (project:6.2.15.044JO).Author Contributions: S.D.P., F.K., R.B., and N.H.T.t.H. providedthe conception and design of the study; S.D.P. provided the drafting of themanuscript; and S.D.P., F.K., R.B., and N.H.T.t.H. provided revision of themanuscript.Originally Published in Press as DOI: 10.1164/rccm.201902-0356LE onMarch 19, 2019This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contributions: R.A.S. wrote the initial response. D.H., B.R.C., andD.S. critically appraised and added to the content, and approved the finalsubmission.Originally Published in Press as DOI: 10.1164/rccm.201903-0573LE onMarch 19, 2019CORRESPONDENCE114 American Journal of Respiratory and Critical Care Medicine Volume 200 Number 1 | July 1 2019

   University of GroningenConfounding Factors Affecting sRAGE as Biomarker for COPDPouwels, Simon D; Klont, Frank; Bischoff, Rainer; Ten Hacken, Nick H TPublished in:American Journal of Respiratory and Critical Care MedicineDOI:10.1164/rccm.201902-0356LEIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Pouwels, S. D., Klont, F., Bischoff, R., & Ten Hacken, N. H. T. (2019). Confounding Factors AffectingsRAGE as Biomarker for COPD. American Journal of Respiratory and Critical Care Medicine, 200(1), 114.https://doi.org/10.1164/rccm.201902-0356LECopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 01-11-202320. Health Effects Institute. Traffic-related air pollution: a critical review ofthe literature on emissions, exposure, and health effects. Boston,MA: Health Effects Institute; 2010. Special Report 17.Copyright © 2019 by the American Thoracic SocietyConfounding Factors Affecting sRAGE as a Biomarkerfor Chronic Obstructive Pulmonary DiseaseTo the Editor:In a review paper recently published in the Journal, Stockley andcolleagues provide an excellent overview of the current literature and thenecessity and limitations of currently available and future chronicobstructive pulmonary disease (COPD) biomarkers (1). In their review,Stockley and colleagues state that the circulating level of sRAGE (solublereceptor for advanced glycation end-products) is the best knownbiomarker for the COPD phenotype emphysema, yet some limitationsprohibit the current use of sRAGE in the clinic, including largeinterindividual variation with overlap between healthy controls andpatients with COPD and limited knowledge on confounding factorssuch as smoking behavior. Although Stockley and colleagues provide athorough overview of the currently available data on sRAGE as abiomarker for COPD, they overlooked key publications by our groupon the role of sRAGE as a COPD biomarker. Stockley and colleaguesspeculate about the potential effects of smoking on circulating sRAGElevels, and state that this needs to be investigated further. In fact, wehave recently addressed these issues, as we have shown that smokingacutely and severely decreases serum sRAGE levels by up to 50% within2 hours after smoking three cigarettes (2). We validated these resultsusing two distinct quantitative sRAGE assays to exclude the possibilityof a technical artifact. Furthermore, in a second study, we showed thatthis difference is not caused by chronic smoke exposure, as we did notfind significant differences in serum sRAGE levels among age-, sex-,and body mass index–matched, young and old smokers and neversmokers (3, 4). These data indicate that smoking acutely andtemporarily decreases serum sRAGE levels, which may cause largeinterindividual variations in serum sRAGE levels, as reviewed byStockley and colleagues. Therefore, we proposed that smoking cessationin the hours before blood sampling may decrease the variation in serumsRAGE levels and increase the discriminative value of sRAGE as abiomarker for COPD. Furthermore, Stockley and colleagues state thatmore studies are needed investigating the effect of COPD exacerbationson serum sRAGE levels. Indeed, we investigated this using serumsamples of 14 patients with COPD that were in stable disease,and serum samples from the same patients when they wereexperiencing an exacerbation (5). Here, we showed that serum sRAGElevels are significantly decreased during an exacerbation, althoughthere is no difference in the expression of the gene encoding RAGE ingranulocytes. In summary, our results are in line with Stockley andcolleagues, that more research on confounding factors is needed beforesRAGE can be implemented as a clinically usable COPD biomarker.nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Simon D. Pouwels, Ph.D.*Frank Klont, Ph.D.Rainer Bischoff, Ph.D.Nick H. T. ten Hacken, M.D., Ph.D.University Medical Center Groningen (UMCG)Groningen, the NetherlandsORCID ID: 0000-0001-7345-8061 (S.D.P.).*Corresponding author (e-mail: s.d.pouwels@umcg.nl).References1. Stockley RA, Halpin DMG, Celli BR, Singh D. Chronic obstructivepulmonary disease biomarkers and their interpretation. Am J RespirCrit Care Med 2019;199:1195–1204.2. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Cigarette smoking acutely decreases serum levels ofthe chronic obstructive pulmonary disease biomarker sRAGE. Am JRespir Crit Care Med 2018;198: 1456–1458.3. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Reply to Biswas: acute and chronic effects of cigarettesmoking on sRAGE. Am J Respir Crit Care Med 2019;199:806–807.4. Biswas SK. Acute and chronic effects of cigarette smoking on sRAGE.Am J Respir Crit Care Med 2019;199:805.5. Pouwels SD, van Geffen WH, Jonker MR, Kerstjens HAM,Nawijn MC, Heijink IH. Increased neutrophil expression ofpattern recognition receptors during COPD exacerbations.Respirology 2017;22:401–404.Copyright © 2019 by the American Thoracic SocietyReply to Pouwels et al.From the Authors:We welcome the letter from Pouwels and colleagues, who providerecent and historical evidence to amplify the issues related to the roleof smoking and exacerbations in the interpretation of sRAGE(soluble receptor for advanced glycation end-products) data (andThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Supported by the Netherlands Organization for Scientific Research NWO(Domain Applied and Engineering Sciences; Perspectief program P12-04;projects: 13541 and 13544) and the Lung Foundation Netherlands (project:6.2.15.044JO).Author Contributions: S.D.P., F.K., R.B., and N.H.T.t.H. providedthe conception and design of the study; S.D.P. provided the drafting of themanuscript; and S.D.P., F.K., R.B., and N.H.T.t.H. provided revision of themanuscript.Originally Published in Press as DOI: 10.1164/rccm.201902-0356LE onMarch 19, 2019This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contributions: R.A.S. wrote the initial response. D.H., B.R.C., andD.S. critically appraised and added to the content, and approved the finalsubmission.Originally Published in Press as DOI: 10.1164/rccm.201903-0573LE onMarch 19, 2019CORRESPONDENCE114 American Journal of Respiratory and Critical Care Medicine Volume 200 Number 1 | July 1 2019

   University of GroningenConfounding Factors Affecting sRAGE as Biomarker for COPDPouwels, Simon D; Klont, Frank; Bischoff, Rainer; Ten Hacken, Nick H TPublished in:American Journal of Respiratory and Critical Care MedicineDOI:10.1164/rccm.201902-0356LEIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Pouwels, S. D., Klont, F., Bischoff, R., & Ten Hacken, N. H. T. (2019). Confounding Factors AffectingsRAGE as Biomarker for COPD. American Journal of Respiratory and Critical Care Medicine, 200(1), 114.https://doi.org/10.1164/rccm.201902-0356LECopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 11-12-201920. Health Effects Institute. Trafﬁc-related air pollution: a critical review ofthe literature on emissions, exposure, and health effects. Boston,MA: Health Effects Institute; 2010. Special Report 17.Copyright © 2019 by the American Thoracic SocietyConfounding Factors Affecting sRAGE as a Biomarkerfor Chronic Obstructive Pulmonary DiseaseTo the Editor:In a review paper recently published in the Journal, Stockley andcolleagues provide an excellent overview of the current literature and thenecessity and limitations of currently available and future chronicobstructive pulmonary disease (COPD) biomarkers (1). In their review,Stockley and colleagues state that the circulating level of sRAGE (solublereceptor for advanced glycation end-products) is the best knownbiomarker for the COPD phenotype emphysema, yet some limitationsprohibit the current use of sRAGE in the clinic, including largeinterindividual variation with overlap between healthy controls andpatients with COPD and limited knowledge on confounding factorssuch as smoking behavior. Although Stockley and colleagues provide athorough overview of the currently available data on sRAGE as abiomarker for COPD, they overlooked key publications by our groupon the role of sRAGE as a COPD biomarker. Stockley and colleaguesspeculate about the potential effects of smoking on circulating sRAGElevels, and state that this needs to be investigated further. In fact, wehave recently addressed these issues, as we have shown that smokingacutely and severely decreases serum sRAGE levels by up to 50% within2 hours after smoking three cigarettes (2). We validated these resultsusing two distinct quantitative sRAGE assays to exclude the possibilityof a technical artifact. Furthermore, in a second study, we showed thatthis difference is not caused by chronic smoke exposure, as we did notﬁnd signiﬁcant differences in serum sRAGE levels among age-, sex-,and body mass index–matched, young and old smokers and neversmokers (3, 4). These data indicate that smoking acutely andtemporarily decreases serum sRAGE levels, which may cause largeinterindividual variations in serum sRAGE levels, as reviewed byStockley and colleagues. Therefore, we proposed that smoking cessationin the hours before blood sampling may decrease the variation in serumsRAGE levels and increase the discriminative value of sRAGE as abiomarker for COPD. Furthermore, Stockley and colleagues state thatmore studies are needed investigating the effect of COPD exacerbationson serum sRAGE levels. Indeed, we investigated this using serumsamples of 14 patients with COPD that were in stable disease,and serum samples from the same patients when they wereexperiencing an exacerbation (5). Here, we showed that serum sRAGElevels are signiﬁcantly decreased during an exacerbation, althoughthere is no difference in the expression of the gene encoding RAGE ingranulocytes. In summary, our results are in line with Stockley andcolleagues, that more research on confounding factors is needed beforesRAGE can be implemented as a clinically usable COPD biomarker.nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Simon D. Pouwels, Ph.D.*Frank Klont, Ph.D.Rainer Bischoff, Ph.D.Nick H. T. ten Hacken, M.D., Ph.D.University Medical Center Groningen (UMCG)Groningen, the NetherlandsORCID ID: 0000-0001-7345-8061 (S.D.P.).*Corresponding author (e-mail: s.d.pouwels@umcg.nl).References1. Stockley RA, Halpin DMG, Celli BR, Singh D. Chronic obstructivepulmonary disease biomarkers and their interpretation. Am J RespirCrit Care Med 2019;199:1195–1204.2. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Cigarette smoking acutely decreases serum levels ofthe chronic obstructive pulmonary disease biomarker sRAGE. Am JRespir Crit Care Med 2018;198: 1456–1458.3. Pouwels SD, Klont F, Kwiatkowski M, Wiersma VR, Faiz A, van denBerge M, et al. Reply to Biswas: acute and chronic effects of cigarettesmoking on sRAGE. Am J Respir Crit Care Med 2019;199:806–807.4. Biswas SK. Acute and chronic effects of cigarette smoking on sRAGE.Am J Respir Crit Care Med 2019;199:805.5. Pouwels SD, van Geffen WH, Jonker MR, Kerstjens HAM,Nawijn MC, Heijink IH. Increased neutrophil expression ofpattern recognition receptors during COPD exacerbations.Respirology 2017;22:401–404.Copyright © 2019 by the American Thoracic SocietyReply to Pouwels et al.From the Authors:We welcome the letter from Pouwels and colleagues, who providerecent and historical evidence to amplify the issues related to the roleof smoking and exacerbations in the interpretation of sRAGE(soluble receptor for advanced glycation end-products) data (andThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Supported by the Netherlands Organization for Scientific Research NWO(Domain Applied and Engineering Sciences; Perspectief program P12-04;projects: 13541 and 13544) and the Lung Foundation Netherlands (project:6.2.15.044JO).Author Contributions: S.D.P., F.K., R.B., and N.H.T.t.H. providedthe conception and design of the study; S.D.P. provided the drafting of themanuscript; and S.D.P., F.K., R.B., and N.H.T.t.H. provided revision of themanuscript.Originally Published in Press as DOI: 10.1164/rccm.201902-0356LE onMarch 19, 2019This article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contributions: R.A.S. wrote the initial response. D.H., B.R.C., andD.S. critically appraised and added to the content, and approved the finalsubmission.Originally Published in Press as DOI: 10.1164/rccm.201903-0573LE onMarch 19, 2019CORRESPONDENCE114 American Journal of Respiratory and Critical Care Medicine Volume 200 Number 1 | July 1 2019

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Confounding Factors Affecting sRAGE as Biomarker for COPD

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