Monday, August 5, 2013

IPF Improved Survival Rate with Possible Ties to Proton Pump Inhibitors

It is so interesting that the researchers are at the very beginnings of discovering a possible connection and a higher survival rate for idiopathic pulmonary fibrosis (IPF) if treatment includes proton pump inhibitors (PPIs), usually the treatment for GERD. This includes patients who had no symptoms of GERD. It may be tied to microaspiration. 

Background information on microaspirations  http://livingwellwithabaddiagnosis.blogspot.com/2012/06/gerd-and-lung-disease-day-3.html

Much more research needs to be done but it is interesting.

Thanks to Susan at the ILD Support Group, I received the below which was presented at the 2013 American Thoracic Society Conference:

Reflux Medicine Boosts Survival in Lung Disease
Published: May 24, 2013 | Updated: May 24, 2013

Action Points


  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • A retrospective review indicates that patients with idiopathic pulmonary fibrosis who were taking proton pump inhibitors had increased survival whether or not symptoms of gastroesophageal reflux were present.
PHILADELPHIA -- Survival in idiopathic pulmonary fibrosis (IPF) improved significantly in patients treated with proton pump inhibitors (PPIs), adding to a body of literature supporting PPI benefits in IPF, investigators in a retrospective review concluded.
Patients treated with PPIs had a mean transplant-free survival of 3.4 years compared with 1.4 years in a group of patients who did not receive the drugs. Patients with no history of gastroesophageal reflux (GER) or history of PPI use derived even greater benefit from the antireflux therapy.
Subsequent laboratory studies suggested a mechanism for the benefit, beyond antireflux effects: inhibition of dimethylarginine dimethylaminohydrolase (DDAH), which regulates nitric oxide synthetase in fibroblasts from IPF.
"Our study confirmed previous literature that suppression of gastroesophageal reflux is an independent predictor of improved survival in IPF," Lawrence Ho, MD, of Stanford University, said here at the American Thoracic Society International Conference. "We found that PPIs improved survival in IPF patients without GER symptoms or history of PPI use."
"DDAH and inducible nitric oxide synthetase are increased in lung epithelium and fibroblastic foci in IPF, and we found that proton pump inhibitors inhibit DDAH."
"These findings suggest a novel antifibrotic and pro-survival mechanism for PPIs in IPF patients," he added.
For reasons that remain unclear, patients with IPF have a high prevalence of GER. Reflux has been hypothesized to contribute to IPF etiology by induction of chronic microaspiration.
In one small clinical study 24-hour esophageal pH monitoring showed that two thirds of patients with IPF had abnormal acid exposure despite treatment for GER (Eur Respir J2006;27:136-142).
Several studies have shown that treatment of GER is associated with improved prognosis in IPF, including lower radiographic fibrosis scores, improved survival, and stabilization or improvement in pulmonary function.
"The survival benefit was present in patients with GER symptoms and GER diagnosis, which would lead us to believe that the medications were used for GER," said Ho.
However, some evidence has demonstrated a survival benefit in patients with IPF, irrespective of GER status, suggesting a non-reflux mechanistic explanation for the benefit, he added.
To add to the clinical database and explore potential mechanisms for GER medications' benefits in IPF, Ho and colleagues searched Stanford medical records for patients with IPF diagnoses during 2003 to 2007 and with 5-year follow-up data (or until a primary outcome of lung transplantation or death). They excluded patients who had an FEV1/FVC ratio ¡Ü0.70 or who received PPIs for less than a year for reasons other than transplantation or death.
The search identified 131 patients, 85 of whom received PPIs and 46 who did not. Clinical and demographic characteristics did not differ significantly between the PPI and non-PPI groups. However, transplant-free survival did differ significantly between the groups and favored PPI treatment (P=0.018).
An analysis of 5-year survival showed that almost 60% of the PPI users were alive at 5 years versus about 35% of patients who did not receive antireflux therapy (P=0.013). When the analysis was limited to patients with no history of GER or use of PPIs, the survival benefit persisted as more than 60% of PPI users remained alive at 5 years (P=0.013).
The observation that PPI treatment benefited patients irrespective of GERD status and PPI history led Ho and colleagues to examine alternative explanations to suppression of acid secretion as the reason for the benefit. Recent preclinical studies showed high levels of DDAH and iNOS in lung epithelium and fibroblastic foci. Inhibitors of iNOS and DDAH attenuated many of the features of IPF in a mouse model (Sci Transl Med 2011;3:87ra53, J Pathol 2013;229:242-249).
DDAH drives the metabolism of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of iNOS. Under normal conditions, L-arginine undergoes nitrosative stress mediated by iNOS to generate reactive nitrogen species (RNS) and reactive oxygen species (ROS). ADMA brakes iNOS activity via competitive binding of NOS, said Ho.
In IPF, increased DDAH activity impairs ADMA-mediated control of iNOS, leading to increased generation of RNS and ROS.
"Radicals produced by iNOS exacerbate an already dysfunctional pulmonary milieu by modifying cell signaling pathways in a manner that promotes local inflammation, increases aberrant cell proliferation, and accelerates matrix degradation," said Ho.
A comparison of tissue from donor and IPF lungs showed localization of DDAH to fibroblasts in IPF, and levels of both DDAH and iNOS were three times higher in the IPF tissue compared with the donor tissue, he added.
In a mouse model of IPF, treatment with a selective inhibitor of DDAH led to decreased enzymatic activity in lung lysates. The fibrosis score decreased significantly and lung function improved, as determined by lung compliance.
Using a high-throughput drug screening system, Ho and colleagues confirmed that PPIs are potent inhibitors of DDAH and found that lansoprazole was the most active inhibitor of DDAH in the PPI class. Mice treated with lansoprazole for 5 weeks had persistent 20% to 30% increases in plasma ADMA compared with a vehicle-treated animals.
The studies also showed that PPI inhibition of DDAH eliminated aberrant signaling in the transforming growth factor-beta pathway, which inhibits collagen production.
In the discussion that followed the presentation, an unidentified member of the audience said, "I have a little issue with the statement that PPIs improve survival. I don't think that's what you've shown. I think you've shown a relationship between PPI use and outcomes. I would be interested to know about confounders that might account for this relationship. For example, things that drive PI use, such as obesity, nonsteroidal anti-inflammatory use, concomitant disease, and so on."
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Dr. Joyce Lee, UCSF pulmonologist, critical care specialist, and the director of the Interstitial Lung Disease (ILD) Clinic, provided comment on the article:
There is increasing evidence to suggest that treatment (both medical and surgical) of gastroesophageal reflux disease may benefit patients with idiopathic pulmonary fibrosis (IPF). The data by Ho and colleagues are intriguing and suggests that proton pump inhibitors might have effects outside of reducing the acidity of the reflux and microaspirate. However, these data are preliminary and do not provide information on the effect of PPI on DDAH in either mouse models of fibrosis or in humans. There is little data at this time to suggest a non-reflux mediated benefit of proton pump inhibitor therapy in IPF. More research needs to be done in this area, including a randomized controlled trial of medical therapy for gastroesophageal reflux in order to determine the actual efficacy of proton pump inhibitors in patients with IPF. Until such a trial is performed, the benefit of proton pump inhibitors in IPF will remain uncertain.

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