Can the gut affect the lungs in scleroderma?

Elizabeth RenzoniILD Unit

Royal Brompton Hospital

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

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

•What is the relationship between reflux and interstitial lung disease (ILD) in scleroderma ?

AIR SAC

O2

CO2

In interstitial lung diseases, the interstitium is thickened by inflammation and scar tissue

Normal interstitium Interstitium thickened by cells and connective tissue in SSc-ILD

Interstitial lung disease (ILD) is frequent in scleroderma, but in many

patients it is limited

SSc-ILD: a wide spectrum of disease

Intensive treatment vs MICO therapy

In a minority, ILD can be severe and progressive

INJURY

Products of epithelial injury

Activated myofibroblasts

Scar tissue

Inflammatory cells

MICROASPIRATION?

Serum KL-6 elevated after alveolar epithelium injury

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Unpublished data, Goh et al

Is microaspiration of gastric contents associated with lung

fibrosis in scleroderma?

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

Failed peristalsis with preserved amplitudes in upper gullet LOS diaphragm

Patient with SclerodermaHealthy individual

24 hour impedance: allows measurement of duration and frequency of both acid and non

acid reflux

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)

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

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?

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

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

•Correlate markers of microaspiration with serum KL6, a marker measured in the blood that reflects epithelial damage in the lungs

Inclusion criteria-SSc with lung fibrosis (CT extent > 5 %)-age > 18

Exclusion criteria: -current smoker -Barrett’s esophagus

GER in SSc-ILD

GER and pulmonary fibrosis in scleroderma

ScreenConsenthistory

Baselinephysical examFull lung functionHRCT chestBlood for serumRespiratory and gut symptomsManometry24 hour impedanceExhaled breath condensate/SalivaBAL

6 monthsExam and historyFull lung functionRespiratory symptomsGut/reflux symptoms(Blood for serum)Exhaled breath condensateSaliva

12 monthsExam and historyFull lung functionRespiratory symptomsGut/reflux symptomsBlood for serumExhaled breath condensateSaliva

18 monthsExam and historyFull lung functionRespiratory symptomsGut/reflux symptomsExhaled breath condensateSaliva

Ongoing 6-12 monthly reviews with lung function tests

Patients (Number) 27Age (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

•Preliminary results…

Medications for GER

•6% on no GER treatment

•47% on proton pump inhibitor (PPI) alone

•29% on PPI + ranitidine

•18% on PPI + ranitidine + domperidone

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.

NS

P=0.06

Even on proton pump inhibitors, roughly half of patients felt stomach pain and/or bloating could

interfere with social activities

LEICESTER COUGH QUESTIONNAIRE

*p<0.05

* * **

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

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

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

R=0.44; p=0.02 R=0.43; p=0.03

Lung function parameters correlate with lower oesophageal sphincter pressures

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

•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

•Planned recruitment of international centres (Heidelberg, Leuven, Parma) to aid in achieving adequate patient recruitment

Acknowledgements

•Royal Brompton Hospital

•Angelo de Lauretis•Simon Ward•Omar Usmani•Carmel Stock•Andras Bikov•Gisela Lindahl•Athol Wells

•Royal Free Hospital

•Chris Denton•Charles Murray•Claudia Clayman•Voon Ong•David Abraham

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%)

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

Common events in fibrosis progression across different tissues

Friedman et al 2013