Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD

Abstract

Background: Roflumilast is a targeted oral once-daily administered phosphodiesterase 4 (PDE4) inhibitor with clinical efficacy in chronic obstructive pulmonary disease (COPD). Results from in vitro studies with roflumilast indicate that it has anti-inflammatory properties that may be applicable for the treatment of COPD. Methods: In a crossover study, 38 patients with COPD (mean (SD) age 63.1 (7.0) years, post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 61.0 (12.6)% predicted) received 500 mg roflumilast or placebo once daily for 4 weeks. Induced sputum samples were collected before and after 2 and 4 weeks of treatment. Differential and absolute cell counts were determined in whole sputum samples. Markers of inflammation were determined in sputum supernatants and blood. Spirometry was performed weekly. Results: Roflumilast significantly reduced the absolute number of neutrophils and eosinophils/g sputum compared with placebo by 35.5% (95% CI 15.6% to 50.7%; p = 0.002) and 50.0% (95% CI 26.8% to 65.8%; p,0.001), respectively. The relative proportion of sputum neutrophils and eosinophils was not affected by treatment (p.0.05). Levels of soluble interleukin-8, neutrophil elastase, eosinophil cationic protein and a 2 -macroglobulin in sputum and the release of tumour necrosis factor a from blood cells were significantly reduced by roflumilast compared with placebo treatment (p,0.05 for all). Post-bronchodilator FEV 1 improved significantly during roflumilast compared with placebo treatment with a mean difference between treatments of 68.7 ml (95% CI 12.9 to 124.5; p = 0.018). Conclusion: PDE4 inhibition by roflumilast treatment for 4 weeks reduced the number of neutrophils and eosinophils, as well as soluble markers of neutrophilic and eosinophilic inflammatory activity in induced sputum samples of patients with COPD. This anti-inflammatory effect may in part explain the concomitant improvement in post-bronchodilator FEV 1 .

Systemic manifestations and comorbidities of COPD

“…A selective PDE4 inhibitor, roflumilast, inhibits lung inflammation and emphysema in a smoking model of COPD in mice [202]. In COPD patients, oral roflumilast given over 4 weeks significantly reduces the number of neutrophils (by 36%) and CXCL8 concentrations in sputum [203]. In clinical trials, roflumilast given over 6 or 12 months improves lung function in COPD patients to a small extent but has no significant effect in reducing exacerbations or improving health status [204,205].…”

PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease

“…The mortality due to COPD was similar in both treatment-arms in both studies The mechanism of the improvements in lung function, exacerbation rates and quality of life scores cannot be attributed to a direct bronchodilating action of this drug class, as we have previously discussed for cilomilast. It is more likely that these beneficial actions are secondary to an anti-inflammatory activity of roflumilast, although the reduction in pro-inflammatory cell numbers found in two other studies was modest, reflecting a 30-50% suppression of inflammatory cell numbers [43,44] and reduced the number of airway CD8+ T lymphocytes and CD68+ macrophages by approximately 40-50% [30]. Other evidence of an anti-inflammatory mechanism stems from in vitro studies which reported that cilomilast reduced the level of TNF-alpha (25% decrease), GMCSF (46% decrease) and neutrophil chemotactic factors (35% decrease) with no effect on IL-8 released by epithelial cells from COPD patients [45].…”

“…Indeed, roflumilast treatment alone failed to significantly increase macrophage and neutrophil cell number in the lung in a preclinical model of smoke-induced inflammation, but reduced the rise in macrophage and neutrophil cell numbers caused by cigarette smoke exposure [18,66]. Similarly, human clinical data shows that the PDE4-inhibitors, cilomilast and roflumilast, reduce inflammatory cell numbers in the lung compartment [43,67]. In conclusion, ample evidence has been provided that the PDE4-inhibitors cilomilast and roflumilast, at a clinically relevant dose, are capable of reducing airway inflammation.…”

Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases

“…Despite that chronic cough and sputum production are characteristics of bronchiectasis, they have been suggested as a risk factor for exacerbations of COPD (68,69). Roflumilast has been shown benefit for inhibiting neutrophilic airway inflammation in COPD and preventing exacerbation in COPD with chronic bronchitis (46,54). In addition, neutrophils are prominent cell type involved in bronchiectasis and neutrophilic inflammation is key pathogenesis of COPD (70)(71)(72).…”

“…Another placebo-controlled study showed roflumilast decreased sputum cell counts, both eosinophils and neutrophils. In addition to its effect on inflammatory cells, roflumilast reduced neutrophilic and eosinophilic inflammatory mediators in sputum of COPD patients (46). The difference between the efficacy of cilomilast and roflumilast is associated with the different IC 50 ; roflumilast is more potent than cilomilast for PDE4B inhibition in inflammatory cells (35).…”