Montuschi )ra80 /ye70 lm60 (150 V40 F30 E in20 ien10 lc 0 e d f o e t a R Placebo Inhaledglucocorticoids CCLS EUROSCOP ISOLDE LHS2 Figure 1 Rate of decline in forced expiratory volume in one second (FEV1) after administration of placebo or inhaled glucocorticoids in four randomized controlled multicenter clinical trials: Copenhagen City Lung Study (CCLS), European Respiratory Society study On Chronic Obstructive Pulmonary disease (EUROSCOP), Inhaled Steroids in Obstructive Lung Disease (ISOLDE), and Lung Health Study 2 (LHS2). Inhaled glucocorticoids did not have a signiﬁcant effect on the rate of decline in FEV1 in any of the clinical trials. certain is that glucocorticoids do not modify the natural history of COPD, as measured by the rate of decline in FEV1 (Figure 1). Four large randomized placebo- controlled multicenter clinical trials (European Respiratory Society study on chronic obstructive pulmonary disease [EUROSCOP], Copenhagen City Lung Study, Inhaled Steroids in Obstructive Lung Disease in Europe [ISOLDE], and Lung Health Study 2 [Pauwels et al 1999; Vestbo et al 1999; Burge et al 2000; LHSRG 2000]) all found that inhaled glucocorticoids had no signiﬁcant effects on the progressive decline in FEV1 in patients with mild and moderate to severe COPD. One of these studies (Burge et al 2000) in patients with more severe COPD showed a reduction in the frequency of exacerbations (from 1.33 to 0.99 per year, a reduction of 25%). Other clinical trials with both ﬂuticasone and budesonide showed that inhaled glucocorticoids reduce COPD exacerbation rate (Calverley, Pauwels, et al 2003; Jones et al 2003; Szafranski et al 2003), although the mechanism for this effect is currently unknown. However, an earlier study on a smaller sample showed a reduction in severity, but not in the frequency of exacerbations with inhaled glucocorticoids (Paggiaro et al 1998). From these clinical trials it is concluded that inhaled glucocorticoids should only be administered to patients with severe to very severe COPD (post-bronchodilator FEV1 ≤50% of the predicted value) with frequent exacerbations requiring treatment with antibiotics or oral glucocorticoids (GICOPD 2001). The dose of glucocorticoids required to reduce the frequency of exacerbations in these patients with COPD is not known (MacNee and Calverley 2003). Improvement in airﬂow in patients with COPD after chronic treatment with inhaled glucocorticoids is very 414 modest (Pauwels et al 1999; Burge et al 2000). However, some studies reported further improvement in airflow when glucocorticoids are added to long-acting β2-agonist bronchodilators (Mahler et al 2002; Calverley, Pauwels, et al 2003; Szafranski et al 2003). One study reported that withdrawal of fluticasone propionate from combined salmeterol–fluticasone treatment in patients with COPD resulted in acute and persistent deterioration in lung function and dyspnoea and in increase in mild exacerbations (Wouters et al 2005). However, median percentage predicted FEV1 at start of the 3 month run-in period was about 50% implying that a considerable number of patients included in this study had moderate COPD (FEV1 ≥50% of the predicted value) for which inhaled glucocorticoids are not indicated (GICOPD 2001). On the other hand, all the patients in this study had a history of at least 2 COPD exacerbations in the last year treated with oral glucocorticoids and/or antibiotics which suggest chronic treatment with inhaled glucocorticoids (GICOPD 2001). The effect of inhaled glucocorticoids on mortality for COPD is controversial and mainly based on retrospective data (Sin and Tu 2001; Soriano et al 2002; Fan et al 2003; Suissa 2003; Sin et al 2005). Prospective studies assessing the effect of inhaled glucocorticoids and long- acting β2-agonists, alone or in combination, on mortality in patients with COPD are in progress (Rennard 2004; Vestbo 2004). Oral glucocorticoids are not generally recommended for the treatment of stable COPD due to their limited therapeutic effects and numerous systemic side effects. International Journal of COPD 2006:1(4)