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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  Gastro-oesophageal reflux disease (GERD) is an important problem in systemic sclerosis due to impaired salivation and oesophageal function.

Aim  To determine the efficacy of adding ranitidine at bedtime to control nocturnal acid breakthrough (NAB) and GERD in patients with systemic sclerosis already prescribed high-dose omeprazole.

Methods  Patients with systemic sclerosis and GERD symptoms (n = 14) were treated with omeprazole 20 mg b.d. and either placebo or ranitidine 300 mg at bedtime for 6 weeks in a randomized, cross-over, placebo controlled study. At the end of each period a 24 h pH-study with intragastric and oesophageal pH measurement was performed.

Results  Pathological acid reflux occurred in eight patients with omeprazole/placebo and in seven with omeprazole/ranitidine (P = ns) with technically adequate oesophageal pH-studies (n = 13). NAB was present in eight patients with omeprazole/placebo and six with omeprazole/ranitidine (P = ns) in whom technically adequate gastric pH-studies were obtained (n = 10). The addition of ranitidine had no consistent effect on patient symptoms or quality of life.

Conclusion  Many patients with systemic sclerosis experienced NAB and pathological oesophageal acid exposure despite high-dose acid suppression with omeprazole b.d. Adding ranitidine at bedtime did not improve NAB, GERD or quality of life in this population.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Gastro-oesophageal reflux disease (GERD) is a major problem in patients with systemic sclerosis, leading to significant morbidity and reduced patient-rated quality of life. Decreased lower oesophageal sphincter pressure, impaired peristalsis, diminished saliva production, and delayed gastric emptying may also be present and play a role in the pathogenesis of GERD.1 High-dose acid suppression is important in this group of patients to avoid severe oesophagitis and complications such as oesophageal strictures and Barrett’s oesophagus; however, there is limited information on the optimal therapy of acid reflux in systemic sclerosis.

The circadian rhythm of gastric acid secretion exhibits low secretion in the morning, greater output in the evening and peak secretion around midnight.2 Studies have shown a drop in nocturnal gastric pH in patients and healthy volunteers taking a proton pump inhibitor twice daily (PPI b.d.).3, 4 This drop in gastric pH, termed nocturnal acid breakthrough (NAB), is defined as a gastric pH < 4 for at least one continuous hour during the night. The percentage of healthy volunteers with NAB ranged from 35% to 75% and in patients with GERD from 67% to 100%.4–7.This is clinically important because the prevalence of abnormal oesophageal acid exposure during NAB is much higher in patients with GERD (33%) and Barrett’s oesophagus (50%) compared with that in healthy volunteers (8%).5 Patients with systemic sclerosis have a high prevalence of GERD and its complications. Prolonged oesophageal acid exposure at night secondary to NAB is prevalent in these patients because of weak lower oesophageal sphincter function and poor oesophageal motility. Thus, patients with systemic sclerosis are a relevant group to study the clinical impact and the appropriate treatment directed at the control of NAB.

Studies indicate that, for patients requiring more than a standard daily dose of a PPI, adding a second dose before dinner leads to a 24 h acid control superior to doubling the morning dose.8, 9 Twice daily omeprazole together with ranitidine at bedtime proved to be the optimal regimen to reduce NAB in normal volunteers.10, 11 The aim of this randomized, double blind, placebo controlled study was to evaluate the role of adding ranitidine to twice daily omeprazole in controlling gastric and oesophageal pH for patients with systemic sclerosis complaining of typical reflux symptoms.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients and study design

Patients meeting the American Rheumatism Association criteria for systemic sclerosis and a history suggesting of GERD were entered into the study. Patients were recruited from the systemic sclerosis patient self-help group of the German speaking part of Switzerland. Inclusion criteria were the presence of typical reflux symptoms (heartburn or acid regurgitation). There was no requirement for ‘classic’ changes in systemic sclerosis on oesophageal motility. Exclusion criteria were pregnancy or lactation, alcohol or drug abuse, severe concomitant organic or psychiatric disease and previous oesophageal or gastric surgery. Acid suppression therapy with H2-receptor antagonists was discontinued for at least 2 weeks prior to the study. The study fulfilled the principles of the ‘Declaration of Helsinki’ and was approved by the local Ethics committee of the University Hospital of Zurich. Written informed consent was obtained.

Patients were studied in a randomized, double-blind, cross-over, placebo controlled study lasting 12 weeks. Each patient was treated with omeprazole (AstraZeneca, Zug, Switzerland) 20 mg b.d. and bedtime placebo for 6 weeks (Arm 1) and omeprazole 20 mg b.d. and bedtime ranitidine 300 mg for 6 weeks (Arm 2) (omeprazole taken before breakfast and dinner). At baseline upper gastrointestinal endoscopy was performed and standardized, validated questionnaires to assess gastrointestinal related quality of life12 reflux symptoms13 and the burden of disease related to systemic sclerosis,14 were completed. In each 6-week treatment period, 3 weeks after start of dosing, quality of life and reflux symptoms were assessed by a telephone interview. At the end of each 6 weeks treatment period an upper endoscopy and a 24 h pH-study were performed and patients were asked again to complete the questionnaires regarding quality of life and reflux symptoms.

Methods

Physiological measurements of gastro-oesophageal function

High resolution manometry (Advanced Manometry Systems, Melbourne, Australia) using a 22 channel water perfused catheter with a sleeve sensor (Dentsleeve, Wayville, South Australia) was performed to document lower oesophageal sphincter function and oesophageal motility, as described previously.15 Manometry results were analysed using Trace! Software (Advanced Manometry Systems) and classified according to standard criteria.16

The 24 h pH-study was performed using two catheters. The oesophageal pH-study was performed with a catheter containing four 5 cm spaced solid state pressure transducers and a pH glass-electrode mounted at the tip of the catheter (Unisensor, Attikon, Switzerland). After an over night fast a pull-through manometry with the solid state pressure catheter was performed first to define the position of the lower oesophageal sphincter. The catheter was positioned with the oesophageal pH-electrode to be 5 cm above the lower oesophageal sphincter. Intragastric pH was monitored by a second glass electrode (Ingold, Urdorf, Switzerland) and was placed 10 cm below the lower end of the lower oesophageal sphincter. Patients were instructed to continue their normal daily activities, to indicate changes in their body position, start and end of meals and time of drug intake on a digital data logger. Each individual was free to choose from a selection of three standardized meals for breakfast, lunch and dinner on all occasions when a 24 h pH-measurement was monitored. The standardized meals were the same during both 24 h pH-studies.

To analyse the nocturnal gastric and oesophageal pH, the pH-data were synchronized to the individual time of drug intake and truncated from 2 h before to 10 h after the intake of ranitidine or placebo. The 2 h pH-data prior to the drug-intake give the baseline values. For the gastric and oesophageal pH-data the median intragastric pH values in intervals of 2 h were computed. NAB was defined as a drop of intragastric pH below 4 for at least 1 h or more during the nocturnal period. Gastro-oesophageal reflux was defined as a drop of oesophageal pH < 4. The oesophageal pH data were analysed for the same 10 h nocturnal period as the intragastric pH-data and the fraction of time below pH 4 was computed in 2 h intervals. Pathological acid reflux on treatment (i.e., failure of acid suppression) was defined as >1.6% time with pH < 4 during the test period.5

Upper endoscopy

In all patients upper endoscopy was performed at baseline, after 6 and 12 weeks with standard flexible endoscope by two experienced clinicians. Reflux oesophagitis was graded according to the modified Savary-Miller-Monnier classification.

Statistical analysis

Power calculations indicate that, assuming a 30% day to day intra-individual variation in oesophageal pH and symptom measurement,17, 18 a study population of 14 patients provides a 90% chance of detecting a clinically meaningful (30%) improvement in measured variables for alpha <0.05. A study size of 10 patients would provide an 80% chance of detecting the same improvement.

Data from the clinical records were manually entered into a relational database system, the 24-h pH monitoring was analysed with a modified version of the program Scan (Medical Instruments Corporation, Solothurn, Switzerland); extracted indices were directly imported into a database by a custom computer program. Statistical analysis for the pH data was performed with the program Statistica 5.5 (Statsoft, Tulsa, OK, USA). Oesophageal and intra-gastric pH data were analysed by repeated measurement anova.

Symptom scores were analysed with a mixed model using the program R.19 To compensate for study effects, a linear regression model with the five visits as time axis, common slope and separate intercepts were fitted to the total symptom score. Three levels of treatment (baseline, omeprazole + placebo and omeprazole + ranitidine) were included as factors. Contrasts and their significances of both were computed.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patient characteristics

Fourteen systemic sclerosis patients with gastrointestinal involvement (12 women and 2 men, age range 51–79) participated in this study whose baseline characteristics are shown in Table 1. Gastric and oesophageal pH measurements were not available for one patient following the second treatment arm because of failed placement of the pH probe. Thus 13/14 patients completed the study, in addition three gastric 24 h pH recordings during treatment with omeprazole/ranitidine were unsuccessful for reasons of technical failure (excluded from gastric pH analysis).

Table 1.   Baseline characteristics of the study population
Mean age (range)61.7 (51–79)
Sex2 men/12 women
Helicobacter pylori status1 positive/14 negative
Systemic sclerosis subgroup (n)
 Unclassified1
 Diffuse8
 Limited5
Years since disease onset15.6 years (6–36)
Years since gut involvement7.6 years (1–25)

High resolution manometry

Classic findings of aperistalsis with weak lower oesophageal sphincter pressure (<12 mmHg) were present in 5/13 systemic sclerosis patients (Figure 3a), all but one of whom had persistent pathological oesophageal acid exposure despite high-dose omeprazole treatment. Hypotensive, ineffective motility (<30 mmHg in distal oesophagus) was present in six patients, two of whom had an incompetent reflux barrier (Figure 3b). Normal oesophageal function was found in 2/13 patients (Figure 3c). Pathological acid exposure on omeprazole b.d. was present also in 5/8 patients with some preservation of oesophageal function (P = ns; compared to aperistaltic group). In this small group, there was no correlation between oesophageal dysmotility and reflux severity. There was also no association between severe skin and oesophageal disease.

image

Figure 3.  High resolution manometry from representative patients recruited in the study. Spatiotemporal plots display oesophageal pressure activity. Time is on the x-axis, distance from the nares on the y axis and pressure is represented by colour legend (right of figures).15 (a) Classic ‘scleroderma oesophagus’ with aperistalsis and weak lower oesophageal sphincter (LOS) pressure (5/13). Also note raised intra-bolus pressure indicating poor oesophageal clearance of swallowed fluid. (b) Hypotensive, ineffective motility with failure to maintain pressure >30 mmHg in distal oesophagus (6/13). (c) Normal oesophageal and LOS motility (2/13).

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Gastric pH-measurement

The 24-h intragastric pH profile (Table 2) and median intragastric pH in the 10-h nocturnal period were similar during both treatment regimens (Figure 1), and there were no significant differences in mean gastric pH during the 10-h nocturnal study period and the full 24-h period in the placebo (pH 4.5; 3.1–6.6 vs. pH 4.9; 3.2–6.1) or ranitidine (pH 4.3; 1.7–7.0 vs. pH 4.4; 1.8–7.0) study arms. Similar pH tracings were obtained from 2 h before to 4 h after drug intake, suggesting reliable measurements and good synchronization with drug intake. The pH recordings showed a high intra- and inter-individual variability. NAB was similar with both treatments and occurred in 8/10 patients treated with omeprazole/placebo and in 6/10 patients treated with omeprazole/ranitidine (P = ns).

Table 2.   Median 24 h intragastric pH
Median 24 h intragastric pH
 MinQ25MedianQ75Max
Omeprazole/placebo3.23.64.95.06.2
Omeprazole/ranitidine1.83.24.45.77.0
All1.83.64.75.47.0
image

Figure 1.  Median intragastric pH during the nocturnal period after ingestion of placebo or ranitidine in addition to high-dose acid suppression (proton pump inhibitor b.d.).

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Acid reflux occurred most often during periods of NAB; however, discrepancies during simultaneous pH recording between the electrodes occurred in approximately one quarter of the cases. Moreover the duration of NAB did not correlate closely with the duration of pathologic nocturnal oesophageal acid exposure (a fraction of the overall duration of NAB), and intra-oesophageal acid exposure was similar during the nocturnal period for both treatment regimens (Figure 2).

image

Figure 2.  Fraction of time with oesophageal pH < 4 after ingestion of placebo or ranitidine in addition to high-dose acid suppression (proton pump inhibitor b.d.).

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Oesophageal pH-measurement

The percentage of total time for oesophageal pH < 4 during the 24-h period was similar in the omeprazole/placebo group (2.4%; 0–30) and the omeprazole/ranitidine group (2.1%; 0.2–21.6) and there were no significant differences between pH measurements obtained during the 10-h nocturnal study period and the full 24-h period in the placebo (0.8%; 0–24.5 vs. 2.4%; 0–30) or ranitidine (1.5%; 0–40.6 vs. 2.1%; 0.2–21.6) study arms. Pathological reflux on treatment (pH < 4 for more than 1.6% of total time; normal limit under PPI treatment) occurred in 8/13 patients (62%) in the omeprazole/placebo group and in 7/13 patients (54%) in the omeprazole/ranitidine group (P = ns). The DeMeester score was pathological in 4/14 patients (29%) with omeprazole/placebo (median 7.6) and in 5/13 patients (38%) with omeprazole/ranitidine (median 8.2; P = ns) (Table 3).

Table 3.   Results of 24 h oesophageal 24 h pH measurements for omeprazole/placebo and omeprazole/ranitidine
pH-studyOmeprazole/ placeboOmeprazole/ ranitidine
% of time oesophageal pH < 42.35 (0–30)2.1 (0.2–21.6)
DeMeester score7.6 (0.2–63.8)8.2 (1.0–94.5)
Oesophageal acid exposure >1.6%/24 h8/137/13
Oesophageal acid exposure >1.6%/10 h4/136/13

Endoscopies

Eight patients had normal baseline endoscopies; one patient had a grade 4, 3 and 2 oesophagitis respectively and two grade 1 oesophagitis. In six patients the severity of oesophagitis improved over the treatment period [normal endoscopy (n = 5), decreased grade 3 to grade 1 (n = 1)], one patient developed oesophagitis grade 1. There were no differences between the groups.

Disease severity, symptom and quality of life scores

The median systemic sclerosis skin score reported by patients enrolled in the study was 26.5 (5–35). The mean baseline value of the gastrointestinal-related quality of life score was 93.6, s.d. ±12.8. There was a non-significant increase of 0.5 score units per visit as a non-treatment related study effect. At the end of the omeprazole/placebo treatment phase a non-significant increase of 3.8 units compared to baseline was found (P = 0.24). In the omeprazole/ranitidine period the score increased by 7.3 units (95% CI 1.4–13.1, P < 0.02) compared to baseline; however, there was no difference in scores (or improvement in scores) between the treatment groups (P = 0.26). In addition, no correlation was present between the quality of life assessment and intra-oesophageal acid exposure.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study confirms that NAB and prolonged, nocturnal oesophageal acid exposure are common in patients with systemic sclerosis despite high-dose acid suppression with omeprazole 20 mg b.d. Adding ranitidine at bedtime did not significantly increase intragastric pH, reduce gastro-oesophageal acid reflux or improve symptoms in this population. Gastrointestinal-related quality of life improved slightly on combined ranitidine and omeprazole acid suppression; however, there was no difference in symptom scores between the two arms of the study. Moreover there was no association between the presence of NAB and pathological oesophageal acid exposure with quality of life or reflux symptoms.

There are several possible explanations for the negative findings of this study. The number of patients with systemic sclerosis recruited was relatively small, although comparable to most treatment trials in this rare condition (compliance was excellent in this informed and motivated population). In addition, as reported previously,2, 7, 20, 21 the variability of gastric acid secretion and suppression with PPIs and H2-receptor-anatagonists (H2RAs) was high, which impacts on the power of the study to show significant effects. This is likely because of inhomogeneous mixing of acid with the meal, anatomical variations of intragastric pH (antrum < fundus), entrapment of pH electrodes within mucosal folds and the loss of fluid contact by the probe when positioned in an air pocket.2, 22 Notwithstanding these technical limitations, the most likely explanation for this negative finding is that H2RA such as ranitidine lose the ability to inhibit acid secretion on prolonged administration.20, 21 Fackler et al. demonstrated a significant increase in gastric pH in healthy volunteers and patients with GERD after 1 day of additional H2RA-therapy.21 However, in a study comparing several regimens of acid suppression in patients with GERD over 14 days (omeprazole b.d., omeprazole every 8 h, omeprazole before breakfast and at bedtime and omeprazole b.d. with ranitidine at bedtime), no single treatment regimen resulted in a more significant suppression of NAB than the others.20 Consistent with the latter finding, this study found no significant effect of adding ranitidine to omeprazole b.d. treatment 3 and 6 weeks after the start of treatment. To date the mechanisms behind the development of tolerance of H2RAs remain unclear, but may include the up-regulation of H2-receptors in response to acid suppression.23 In contrast, the efficacy of acid suppression with omeprazole remains unchanged after continuous intake.2

Similar to previous reports, we observed a drop in gastric pH in the late evening. This circadian pattern has been demonstrated in healthy volunteers with placebo and persists after administration of omeprazole;2 however, the hypothesis that NAB is an important mechanism in reflux disease affecting patients with systemic sclerosis could not be confirmed. Many of the patients continued to have severe acid reflux despite omeprazole 20 mg b.d. Although acid reflux occurred most often during periods in which gastric contents were acid, the duration of NAB did not correlate with the duration of pathologic nocturnal oesophageal acid exposure (a fraction of the overall duration of NAB) or symptoms. This suggests that although NAB may be prerequisite for nocturnal acid reflux, factors other than the presence of NAB (e.g. structure and function of the gastro-oesophageal junction, oesophageal clearance) appear to determine the severity of nocturnal oesophageal acid exposure in systemic sclerosis. Consistent with this statement, most of the systemic sclerosis patients studied had moderate to severe oesophageal dysfunction and an incompetent reflux barrier (Figure 3). The indirect mechanistic association between the presence of gastric acid and the occurrence of reflux probably explains the lack of association between NAB and oesophageal acid exposure in small studies in GERD,20 whereas a larger study by Xue et al. documented a weak, but significant, link.24 This study was not powered to establish this link in systemic sclerosis. Suboptimal acid suppression could also mask the contribution of NAB; however, Hendel et al. reported that patients with systemic sclerosis taking doses up to 80 mg omeprazole daily still showed acid reflux on oesophageal pH-measurements.25 Other mechanisms, such as digestive dysmotility and impaired intestinal absorption in this group of patients, may lead to altered and lower bioavailability of acid suppressant medications. Similar reasons may explain the relative failure to control symptoms in this population. Non-acid, ‘volume’ reflux through an incompetent gastro-oesophageal junction and poor clearance of refluxate because of ineffective oesophageal motility persist despite treatment with PPI. These issues cannot be assessed by pH monitoring (requires the addition of impedance techniques).

In conclusion, the addition of ranitidine at night to high-dose acid suppression with omeprazole 20 mg b.d. did not reduce NAB or acid reflux in patients with systemic sclerosis. Thus, adding a regular H2RA at bedtime is not a useful therapeutic strategy in this population, although use of these medications may be beneficial for short-term acid and symptom control in an on-demand basis.21

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Declaration of personal interests: None. Declaration of funding interests: None.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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