Proton pump inhibitors improve survival in systemic sclerosis-associated ILD
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The use of proton pump inhibitors improves overall and progression-free survival in patients with systemic sclerosis-associated interstitial lung disease, according to data published in Rheumatology.
Meanwhile, the researchers additionally concluded that gastroesophageal reflux disease (GERD) has no impact on survival in either SSc or SSc-ILD.
“GERD, which is frequently treated with proton-pump inhibitors (PPI), is common in SSc and pre-clinical data have suggested a persistent inflammation of the lung tissue caused by micro-aspiration of acidic reflux material potentially leading to accelerated disease progression of ILD,” Michael Kreuter, MD, of the University of Heidelberg, in Germany, told Healio. “We therefore aimed to analyze the registry of the German Network for Systemic Sclerosis (DNSS) for whether progression of SSc-ILD is associated with GERD, and whether PPIs impact the progression of SSc-ILD.”
To investigate the relationship between SSc-ILD outcomes and PPIs or GERD, Kreuter and colleagues conducted a retrospective analysis of patients aged 18 years or older from the DNSS with SSc who were registered in the system from 2003 to present. The analysis included two sets of patients. The first set consisted of every patient diagnosed with SSc or SSc-ILD and every clinical visit since their initial diagnosis. The second set was a subset of the first, and included all patients with SSc-ILD as well as all visits since their ILD diagnosis.
The primary outcome was overall survival, defined as the time from the initial SSc or SSc-ILD diagnosis until death. The researchers additionally analyzed progression-free survival, defined as the time from initial SSc diagnosis, or ILD diagnosis, until disease progression or death.
The analysis included 4,306 patients with SSc and 1,931 patients with SSc-ILD. Of these patients, 63% with SSc, and 62% with SSc-ILD, had GERD. In both sets of patients, GERD did not appear to be associated with less overall survival or progression-free survival, according to the researchers. However, in patients with SSc-ILD, PPI use (98.4%; 95% CI, 97.6-99.3) associated with better overall survival at 1 year, compared with patients not receiving PPIs (90.8%; 95% CI, 87.9-93.8). The same was true at 5 years, with 91.4% for PPI users (95% CI, 89.2-93.8) and 70.9% (95% CI, 65.2-77.1) for non-users.
Patients receiving PPI therapy also demonstrated better rates of progression-free survival than patients not receiving PPIs, both after 1 year — 95.9% (95% CI, 94.6-97.3) vs. 86.4% (95% CI, 82.9-90.1), respectively — and 5 years — 66.8% (95% CI, 63-70.8) vs. 45.9% (95% CI, 39.6-53.2), respectively.
“We found that while 63% registered patients with SSc and 62% with SSc-ILD had reflux disease, GERD was not associated with decreased overall or progression free survival,” Kreuter said. “However, in SSc-ILD, use of PPIs was related to statistically and clinically meaningful improved overall and progression-free survival. These results generate the hypothesis that PPI use may have beneficial effects in SSc-ILD.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Multiple published studies reveal that patients with idiopathic pulmonary fibrosis (IPF), systemic sclerosis, asthma and COPD are affected by gastroesophageal reflux disease (GERD) at a higher prevalence than in the general population. Recently, the prevalence of GERD has increased all over the world, impacting 28% of the general population of the United States and 26% of European citizens.
GERD is frequent in SSc, with studies finding a prevalence range 30% to 96%. In other studies, GERD occurs with higher frequency and greater severity in SSc with interstitial lung disease (ILD) — both diffuse cutaneous SSc and limited cutaneous SSc subsets — than in SSc without ILD. However, it was not known, prior to the present study, whether GERD was associated with an increased risk for disease progression or death in SSc or SSc-ILD.
A causal relationship between GERD and IPF or SSc-ILD is not well defined yet. The fundamental question remains whether GERD is a consequence of IPF or SSc-ILD, or a risk factor for it. Several studies have supported the hypothesis that decreased pressures in the upper and lower esophageal sphincters (LES) and relaxation of the LES may contribute to microaspiration of small droplets of refluxate, which causes, over long periods of time, subclinical lung injury and fibroproliferative responses at the molecular and cellular levels, leading to pulmonary fibrosis.
This hypothesis is also supported by the detection of gastric contents — acids and pepsin — in the bronchoalveolar lavage fluid of patients with IPF and particularly SSC-ILD. On the other hand, some studies have hypothesized that GERD in IPF is more frequent because of potential confounding factors, such as advancing age and smoking, which weakens the sphincter. IPF or SSc-ILD may increase intrathoracic pressure, which can worsen GERD. With GERD and IPF or SSc-ILD, there is continued debate about which came first, GERD or pulmonary fibrosis.
In the above study, GERD was not associated with worsening outcomes of the SSc patients with or without ILD. The use of proton pump inhibitors (PPIs) was associated with improved outcomes after 1 year and 5 years of therapy, particularly in the SSc-ILD group.
Currently, antacid therapy (eg, PPIs and histamine-2-blocker receptor antagonists) for patients with IPF and GERD symptoms has only a conditional recommendation according to IPF guidelines. The 2022 update to the guidelines include these two new recommendations: 1) Patients with IPF should not be treated with antacid medication, with the aim of improving respiratory outcomes; 2) Patients with IPF should not be referred for anti-reflux surgery, with the aim of improving respiratory outcomes.
The debate continues.
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