Differential response to roflumilast in patients with chronic obstructive pulmonary disease: real-world evidence

Introduction

Roflumilast is a selective phosphodiesterase 4 inhibitor that exerts anti-inflammatory effects by reducing the hydrolysis of intracellular cyclic adenosine monophosphate (cAMP) (1). cAMP is an intracellular mediator of anti-inflammatory activity in chronic airway diseases (2,3). Although roflumilast was originally developed to treat asthma, growing evidence has supported its clinical benefits for chronic obstructive pulmonary disease (COPD). Several clinical trials have shown that roflumilast reduced moderate-to-severe exacerbations and improved lung function in patients with COPD (4-6). The potential benefit of roflumilast in the prevention of acute exacerbation of COPD (AE-COPD) outweighed the risk in a pooled analysis of randomised controlled trials (7). In particular, the benefit of roflumilast was evident in patients with COPD at a higher risk of severe exacerbation (8). Currently, roflumilast is recommended for only a small proportion of COPD patients.

The benefit of roflumilast in reducing AEs may be extended to a wider range of patients with COPD. Several attempts have been made to identify variables or subgroups related to the benefits of roflumilast. The risk of AE was predominantly reduced by roflumilast in patients with COPD with a history of exacerbation and chronic bronchitis (9-11). A pooled analysis of two clinical trials found that the risk of moderate-to-severe exacerbation was reduced by roflumilast in patients with higher severity or greater frequency of previous exacerbation and higher eosinophil count (12). However, subgroups with a potential benefit of roflumilast have not been sufficiently identified in controlled settings. More potential variables associated with the benefits of roflumilast need to be investigated in real-world large-scale data.

Therefore, we aimed to determine which variable or subgroup was significantly related to the effect of roflumilast on moderate-to-severe AE in patients with COPD. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1129/rc) (13).

Methods

Study design and participants

This population-based cohort study was designed using claims data from the Health Insurance Review and Assessment Service (HIRA), which covers the total population in South Korea from 2010 to 2020. Detailed information concerning this data has been published previously (14). No considerable change in nationwide health policies for roflumilast use was found during the study period. The eligibility criteria were: (I) age ≥40 years; (II) newly diagnosed with COPD [International Classification of Diseases 10th revision (ICD-10) codes J43 and J44 as the primary diagnosis or sub-diagnosis] from 2012 to 2020 after a 2-year washout period; and (III) ≥2 visits to the outpatient clinic with the prescription of COPD medications or ≥1 admission for treatment with systemic steroids followed by outpatient visits with the prescription of COPD medications. COPD medications included inhaled therapies [short-acting beta-agonists, long-acting beta-agonists (LABA), short-acting muscarinic antagonists (SAMA), long-acting muscarinic antagonists (LAMA), inhaled corticosteroids (ICS), ICS/LABA, LABA/LAMA, and ICS/LABA/LAMA] and oral medications (methylxanthine, phosphodiesterase-4 inhibitor, and oral corticosteroids). COPD was defined based on previous references (15,16).

Variables

We obtained baseline information, including age, sex, Charlson comorbidity index (CCI), previous history of moderate-to-severe exacerbation, history of bronchiectasis, history of chronic bronchitis, regular inhaled treatments, and oral medications. A history of bronchiectasis was identified using the ICD-10 codes (J47 and Q33.4) (17,18). A history of chronic bronchitis was identified using ICD-10 codes (J41 and J42). Regular inhaled treatments included LABA, LAMA, ICS/LABA, LABA/LAMA, and ICS/LABA/LAMA. Anti-inflammatory oral medications included roflumilast, statins, and renin-angiotensin blockers (angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers). Anti-inflammatory oral medications were identified using Anatomical Therapeutic Chemical (ATC) codes.

Outcomes

The present study aimed to determine the subgroups that benefit from roflumilast in reducing moderate-to-severe AE-COPD. AE-COPD severity was defined based on a previous study (19). Moderate exacerbation was defined as use of antibiotics or systemic corticosteroids. Severe exacerbation was defined as a visit to the emergency room or hospitalisation. Considering the indication of roflumilast, a considerable bias was expected because it was likely that more patients at high risk of AE-COPD were included in the roflumilast group. The HIRA data do not provide sufficient clinical information for propensity-score matching or adjustment for clinical variables. Therefore, we estimated the ratio of hazard ratio (RHR) of roflumilast for moderate-to-severe AE-COPD in different subgroups. The prespecified subgroups were age (<50, ≥50 and <65, and ≥65 years), sex, CCI (0, 1, 2, and ≥3), previous history of moderate-to-severe exacerbation, history of bronchiectasis, history of chronic bronchitis, regular inhaled treatment (mono-bronchodilator, ICS/LABA, LABA/LAMA, and ICS/LABA/LAMA), and oral medications (methylxanthines, statins, and renin-angiotensin blockers).

Statistical analysis

We compared baseline characteristics based on roflumilast use using Pearson’s chi-square test for categorical variables and t-test for continuous variables. We performed analyses using a Cox regression model with time-dependent covariates to examine whether roflumilast use was associated with the incidence of moderate-to-severe AE-COPD. To investigate the trends in risks according to the duration of roflumilast exposure, we performed analysis according to split the two-time segments focusing on 90 days since the first roflumilast prescription. For determination of the heterogeneity of the hazard ratio (HR) of roflumilast for moderate-to-severe AE-COPD, subgroup analyses were performed according to age, sex, CCI score, history of moderate to severe exacerbation, history of bronchiectasis, regular inhaled treatment, statin use and renin-angiotension blocker use using Cox regression model. A P value for interaction between roflumilast use and subgroup was calculated. For each subgroup variable, we calculated RHRs and 95% confidence interval (CI) of that as a summary measure of the difference between the HRs of roflumilast for moderate-to-severe AE-COPD in subgroups. An RHR <1.0 indicated that the HR of roflumilast in the subgroup was smaller than that in a reference group. P value <0.05 was considered as statistical significance.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Institutional Review Board of Seoul National University Seoul Metropolitan Government (SNU-SMG) Boramae Medical Center approved the present study (IRB No. 07-2021-22) and waived the need for informed consent for access to HIRA data.

Results

Baseline characteristics

Among the 1,034,697 patients who had ICD-10 code for COPD from 2010 to 2020, 210,835 were excluded who were in washout period from 2010 to 2011. We identified 823,862 patients who were newly diagnosed with COPD from 2012 to 2020 and classified them into roflumilast group (n=5,093, 0.6%) and non-roflumilast group (n=818,769, 99.4%) (Figure 1). The duration of observation was median 24.2 [interquartile range (IQR), 7.0–49.4] months. In roflumilast group, the treatment duration of roflumilast was median 2.4 (IQR, 0.8–9.4) months.

Figure 1 Flow diagram of inclusion and exclusion of patients with COPD. COPD, chronic obstructive pulmonary disease; ICD-10, International Classification of Diseases 10th revision.

The patients in roflumilast group were more likely to be male and had more comorbidities (Table 1). History of moderate-to-severe exacerbation in previous year was found 50.7% in roflumilast group and 30.5% in non-roflumilast group. Diagnosis of bronchiectasis was found 32.8% in roflumilast group and 20.3% in non-roflumilast group. Diagnosis of chronic bronchitis was found 71.7% in roflumilast group and 39.7% in non-roflumilast group. Regular inhaled therapy was used in 93.3% of roflumilast group and 70.9% of non-roflumilast group. The most frequently prescribed inhaled therapy was LABA/LAMA (24.7%) and the second most frequently prescribed inhaled therapy was LABA (23.5%). Methylxanthine was more used in roflumilast group compared with non-roflumilast group.

Variables associated with moderate-to-severe exacerbation

In univariable time-dependent Cox regression analyses, age, sex, history of moderate-to-severe exacerbation in previous year, bronchiectasis, chronic bronchitis, regular inhaled treatment, use of statin, use of renin-angiotensin blocker, and use of roflumilast showed an increased HR for moderate-to-severe exacerbation (Table 2). In multivariable time-dependent Cox regression analyses, the HR for moderate-to-severe exacerbation was numerically lower in patients with a longer duration of roflumilast use (≥3 months, HR =2.131) compared to those with shorter duration of roflumilast use (<3 months, HR=3.842). The HR of roflumilast for moderate-to-severe exacerbation was significantly reduced when roflumilast was treated for ≥3 months compared to <3 months (RHR =0.555; 95% CI: 0.520–0.592).

Interaction effect of variables

The interaction effects between the variables on HR of roflumilast for moderate-to-severe exacerbation were summarized in Table 3. We found significant interaction effects on HR of roflumilast for moderate-to-severe exacerbation according to CCI (P value <0.001), history of moderate-to-severe exacerbation in previous year (P value <0.001), history of bronchiectasis (P value <0.001), history of chronic bronchitis (P value <0.001), regular inhaled treatment (P value <0.001), and use of methylxanthine (P value <0.001).

Demographic and comorbidity factors

Differential efficacy of roflumilast in reducing moderate-to-severe exacerbation according to demographic and comorbidity factors was summarized in Figure 2. The adjusted HR of roflumilast in reducing moderate-to-severe exacerbation exhibited a notable decrease in patients aged ≥50 & <65 years (RHR =0.838; 95% CI: 0.706–0.996) and those aged ≥65 years (RHR =0.818; 95% CI: 0.692–0.966) compared to their younger counterparts aged <50 years. The adjusted HR of roflumilast for moderate-to-severe exacerbation was statistically reduced in patients with a CCI score of 1 (RHR =0.843; 95% CI: 0.716–0.992), 2 (RHR =0.814; 95% CI: 0.685–0.966), or ≥3 (RHR =0.803; 95% CI: 0.677–0.952) in comparison to those with a CCI score of 0. The effectiveness of roflumilast in reducing moderate-to-severe exacerbations was more pronounced in patients with a documented history of moderate-to-severe exacerbations in the previous year (RHR =0.913; 95% CI: 0.855–0.974). Additionally, patients with bronchiectasis or chronic bronchitis experienced significant benefits from roflumilast therapy, as their adjusted HR for moderate-to-severe exacerbations was markedly reduced (bronchiectasis, RHR =0.791, 95% CI: 0.740–0.846; chronic bronchitis, RHR =0.793, 95% CI: 0.737–0.854).

Figure 2 The RHR of roflumilast for moderate-to-severe exacerbation according to different variables. aHR, adjusted hazard ratio; CI, confidence interval; RHR, ratio of hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist.

Treatment factors

Differential efficacy of roflumilast on reducing moderate-to-severe exacerbation according to treatment factors was summarized in Figure 2. The adjusted HR of roflumilast for moderate-to-severe exacerbation was significantly reduced in the patients who were prescribed with mono-bronchodilator [LABA or LAMA, RHR =0.794 (95% CI: 0.689–0.914); ICS/LABA RHR =0.586 (95% CI: 0.509–0.673); LABA/LAMA, RHR =0.802 (95% CI: 0.696–0.924); and ICS/LABA/LAMA, RHR =0.570 (95% CI: 0.400–0.812)] compared to those without regular inhaled treatment. Notably, the effectiveness of roflumilast for moderate-to-severe exacerbations was even more pronounced among patients receiving ICS/LABA therapy compared to those with mono-bronchodilator (RHR =0.717, 95% CI: 0.662–0.777) or LABA/LAMA (RHR =0.719, 95% CI: 0.663–0.779). The patients treated with methylxanthine (RHR =0.888, 95% CI: 0.807–0.977) and statins (RHR =0.897, 95% CI: 0.818–0.984) experienced a significantly reduced risk of moderate-to-severe exacerbations when administered with roflumilast.

Discussion

In the present study, patients with COPD who used roflumilast had more risk factors for AE-COPD. Contrary to what guidance for COPD management has suggested, roflumilast was pre-emptively prescribed before triple therapy was initiated. In the time-dependent Cox regression analysis, roflumilast was more frequently prescribed in patients with COPD at a higher risk of moderate-to-severe exacerbation. We analyzed significant interaction effects between several variables and roflumilast use on the HR for moderate-to-severe exacerbation. Our results suggest that the effect of roflumilast in reducing moderate-to-severe exacerbation may be better in elderly patients, patients with more comorbidities, patients with a history of moderate-to-severe exacerbation in the previous year, patients with bronchiectasis or chronic bronchitis, and patients who used inhaled therapy, methylxanthine, or statins. In addition, the HR of roflumilast for moderate-to-severe AE was lower in patients who used ICS/LABA than in those who used a mono-bronchodilator or LABA/LAMA. Considering that the effect of roflumilast on moderate-to-severe exacerbation differed by subgroup, individualised approaches based on clinical phenotypes would improve the clinical outcomes of COPD patients treated with roflumilast.

Our results were consistent with those of previous studies that evaluated subgroups in which roflumilast was effective. In COPD patients who used roflumilast with a post-bronchodilator forced expiratory volume in one second (FEV₁) <50%, the risk of exacerbation was significantly reduced in those >65 years and with previous history of exacerbation and hospitalisation (12). The effect of roflumilast on moderate-to-severe exacerbations did not differ according to sex (11,12). In other studies, roflumilast reduced AEs in a subgroup of COPD patients who used ICS or LABA (11,20). These findings suggest that roflumilast provides greater clinical benefits to COPD patients with more severe airway inflammation. Notably, our study included more patients with COPD in the early stages of the disease, while previous clinical trials for roflumilast included patients with more severe or advanced stages of COPD. Therefore, even in patients with milder severity or at earlier stages of COPD with pronounced airway inflammation, roflumilast can be considered to reduce AEs in COPD patients with specific clinical phenotypes.

Our novel finding was that the effect of roflumilast on reducing moderate-to-severe exacerbation was greater in COPD patients with bronchiectasis. Bronchiectasis is a chronic lung disease characterised by neutrophilic airway inflammation and is detected in 4–72% of patients with COPD (21). Bronchiectasis causes cough and sputum production and increases the risk of exacerbation and mortality (22). COPD patients with bronchiectasis experience more exacerbations than those without (23). Therefore, anti-inflammatory therapies have been used to improve the clinical symptoms and prognosis of patients with bronchiectasis. ICS reduces the levels of sputum leukocytes and inflammatory cytokines, improves the quality of life, and reduces mortality in patients with bronchiectasis (24-26). A clinical trial showed that statins reduced serum pro-inflammatory cytokines related to neutrophils and improved St. George’s Respiratory Questionnaire (SGRQ) scores in patients with bronchiectasis (27). Roflumilast may improve lung function in patients with bronchiectasis (28). However, it has rarely been studied whether the effect of roflumilast on clinical outcomes differs according to the presence of bronchiectasis in patients with COPD. Our study showed a potential benefit of roflumilast in reducing the HR of moderate-to-severe exacerbation when COPD and bronchiectasis overlap. Further randomised controlled trials are needed to evaluate the effect of roflumilast in reducing AE in COPD patients with bronchiectasis.

Additive effects in combination with roflumilast and inhaled therapies, methylxanthine, or statins were observed in our study. LABA may strengthen the anti-inflammatory effect of roflumilast by increasing intracellular levels of cAMP (29). Combination treatment with roflumilast and a beta-2 adrenergic receptor agonist reduces pro-inflammatory and profibrotic mediators (30). In a clinical trial, a reduced risk of moderate-to-severe exacerbation by roflumilast was evident in COPD patients who used LABA (31). Combination treatment with LAMA and roflumilast has rarely been reported. In one study, the combination of glycopyrrolate and roflumilast did not improve lung function or exercise tolerance compared to glycopyrrolate alone in severe COPD patients (32). Several studies have reported synergistic benefits of ICS and roflumilast. In vitro evidence showed that combination treatment with roflumilast and corticosteroids reduced lung inflammation by more than one of them alone (33). The potential mechanism of the synergistic effect was explained by the reduced corticosteroid resistance by roflumilast (34). In clinical studies, further benefits were observed when roflumilast was added to ICS/LABA or ICS/LABA/LAMA (35,36). In a post-hoc analysis of two randomised controlled trials, the benefit of roflumilast in reducing AE-COPD was clearer in the subgroup with concurrent use of ICS (11). Co-administration of roflumilast and methylxanthine can increase the serum levels of roflumilast (37). In our study, the efficacy of roflumilast was potentiated by methylxanthine. In addition, statins may have additive beneficial effects in patients using roflumilast. An experimental study showed that the combination of simvastatin and roflumilast prevented alveolar epithelial-mesenchymal transition induced by cigarette smoke extract (38). In a clinical study, a greater reduction in exacerbation was found in patients who used statin (39).

Our study has several limitations. First, because of the retrospective study design using claim data, adjusting for confounding clinical variables, such as symptoms or lung function, was not sufficiently conducted. Therefore, the future risk of AE was not controlled at the baseline assessment between the roflumilast and non-roflumilast groups. Second, the diagnosis of COPD was operationally defined using ICD-10 codes and COPD medications rather than using spirometric criteria. Therefore, patients without airflow limitations may have been included in our study. However, the prescription of roflumilast is considered a very specific indicator of COPD in South Korea because of the strict health insurance criteria: chronic bronchitis with FEV₁ <50% or a history of ≥2 moderate-to-severe exacerbations. In addition, our results would not change significantly even if COPD patients defined by spirometric criteria were exclusively analysed because the beneficial effect of roflumilast becomes clearer in COPD patients at a higher risk of exacerbation. Third, the duration of treatment with roflumilast varied among patients in the roflumilast group. Therefore, we used a time-dependent Cox regression model to estimate the HR of roflumilast for moderate-to-severe exacerbation. Fourth, it was difficult to determine causality, even though the temporal relationship between exposure and outcome was analysed longitudinally. The adjusted HR for moderate-to-severe exacerbation was higher in the roflumilast group. However, it should be interpreted that roflumilast was prescribed more for patients with a higher risk of moderate-to-severe exacerbation.

Conclusions

The benefit of roflumilast on moderate-to-severe exacerbations differed according to subgroups of patients with COPD. A greater benefit of roflumilast can be expected in patients with more comorbidities, a previous history of exacerbation, bronchiectasis, chronic bronchitis, and inhaled therapy. For a more effective treatment of roflumilast in COPD patients, a personalised approach based on clinical phenotypes needs to be considered.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1129/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1129/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1129/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1129/coif). C.K.R. serves as an unpaid editorial board member of Journal of Thoracic Disease. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Institutional Review Board of Seoul National University Seoul Metropolitan Government (SNU-SMG) Boramae Medical Center approved the present study (IRB No. 07-2021-22) and waived the need for informed consent for access to HIRA data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol 2011;163:53-67. [Crossref] [PubMed]
2. Rabe KF, Watz H, Baraldo S, et al. Anti-inflammatory effects of roflumilast in chronic obstructive pulmonary disease (ROBERT): a 16-week, randomised, placebo-controlled trial. Lancet Respir Med 2018;6:827-36. [Crossref] [PubMed]
3. Tavares LP, Negreiros-Lima GL, Lima KM, et al. Blame the signaling: Role of cAMP for the resolution of inflammation. Pharmacol Res 2020;159:105030. [Crossref] [PubMed]
4. Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685-94. [Crossref] [PubMed]
5. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009;374:695-703. [Crossref] [PubMed]
6. Martinez FJ, Calverley PM, Goehring UM, et al. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015;385:857-66. [Crossref] [PubMed]
7. Yuan L, Dai X, Yang M, et al. Potential treatment benefits and safety of roflumilast in COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis 2016;11:1477-83. [Crossref] [PubMed]
8. Yu T, Fain K, Boyd CM, et al. Benefits and harms of roflumilast in moderate to severe COPD. Thorax 2014;69:616-22. [Crossref] [PubMed]
9. Rabe KF, Calverley PMA, Martinez FJ, et al. Effect of roflumilast in patients with severe COPD and a history of hospitalisation. Eur Respir J 2017;50:1700158. [Crossref] [PubMed]
10. Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2017;9:CD002309. [Crossref] [PubMed]
11. Rennard SI, Calverley PM, Goehring UM, et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast--the importance of defining different subsets of patients with COPD. Respir Res 2011;12:18. [Crossref] [PubMed]
12. Martinez FJ, Rabe KF, Calverley PMA, et al. Determinants of Response to Roflumilast in Severe Chronic Obstructive Pulmonary Disease. Pooled Analysis of Two Randomized Trials. Am J Respir Crit Care Med 2018;198:1268-78. [Crossref] [PubMed]
13. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med 2007;4:e296. [Crossref] [PubMed]
14. Kim JA, Yoon S, Kim LY, et al. Towards Actualizing the Value Potential of Korea Health Insurance Review and Assessment (HIRA) Data as a Resource for Health Research: Strengths, Limitations, Applications, and Strategies for Optimal Use of HIRA Data. J Korean Med Sci 2017;32:718-28. [Crossref] [PubMed]
15. Park HJ, Kim SR, Kim S, et al. Influence of government-driven quality assessment program on patients with chronic obstructive pulmonary disease. Respir Res 2021;22:87. [Crossref] [PubMed]
16. Kim J, Rhee CK, Yoo KH, et al. The health care burden of high grade chronic obstructive pulmonary disease in Korea: analysis of the Korean Health Insurance Review and Assessment Service data. Int J Chron Obstruct Pulmon Dis 2013;8:561-8. [Crossref] [PubMed]
17. Diel R, Ewig S, Blaas S, et al. Incidence of patients with non-cystic fibrosis bronchiectasis in Germany - A healthcare insurance claims data analysis. Respir Med 2019;151:121-7. [Crossref] [PubMed]
18. Huang HY, Chung FT, Lo CY, et al. Etiology and characteristics of patients with bronchiectasis in Taiwan: a cohort study from 2002 to 2016. BMC Pulm Med 2020;20:45. [Crossref] [PubMed]
19. "Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary." Claus F. Vogelmeier, Gerard J. Criner, Fernando J. Martinez, Antonio Anzueto, Peter J. Barnes, Jean Bourbeau, Bartolome R. Celli, Rongchang Chen, Marc Decramer, Leonardo M. Fabbri, Peter Frith, David M.G. Halpin, M. Victorina López Varela, Masaharu Nishimura, Nicolas Roche, Roberto Rodriguez-Roisin, Don D. Sin, Dave Singh, Robert Stockley, Jørgen Vestbo, Jadwiga A. Wedzicha and Alvar Agusti. Eur Respir J 2017; 49: 1700214. Eur Respir J 2017;49:1750214. [Crossref] [PubMed]
20. Hanania NA, Calverley PM, Dransfield MT, et al. Pooled subpopulation analyses of the effects of roflumilast on exacerbations and lung function in COPD. Respir Med 2014;108:366-75. [Crossref] [PubMed]
21. Martinez-Garcia MA, Miravitlles M. Bronchiectasis in COPD patients: more than a comorbidity? Int J Chron Obstruct Pulmon Dis 2017;12:1401-11. [Crossref] [PubMed]
22. Hill AT, Sullivan AL, Chalmers JD, et al. British Thoracic Society Guideline for bronchiectasis in adults. Thorax 2019;74:1-69. [Crossref] [PubMed]
23. Kim Y, Kim K, Rhee CK, et al. Increased hospitalizations and economic burden in COPD with bronchiectasis: a nationwide representative study. Sci Rep 2022;12:3829. [Crossref] [PubMed]
24. Tsang KW, Ho PL, Lam WK, et al. Inhaled fluticasone reduces sputum inflammatory indices in severe bronchiectasis. Am J Respir Crit Care Med 1998;158:723-7. [Crossref] [PubMed]
25. Martínez-García MA, Perpiñá-Tordera M, Román-Sánchez P, et al. Inhaled steroids improve quality of life in patients with steady-state bronchiectasis. Respir Med 2006;100:1623-32. [Crossref] [PubMed]
26. Håkansson KEJ, Fjaellegaard K, Browatzki A, et al. Inhaled Corticosteroid Therapy in Bronchiectasis is Associated with All-Cause Mortality: A Prospective Cohort Study. Int J Chron Obstruct Pulmon Dis 2021;16:2119-27. [Crossref] [PubMed]
27. Bedi P, Chalmers JD, Graham C, et al. A Randomized Controlled Trial of Atorvastatin in Patients With Bronchiectasis Infected With Pseudomonas Aeruginosa: A Proof of Concept Study. Chest 2017;152:368-78. [Crossref] [PubMed]
28. Juthong S, Panyarath P. Efficacy of Roflumilast in Bronchiectasis Patients with Frequent Exacerbations: A Double-Blinded, Randomized, Placebo-Controlled Pilot Clinical Trial. Tuberc Respir Dis (Seoul) 2022;85:67-73. [Crossref] [PubMed]
29. Billington CK, Penn RB, Hall IP. β(2) Agonists. Handb Exp Pharmacol 2017;237:23-40. [Crossref] [PubMed]
30. Tannheimer SL, Wright CD, Salmon M. Combination of roflumilast with a beta-2 adrenergic receptor agonist inhibits proinflammatory and profibrotic mediator release from human lung fibroblasts. Respir Res 2012;13:28. [Crossref] [PubMed]
31. Bateman ED, Rabe KF, Calverley PM, et al. Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history. Eur Respir J 2011;38:553-60. [Crossref] [PubMed]
32. Rogliani P, Ora J, Puxeddu E, et al. Effect of adding roflumilast or ciclesonide to glycopyrronium on lung volumes and exercise tolerance in patients with severe COPD: A pilot study. Pulm Pharmacol Ther 2018;49:20-6. [Crossref] [PubMed]
33. Park CK, An TJ, Kim JH, et al. Synergistic effect of roflumilast with dexamethasone in a neutrophilic asthma mouse model. Clin Exp Pharmacol Physiol 2022;49:624-32. [Crossref] [PubMed]
34. Milara J, Morell A, Ballester B, et al. Roflumilast improves corticosteroid resistance COPD bronchial epithelial cells stimulated with toll like receptor 3 agonist. Respir Res 2015;16:12. [Crossref] [PubMed]
35. Martinez FJ, Rabe KF, Sethi S, et al. Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial. Am J Respir Crit Care Med 2016;194:559-67. [Crossref] [PubMed]
36. De Backer W, Vos W, Van Holsbeke C, et al. The effect of roflumilast in addition to LABA/LAMA/ICS treatment in COPD patients. Eur Respir J 2014;44:527-9. [Crossref] [PubMed]
37. Böhmer G, Gleiter CH, Hünnemeyer A, et al. Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults. Int J Clin Pharmacol Ther 2011;49:451-60. [Crossref] [PubMed]
38. Milara J, Peiró T, Serrano A, et al. Simvastatin Increases the Ability of Roflumilast N-oxide to Inhibit Cigarette Smoke-Induced Epithelial to Mesenchymal Transition in Well-differentiated Human Bronchial Epithelial Cells in vitro. COPD 2015;12:320-31. [Crossref] [PubMed]
39. Vignola AM. PDE4 inhibitors in COPD--a more selective approach to treatment. Respir Med 2004;98:495-503. [Crossref] [PubMed]