Anti-inflammatory Drugs

Glucocorticosteroids

The main anti-inflammatory drugs used in COPD are glucocorticosteroids (corticosteroids); however, the effects of both oral and inhaled corticosteroids are much less dramatic in COPD than in asthma, and their role in the management of stable COPD is limited to patients with frequent exacerbations despite treatment with long-acting bronchodilators (GOLD Groups C and D).1 With the exception of a few countries, ICS are not licensed as a monotherapy in COPD; instead they are used in combination with a LABA. Corticosteroids exert their therapeutic effect by binding to glucocorticoid receptors on the bronchial epithelium.92,93 Stimulation of these receptors alters the expression of genes involved in the inflammatory response. In COPD, corticosteroids are most frequently administered by inhalation, but they can also be administered orally, intravenously or intramuscularly to treat exacerbations. 

Phosphodiesterase-4 inhibitors

PDE-4 inhibitors (PDE-4i) inhibit the breakdown of the intracellular messenger, cAMP, thereby reducing inflammation.94

Roflumilast is the first PDE-4i to become available, having received approval in the EU, US and Canada. Roflumilast may be used to reduce exacerbations in patients with chronic bronchitis, severe and very severe COPD and frequent exacerbations that are not adequately controlled by long-acting bronchodilators.1 

In a specific subset of patients with severe COPD, chronic bronchitis and a history of exacerbations, the frequency of COPD exacerbations was shown to be significantly reduced with roflumilast compared with placebo (Figure 7).95 Although roflumilast has no direct bronchodilator activity, it has been shown to improve FEV1 in patients also receiving salmeterol or tiotropium.96 More recently, in a population of patients with severe COPD, symptoms of chronic bronchitis and ≥2 exacerbations in the previous year, roflumilast 500 μg together with an ICS and long-acting β2-agonist significantly reduced the rate of moderate-to-severe exacerbations by 13.2% versus placebo.97

Effect of roflumilast 500 µg once-daily on exacerbation rate/per patient/year, in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

Figure 7. Effect of roflumilast 500 µg once-daily on exacerbation rate/per patient/year, in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.95

Combinations of anti-inflammatory drugs and bronchodilators

Combinations of an ICS plus a LABA have been shown to be more effective than either component alone in improving lung function, health status and reducing the frequency of COPD exacerbations in patients with moderate-to-very severe COPD. ICS/LABA combinations are recommended in patients with more severe COPD (GOLD C and D) who experience frequent exacerbations despite long-acting bronchodilator treatment.1

In general, ICS/LABA combination products are licensed for use in moderate-to-severe COPD. Studies have shown that, in comparison with the individual components and/or placebo, combined therapy with an ICS and a LABA reduced the exacerbation rate (Figure 8) and improved health status and spirometric values.40 

Annual rate of COPD exacerbations by treatment group in patients receiving salmeterol/fluticasone combination, salmeterol, fluticasone or placebo.

Figure 8. Annual rate of COPD exacerbations by treatment group in patients receiving salmeterol/fluticasone combination, salmeterol, fluticasone or placebo.40
*p<0.05 vs placebo.

However, because combination therapy includes an ICS component, it was also associated with a significantly greater risk of developing pneumonia compared with LABA alone or placebo (p<0.001).98 Evidence also points to a clear dose-response relationship, with an increased risk of pneumonia with increasing ICS dose.99

ICS plus LABA is recommended for use only in patients with more severe COPD who experience frequent exacerbations despite treatment with long-acting bronchodilators (i.e. GOLD Groups C and D).1 However, a survey of a real-world international COPD population sampled from the Adelphi Respiratory Disease Specific Programme found that despite recommendations, many patients at lower risk of exacerbation in the early stages of the disease (i.e. GOLD Groups A and B) are treated with ICS/ICS-containing regimens (Figure 9).100

Despite recommendations, ICS is used often in early-stage COPD.

Figure 9. Despite recommendations, ICS is used often in early-stage COPD.100
Data were drawn from the Adelphi Disease Specific Programme, a large multinational (France, Germany, Italy, Spain, UK, USA) cross-sectional survey generating real-world data based on actual clinical practice. GOLD 2011 classification. N=1508.2
GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.

Evidence suggests that the combined use of an ICS and a LABA may reduce exacerbations versus monotherapy, but the risk/benefit profile limits the use of ICS to patients at high risk of exacerbation, as an alternative to recommended treatments.1

The benefits of ICS/LABA combination products should be weighed against the increased risk of side effects.101 There are a number of dose-related side effects associated with ICS use such as increased risk of cataracts, diabetes, pulmonary tuberculosis and pneumonia, and reduced bone density. 99,102,103

Evidence is accumulating on the potential to withdraw non-recommended ICS safely from combination therapy comprising long-acting bronchodilators.104 In a real-life study in patients with moderate COPD at low risk of exacerbation, ICS could be withdrawn without increasing the risk of exacerbations in patients maintained on long-acting bronchodilators.105 In patients with severe-to-very severe COPD and at least one exacerbation in the previous 12 months (i.e. high risk), progressive ICS withdrawal was also shown to be non-inferior to ICS continuation in terms of moderate-to-severe exacerbations.106