How Phosphodiesterase 4 Inhibitors Work in Patients with Chronic Obstructive Pulmonary Disease of the Severe, Bronchitic, Frequent Exacerbator Phenotype

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Key points

  • The novel, antiinflammatory drug, roflumilast, is efficacious in patients with severe chronic obstructive pulmonary disease (COPD) who have chronic bronchitis and a history of frequent exacerbations.

  • This COPD phenotype is associated with mucus hypersecretion, an increased risk of bacterial colonization and infection, and a high level of inflammation. Such patients are most likely to derive clinical benefit from antiinflammatory drugs, such as the phosphodiesterase 4 inhibitor, roflumilast.

  • The

PDE4 inhibitors and COPD

PDEs represent a superfamily of enzymes that degrade the second messenger molecules cyclic adensosine-3′,5′-monophosphate (cAMP) and/or cyclic guanosine-3′,5′-monophophate to the catalytically inactive, corresponding 5′-nucleoside monophosphates. Following the first identification of a PDE activity more than 50 years ago,15 11 molecularly, biochemically, and immunologically distinct enzyme families have been clearly defined.16 Since then, there has been considerable interest in the

A triple combination therapy?

GOLD recently updated its recommendations for the treatment of stable COPD to include roflumilast as a second-choice medication in high-risk patients with severe (stages 3–4) symptomatic disease (www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf). This clinical positioning dictates that roflumilast should be prescribed to patients with severe disease (defined as group D patients in both of the classifications shown in Fig. 1) taking, minimally, an inhaled corticosteroid

Scientific rationale for adding on a PDE4 inhibitor to an ICS/LABA combination therapy: a case for gene transactivation

Glucocorticoids as a monotherapy are poorly effective in COPD (cf asthma) and are contraindicated31 because of doubts about efficacy and potential adverse effects including pneumonia and tuberculosis.32, 33 Nevertheless, the results of a recent meta-analysis suggest that the potential benefit of an ICS/LABA combination therapy is a reduction in acute exacerbations.29 From a clinical perspective, this suggests that ICS/LABA combination therapies should only be used in patients classified as

Why ICS/LABA combination therapies are not enough

Logic dictates that, for a glucocorticoid and a LABA to interact additively or synergistically, target tissues must express functional GR and β2-adrenceptors in sufficient numbers. Although GR is expressed ubiquitously, consistent with the pleiotropic effects produced by cortisol in humans, its density varies considerably across tissues.54 In immune and proinflammatory cells, the rank order of GR expression (high to low) is estimated to be airway smooth muscle ≥ bronchial epithelium > alveolar

Candidate antiinflammatory genes

Several glucocorticoid and/or cAMP-inducible genes have recently been identified that, when expressed together, could collectively impart a clinically beneficial impact on those mechanisms that promote inflammation and predispose susceptible patients to acute exacerbations (vide infra). Moreover, their expression could contribute to the therapeutic benefit of roflumilast seen in patients with severe, bronchitic disease who have frequent, acute exacerbations. As transactivation becomes more

Gene transactivation and glucocorticoid resistance

The concept of gene transactivation as a mechanism of action of glucocorticoids also has relevance to the clinical phenomenon of reduced glucocorticoid responsiveness (variably reported as resistance, tolerance, insensitivity, or subsensitivity) such as that seen in COPD. Compelling evidence is available that the ability of glucocorticoids to induce transcriptional responses is impaired by a variety of proinflammatory stimuli including tobacco smoke extract, cytokines, growth factors, and

A note on cAMP-induced, adverse-effect genes

A clinical concern of β2-adrenoceptor agonists as monotherapies is their ability to upregulate the expression of a variety of proinflammatory signaling molecules including IL-6, IL-6R, IL-8, IL-11, IL-15, and IL-20Rβ (authors’ unpublished observations).128 In asthmatic patients, this is an important issue because regular administration of β2-adrenoceptor agonists is reported to promote pulmonary eosinophilia.129, 130 Whether this proinflammatory liability is also realized in patients with COPD

Summary and future directions

Current international guidelines recommend that roflumilast be added on to an ICS/LABA combination therapy in high-risk patients with severe, bronchitic COPD who have frequent acute exacerbations. Evidence is presented here that a glucocorticoid, LABA, and PDE4 inhibitor in combination can interact in a complex manner to induce a panel of genes that could act collectively to suppress inflammation and improve lung function. Central to this concept is that this drug combination produces a unique

Acknowledgments

We thank our colleague, Dr Richard Leigh, Department of Medicine, University of Calgary, for constructive comments on this article.

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    Financial disclosures and conflicts of interest: Grant support for M.A. Giembycz is from the Canadian Institutes for Health Research (CIHR; MOP 93742), the Lung Association, Alberta and North West Territories, Takeda, Gilead Sciences, GlaxoSmithKline, and AstraZeneca. Grant support for R. Newton is from the CIHR (MOP 68828), the Lung Association, Alberta and North West Territories, Takeda, Gilead Sciences, GlaxoSmithKline, and AstraZeneca. The authors state no conflict of interest.

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