Aerts, Joachim G J V

Chalmers, James D

Djamin, Remco S

Huang, Jeffrey T-J

Keir, Holly R

Schouten, Marjolijn

Tan, Brendan

van der Eerden, Menno

Chalmers, JD

Djamin, RS (Remco)

Schouten, M

Keir, HR

Tan, B

Aerts, Joachim

Huang, JT

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Circulating desmosine as a biomarker of azithromycin treatment response: a post hoc analysis of the COLUMBUS randomised controlled trial

James D. Chalmers

Remco S. Djamin

Marjolijn Schouten

Holly R. Keir

Brandon Tan

Joachim G.J.V. Aerts

Jeffrey T-J. Huang

Menno van der Eerden

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Circulating desmosine is not reduced by treatment with azithromycin in COPD but elevated desmosine may identify a patient group with a greater treatment response http://ow.ly/vN6N30mhBA1.</p

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                                                              University of DundeeCirculating desmosine as a biomarker of azithromycin treatment responseChalmers, James D; Djamin, Remco S; Schouten, Marjolijn; Keir, Holly R; Tan, Brendan;Aerts, Joachim G J V; Huang, Jeffrey T-J; van der Eerden, MennoPublished in:ERJ Open ResearchDOI:10.1183/23120541.00136-2018Publication date:2018Link to publication in Discovery Research PortalCitation for published version (APA):Chalmers, J. D., Djamin, R. S., Schouten, M., Keir, H. R., Tan, B., Aerts, J. G. J. V., ... van der Eerden, M.(2018). Circulating desmosine as a biomarker of azithromycin treatment response: a post hoc analysis of theCOLUMBUS randomised controlled trial. ERJ Open Research, 4(4), 1-4.https://doi.org/10.1183/23120541.00136-2018General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.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.Download date: 05. Apr. 2019Circulating desmosine as a biomarker ofazithromycin treatment response: a posthoc analysis of the COLUMBUSrandomised controlled trialTo the Editor:Elastin degradation in the lung, leading to emphysema, and elastin degradation in blood vessels, leading toatherosclerosis, are key mechanisms in the development and progression of chronic obstructive pulmonarydisease (COPD) [1]. Elastin degradation can be measured in blood through quantification of desmosineand its isomer iso-demosine, which are released specifically through cleavage of mature elastin [2]. SevereCOPD is frequently associated with chronic neutrophil-mediated inflammation and airway microbialdysbiosis [3]. Neutrophils release harmful proteases through the processes of degranulation and neutrophilextracellular trap formation that degrade extracellular matrix, including elastin, leading to diseaseprogression [3, 4].The management of COPD seeks to reduce symptoms with long-acting bronchodilators and pulmonaryrehabilitation and to reduce exacerbations [5]. Recent data suggest that the most widely usedanti-inflammatory drugs, inhaled corticosteroids, predominantly reduce eosinophilic airway inflammation,reduce exacerbations and slow lung function decline in patients with elevated blood eosinophils [5–7]. Todate there are no treatments that are indicated specifically for the treatment of neutrophilic COPD andnone have been shown to slow neutrophil-driven elastin degradation. Macrolide antibiotics such asazithromycin may, however, be a potential therapy to target neutrophilic inflammation [7–9]. Theyenhance the clearance of apoptotic neutrophils, reduce neutrophil oxidative burst and enhance neutrophilchemotaxis among their other effects on innate immunity [6–8]. The impact of these anti-inflammatoryand antimicrobial effects is the demonstrated efficacy of macrolides to reduce exacerbations in patientswith neutrophil-dominated lung diseases such as bronchiectasis and cystic fibrosis [9, 10].The COLUMBUS randomised controlled trial was a double-blind placebo-controlled single-centre study inthe Netherlands performed between May 2010 and June 2013 [11]. Patients had a diagnosis of COPD byGlobal Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and a history of at least threeexacerbations in the previous year. All patients were receiving standard care for frequently exacerbatingCOPD including inhaled corticosteroids at baseline. Patients were randomised to receive either 500 mgazithromycin three times per week or matched placebo three times per week. The total follow-up durationwas 12 months. The primary end-point of the original trial was the rate of moderate and severe COPDexacerbations by intention to treat. The trial was registered at ClinicalTrials.gov with identifierNCT00985244 [11].The study randomised 92 patients to azithromycin (n=47) or placebo (n=45) for 12 months, and found asignificant reduction in exacerbations favouring treatment with azithromycin (rate ratio 0.58, 95% CI0.42–0.79; p=0.001) [11].@ERSpublicationsCirculating desmosine is not reduced by treatment with azithromycin in COPD but elevateddesmosine may identify a patient group with a greater treatment responsehttp://ow.ly/vN6N30mhBA1Cite this article as: Chalmers JD, Djamin RS, Schouten M, et al. Circulating desmosine as abiomarker of azithromycin treatment response: a post hoc analysis of the COLUMBUS randomisedcontrolled trial. ERJ Open Res 2018; 4: 00136-2018 [https://doi.org/10.1183/23120541.00136-2018].Copyright ©ERS 2018. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.https://doi.org/10.1183/23120541.00136-2018 ERJ Open Res 2018; 4: 00136-2018ORIGINAL RESEARCH LETTERSeeking evidence that macrolides may be effective in subgroups of patients with neutrophil-mediated lungdisease, and that macrolides may slow the progression of COPD by reducing elastin degradation, weconducted a post hoc analysis of the COLUMBUS trial participants. Serum samples had been obtained atbaseline (prior to macrolide treatment) and at 12 months (end of study).Total serum desmosine (sDES) concentration was measured using a liquid chromatography with massspectrometry method [2]. Our exploratory objectives were: 1) to determine if baseline sDES predictedresponse to azithromycin in terms of exacerbation reduction; and 2) to determine if azithromycintreatment resulted in a reduction in sDES from baseline compared to placebo. Finally, in a subgroup ofpatients, we measured whether sDES changed at onset of acute exacerbation.A priori, we determined that we would split patients into two groups based on sDES levels above andbelow the median level in the population (0.39 ng·mL−1). This included n=46 for >0.39 ng·mL−1 (n=26azithromycin-treated, n=20 placebo) and n=45 for <0.39 ng·mL−1 (n=21 azithromycin-treated, n=24placebo). As has been previously reported, sDES was strongly correlated with age (r=0.53, p<0.0001).Inhaled corticosteroid dose was not different between the two groups (p=0.7).We chose to split exacerbations into moderate and severe exacerbations, based on recent data frombronchiectasis suggesting that elevated circulating desmosine was a predictor of severe exacerbations [4].We analysed frequency of exacerbations using Poisson regression.The patient characteristics have been previously reported. The mean age was 65 years, patients had a meanof four exacerbations per year at baseline and the mean lung function suggested severe airflow obstruction.Patients were commenced on azithromycin or placebo at baseline, while clinically stable and free fromexacerbation, as previously described [11].The median level of sDES was 0.39 ng·mL−1 (interquartile range (IQR) 0.25–0.51 ng·mL−1). sDES wassimilar at baseline between azithromycin and placebo groups (median (IQR) 40 (28–51) versus 37(24–54) ng·mL−1, respectively; p=0.5).In the first analysis of whether sDES could predict macrolide response, there was a significant reduction inthe frequency of exacerbations (incident rate ratio (IRR) 0.52, 95% CI 0.35–0.79), a reduction in moderateexacerbations (IRR 0.52, 95% CI 0.33–0.83) and a reduced time to first exacerbation (hazard ratio (HR)0.36, 95% CI 0.18–0.70) comparing azithromycin versus placebo in patients with sDES >0.39 ng·L−1. Therewas a trend to reduction in severe exacerbations (IRR 0.53, 95% CI 0.22–1.31) (figure 1).In those with the lower sDES levels, there was no significant reduction in the frequency of exacerbations(IRR 0.74, 95% CI 0.51–1.07), moderate exacerbations (IRR 0.63, 95% CI 0.40–1.00), time to firstexacerbation (HR 0.58, 95% CI 0.31–1.10) or severe exacerbations (IRR 1.02, 95% CI 0.53–1.96).Exploratory tests of interaction between these groups were statistically nonsignificant, but this was to beexpected with this sample size (interaction for total exacerbations −1.26, p=0.1; severe exacerbations −1.16,p=0.1; time to first exacerbation −1.00, p=0.1).The apparent difference in response was not driven by desmosine enriching for frequently exacerbatingpatients in the high-desmosine group, as baseline desmosine did not correlate with risk of exacerbationsDesmosine >0.39 ng·mL–1Desmosine <0.39 ng·mL–1Desmosine >0.39 ng·mL–1Desmosine <0.39 ng·mL–1Desmosine >0.39 ng·mL–1Desmosine <0.39 ng·mL–1Desmosine >0.39 ng·mL–1Desmosine <0.39 ng·mL–1Frequency of exacerbationsSevere exacerbationsModerate exacerbationsTime to first exacerbationEffect estimate (95% CI)0.2 0.4 0.60.0 0.8 1.21.0 1.4 1.6 1.8 2.0FIGURE 1 Forest plot displaying the effect estimates comparing azithromycin and placebo treatment insubgroups defined by above (>0.39 ng·mL−1) or below (<0.39 ng·mL−1) the median level of serum desmosine forthe COLUMBUS trial population. The effect estimate shown is incident rate ratio for frequency of exacerbations,severe exacerbations and moderate exacerbations, and hazard ratio for time to first exacerbation.https://doi.org/10.1183/23120541.00136-2018 2ORIGINAL RESEARCH LETTER | J.D. CHALMERS ET AL.(IRR 0.92, 95% CI 0.70–1.20; IRR 0.90, 95% CI 0.68–1.17 after adjustment for treatment allocation) ortime to first exacerbation (HR 0.88, 95% CI 0.56–1.38; HR 0.93, 95% CI 0.59–1.47 after adjustment fortreatment allocation).For our secondary objective of determining whether azithromycin reduced sDES after 12 months oftreatment, we observed that desmosine reduced over the study by −0.03 ng·mL−1 in the azithromycingroup (standard deviation of change 0.23) but did not change in the placebo group (mean difference 0,standard deviation of change 0.17). When the statistical difference between groups was evaluated,azithromycin did not reduce sDES (p=0.4).We compared desmosine in 24 patients at baseline and during an acute exacerbation. No difference insDES was observed (median (IQR) 0.36 (23–47) versus 0.36 (23–48) ng·mL−1; p=1.0).We conclude that azithromycin treatment does not have an impact upon elastin degradation in patientswith COPD, but that patients with higher levels of sDES may have a greater response to azithromycintreatment when compared to patients with lower sDES, in terms of reducing exacerbations. This study wasexploratory and should be regarded as hypothesis-generating, as the COLUMBUS study was not designedto test for biomarkers of azithromycin response [11]. We observed that sDES did not change during acuteexacerbations of COPD and that sDES was not a predictor of future risk of exacerbations or time to firstexacerbation. This study is among the first to seek biologically relevant determinants of macrolideresponse in COPD. Several studies have now shown the value of macrolides to reduce exacerbations inpatients with COPD [11–14]. Clinical predictors of macrolide response were sought by HAN et al. [14],who examined data from a trial in the USA of 1142 patients with COPD treated with azithromycin250 mg daily or placebo. They found few clinical predictors of macrolide response, with no difference inresponse detected by lung function, sex, presence of chronic bronchitis or prior therapy. Interestingly, onlycurrent smoking and age >65 years were associated with improved response. sDES and other biologicalmarkers were not measured in the study [14].Our study also adds to the available data regarding sDES as a biomarker of COPD. Previous studies in theECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points) cohort andother large cohorts found associations between desmosine and age, coronary artery calcification, MedicalResearch Council dyspnoea score and airflow obstruction, but did not demonstrate a link with emphysemaor emphysema progression. Desmosine nevertheless was an independent predictor of mortality in 1177COPD patients [1, 15].In summary, we show that azithromycin use does not reduce sDES over 12 months, but patients withhigher levels of sDES may be more responsive to azithromycin treatment. This would justify larger studiesof sDES to phenotype patients in COPD.James D. Chalmers1, Remco S. Djamin2, Marjolijn Schouten2, Holly R. Keir1, Brandon Tan1,Joachim G.J.V. Aerts3, Jeffrey T-J. Huang1 and Menno van der Eerden31Scottish Centre for Respiratory Research, University of Dundee, Ninewells Hospital and Medical School,Dundee, UK. 2Dept of Respiratory Medicine, Amphia Hospital, Breda, The Netherlands. 3Dept ofRespiratory Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.Correspondence: James D. Chalmers, Division of Molecular and Clinical Medicine, University of Dundee,Dundee, DD1 9SY, UK. E-mail: jchalmers@dundee.ac.ukReceived: Aug 12 2018 | Accepted after revision: Oct 11 2018Author contributions: Conception and design: J.D. Chalmers, M. Schouten, H.R. Keir, J.T-J. Huang and M. van derEerden. All authors participated in data analysis and interpretation of the data. All authors were involved in writing andrevising the article prior to submission.Conflict of interest: J.D. Chalmers reports grants and personal fees from GlaxoSmithKline (research grants for COPD),grants and personal fees from Boehringer Ingelheim (research grants for COPD studies), grants from AstraZeneca(research grants for COPD), grants and personal fees from Pfizer (research grants for COPD), grants and personal feesfrom Bayer Healthcare, and personal fees from Grifols and Napp, all outside the submitted work. R.S. Djamin hasnothing to disclose. M. Schouten has nothing to disclose. H.R. Keir has nothing to disclose. B. Tan has nothing todisclose. J.G.J.V. Aerts has nothing to disclose. J.T-J. Huang has nothing to disclose. M. van der Eerden has nothing todisclose.Support statement: J.D. Chalmers is supported by the GlaxoSmithKline/British Lung Foundation Chair of RespiratoryResearch. The original COLUMBUS study was funded by the SoLong Trust. Funding information for this article hasbeen deposited with the Crossref Funder Registry.https://doi.org/10.1183/23120541.00136-2018 3ORIGINAL RESEARCH LETTER | J.D. CHALMERS ET AL.References1 Rabinovich RA, Miller BE, Wrobel K, et al. Circulating desmosine levels do not predict emphysema progressionbut are associated with cardiovascular risk and mortality in COPD. Eur Respir J 2016; 47: 1365–1373.2 Huang JT, Chaudhuri R, Albarbarawi O, et al. Clinical validity of plasma and urinary desmosine as biomarkers forchronic obstructive pulmonary disease. Thorax 2012; 67: 502–508.3 Dicker AJ, Crichton ML, Pumphrey EG, et al. Neutrophil extracellular traps are associated with disease severityand microbiota diversity in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 2018;141: 117–127.4 Chalmers JD, Moffitt KL, Suarez-Cuartin G, et al. Neutrophil elastase activity is associated with exacerbations andlung function decline in bronchiectasis. Am J Respir Crit Care Med 2017; 195: 1384–1393.5 Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global Strategy for the Diagnosis, Management, and Prevention ofChronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Eur Respir J 2017; 49: 1700214.6 Barnes NC, Sharma R, Lettis S, et al. Blood eosinophils as a marker of response to inhaled corticosteroids inCOPD. Eur Respir J 2016; 47: 1374–1382.7 Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of chronic airway diseases. EurRespir J 2016; 47: 410–419.8 Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European RespiratorySociety/American Thoracic Society guideline. Eur Respir J 2017; 50: 1602265.9 Chalmers JD, Aliberti S, Blasi F. Management of bronchiectasis in adults. Eur Respir J 2015; 45: 1446–1462.10 Mustafa MH, Khandekar S, Tunney MM, et al. Acquired resistance to macrolides in Pseudomonas aeruginosafrom cystic fibrosis patients. Eur Respir J 2017; 49: 1601847.11 Uzun S, Djamin RS, Kluytmans JA, et al. Azithromycin maintenance treatment in patients with frequentexacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2014; 2: 361–368.12 Seemungal TA, Wilkinson TM, Hurst JR, et al. Long-term erythromycin therapy is associated with decreasedchronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008; 178: 1139–1147.13 Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med2011; 365: 689–698.14 Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction inresponse to daily azithromycin therapy. Am J Respir Crit Care Med 2014; 189: 1503–1508.15 Huang JT, Bolton CE, Miller BE, et al. Age-dependent elastin degradation is enhanced in chronic obstructivepulmonary disease. Eur Respir J 2016; 48: 1215–1218.https://doi.org/10.1183/23120541.00136-2018 4ORIGINAL RESEARCH LETTER | J.D. CHALMERS ET AL.

Circulating desmosine as a biomarker of azithromycin treatment response:a post hoc analysis of the COLUMBUS randomised controlled trial

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Circulating desmosine as a biomarker of azithromycin treatment response: a
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Circulating desmosine as a biomarker of azithromycin treatment response:a post hoc analysis of the COLUMBUS randomised controlled trial

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