Comment
Laguna Design/Science Photo Library
to have the most profound effect for the ADRB2 receptor compared with other functionally known variants in ADRB2. Should the results provided by Rabe and colleagues be implicated when instituting inhalation therapies in COPD? Previous studies have shown conflicting results, and confirmation of the present data is needed; however, if validated the results could have value in future prediction tools in concert with other pharmacogenetic determinants of response to COPD therapy. The results of the study by Rabe and colleagues will hopefully stimulate further research into the role of ADRB2 variants in the management of patients with COPD. Camilla Steen Jensen, *Morten Dahl by antagonising the induction of bronchoconstriction. The β2-adrenergic receptor is mainly expressed on the surface of smooth muscle cells, but it is also expressed to a lesser degree on mast cells, endothelial cells, epithelial cells, and type II cells in the lungs.8 The number of β2adrenergic receptors generally increase with increasing airway generation in the lungs, and the alveolar wall has the highest concentration of the β2-adrenergic receptor. Corticosteroids might promote β2-adrenergic receptor function in the lungs—eg, by increasing β2-adrenergic receptor gene expression.8 Rabe and colleagues showed in analyses stratified for corticosteroids at baseline that the effect of ADRB2 genotype on treatment response to salmeterol differed by corticosteroid use among Arg16Gly heterozygotes. Importantly, their results for patients homozygous for Arg16 remained statistically significant in both study groups irrespective of corticosteroid status at baseline. Candidate gene studies have identified genetic associations for COPD that might be relevant for future pharmacogenetic studies.4 In addition to Arg16, the Ile164 variant in ADRB2 could be a good candidate because it might link to the pathogenesis of COPD11 and it seems
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark [email protected] We declare that we have no conflicts of interest. Both authors contributed equally. 1 2
3 4 5 6
7
8 9
10
11
Decramer M, Janssens W, Miravitlles M. Chronic obstructive pulmonary disease. Lancet 2012; 379: 1341–51. Tashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010; 11: 149. Hizawa N. Pharmacogenetics of chronic obstructive pulmonary disease. Pharmacogenomics 2013; 14: 1215–25. Hersh CP. Pharmacogenetics of chronic obstructive pulmonary disease: challenges and opportunities. Pharmacogenomics 2010; 11: 237–47. Bleecker ER, Meyers DA, Bailey WC, et al. ADRB2 polymorphisms and budesonide/formoterol responses in COPD. Chest 2012; 142: 320–28. Yelensky R, Li Y, Lewitzky S, et al. A pharmacogenetic study of ADRB2 polymorphisms and indacaterol response in COPD patients. Pharmacogenomics J 2012; 12: 484–88. Rabe KF, Fabbri LM, Israel E, et al. Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial. Lancet Respir Med 2013; published online Dec 5. http://dx.doi.org/10.1016/S2213-2600(13)70248-0. Johnson M. Molecular mechanisms of β2-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 2006; 117: 18–24. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–19. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of β2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995; 13: 25–33. Thomsen M, Nordestgaard BG, Sethi AA, Tybjærg-Hansen A, Dahl M. β2-adrenergic receptor polymorphisms, asthma and COPD: two large population-based studies. Eur Respir J 2012; 39: 558–66.
The rise and fall of COPD mortality Published Online December 6, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70257-1 See Articles page 54
4
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide.1 Although COPD mortality has been projected to increase,2 studies have reported decreasing trends in the past two decades.1 In this issue of The Lancet Respiratory Medicine, Jose Luis López-Campos and colleagues provide data for
trends in COPD mortality rates for the 27 countries of the European Union (EU) between 1994 and 2010.3 Their findings are encouraging. Overall in the EU, the age-standardised mortality rate from COPD decreased substantially for men over the period, from 90·1 to 61·3 deaths per 100 000 person-years. For women, www.thelancet.com/respiratory Vol 2 January 2014
Comment
www.thelancet.com/respiratory Vol 2 January 2014
have two or more chronic diseases.6 In this setting, the value of the underlying cause of death is questionable. Classification of what an elderly person with several diseases died from, or died with, can be difficult if not impossible. In people with COPD as a contributing cause of death, only half have COPD reported as the underlying cause of death.7 The underlying cause thus underestimates the true mortality from COPD.7 How can estimates of mortality trends be improved? To estimate change in mortality attributable to COPD, the analysis should focus not on the underlying cause, but on the trend for COPD as a contributing cause of death. Contributing causes include all pathological processes that result in an earlier death.8 Misclassification of COPD deaths remains a problem; even in very severe COPD, only half of patients have the disease listed as a contributing cause of death. The rate is even lower in less severe COPD, which constitutes most patients.7 Over-reporting of COPD as a cause of death is also a problem in people without COPD, as well as in patients with COPD but whose deaths were unrelated to the disorder.7 Standardisation and analysis of contributing causes is fundamental to the estimation of trends in the burden of COPD deaths, and is an important area for increased future research. The study by López-Campos and colleagues, with the above mentioned limitations, provides a comprehensive analysis of available mortality data and provides strong evidence of a clear change in the trend of COPD mortality in most countries in Europe. However, mortality still increased in men in five countries and in women in 14 countries during the study.3 The differences in mortality are largely attributable to changes in smoking prevalence. Although smoking has decreased across the EU, many countries have increasing rates of youth smoking, especially in women.9 LópezCampos and colleagues’ findings draw attention to the importance of intensified actions to prevent and treat the effects of smoking.10 Health policy makers should look closely at these findings, which could be used to assess causes and interventions underpinning local mortality trends, and to encourage new initiatives to combat COPD deaths. These changing trends in COPD mortality seem to be a cause for optimism. The first sentence of many COPD papers—COPD is a leading cause of mortality worldwide—will hopefully have to be revised.
Leonello Calvetti/Science Photo Library
the mortality rate decreased slightly from 27·0 to 25·2 deaths per 100 000 person-years. The investigators did a commendable job in also analysing the timing of trend changes for men and women for the EU as a whole and for each separate country. Mortality rates and time trends differed between countries, with high mortality in, for example, Denmark, Hungary, the UK, and Spain. Surprisingly, Bulgaria, Cyprus, and Greece had rates of COPD deaths below the EU average, despite high rates of smoking.3 One question present itself— can these mortality data be trusted? And is this really the beginning of the end of rising COPD mortality rates in Europe, or is this the end of the beginning of COPD mortality statistics? In answering these questions, it is important to consider how death data are obtained. Causes of death were first systematically collected in England in the 16th century and were categorised mainly as plague or non-plague.4 With an increased demand for detail, mortality statistics have expanded into a complex system standardised by WHO through the International Classification of Diseases (ICD).5 Death certificates include the disorders that cause death, as well as those that indirectly contribute. The mortality registry gives each disorder an ICD code and selects the underlying cause of death by use of a complex computerised algorithm, which is continuously updated.5 The underlying cause is defined by the WHO as the disease and injury that initiates the train of morbid events leading directly to death.5 Use of the underlying cause is advantageous because it is the most standardised statistic for comparing mortality and is used by many investigators, including LópezCampos and colleagues.3 However, the measurement of causes of death is not without complications. First, data obtained from such analyses are only as good as the data—information on death certificates—recorded. Other influential factors include differences in disease prevalence, awareness and diagnostics (including autopsies), the certifying physician’s familiarity with the patient, the current perception of the associations between disorders and the risk of death, changes in ICD coding, and the selection of the underlying cause. A major limitation is the idea of a single underlying cause itself. The EU population is increasingly ageing and individuals have multiple morbidities—most people older than 65 years
5
Comment
Magnus P Ekström
5
Department of Clinical Sciences, Division of Respiratory Medicine and Allergology, Lund University, Lund, Sweden, and Department of Medicine, Blekinge Hospital, Karlskrona, Sweden [email protected]
6
I declare that I have no conflicts of interest. 1
2 3
4
Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095–128. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS medicine 2006; 3: e442. López-Campos JL, Ruiz-Ramos M, Soriano JB. Mortality trends in chronic obstructive pulmonary disease in Europe, 1994–2010: a joinpoint regression analysis. Lancet Respir Med 2013; Dec 6. http://dx.doi. org/10.1016/S2213-2600(13)70232-7. Moriyama I, Loy R, Robb-Smith A. History of the statistical classification of diseases and causes of death. Hyattsville, MD, USA: National Center for Health Statistics. 2011.
7 8
9
10
WHO. Manual of the International Statistical Classification of Diseases and Health Related Problems. 10th revision. Geneva, Switzerland: World Health Organization; 1992. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 2012; 380: 37–43. Jensen HH, Godtfredsen NS, Lange P, Vestbo J. Potential misclassification of causes of death from COPD. Eur Respir J 2006; 28: 781–85. Rothman KJ, Greenland S, Poole C, Lash TL. Rothman KJ, Greenland S, Lash TL, eds. Modern epidemiology. Philadelphia: Lippincott Williams and Wilkins, 2008: 5–31. Mladovsky P, Allin S, Masseria C, Hernández-Quevedo C, McDaid D, Mossialos E. Health in the European Union: trends and analysis. Observatory studies series, no 19. Copenhagen, Denmark: World Health Organization, European Observatory on Health Systems and Policies, 2009. Pirie K, Peto R, Reeves GK, Green J, Beral V. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. Lancet 2013; 381: 133–41.
Astier/BSIP/Science Photo Library
New treatments for COPD: many miles still to go
Published Online December 5, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70242-X See Articles page 63
6
Primary and secondary preventive measures are of enormous importance for management of chronic obstructive pulmonary disease (COPD), but the residual disability associated with established COPD has led to much research on new ways to treat this intractable condition. At present, treatment focuses on decreasing airway smooth-muscle tone by bronchodilator drugs and modulating pulmonary inflammation with inhaled corticosteroids or the phosphodiesterase type 4 inhibitor roflumilast. Both approaches can improve lung function, as shown in recent trials of combined treatment,1,2 whereas evidence of a reduction of mortality3 and cardiac events4 is less consistent. However, at best, these drugs decrease the effect of COPD on health status, exercise capacity, and exacerbation frequency leaving the patients feeling better but not completely well. Modulating inflammation more effectively has been a particular target for COPD research. Data suggest that inhaled corticosteroids combined with longacting β-agonists or use of a phosphodiesterase type 4 inhibitor can decrease inflammatory cell infiltration in patients with COPD.5 Several other drugs that modulate anti-inflammatory pathways have been investigated and inhibition of the p38 mitogen-activated kinase (MAPK) is particularly promising according to evidence from in vitro studies. This pathway involves phosphorylation of several proteins involved in the generation of inflammatory cytokines. MAPK is a good
target because it is involved in multiple inflammatory pathways and might have a role in modulation of systemic inflammation, which occurs in some patients with COPD.6 Data from a 6-week study7 of a p38 MAPK inhibitor for treatment of patients defined as having moderate disease by spirometry reported an increase in forced expiratory volume in 1 s (FEV1) of 86–92 mL in the treated group. However, these data should be treated with caution, not least because of the modest size of the change but also because patients with less severe disease show a greater capacity to respond spirometrically to treatment interventions.8 A more robust test of the benefits of this type of antiinflammatory drug would involve more patients with more severe disease studied for longer, together with relevant symptomatic endpoints. In the Lancet Respiratory Medicine Henrik Watz and colleagues9 report the results of such a trial. They tested three doses (2·5 mg, 7·5 mg, and 15 mg twice daily) of the oral p38 MAPK antagonist losmapimod compared with placebo. They assessed the effects of the drug on patients with COPD (mean FEV1 postbronchodilator roughly 45% of that predicted) and measured lung function, health status by St George’s Respiratory Questionnaire (SGRQ), and exacerbations. The primary outcome was the difference in 6 min walking distance, which the investigators reasoned would be an integrated measure of the effect of COPD on patients and the response to treatment. www.thelancet.com/respiratory Vol 2 January 2014
Laguna Design/Science Photo Library
to have the most profound effect for the ADRB2 receptor compared with other functionally known variants in ADRB2. Should the results provided by Rabe and colleagues be implicated when instituting inhalation therapies in COPD? Previous studies have shown conflicting results, and confirmation of the present data is needed; however, if validated the results could have value in future prediction tools in concert with other pharmacogenetic determinants of response to COPD therapy. The results of the study by Rabe and colleagues will hopefully stimulate further research into the role of ADRB2 variants in the management of patients with COPD. Camilla Steen Jensen, *Morten Dahl by antagonising the induction of bronchoconstriction. The β2-adrenergic receptor is mainly expressed on the surface of smooth muscle cells, but it is also expressed to a lesser degree on mast cells, endothelial cells, epithelial cells, and type II cells in the lungs.8 The number of β2adrenergic receptors generally increase with increasing airway generation in the lungs, and the alveolar wall has the highest concentration of the β2-adrenergic receptor. Corticosteroids might promote β2-adrenergic receptor function in the lungs—eg, by increasing β2-adrenergic receptor gene expression.8 Rabe and colleagues showed in analyses stratified for corticosteroids at baseline that the effect of ADRB2 genotype on treatment response to salmeterol differed by corticosteroid use among Arg16Gly heterozygotes. Importantly, their results for patients homozygous for Arg16 remained statistically significant in both study groups irrespective of corticosteroid status at baseline. Candidate gene studies have identified genetic associations for COPD that might be relevant for future pharmacogenetic studies.4 In addition to Arg16, the Ile164 variant in ADRB2 could be a good candidate because it might link to the pathogenesis of COPD11 and it seems
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark [email protected] We declare that we have no conflicts of interest. Both authors contributed equally. 1 2
3 4 5 6
7
8 9
10
11
Decramer M, Janssens W, Miravitlles M. Chronic obstructive pulmonary disease. Lancet 2012; 379: 1341–51. Tashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010; 11: 149. Hizawa N. Pharmacogenetics of chronic obstructive pulmonary disease. Pharmacogenomics 2013; 14: 1215–25. Hersh CP. Pharmacogenetics of chronic obstructive pulmonary disease: challenges and opportunities. Pharmacogenomics 2010; 11: 237–47. Bleecker ER, Meyers DA, Bailey WC, et al. ADRB2 polymorphisms and budesonide/formoterol responses in COPD. Chest 2012; 142: 320–28. Yelensky R, Li Y, Lewitzky S, et al. A pharmacogenetic study of ADRB2 polymorphisms and indacaterol response in COPD patients. Pharmacogenomics J 2012; 12: 484–88. Rabe KF, Fabbri LM, Israel E, et al. Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial. Lancet Respir Med 2013; published online Dec 5. http://dx.doi.org/10.1016/S2213-2600(13)70248-0. Johnson M. Molecular mechanisms of β2-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 2006; 117: 18–24. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–19. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of β2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995; 13: 25–33. Thomsen M, Nordestgaard BG, Sethi AA, Tybjærg-Hansen A, Dahl M. β2-adrenergic receptor polymorphisms, asthma and COPD: two large population-based studies. Eur Respir J 2012; 39: 558–66.
The rise and fall of COPD mortality Published Online December 6, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70257-1 See Articles page 54
4
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide.1 Although COPD mortality has been projected to increase,2 studies have reported decreasing trends in the past two decades.1 In this issue of The Lancet Respiratory Medicine, Jose Luis López-Campos and colleagues provide data for
trends in COPD mortality rates for the 27 countries of the European Union (EU) between 1994 and 2010.3 Their findings are encouraging. Overall in the EU, the age-standardised mortality rate from COPD decreased substantially for men over the period, from 90·1 to 61·3 deaths per 100 000 person-years. For women, www.thelancet.com/respiratory Vol 2 January 2014
Comment
www.thelancet.com/respiratory Vol 2 January 2014
have two or more chronic diseases.6 In this setting, the value of the underlying cause of death is questionable. Classification of what an elderly person with several diseases died from, or died with, can be difficult if not impossible. In people with COPD as a contributing cause of death, only half have COPD reported as the underlying cause of death.7 The underlying cause thus underestimates the true mortality from COPD.7 How can estimates of mortality trends be improved? To estimate change in mortality attributable to COPD, the analysis should focus not on the underlying cause, but on the trend for COPD as a contributing cause of death. Contributing causes include all pathological processes that result in an earlier death.8 Misclassification of COPD deaths remains a problem; even in very severe COPD, only half of patients have the disease listed as a contributing cause of death. The rate is even lower in less severe COPD, which constitutes most patients.7 Over-reporting of COPD as a cause of death is also a problem in people without COPD, as well as in patients with COPD but whose deaths were unrelated to the disorder.7 Standardisation and analysis of contributing causes is fundamental to the estimation of trends in the burden of COPD deaths, and is an important area for increased future research. The study by López-Campos and colleagues, with the above mentioned limitations, provides a comprehensive analysis of available mortality data and provides strong evidence of a clear change in the trend of COPD mortality in most countries in Europe. However, mortality still increased in men in five countries and in women in 14 countries during the study.3 The differences in mortality are largely attributable to changes in smoking prevalence. Although smoking has decreased across the EU, many countries have increasing rates of youth smoking, especially in women.9 LópezCampos and colleagues’ findings draw attention to the importance of intensified actions to prevent and treat the effects of smoking.10 Health policy makers should look closely at these findings, which could be used to assess causes and interventions underpinning local mortality trends, and to encourage new initiatives to combat COPD deaths. These changing trends in COPD mortality seem to be a cause for optimism. The first sentence of many COPD papers—COPD is a leading cause of mortality worldwide—will hopefully have to be revised.
Leonello Calvetti/Science Photo Library
the mortality rate decreased slightly from 27·0 to 25·2 deaths per 100 000 person-years. The investigators did a commendable job in also analysing the timing of trend changes for men and women for the EU as a whole and for each separate country. Mortality rates and time trends differed between countries, with high mortality in, for example, Denmark, Hungary, the UK, and Spain. Surprisingly, Bulgaria, Cyprus, and Greece had rates of COPD deaths below the EU average, despite high rates of smoking.3 One question present itself— can these mortality data be trusted? And is this really the beginning of the end of rising COPD mortality rates in Europe, or is this the end of the beginning of COPD mortality statistics? In answering these questions, it is important to consider how death data are obtained. Causes of death were first systematically collected in England in the 16th century and were categorised mainly as plague or non-plague.4 With an increased demand for detail, mortality statistics have expanded into a complex system standardised by WHO through the International Classification of Diseases (ICD).5 Death certificates include the disorders that cause death, as well as those that indirectly contribute. The mortality registry gives each disorder an ICD code and selects the underlying cause of death by use of a complex computerised algorithm, which is continuously updated.5 The underlying cause is defined by the WHO as the disease and injury that initiates the train of morbid events leading directly to death.5 Use of the underlying cause is advantageous because it is the most standardised statistic for comparing mortality and is used by many investigators, including LópezCampos and colleagues.3 However, the measurement of causes of death is not without complications. First, data obtained from such analyses are only as good as the data—information on death certificates—recorded. Other influential factors include differences in disease prevalence, awareness and diagnostics (including autopsies), the certifying physician’s familiarity with the patient, the current perception of the associations between disorders and the risk of death, changes in ICD coding, and the selection of the underlying cause. A major limitation is the idea of a single underlying cause itself. The EU population is increasingly ageing and individuals have multiple morbidities—most people older than 65 years
5
Comment
Magnus P Ekström
5
Department of Clinical Sciences, Division of Respiratory Medicine and Allergology, Lund University, Lund, Sweden, and Department of Medicine, Blekinge Hospital, Karlskrona, Sweden [email protected]
6
I declare that I have no conflicts of interest. 1
2 3
4
Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095–128. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS medicine 2006; 3: e442. López-Campos JL, Ruiz-Ramos M, Soriano JB. Mortality trends in chronic obstructive pulmonary disease in Europe, 1994–2010: a joinpoint regression analysis. Lancet Respir Med 2013; Dec 6. http://dx.doi. org/10.1016/S2213-2600(13)70232-7. Moriyama I, Loy R, Robb-Smith A. History of the statistical classification of diseases and causes of death. Hyattsville, MD, USA: National Center for Health Statistics. 2011.
7 8
9
10
WHO. Manual of the International Statistical Classification of Diseases and Health Related Problems. 10th revision. Geneva, Switzerland: World Health Organization; 1992. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 2012; 380: 37–43. Jensen HH, Godtfredsen NS, Lange P, Vestbo J. Potential misclassification of causes of death from COPD. Eur Respir J 2006; 28: 781–85. Rothman KJ, Greenland S, Poole C, Lash TL. Rothman KJ, Greenland S, Lash TL, eds. Modern epidemiology. Philadelphia: Lippincott Williams and Wilkins, 2008: 5–31. Mladovsky P, Allin S, Masseria C, Hernández-Quevedo C, McDaid D, Mossialos E. Health in the European Union: trends and analysis. Observatory studies series, no 19. Copenhagen, Denmark: World Health Organization, European Observatory on Health Systems and Policies, 2009. Pirie K, Peto R, Reeves GK, Green J, Beral V. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. Lancet 2013; 381: 133–41.
Astier/BSIP/Science Photo Library
New treatments for COPD: many miles still to go
Published Online December 5, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70242-X See Articles page 63
6
Primary and secondary preventive measures are of enormous importance for management of chronic obstructive pulmonary disease (COPD), but the residual disability associated with established COPD has led to much research on new ways to treat this intractable condition. At present, treatment focuses on decreasing airway smooth-muscle tone by bronchodilator drugs and modulating pulmonary inflammation with inhaled corticosteroids or the phosphodiesterase type 4 inhibitor roflumilast. Both approaches can improve lung function, as shown in recent trials of combined treatment,1,2 whereas evidence of a reduction of mortality3 and cardiac events4 is less consistent. However, at best, these drugs decrease the effect of COPD on health status, exercise capacity, and exacerbation frequency leaving the patients feeling better but not completely well. Modulating inflammation more effectively has been a particular target for COPD research. Data suggest that inhaled corticosteroids combined with longacting β-agonists or use of a phosphodiesterase type 4 inhibitor can decrease inflammatory cell infiltration in patients with COPD.5 Several other drugs that modulate anti-inflammatory pathways have been investigated and inhibition of the p38 mitogen-activated kinase (MAPK) is particularly promising according to evidence from in vitro studies. This pathway involves phosphorylation of several proteins involved in the generation of inflammatory cytokines. MAPK is a good
target because it is involved in multiple inflammatory pathways and might have a role in modulation of systemic inflammation, which occurs in some patients with COPD.6 Data from a 6-week study7 of a p38 MAPK inhibitor for treatment of patients defined as having moderate disease by spirometry reported an increase in forced expiratory volume in 1 s (FEV1) of 86–92 mL in the treated group. However, these data should be treated with caution, not least because of the modest size of the change but also because patients with less severe disease show a greater capacity to respond spirometrically to treatment interventions.8 A more robust test of the benefits of this type of antiinflammatory drug would involve more patients with more severe disease studied for longer, together with relevant symptomatic endpoints. In the Lancet Respiratory Medicine Henrik Watz and colleagues9 report the results of such a trial. They tested three doses (2·5 mg, 7·5 mg, and 15 mg twice daily) of the oral p38 MAPK antagonist losmapimod compared with placebo. They assessed the effects of the drug on patients with COPD (mean FEV1 postbronchodilator roughly 45% of that predicted) and measured lung function, health status by St George’s Respiratory Questionnaire (SGRQ), and exacerbations. The primary outcome was the difference in 6 min walking distance, which the investigators reasoned would be an integrated measure of the effect of COPD on patients and the response to treatment. www.thelancet.com/respiratory Vol 2 January 2014
