Comment
Anti-acid treatment for idiopathic pulmonary fibrosis Published Online June 14, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70121-8
Miriam Maslo/Science Photo Library
See Articles page 369
348
The idea that idiopathic pulmonary fibrosis (IPF) could be mechanistically and pathogenetically attributed to repeated, often silent events of gastric fluid microaspiration (so-called lungburns) was first introduced almost 40 years ago.1 Since then, an increasing body of evidence has provided useful insights about a potential link between diffuse lung fibrosis and gastro-oesophageal reflux. A high prevalence of abnormal acid gastro-oesophageal reflux (identified by 24-h pH monitoring) in patients with IPF—almost 90%—was first reported in two different cohorts.2,3 However, a much smaller proportion of patients complain of heartburn-related symptoms,4 rendering the diagnosis of abnormal acid gastrooesophageal reflux clinically occult and thus insidious. Several reports have associated anti-reflux treatment with improved survival and substantial functional and radiological benefits in patients with IPF.5 Additionally, increased amounts of microaspiration biomarkers, such as pepsin, in bronchoalveolar lavage fluid of patients with IPF experiencing an acute exacerbation6 directly implicates clinically silent microaspiration of gastric fluid as a triggering factor of fibrogenesis.5 In The Lancet Respiratory Medicine, Joyce Lee and colleagues present results of an analysis of the potential usefulness of anti-acid treatment (protonpump inhibitors [PPIs] and histamine-receptor-2 [H2] blockers) in patients with IPF.7 Their method was well designed: they used prospectively obtained data from the placebo groups of the three randomised
clinical trials from the Idiopathic Pulmonary Fibrosis Clinical Research Network (PANTHER, ACE, and STEP). They assessed the effect of anti-acid treatment on functional deterioration in a 30-week period for 242 patients. The most important finding of their study was that patients taking anti-acid treatment (n=124) had a significantly smaller decrease in forced vital capacity (–0·06 L, 95% CI –0·11 to –0·01) than did those who were not taking anti-acid treatment (n=118; –0·12 L, –0·17 to –0·08; difference 0·07 L, 0–0·14; p=0·05). Moreover, patients taking anti-acid treatment had significantly fewer acute exacerbations (no events) than did those who were not (nine events; p=0·0017). Although the results suggested improved survival with anti-acid treatment, the difference was not significant (p=0·12). Nevertheless, several mechanistic issues and safety concerns should be addressed before antiacid treatment in patients with IPF can be widely implemented. So far, no rigid pathogenetic link between gastro-oesophageal reflux and IPF has been identified, and anti-acid treatment has inconsistent effects on survival, because it does not inhibit reflux.5 Patients included in Lee and colleagues’ analysis,7 and those in previous retrospective analyses,8 were heterogeneous in terms of disease severity and presence of comorbidities, such as sleep apnoea, that can significantly affect survival and cause further deterioration of abnormal gastro-oesophageal reflux. Finally, assessment of abnormal acid gastrooesophageal reflux and gastro-oesophageal reflux disease was superficially based solely on heartburn symptoms in most patients; endoscopy was used in a small proportion of patients. But do physicians really need to treat symptoms of gastro-oesophageal reflux? Or should the primary outcome be to prevent further lung injuries by intervening directly in the fibrogenic cascade? A study by Ho and colleagues8 extended the beneficial contribution of PPIs beyond neutralisation of highly acidic gastric juice. The investigators concluded that PPI inhibition of dimethylarginine dimethylaminohydrolase and inducible nitric oxide synthase, which are known to be increased within lung www.thelancet.com/respiratory Vol 1 July 2013
Comment
epithelium and fibroblastic foci,9,10 eliminated aberrant signalling in the TGF-β pathway, ultimately leading to decreased collagen production in an experimental model of lung fibrosis. These findings suggest a novel antifibrotic mechanism for PPIs in patients with IPF. Another crucial issue is to clarify whether antiacid treatments will be used as adjunctive or primary therapeutic regimens. Many questions about which patients, the length of treatment, and what doses to use remain unanswered. The idea that all patients with IPF could receive anti-acid treatment as prophylaxis could be risky in view of the potentially harmful sideeffects, such as infections, electrolyte disturbances, and, importantly, drug interactions. H2 blockers and PPIs are potent inducers of P450 enzymes, particularly CYP1A2, and therefore might limit the plasma concentrations of several antifibrotic agents, including pirfenidone, which has been approved for IPF treatment.11 Overall, a randomised placebo-controlled trial of patients with IPF, with and without symptoms of gastro-oesophageal reflux, is needed. Assessment of agent-specific and dose-dependent therapeutic outcomes will be necessary to better define individuals who could benefit from such interventions.
Argyris Tzouvelekis, *Demosthenes Bouros Department of Pneumonology, Medical School, Democritus University of Thrace, Alexandroupolis 68100, Greece [email protected] We declare that we have no conflicts of interest. 1
2
3
4
5 6 7
8
9
10
11
Mays EE, Dubois JJ, Hamilton GB. Pulmonary fibrosis associated with tracheobronchial aspiration: a study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology. Chest 1976; 69: 512–15. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006; 27: 136–42. Tobin RW, Pope CE, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 158: 1804–08. Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184: 1390–94. Lee JS, Collard HR, Raghu G, et al. Does chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med 2010; 123: 304–11. Raghu G, Meyer KC. Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J 2012; 39: 242–45. Lee JS, Collard HR, Anstrom KJ, et al, for the IPFnet Investigators. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med 2013; published online June 14. http://dx.doi.org/10.1016/S2213-2600(13)70105-X. Ho L, Ghebremariam Y, Cooke J, Rosen G. Proton pump inhibitors inhibit DDAH and improve survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2013; 187: A5710. Janssen W, Pullamsetti SS, Cooke J, Weissmann N, Guenther A, Schermuly RT. The role of dimethylarginine dimethylaminohydrolase (DDAH) in pulmonary fibrosis. J Pathol 2013; 229: 242–49. Pullamsetti SS, Savai R, Dumitrascu R, et al. The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis. Sci Transl Med 2011; 3: 87ra53. Bouros D. Pirfenidone for idiopathic pulmonary fibrosis. Lancet 2011; 377: 1727–29.
Brittle bones have been reported in children, adolescents, and adults with cystic fibrosis. Patients with cystic fibrosis bone disease (osteopenia and osteoporosis) have an increased risk of vertebral and rib fractures, which can accelerate the decline of lung function and increase exacerbations. Although nutritional deficiencies, vitamin D deficiency, delayed puberty, chronic pulmonary infection, reduced physical activity, and frequent use of glucocorticoid drugs can all jeopardise bone health in patients with cystic fibrosis, the pathogenesis of cystic fibrosisrelated low bone mineral density is still unknown.1 Furthermore, low bone mineral density has been reported in children with cystic fibrosis (even those younger than 6 years) who have moderate lung disease and normal nutritional status,2,3 suggesting that low bone mineral density might be caused by the primary defect—ie, CFTR dysfunction in bone www.thelancet.com/respiratory Vol 1 July 2013
tissue, as noted in young and adult F508del Cftr mice.4 Therefore, fully understanding the mechanisms of early bone defects could help to provide new treatment strategies. To reduce the risk of bone disease in adults with cystic fibrosis, European guidelines5 recommend optimising nutrition to gain a normal bodymass index, vitamin D, vitamin K, and calcium supplementation, and weight-bearing exercise for 30 min three times a week. Oral or intravenous bisphosphonates are recommended for patients whose T score or Z score is lower than –2, who are on the transplant waiting list, or whose bone mineral density is falling by more than 3–5% per year.5 Bisphosphonates are potent inhibitors of osteoclastic bone resorption and numerous clinical trials6 have reported that they improve bone mineral density without decreasing fracture risk in adults with cystic
Zephyr/Science Photo Library
Bone health in cystic fibrosis: use of oral bisphosphonates
Published Online June 2, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70096-1 See Articles page 377
349
Anti-acid treatment for idiopathic pulmonary fibrosis Published Online June 14, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70121-8
Miriam Maslo/Science Photo Library
See Articles page 369
348
The idea that idiopathic pulmonary fibrosis (IPF) could be mechanistically and pathogenetically attributed to repeated, often silent events of gastric fluid microaspiration (so-called lungburns) was first introduced almost 40 years ago.1 Since then, an increasing body of evidence has provided useful insights about a potential link between diffuse lung fibrosis and gastro-oesophageal reflux. A high prevalence of abnormal acid gastro-oesophageal reflux (identified by 24-h pH monitoring) in patients with IPF—almost 90%—was first reported in two different cohorts.2,3 However, a much smaller proportion of patients complain of heartburn-related symptoms,4 rendering the diagnosis of abnormal acid gastrooesophageal reflux clinically occult and thus insidious. Several reports have associated anti-reflux treatment with improved survival and substantial functional and radiological benefits in patients with IPF.5 Additionally, increased amounts of microaspiration biomarkers, such as pepsin, in bronchoalveolar lavage fluid of patients with IPF experiencing an acute exacerbation6 directly implicates clinically silent microaspiration of gastric fluid as a triggering factor of fibrogenesis.5 In The Lancet Respiratory Medicine, Joyce Lee and colleagues present results of an analysis of the potential usefulness of anti-acid treatment (protonpump inhibitors [PPIs] and histamine-receptor-2 [H2] blockers) in patients with IPF.7 Their method was well designed: they used prospectively obtained data from the placebo groups of the three randomised
clinical trials from the Idiopathic Pulmonary Fibrosis Clinical Research Network (PANTHER, ACE, and STEP). They assessed the effect of anti-acid treatment on functional deterioration in a 30-week period for 242 patients. The most important finding of their study was that patients taking anti-acid treatment (n=124) had a significantly smaller decrease in forced vital capacity (–0·06 L, 95% CI –0·11 to –0·01) than did those who were not taking anti-acid treatment (n=118; –0·12 L, –0·17 to –0·08; difference 0·07 L, 0–0·14; p=0·05). Moreover, patients taking anti-acid treatment had significantly fewer acute exacerbations (no events) than did those who were not (nine events; p=0·0017). Although the results suggested improved survival with anti-acid treatment, the difference was not significant (p=0·12). Nevertheless, several mechanistic issues and safety concerns should be addressed before antiacid treatment in patients with IPF can be widely implemented. So far, no rigid pathogenetic link between gastro-oesophageal reflux and IPF has been identified, and anti-acid treatment has inconsistent effects on survival, because it does not inhibit reflux.5 Patients included in Lee and colleagues’ analysis,7 and those in previous retrospective analyses,8 were heterogeneous in terms of disease severity and presence of comorbidities, such as sleep apnoea, that can significantly affect survival and cause further deterioration of abnormal gastro-oesophageal reflux. Finally, assessment of abnormal acid gastrooesophageal reflux and gastro-oesophageal reflux disease was superficially based solely on heartburn symptoms in most patients; endoscopy was used in a small proportion of patients. But do physicians really need to treat symptoms of gastro-oesophageal reflux? Or should the primary outcome be to prevent further lung injuries by intervening directly in the fibrogenic cascade? A study by Ho and colleagues8 extended the beneficial contribution of PPIs beyond neutralisation of highly acidic gastric juice. The investigators concluded that PPI inhibition of dimethylarginine dimethylaminohydrolase and inducible nitric oxide synthase, which are known to be increased within lung www.thelancet.com/respiratory Vol 1 July 2013
Comment
epithelium and fibroblastic foci,9,10 eliminated aberrant signalling in the TGF-β pathway, ultimately leading to decreased collagen production in an experimental model of lung fibrosis. These findings suggest a novel antifibrotic mechanism for PPIs in patients with IPF. Another crucial issue is to clarify whether antiacid treatments will be used as adjunctive or primary therapeutic regimens. Many questions about which patients, the length of treatment, and what doses to use remain unanswered. The idea that all patients with IPF could receive anti-acid treatment as prophylaxis could be risky in view of the potentially harmful sideeffects, such as infections, electrolyte disturbances, and, importantly, drug interactions. H2 blockers and PPIs are potent inducers of P450 enzymes, particularly CYP1A2, and therefore might limit the plasma concentrations of several antifibrotic agents, including pirfenidone, which has been approved for IPF treatment.11 Overall, a randomised placebo-controlled trial of patients with IPF, with and without symptoms of gastro-oesophageal reflux, is needed. Assessment of agent-specific and dose-dependent therapeutic outcomes will be necessary to better define individuals who could benefit from such interventions.
Argyris Tzouvelekis, *Demosthenes Bouros Department of Pneumonology, Medical School, Democritus University of Thrace, Alexandroupolis 68100, Greece [email protected] We declare that we have no conflicts of interest. 1
2
3
4
5 6 7
8
9
10
11
Mays EE, Dubois JJ, Hamilton GB. Pulmonary fibrosis associated with tracheobronchial aspiration: a study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology. Chest 1976; 69: 512–15. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006; 27: 136–42. Tobin RW, Pope CE, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 158: 1804–08. Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184: 1390–94. Lee JS, Collard HR, Raghu G, et al. Does chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med 2010; 123: 304–11. Raghu G, Meyer KC. Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J 2012; 39: 242–45. Lee JS, Collard HR, Anstrom KJ, et al, for the IPFnet Investigators. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med 2013; published online June 14. http://dx.doi.org/10.1016/S2213-2600(13)70105-X. Ho L, Ghebremariam Y, Cooke J, Rosen G. Proton pump inhibitors inhibit DDAH and improve survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2013; 187: A5710. Janssen W, Pullamsetti SS, Cooke J, Weissmann N, Guenther A, Schermuly RT. The role of dimethylarginine dimethylaminohydrolase (DDAH) in pulmonary fibrosis. J Pathol 2013; 229: 242–49. Pullamsetti SS, Savai R, Dumitrascu R, et al. The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis. Sci Transl Med 2011; 3: 87ra53. Bouros D. Pirfenidone for idiopathic pulmonary fibrosis. Lancet 2011; 377: 1727–29.
Brittle bones have been reported in children, adolescents, and adults with cystic fibrosis. Patients with cystic fibrosis bone disease (osteopenia and osteoporosis) have an increased risk of vertebral and rib fractures, which can accelerate the decline of lung function and increase exacerbations. Although nutritional deficiencies, vitamin D deficiency, delayed puberty, chronic pulmonary infection, reduced physical activity, and frequent use of glucocorticoid drugs can all jeopardise bone health in patients with cystic fibrosis, the pathogenesis of cystic fibrosisrelated low bone mineral density is still unknown.1 Furthermore, low bone mineral density has been reported in children with cystic fibrosis (even those younger than 6 years) who have moderate lung disease and normal nutritional status,2,3 suggesting that low bone mineral density might be caused by the primary defect—ie, CFTR dysfunction in bone www.thelancet.com/respiratory Vol 1 July 2013
tissue, as noted in young and adult F508del Cftr mice.4 Therefore, fully understanding the mechanisms of early bone defects could help to provide new treatment strategies. To reduce the risk of bone disease in adults with cystic fibrosis, European guidelines5 recommend optimising nutrition to gain a normal bodymass index, vitamin D, vitamin K, and calcium supplementation, and weight-bearing exercise for 30 min three times a week. Oral or intravenous bisphosphonates are recommended for patients whose T score or Z score is lower than –2, who are on the transplant waiting list, or whose bone mineral density is falling by more than 3–5% per year.5 Bisphosphonates are potent inhibitors of osteoclastic bone resorption and numerous clinical trials6 have reported that they improve bone mineral density without decreasing fracture risk in adults with cystic
Zephyr/Science Photo Library
Bone health in cystic fibrosis: use of oral bisphosphonates
Published Online June 2, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70096-1 See Articles page 377
349
