The
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Glucocorticoids and Mepolizumab in Eosinophilic Asthma To the Editor: Bel et al. (Sept. 25 issue)1 report that treatment with mepolizumab, a monoclonal antibody against interleukin-5, allowed a modest reduction in the maintenance dose of oral glucocorticoids in patients who had severe eosinophilic asthma. The absolute reduction in the median dose of prednisone in the mepolizumab group was from 10.0 mg per day to 3.1 mg per day (as compared with a reduction from 12.5 mg per day to 10.0 mg per day in the placebo group). Is there reason to believe that the magnitude of the achieved reduction will be clinically relevant to patients? Will it reduce glucocorticoidinduced side effects, and will the other benefits to patients that were described in the study mitigate the costs of treatment with mepolizumab? Did the authors obtain any objective measures of adherence to prednisone, such as contemporaneous serum prednisone and cortisol levels?2 If so, could be these measures be used to identify patients who were unable to withdraw from prednisone because of adrenal suppression rather than because of loss of asthma control? John T. Lindsay, M.R.C.P. Liam Heaney, M.D.
2. Gamble J, Stevenson M, McClean E, Heaney LG. The preva-
lence of nonadherence in difficult asthma. Am J Respir Crit Care Med 2009;180:817-22. DOI: 10.1056/NEJMc1412892
To the Editor: Bel and colleagues report that the rate of total cessation of daily use of oral glucocorticoids in patients with glucocorticoiddependent asthma was 14% in the mepolizumab group and 8% in the placebo group. Considering the percentage of the patients who received placebo and successfully withdrew from treatment with systemic glucocorticoids, we wonder whether these patients actually had glucocorticoid-dependent asthma. Since the minimum dose of prednisone after the optimization phase was 5.0 mg, it is possible that some patients received systemic glucocorticoids because of poor adherence to the other prescribed therapy before the run-in period; with better adherence, they may not have been glucocorticoid-dependent. Because the duration of the study was only 24 weeks, some of the patients who had seasonal exacerbations of asthma this week’s letters
Queens University Belfast Belfast, United Kingdom
[email protected]
2433 Glucocorticoids and Mepolizumab in Eosinophilic Asthma
Dr. Lindsay reports receiving lecture fees from GlaxoSmithKline; and Prof. Heaney, grant funding from MedImmune, Novartis UK, Roche/Genentech, and GlaxoSmithKline, fees from GlaxoSmithKline, Merck Sharp & Dohme, Nycomed, Boehringer Ingelheim, Novartis, and AstraZeneca for participation in advisory boards and lectures, funding from AstraZeneca, Chiesi, Novartis, Boehringer Ingelheim, and GlaxoSmithKline to attend international meetings on respiratory medicine, and fees to his institution from GlaxoSmithKline, Schering-Plough, Synairgen, and Roche/Genentech for participating in clinical trials of treatments for asthma. No other potential conflict of interest relevant to this letter was reported. 1. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-
sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014;371:1189-97.
2435 Ivabradine in Stable Coronary Artery Disease 2435 Multidrug-Resistant Tuberculosis and Bedaquiline 2436 Ethical Challenges in Treating Friends and Family 2437 More on Shift of HIV Tropism in Stem-Cell Transplantation with CCR5 Delta32/Delta32 Mutation 2439 The First Case of Ebola Virus Disease Acquired outside Africa
n engl j med 371;25 nejm.org december 18, 2014
2433
The New England Journal of Medicine Downloaded from nejm.org at NATIONAL CTR FOR GLOBAL HEALTH AND MEDICINE on January 9, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
may have discontinued treatment with oral systemic glucocorticoids for reasons unrelated to their new treatment. Can the authors provide information on whether or not the cessation of use of systemic glucocorticoids continued during the follow-up period? Motoyasu Iikura, M.D., Ph.D. Masayuki Hojo, M.D. Haruhito Sugiyama, M.D., Ph.D. National Center for Global Health and Medicine Tokyo, Japan
[email protected] No potential conflict of interest relevant to this letter was reported. DOI: 10.1056/NEJMc1412892
of
m e dic i n e
corticoids in patients before entry into the study. However, we collected source documentation of the prescription of high-dose inhaled glucocorticoids, and in an electronic diary we documented the daily intake of oral glucocorticoids. Our requirement that patients had to have had a clinically significant deterioration of asthma control (>0.5 points in the Asthma Control Questionnaire 5 score, which ranges from 0 to 6, with higher scores indicating poorer control and 0.5 points representing the minimal clinically important difference) after tapering the dose of oral glucocorticoids before randomization provides additional reassurance that they were adherent to this treatment. It also suggests that deterioration was due to worsening asthma rather than adrenal insufficiency. We agree with Iikura et al. that seasonal fluctuations in the severity of asthma might have explained the discontinuation of oral glucocorticoids in some patients who were receiving low maintenance doses of oral glucocorticoid therapy. However, since this was a randomized, controlled trial, this factor, and those discussed above, are unlikely to explain the between-group differences seen.5 Elisabeth H. Bel, M.D., Ph.D.
The Authors Reply: In reply to Lindsay and Heaney: during the final 4 weeks of the trial, the mepolizumab group received a median dose of 3.1 mg per day of prednisone, as compared with 10.0 mg per day in the placebo group. The clinical relevance of this reduction in the dose of prednisone should not be underestimated. Adverse effects of oral glucocorticoids are cumulative and dose-dependent: a median increase of even 5 mg per day in the prednisone dose after long-term exposure has been shown to be associated with increased odds of vertebral fracture Academic Medical Center (odds ratio, 9.2), cataracts (odds ratio, 3.1), and Amsterdam, the Netherlands muscle weakness (odds ratio, 3.3).1 Despite the
[email protected] reduction in the use of oral glucocorticoids in Hector G. Ortega, M.D., Sc.D. our study, there was a clinically significant im- GlaxoSmithKline provement in quality of life and a 32% reduction Research Triangle Park, NC in asthma exacerbations among patients who Ian D. Pavord, D.M. were randomly assigned to mepolizumab. Stud- University of Oxford Oxford, United Kingdom ies have shown that the reduced use of oral gluSince publication of their article, the authors report no further cocorticoids has led to reduced glucocorticoid- potential conflict of interest. induced long-term adverse effects and a significant 1. Walsh LJ, Wong CA, Oborne J, et al. Adverse effects of oral reduction in costs related to prophylaxis and corticosteroids in relation to dose in patients with lung disease. treatment of these conditions.2,3 Also, the reduc- Thorax 2001;56:279-84. Sarnes E, Crofford L, Watson M, Dennis G, Kan H, Bass D. tion in the number of asthma exacerbations has 2. Incidence and US costs of corticosteroid-associated adverse 4 led to further cost savings. Whether these sav- events: a systematic literature review. Clin Ther 2011;33:1413-32. ings and the gain in quality-adjusted life-years 3. Manson SC, Brown RE, Cerulli A, Vidaurre CF. The cumulaburden of oral corticosteroid side effects and the economic will balance the costs of treatment with mepoliz tive implications of steroid use. Respir Med 2009;103:975-94. umab will depend on the acquisition cost of me- 4. Ivanova JI, Bergman R, Birnbaum HG, Colice GL, Silverman polizumab, which may be evaluated in long-term RA, McLaurin K. Effect of asthma exacerbations on health care costs among asthmatic patients with moderate and severe perprospective cost-effectiveness trials. sistent asthma. J Allergy Clin Immunol 2012;129:1229-35. We did not assess serum levels of prednisone 5. Ortega H, Chupp G, Bardin P, et al. The role of mepolizumab or cortisol as objective measures of adherence to in atopic and nonatopic severe asthma with persistent eosinoprednisone or adrenal insufficiency, nor did we philia. Eur Respir J 2014;44:239-41. measure adherence to high-dose inhaled gluco- DOI: 10.1056/NEJMc1412892
2434
n engl j med 371;25 nejm.org december 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at NATIONAL CTR FOR GLOBAL HEALTH AND MEDICINE on January 9, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
