1. Can the gut affect the lungs in
scleroderma?
Elizabeth Renzoni
ILD Unit
Royal Brompton Hospital
2. Structure of the gullet (esophagus)
Upper esophageal sphincter: bundle of
muscles that keeps food/liquids from going
down the windpipe
Lower esophageal sphincter: bundle of
muscles that keeps the stomach contents
from flowing back up into the gullet
3.
4. The upper gut in scleroderma
•The gullet often affected in scleroderma
•Difficulty swallowing because the muscles in
the wall of the gullet work less well
•The muscle bundles of the lower gullet valve
(LES) don’t close the entrance to the stomach as
tightly, and may cause reflux from the stomach
5. •What is the relationship between reflux and
interstitial lung disease (ILD) in scleroderma ?
13. SSc-ILD
HR 95% CI
p value
Survival
Time to decline in FVC
Time to decline in DLco
Time to progression free
survival
1.35 1.06, 1.65 0.02
1.45 1.22, 1.68 <0.0005
1.30 1.08, 1.52 <0.01
1.36 1.13, 1.58 <0.005
Serum KL6 versus outcome
Unpublished data, Goh et al
14. Is microaspiration of gastric
contents associated with lung
fibrosis in scleroderma?
15. Manometry: measures strength and muscle
coordination of the gullet (oesophagus)
LES pressure may not correlate with reflux - reflux may be due to delayed clearance rather than low LES pressure
16. Failed peristalsis with preserved
amplitudes in upper gullet LOS
diaphragm
Patient with SclerodermaHealthy individual
17. 24 hour impedance: allows measurement of
duration and frequency of both acid and non
acid reflux
18. Gastro-esophageal reflux (GER) in
SSc-ILD
Manometric abnormalities in SSc associated with ILD
and lung function decline at 2 yrs (Marie et al 2001)
Number of acid and non-acid reflux episodes higher in
SSc-ILD than no ILD (Savarino et al 2009)
Baseline manometry did not predict worsening lung
function; however most patients had mild ILD (Gilson
et al 2010)
19. Investigation into the role of GER in
Pulmonary Fibrosis in Scleroderma
(clinicaltrials.gov N: NCT02136394)
Collaboration between RBH ILD Unit and RFH
Rheumatology and Gastroenterology Depts;
funded by the RSA
20. Aims
•What is the impact of reflux on symptoms and quality
of life of patients with scleroderma?
•How frequent is microaspiration into the lungs?
•Is microaspiration into the lungs correlated with
markers of epithelial injury (KL-6)?
•Is microaspiration more frequent in patients with
progressive lung fibrosis?
21. Prospective assessment of patients with
scleroderma associated ILD:
Symptoms of reflux/indigestion/bloating
Symptoms of cough/breathlessness
Gullet involvement: manometry and 24 hr impedance
Lungs: full lung function tests (and CT) and on follow
up
22. Look for markers of microaspiration of stomach
contents (pepsin) into the lungs in:
–Exhaled breath condensate (pepsin, pH)
–Saliva (pepsin)
–In a subset of patients, in bronchoalveolar lavage
23. •Correlate markers of microaspiration with
serum KL6, a marker measured in the blood that
reflects epithelial damage in the lungs
24. Inclusion criteria
-SSc with lung fibrosis (CT extent > 5 %)
-age > 18
Exclusion criteria:
-current smoker
-Barrett’s esophagus
GER in SSc-ILD
25. GER and pulmonary fibrosis in
scleroderma
Screen
Consent
history
Baseline
physical exam
Full lung function
HRCT chest
Blood for serum
Respiratory and gut
symptoms
Manometry
24 hour impedance
Exhaled breath
condensate/Saliva
BAL
6 months
Exam and history
Full lung function
Respiratory symptoms
Gut/reflux symptoms
(Blood for serum)
Exhaled breath
condensate
Saliva
12 months
Exam and history
Full lung function
Respiratory symptoms
Gut/reflux symptoms
Blood for serum
Exhaled breath
condensate
Saliva
18 months
Exam and history
Full lung function
Respiratory symptoms
Gut/reflux symptoms
Exhaled breath
condensate
Saliva
Ongoing 6-12
monthly
reviews with
lung function
tests
26. Patients (Number) 27
Age (years) 57.3 (SD 10)
Female 70.3%
Ever smoker 33.3%
Diffuse SSc 26.1%
Scl-70 antibody 78%
Forced vital capacity 74% (SD 21.8)
Gas transfer (DLCO) 42% (SD 13.4)
On immunosuppression 89%
Characteristics of patients: so far recruited 42, interim analysis
of 27 patients
28. Medications for GER
•6% on no GER treatment
•47% on proton pump inhibitor (PPI) alone
•29% on PPI + ranitidine
•18% on PPI + ranitidine + domperidone
29. Symptoms (gut)
•Heartburn
•Reported by 52% of patients on Proton pump inhibitors
(PPI), and 78% off PPI. Even on PPIs, 40% of patients have at
least 3-4 episodes per week
•Vomiting
•Appx 20% have at least 1-2 episodes per week,
whether on/off PPI
•Swallowing problems
•50% of the patients report at least 1-2 episodes per week,
whether on/off PPI
•Bloating
•Reported by 58% of patients on PPI and 78% off PPIs.
Approximately ¼ have at least 5-7 episodes per day.
30. NS
P=0.06
Even on proton pump inhibitors, roughly half of
patients felt stomach pain and/or bloating could
interfere with social activities
32. PEPSIN MEASUREMENTS
•Pepsin undetected in
exhaled breath
condensate (EBC)
•Pepsin detected in
saliva samples 14/27
patients
•Pepsin detected in all
BAL samples
performed so far
33. Saliva
pepsin
BAL
pepsin
Residual LES pressure 0.4 ns
% upright reflux 0.38 0.8
% recumbent reflux ns 0.7
Total reflux episodes 0.5 0.8
Acid reflux episodes 0.5 ns
Cough index 0.6 ns
Forced vital capacity% ns -0.8
Gas transfer (DLCO)% ns -0.8
Correlation between reflux measurements
and pepsin in saliva and BAL
34. Correlation between oesophageal
measurement and cough
Cough
Questionnaire
Mean UOS pressure 0.52
Mean LOS pressure 0.44
% upright reflux 0.4
% recumbent reflux ns
%total time reflux 0.43
Acid reflux 0.44
Non acid reflux 0.6
Proximal reflux
episodes
0.58
35. R=0.44; p=0.02 R=0.43; p=0.03
Lung function parameters correlate with lower
oesophageal sphincter pressures
36. Preliminary conclusions
•Symptoms related to gullet abnormalities have a
significant impact in patients with scleroderma
•Anti acid reflux drugs (proton pump inhibitors) benefit
only some of the gut symptoms, and reduce frequency
of troublesome cough
•Significant correlation between cough and acid/non
acid reflux measured by 24 hr impedance
•Upright but not recumbent reflux episodes correlate
with cough and with saliva pepsin
37. •Pepsin is measurable in saliva and BAL samples
but not in exhaled breath condensate
•There appears to be a correlation between BAL
pepsin and lung function severity, although still
too few patients
•Further recruitment and ongoing analyses
needed to assess relationship between reflux
and ILD
•Prospective assessment will be crucial to assess
whether microaspiration contributes to lung
disease progression
39. Manometry in keeping
with SSc-related gullet
involvement
57.7%
DeMeester score (overall
acidity exposure, normal <
14.7)
Mean 27.8
(SD 38.32)
% non acid reflux Mean 53% (SD 30.6%)
% time with reflux (acid/nonacid) Mean 4% (SD 10%)
40. Correlation between oesophageal
measurement and cough
Cough
Questionnaire
(off PPI)
Cough
Questionnaire
(on PPIs)
Mean UOS pressure 0.52
Mean LOS pressure 0.44
% upright reflux 0.4 0.7
% recumbent reflux
%total time reflux 0.43 0.7
Acid reflux 0.44
Non acid reflux 0.6
Proximal reflux
episodes
0.58
41. Common events in fibrosis progression across
different tissues
Friedman et al 2013