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Biomarkers to predict inhaled corticosteroid response
Correspondence Biomarkers to predict inhaled corticosteroid response
4. Wilson AM, Lipworth BJ. Short-term dose-response relationships for the relative systemic effects of oral prednisolone and inhaled fluticasone in asthmatic adults. Br J Clin Pharmacol 1999;48:579-85.
To the Editor: The article by Cowan et al1 looked at the relationship between TH2 biomarkers and inhaled corticosteroid (ICS) response over 4 weeks, defined as significant improvements in the Asthma Control Questionnaire (ACQ) score, FEV1, and PC20AMP in 30 patients with eosinophilic asthma. There are several methodological aspects of the study that may have influenced their results. The choice of AMP for indirect bronchial challenge testing was presumably due to it being more sensitive to ICS compared with the more conventional direct-acting methacholine.2,3 Hence, one might not have seen as many ICS responders had methacholine been used instead of AMP. It would also be relevant to know the proportion of patients who ended up with a well-controlled absolute ACQ score of less than 0.75 rather than a change of more than 0.5 in the ACQ score after treatment with ICS. The chosen dose (ex-valve) of fluticasone propionate was rather high at 1000 mg/d, which in real life would be an unlikely starting dose for such patients. Indeed, it has been shown that 1000 mg/d (ie, 440 mg twice a day ex-actuator dose) of inhaled fluticasone propionate leads to systemic corticosteroid activity equivalent to that induced by 8.5 mg/d (95% CI, 5.7-11.2 mg) of oral prednisolone in terms of comparable cortisol suppression in patients with asthma.4 Thus, one may not be able to extrapolate the present biomarker results to what happens with more conventional lower starting doses of ICS devoid of systemic corticosteroid activity. Finally, when inspecting the odds ratios for ICS response with respect to baseline sputum eosinophil levels of more than 3%, very wide 95% CI of 2.31 to 43.09 and 1.73 to 203.7 were revealed for improvements in 2 or 3 clinical outcomes, respectively, with the corresponding 95% CI for exhaled nitric oxide (>35 ppb) being 0.93 to 413.54 and 1.73 to 203.7, in turn, suggesting that such tests are much too variable to be used in everyday practice.
Available online June 9, 2015. http://dx.doi.org/10.1016/j.jaci.2015.04.037
Brian J. Lipworth, MD From the Scottish Centre for Respiratory Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom. E-mail: b.j.lipworth@ dundee.ac.uk. Disclosure of potential conflict of interest: B. J. Lipworth has received research support and consultancy fees from Teva and Chiesi; is a board member for Boehringer Ingelheim, Teva, and Chiesi; has received consultancy fees from Teva, Neopharma, Cipla, and AstraZeneca; has received research support from Almirall, Meda, Roche, Janssen, Pearl, and AstraZeneca; has received lecture fees from Teva and Meda; and has received travel support from Boehringer Ingelheim, Teva, and Chiesi.
REFERENCES 1. Cowan DC, Taylor DR, Peterson LE, Cowan JO, Palmay R, Williamson A, et al. Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol 2015;135:877-83.e1. 2. Wilson AM, Lipworth BJ. Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma. Am J Med 2000; 108:269-75. 3. Dempsey O, Kennedy G, Lipworth B. Comparative efficacy and anti-inflammatory profile of once-daily therapy with leukotriene antagonist or low-dose inhaled corticosteroid in patients with mild persistent asthma. J Allergy Clin Immunol 2002;109:68-74.
Reply To the Editor: We thank Lipworth1 for his comments. Our study included 46 individuals with asthma (30 [65%] of whom had eosinophilic _2%) and 40 healthy asthma with sputum eosinophil counts of > control subjects. The study was not restricted to patients with only eosinophilic asthma. Importantly, this was not determined a priori. The objective of the study was to determine whether a panel of inflammatory biomarkers might accurately predict steroid responsiveness in asthma. As Lipworth indicates, we selected AMP over methacholine because responsiveness to AMP is a more sensitive marker of steroid effect.2,3 Lipworth asked what proportion of patients ended up with a ‘‘well-controlled’’ absolute Asthma Control Questionnaire (ACQ) score of less than 0.75 rather than a change of more than 0.5 in the ACQ score after treatment with inhaled corticosteroid. After inhaled corticosteroid treatment, 23 subjects (53.5%) were well controlled with an ACQ score of less than 0.75 while 20 (46.5%) had an ACQ score of more than 0.75. We agree that the chosen dose (ex-valve) of fluticasone propionate was high at 1000 mg/d and in real life this would be an unlikely starting dose for such patients. However, although 1000 mg/d is not the recommended starting dose, if we had used a lower dose in this study, the reasons for nonresponse would have been open to doubt. Was it due to too low a dose having been used? It was important to identify true nonresponders by using the highest recommended dose. Finally, Lipworth is concerned that the high CIs for the odds ratios might negate the usefulness of these markers for predicting steroid responsiveness. We accept that the 95% CIs were wide for each of the individual biomarkers but suggest that this may be a reflection of the small size of the study population. The significance of the results, where reported, remains. Douglas C. Cowan, BMedSci, MBChB, MRCP, PhDa D. Robin Taylor, MDa Suzy A. A. Comhair, MDb From athe Dunedin School of Medicine, University of Otago, Dunedin, New Zealand, and bthe Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. E-mail: [email protected]. The study was supported by Lottery Health New Zealand, Dunedin School of Medicine, and the National Institutes of Health (grant nos. HL1034531 and HL109250). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. REFERENCES 1. Lipworth BJ. Biomarkers to predict inhaled corticosteroid response. J Allergy Clin Immunol 2015;136:515. 2. Taylor DA, Jensen MW, Kanabar V, Engelst€atter R, Steinijans VW, Barnes PJ, et al. A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-59-monophosphate in asthmatic patients. Am J Respir Crit Care Med 1999;160:237-43.
515
4. Wilson AM, Lipworth BJ. Short-term dose-response relationships for the relative systemic effects of oral prednisolone and inhaled fluticasone in asthmatic adults. Br J Clin Pharmacol 1999;48:579-85.
To the Editor: The article by Cowan et al1 looked at the relationship between TH2 biomarkers and inhaled corticosteroid (ICS) response over 4 weeks, defined as significant improvements in the Asthma Control Questionnaire (ACQ) score, FEV1, and PC20AMP in 30 patients with eosinophilic asthma. There are several methodological aspects of the study that may have influenced their results. The choice of AMP for indirect bronchial challenge testing was presumably due to it being more sensitive to ICS compared with the more conventional direct-acting methacholine.2,3 Hence, one might not have seen as many ICS responders had methacholine been used instead of AMP. It would also be relevant to know the proportion of patients who ended up with a well-controlled absolute ACQ score of less than 0.75 rather than a change of more than 0.5 in the ACQ score after treatment with ICS. The chosen dose (ex-valve) of fluticasone propionate was rather high at 1000 mg/d, which in real life would be an unlikely starting dose for such patients. Indeed, it has been shown that 1000 mg/d (ie, 440 mg twice a day ex-actuator dose) of inhaled fluticasone propionate leads to systemic corticosteroid activity equivalent to that induced by 8.5 mg/d (95% CI, 5.7-11.2 mg) of oral prednisolone in terms of comparable cortisol suppression in patients with asthma.4 Thus, one may not be able to extrapolate the present biomarker results to what happens with more conventional lower starting doses of ICS devoid of systemic corticosteroid activity. Finally, when inspecting the odds ratios for ICS response with respect to baseline sputum eosinophil levels of more than 3%, very wide 95% CI of 2.31 to 43.09 and 1.73 to 203.7 were revealed for improvements in 2 or 3 clinical outcomes, respectively, with the corresponding 95% CI for exhaled nitric oxide (>35 ppb) being 0.93 to 413.54 and 1.73 to 203.7, in turn, suggesting that such tests are much too variable to be used in everyday practice.
Available online June 9, 2015. http://dx.doi.org/10.1016/j.jaci.2015.04.037
Brian J. Lipworth, MD From the Scottish Centre for Respiratory Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom. E-mail: b.j.lipworth@ dundee.ac.uk. Disclosure of potential conflict of interest: B. J. Lipworth has received research support and consultancy fees from Teva and Chiesi; is a board member for Boehringer Ingelheim, Teva, and Chiesi; has received consultancy fees from Teva, Neopharma, Cipla, and AstraZeneca; has received research support from Almirall, Meda, Roche, Janssen, Pearl, and AstraZeneca; has received lecture fees from Teva and Meda; and has received travel support from Boehringer Ingelheim, Teva, and Chiesi.
REFERENCES 1. Cowan DC, Taylor DR, Peterson LE, Cowan JO, Palmay R, Williamson A, et al. Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol 2015;135:877-83.e1. 2. Wilson AM, Lipworth BJ. Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma. Am J Med 2000; 108:269-75. 3. Dempsey O, Kennedy G, Lipworth B. Comparative efficacy and anti-inflammatory profile of once-daily therapy with leukotriene antagonist or low-dose inhaled corticosteroid in patients with mild persistent asthma. J Allergy Clin Immunol 2002;109:68-74.
Reply To the Editor: We thank Lipworth1 for his comments. Our study included 46 individuals with asthma (30 [65%] of whom had eosinophilic _2%) and 40 healthy asthma with sputum eosinophil counts of > control subjects. The study was not restricted to patients with only eosinophilic asthma. Importantly, this was not determined a priori. The objective of the study was to determine whether a panel of inflammatory biomarkers might accurately predict steroid responsiveness in asthma. As Lipworth indicates, we selected AMP over methacholine because responsiveness to AMP is a more sensitive marker of steroid effect.2,3 Lipworth asked what proportion of patients ended up with a ‘‘well-controlled’’ absolute Asthma Control Questionnaire (ACQ) score of less than 0.75 rather than a change of more than 0.5 in the ACQ score after treatment with inhaled corticosteroid. After inhaled corticosteroid treatment, 23 subjects (53.5%) were well controlled with an ACQ score of less than 0.75 while 20 (46.5%) had an ACQ score of more than 0.75. We agree that the chosen dose (ex-valve) of fluticasone propionate was high at 1000 mg/d and in real life this would be an unlikely starting dose for such patients. However, although 1000 mg/d is not the recommended starting dose, if we had used a lower dose in this study, the reasons for nonresponse would have been open to doubt. Was it due to too low a dose having been used? It was important to identify true nonresponders by using the highest recommended dose. Finally, Lipworth is concerned that the high CIs for the odds ratios might negate the usefulness of these markers for predicting steroid responsiveness. We accept that the 95% CIs were wide for each of the individual biomarkers but suggest that this may be a reflection of the small size of the study population. The significance of the results, where reported, remains. Douglas C. Cowan, BMedSci, MBChB, MRCP, PhDa D. Robin Taylor, MDa Suzy A. A. Comhair, MDb From athe Dunedin School of Medicine, University of Otago, Dunedin, New Zealand, and bthe Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. E-mail: [email protected]. The study was supported by Lottery Health New Zealand, Dunedin School of Medicine, and the National Institutes of Health (grant nos. HL1034531 and HL109250). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. REFERENCES 1. Lipworth BJ. Biomarkers to predict inhaled corticosteroid response. J Allergy Clin Immunol 2015;136:515. 2. Taylor DA, Jensen MW, Kanabar V, Engelst€atter R, Steinijans VW, Barnes PJ, et al. A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-59-monophosphate in asthmatic patients. Am J Respir Crit Care Med 1999;160:237-43.
515