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Duration of steroid therapy determines dose response effect
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Brian J Lipworth, Professor of Allergy and Pulmonology University of Dundee,Ninewells Hospital and Medical School
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b.j.lipworth{at}dundee.ac.uk Brian J Lipworth
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The conclusion from Silkoff et al that exhaled NO is superior to methacholine challenge in separating doses of inhaled steroid does not stand up to close scrutiny ,as the the response is depending on the duration of treatment,especially for methacholine challenge. In study A,the duration was only 1 week for each dose level which would be sufficient to show a maximum effect on NO but not for bronchial hyperresponivess.For example Vathenen et al[1] showed with budesonide 800ug bid that the improvement in histamine hyperresponsiveness was 1.3 vs 2.4 doubling doses after 3 and 6 weeks respectively .Kerrebijn[2] et al found a plateau in response to budesonide 200ug tid after 3 months,whilst Van Essen-Zandvliet[3] et al observed a progressive improvment in bronchial hyperresponsiveness over a 20 month period of follow up with budesonide 200ug tid. In other words it is likely that the effect of the last dose after 4 weeks could be due to a carry over from the previous 2 doses.Inspection of their data shows a clear numerical trend of a dose response effect on PC20,even though there was no significant dose separation.It was evident that the variabilty in PC20 was considerable due to a small sample size[n=12] ,which is likely to have contributed to the inability to show a significant dose separation for this variable.For effects on NO there was overlap of the confidence intervals comparing 100ug vs 800ug as was the case for 100ug vs 400ug.Thus,with a larger sample size it is likely that they would have observed better dose separation with methacholine than NO.This is supported by other dose ranging studies with a longer period of dosing at each dose . Data [n=26]from Wilson and Lipworth[4] with budesonide where doses were given for 3 weeks each [400/800/1600ug daily],have shown clear evidence of a significant dose response for improvement in both methacholine and adenosine monophosphate challenge ,with the maximal effect seen at 1600ug ,in contrast to NO where a plateau was seen above 400ug. These are similar to results from Jatakanon et al[5] where effects of budesonide for 4 weeks exhibited a plateau at 400ug/day on NO but at 1600ug/day on methacholine hyperresponiveness. Thus the results of Silkoff et al should be interpreted in the light of other data where treatment has been given for longer preiods and where methacholine challenge has been shown to be superior to NO to evaluate dose response effects of inhaled steroids. References : [1]Vathenen AS,Knox AJ,Wisniewski A,et al .Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma.Am Rev Repsir Dis 1991;143:1317-21 [2]Kerrebijn KF,Van Essen-Zandvliet EEM,Neijens HJ.Effect of long term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma.J Allergy Clin Immunol 1987;79:653-59 [3]Van Essen-Zandvliet EEM,Hughes M,Waalkens H ,et al.Effects of 22 months of treatment with inhaled corticosteroids and or beta-2-agonists on lung function.airway responsiveness and symptoms in children with asthma.Am Rev Repsir Dis 1992;146:547-54. [4]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 [5]Jatakanon A,Kharitinov S,Barnes PJ.Effect of different doses of inhlaed budesonide on markers of airway inflammation in patients with mild asthma.Thorax 1999;54:108-14 |
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