Omalizumab and Changes in Airway Hyperresponsiveness
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《美国医学杂志》
To the Editor:
The article by Djukanovic and colleagues (1) provides insight into the antiinflammatory effects of anti-IgE monoclonal antibody in individuals with mild-to-moderate persistent asthma. However, no effect upon nonspecific airway hyperresponsiveness (AHR) to methacholine was observed after treatment for 16 weeks with omalizumab.
Methacholine is a direct bronchoconstrictor stimulus, which acts upon effector cells such as smooth muscle, causing contraction and narrowing of the airway. Bronchoprovocation with indirect stimuli such as adenosine monophosphate (AMP) and mannitol is considered to be particularly relevant to real-life situations, as cold air, exercise, and allergen also act in a similar fashion in terms of release of proinflammatory mediators such as histamine and leukotrienes from primed mast cells (2). This in turn leads to smooth muscle contraction. Indeed, shifts in the AMP threshold concentration are more closely related to underlying airway inflammation, particularly with sputum eosinophils and exhaled nitric oxide (3, 4), and associated with symptoms of atopic asthma than are direct stimuli such as methacholine (3, 5). Improvements in the AMP threshold concentration are also greater with antiinflammatory therapy than are effects upon the methacholine threshold dose or concentration (6). Moreover, AHR to methacholine is often associated with changes in airway caliber (not observed with omalizumab in the present study) rather than with underlying atopy and inflammation (5).
Thus, despite a significant reduction in airway eosinophils, it may not be surprising that AHR was not altered with omalizumab. It may well be that omalizumab does in fact reduce AHR, but that a more physiologically and clinically relevant bronchoconstrictor stimulus is required to demonstrate it. The jury must therefore still be out in deciding whether anti-IgE therapy does in fact attenuate AHR in individuals with asthma.
Graeme P. Curriea, Sudip Sahab and Daniel K. C. Leec
a Aberdeen Royal Infirmary Aberdeen, United Kingdom
b Raigmore Hospital Inverness, United Kingdom
c Ipswich Hospital Ipswich, United Kingdom
FOOTNOTES
Conflict of Interest Statement: G.P.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.K.C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
REFERENCES
Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, Bao W, Fowler-Taylor A, Matthews J, Busse WW, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 2004;170:583–593.
Currie GP, Jackson CM, Lipworth BJ. Does bronchial hyperresponsiveness matter in asthma? J Asthma 2004;:41:247–258
Van Den Berge M, Meijer RJ, Kerstjens HA, de Reus DM, Ko?ter GH, Kauffman HF, Postma DS. PC(20) adenosine 5'-monophosphate is more closely associated with airway inflammation in asthma than PC(20) methacholine. Am J Respir Crit Care Med 2001;163:1546–1550.
van Den Toorn LM, Prins JB, Overbeek SE, Hoogsteden HC, de Jongste JC. Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000;162:953–957.
De Meer G, Heederik D, Postma DS. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and methacholine differ in their relationship with airway allergy and baseline FEV(1). Am J Respir Crit Care Med 2002;165:327–331.
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;108:269–275.
The article by Djukanovic and colleagues (1) provides insight into the antiinflammatory effects of anti-IgE monoclonal antibody in individuals with mild-to-moderate persistent asthma. However, no effect upon nonspecific airway hyperresponsiveness (AHR) to methacholine was observed after treatment for 16 weeks with omalizumab.
Methacholine is a direct bronchoconstrictor stimulus, which acts upon effector cells such as smooth muscle, causing contraction and narrowing of the airway. Bronchoprovocation with indirect stimuli such as adenosine monophosphate (AMP) and mannitol is considered to be particularly relevant to real-life situations, as cold air, exercise, and allergen also act in a similar fashion in terms of release of proinflammatory mediators such as histamine and leukotrienes from primed mast cells (2). This in turn leads to smooth muscle contraction. Indeed, shifts in the AMP threshold concentration are more closely related to underlying airway inflammation, particularly with sputum eosinophils and exhaled nitric oxide (3, 4), and associated with symptoms of atopic asthma than are direct stimuli such as methacholine (3, 5). Improvements in the AMP threshold concentration are also greater with antiinflammatory therapy than are effects upon the methacholine threshold dose or concentration (6). Moreover, AHR to methacholine is often associated with changes in airway caliber (not observed with omalizumab in the present study) rather than with underlying atopy and inflammation (5).
Thus, despite a significant reduction in airway eosinophils, it may not be surprising that AHR was not altered with omalizumab. It may well be that omalizumab does in fact reduce AHR, but that a more physiologically and clinically relevant bronchoconstrictor stimulus is required to demonstrate it. The jury must therefore still be out in deciding whether anti-IgE therapy does in fact attenuate AHR in individuals with asthma.
Graeme P. Curriea, Sudip Sahab and Daniel K. C. Leec
a Aberdeen Royal Infirmary Aberdeen, United Kingdom
b Raigmore Hospital Inverness, United Kingdom
c Ipswich Hospital Ipswich, United Kingdom
FOOTNOTES
Conflict of Interest Statement: G.P.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.K.C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
REFERENCES
Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, Bao W, Fowler-Taylor A, Matthews J, Busse WW, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 2004;170:583–593.
Currie GP, Jackson CM, Lipworth BJ. Does bronchial hyperresponsiveness matter in asthma? J Asthma 2004;:41:247–258
Van Den Berge M, Meijer RJ, Kerstjens HA, de Reus DM, Ko?ter GH, Kauffman HF, Postma DS. PC(20) adenosine 5'-monophosphate is more closely associated with airway inflammation in asthma than PC(20) methacholine. Am J Respir Crit Care Med 2001;163:1546–1550.
van Den Toorn LM, Prins JB, Overbeek SE, Hoogsteden HC, de Jongste JC. Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000;162:953–957.
De Meer G, Heederik D, Postma DS. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and methacholine differ in their relationship with airway allergy and baseline FEV(1). Am J Respir Crit Care Med 2002;165:327–331.
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;108:269–275.