Inhaled corticosteroids for chronic obstructive pulmonary disease: what is their role in therapy?

Tashkin, Donald P.; Strange, Charlie

doi:10.2147/copd.s172240

Cited by 72 publications

(65 citation statements)

References 90 publications

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“…There are several clinical trials and meta-analyses that suggest a superiority of LABA/ICS combinations to respective monotherapies regarding exacerbation rates, lung function decline, and health status in COPD [2]. Our data might explain this superiority by an increased anti-inflammatory efficacy of the ICS through the reversion of the corticosteroid resistance by LABAs.…”

Section: Discussionmentioning

confidence: 55%

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LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD

Knobloch

Jungck

Kronsbein

et al. 2019

JCM

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Airway inflammation in chronic obstructive pulmonary disease (COPD) is partially insensitive/resistant to inhaled corticosteroids (ICS). ICS plus bronchodilator therapy has been discussed for COPD phenotypes with frequent exacerbations and participation of corticosteroid-sensitive type 2/eosinophilic inflammation. Neutralization of non-type 2/IL-8-associated airway inflammation by reversion of its corticosteroid-resistance might be a future strategy for other phenotypes. Human airway smooth muscle cells (HASMCs) produce corticosteroid-insensitive IL-8 in response to TNFα or LPS in stable disease stages or bacteria-induced exacerbations, respectively. p38-mitogen-activated-protein-kinases (p38MAPKs) are alternative therapeutic targets. Hypothesis: long-acting-β2-agonists (LABAs) reverse the corticosteroid-insensitivity of IL-8 by p38MAPK inhibition in HASMCs. Cultivated HASMCs from COPD subjects were pre-incubated with formoterol, salmeterol, fluticasone-propionate, BIRB796 (p38MAPKα, -γ, -δ inhibitor), and/or SB203580 (p38MAPKα and -β inhibitor) before stimulation with TNFα or LPS. IL-8 and MAPK-activities were measured by ELISA. Formoterol, salmeterol, and fluticasone did not or hardly reduced TNFα- or LPS-induced IL-8. BIRB796 and SB203580 reduced TNFα-induced IL-8. SB203580 reduced LPS-induced IL-8. Fluticasone/formoterol, fluticasone/salmeterol, and fluticasone/BIRB796, but not fluticasone/SB203580 combinations, reduced TNFα-induced IL-8 stronger than single treatments. All combinations including fluticasone/SB203580 reduced LPS-induced IL-8 stronger than single treatments. TNFα induced p38MAPKα and -γ activity. LPS induced p38MAPKα activity. Formoterol reduced TNFα-induced p38MAPKγ and LPS-induced p38MAPKα activity. LABAs reverse the corticosteroid-insensitivity of IL-8 in airway smooth muscles via p38MAPKγ in stable disease and via p38MAPKα in exacerbations. Our pre-clinical data indicate a utility for also adding ICS in non-type 2 inflammatory COPD phenotypes to bronchodilator therapy. Depending on phenotype and disease stage, isoform-specific p38MAPK blockers might also reverse corticosteroid-resistance in COPD.

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Section: Discussionmentioning

confidence: 55%

“…COPD therapy is complicated by the partial resistance/insensitivity of the airway inflammation to inhaled corticosteroids (ICS) [1]. ICS use increases the risk of pneumonia in COPD [2]. Therefore, a careful assessment of ICS use in COPD is required, e.g., by identifying responder phenotypes.…”

Section: Introductionmentioning

confidence: 99%

LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD

Knobloch

Jungck

Kronsbein

et al. 2019

JCM

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“…regimen and dose) and study design-related factors (e.g. patient characteristics and definitions used) [41]. In the present study, the pneumonia risk for single-inhaler triple therapy ranged from no reported increase to a significant increase.…”

Section: Discussionmentioning

confidence: 57%

Single-inhaler triple therapy in patients with chronic obstructive pulmonary disease: a systematic review

Langham¹,

Lewis²,

Pooley³

et al. 2019

Respir Res

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Background: Guidelines recommend that treatment with a long-acting β 2 agonist (LABA), a long-acting muscarinic antagonist (LAMA), and inhaled corticosteroids (ICS), i.e. triple therapy, is reserved for a select group of symptomatic patients with chronic obstructive pulmonary disease (COPD) who continue to exacerbate despite treatment with dual therapy (LABA/LAMA). A number of single-inhaler triple therapies are now available and important clinical questions remain over their role in the patient pathway. We compared the efficacy and safety of single-inhaler triple therapy to assess the magnitude of benefit and to identify patients with the best risk-benefit profile for treatment. We also evaluated and compared study designs and population characteristics to assess the strength of the evidence base. Methods: We conducted a systematic search, from inception to December 2018, of randomised controlled trials (RCTs) of single-inhaler triple therapy in patients with COPD. The primary outcome was the annual rate of moderate and severe exacerbations. Results: We identified 523 records, of which 15 reports/abstracts from six RCTs were included. Triple therapy resulted in the reduction of the annual rate of moderate or severe exacerbations in the range of 15-52% compared with LAMA/LABA, 15-35% compared to LABA/ICS and 20% compared to LAMA. The patient-based number needed to treat for the moderate or severe exacerbation outcome ranged between approximately 25-50 (preventing one patient from having an event) and the event-based number needed to treat of around 3-11 (preventing one event). The absolute benefit appeared to be greater in patients with higher eosinophil counts or historical frequency of exacerbations and ex-smokers. In the largest study, there was a significantly higher incidence of pneumonia in the triple therapy arm. There were important differences in study designs and populations impacting the interpretation of the results and indicating there would be significant heterogeneity in cross-trial comparisons. Conclusion: The decision to prescribe triple therapy should consider patient phenotype, magnitude of benefit and increased risk of adverse events. Future research on specific patient phenotype thresholds that can support treatment and funding decisions is now required from well-designed, robust, clinical trials. Trial registration: PROSPERO #CRD42018102125.

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“…2. Evidence of higher risk of pneumonia and potential fragility fractures while on ICS [18][19][20]; and 3. The availability of safer, effective alternatives such as a combination inhaler for both long acting muscarinic antagonist (LAMA) and long acting beta agonist (LABA) [21].…”

Section: Introductionmentioning

confidence: 99%

Provider anticipation and experience of patient reaction when deprescribing guideline discordant inhaled corticosteroids

et al. 2020

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Introduction Despite evidence of possible patient harm and substantial costs, medication overuse is persistent. Patient reaction is one potential barrier to deprescribing, but little research has assessed this in specific instances of medication discontinuation. We sought to understand Veteran and provider experience when de-implementing guideline-discordant use of inhaled corticosteroids (ICS) in those with mild-to-moderate chronic obstructive pulmonary disease (COPD). Methods We conducted a mixed-methods analysis in a provider-randomized quality improvement project testing a proactive electronic-consultation from pulmonologists recommending ICS discontinuation when appropriate. PCPs at two Veterans Health Administration healthcare systems were included. We completed interviews with 16 unexposed providers and 6 intervention-exposed providers. We interviewed 9 patients within 3 months after their PCP proposed ICS discontinuation. We conducted inductive and deductive content analysis of qualitative data to explore an emergent theme of patient reaction. Forty-eight PCPs returned surveys (24 exposed and 24 unexposed, response rate: 35%).

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Inhaled corticosteroids for chronic obstructive pulmonary disease: what is their role in therapy?

Cited by 72 publications

References 90 publications

LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD

LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD

Single-inhaler triple therapy in patients with chronic obstructive pulmonary disease: a systematic review

Provider anticipation and experience of patient reaction when deprescribing guideline discordant inhaled corticosteroids

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