Introduction

Alginate-based formulations are frequently used as an add-on to proton pump inhibitor (PPI) therapy in patients with partial control of heartburn and regurgitation. Few data are available to inform decision-making on switching to a different PPI or adding an alginate-based formulation to ongoing PPI treatment in partial responders.

Aims & Methods

We aimed to evaluate the effects of a new formulation of sodium alginate, chamomile, and melatonin (Aligastril gel® Aliveda, Pisa, Italy) in improving reflux-related symptoms in patients with persistent symptoms despite once daily PPI versus the switch to a different PPI treatment.
This was a single-center, randomized trial that compared Aligastril gel (3 times/day; Group A) as add-on versus switching to a different PPI once daily (Group B) in patients with incomplete heartburn relief. Reflux symptoms were assessed using the GerdQ and were recorded at baseline and after 8 weeks from PPI switch or add-on of Aligastril gel. Consecutive patients were randomized in a 1:1 ratio to take Aligastril gel (12ml) 3 times per day 30-min after breakfast, lunch, and dinner (treatment group). A control group was randomized to switch to a different PPI. Patients were asked to do the HRDQ questionnaire once a day (evening time). Patients were evaluated again after one month.

Results

90 patients (51 female, mean age 50.7±10.4 yrs) were randomized. Group A included 45 (26 female, mean age 50.7±10.5 yrs) and Group B 45 patients (25 female, 51.1±10.2 yrs) (p=NS). Change in GerdQ score was significantly greater for Group A (mean: -5.0±1.4) than for Group B (mean: -2.6±1.4) P <0.001. The heartburn free days observed from patients were 6.8±1.7 in group A compared to 2.4±2.0 in the Group B (p<0.0001) (Table 1).

Table 1: epidemiological characteristics and summary of the treatment response

	Group A (Aligastril)	Group B (PPI switch)	P
Total patients	45	45	N/A
Female	26	25	>0.99
Mean age	50.7±10.6	51.1±10.2	0.855
BMI	23.6±2.8	23.7±2	0.846
PPI-response rate (VAS)	3.2±1.7	3.3±1.9	0.793
GERDQ (t0)	13.6±2.6	13.2±3.2	0.517
GERDQ (t1)	8.4±2.2	10.6±2.5	<0.001
Delta GERDQ	-5.3±1.4	-2.6±-1.4	<0.001
Consecutive heartburn free days (mean)	6.8±1.7	2.4±2	<0.001

Conclusion

In patients with residual reflux symptoms despite PPI treatment, adding Aligastril gel (alginate+melatonin+chamomille) offered additional decrease in the burden of reflux symptoms compared to switching the PPI treatment. These data support the role of alginate in the add on therapy in patients with poor heartburn control whilst on PPI therapy.

Disclosure

Conference Speech: Reckitt Benckiser; Malesci; Sofar; Alfa-Sigma; Dr Falk; Cadigroup; Sanofi Genzyme
Advisory: Astra Zeneca

Introduction

The evaluation of gastroesophageal reflux disease (GERD) often includes the analysis of symptom-reflux correlation metrics such as the Symptom Index (SI) and Symptom Association Probability (SAP). These tools provide critical insights into the temporal relationship between reflux episodes and symptom perception, aiding in the identification of patients most likely to benefit from a tailored PPI treatment.

Aims & Methods

The aim of this study was to evaluate a continuous series of patients responsive to PPI treatment and differentiate those with GERD and those without. a series of consecutive patients with NERD o grade A esophagitis underwent monitoring tests for esophageal pathophysiology (MIIpH 24h).
All patients were evaluated for epidemiological and anthropometric characteristics and clinical presentation (GERDQ). According to the aim of this study we decided to enroll only patients that were full responders to the treatment with PPIs longer that 3 months. Treatment response was evaluated with (VAS). Evaluated pathophysiological parameters: acid exposure time (AET), reflux number, mean nocturnal baseline impedance (MNBI) and SI and SAP were calculated. Patients were divided in proven GERD or negative GERD according to the Lyon 2.0 Consensus thresholds.

Results

We enrolled throughout the last six months 83 patients (57 female) with an adequate heartburn relief with a standard therapy with PPIs. Patients were divided in proven 26 GERD (16 F, mean age 58.6 yr, BMI 27.9) and 57 Negative GERD (41 F, mean age 53.2 yr, BMI 24.5). Heartburn relief (VAS) was similar in the two different groups (p=NS) and similarly the duration of the treatment with the full dose of PPIs. The parameters able to distinguish GERD from non-GERD were: AET, Reflux events number and MNBI (p<0.01) from pathophysiological point of view and higher BMI and male sex from epidemiological characteristics (p<0.001). For details see Table 1.

	True GERD (26)	Negative GERD (57)	p
Age	58.6±12.7	53.2±14.4	0.104
Female	16/26	41/75	0.001
Heartburn Improvement (VAS)	80.8±14.9	75.6±15.4	0.153
Treatment duration (months)	6.1±2.4	5.9±2.9	0.447
GERDQ	9±2.1	9.1±1.9	0.831
AET	11.6±6.5	1.7±1.5	<0.0001
Reflux events	49.3±23.3	24.7±11.3	<0.0001
SI/SAP positive	2/26	5/57	>0.99
MNBI	1169.7±515.2	3342.4±978.2	<0.0001

Conclusion

Only MIIpH variables are able to distinguish patients with proven GERD from those with no GERD.

References

Gyawali CP, Yadlapati R, Fass R, Katzka D, Pandolfino J, Savarino E, Sifrim D, Spechler S, Zerbib F, Fox MR, Bhatia S, de Bortoli N, Cho YK, Cisternas D, Chen CL, Cock C, Hani A, Remes Troche JM, Xiao Y, Vaezi MF, Roman S. Updates to the modern diagnosis of GERD: Lyon consensus 2.0. GUT 2024 Jan 5;73(2):361-371.

Disclosure

Conference Speech: Reckitt Benckiser; Malesci; Dr Falk, PharmaLine, AlfaSigma, Sanofi-Genzyme.
Advisory Board: Dr Falk; Astra Zeneca; Sanofi Genzyme, AlfaSigma
Research grant: Dr Falk; Sanofi Genzyme

Introduction

The definition of actionable GERD according to the Lyon v2.0 Consensus in patients with inconclusive diagnosis of GERD (acide exposure time [AET] that ranges among 4 and 6%) requires adjunctive metrics such as mean nocturnal baseline impedance (MNBI), total number of reflux events and reflux/symptom association (RSA) indices.

Aims & Methods

The aim of this study was to identify patients most likely to have a positive metrics on prolonged 96 hours wireless pH monitoring (PWPM) among patients with inconclusive AET values on 24 hours pH-impedance monitoring (MII-pH) off PPI. Secondary aim was to identify other MII-pH parameters predictive of GERD diagnosis.
This was a retrospective study that collected a series of patients with typical GERD presentation. All patients underwent:

• Endoscopy, to exclude the presence of erosive esophagitis (grade B or higher according to Los Angeles classification);
• Esophageal HRM to rule out motility disorders and calculate: esophago-gastric junction contractile integral (EGJ-CI), esophagogastric junction (EGJ) morphology, and Milan Score.
• MII-pH monitoring to assess AET values, total reflux events, MNBI, RSA and Lyon Score.
• PWPM performed for 96 hours within 1 month after MII-pH.
• Treatment (PPI) response was evaluated with VAS scale during follow-up.

Patients were categorized into 2 different groups: those with vs. without conclusive GERD on PWPM. MII-pH and HRM parameters were compared between the two groups.

Results

51 consecutive patients (24 female; median age 51yrs) were included: 15 patients (8 female, 49yrs, BMI 22.8) had non-conclusive PWPM for GERD (negative), while GERD was confirmed (positive) in 36 patients (16 female, 53yrs, BMI 26.8). There were no significant demographic differences. Prevalence of heartburn and regurgitation were comparable in both groups. Patients with confirmed GERD were more likely to respond to PPI treatment (positive 69% vs negative 59%, p=0.014).
Patients with confirmed GERD on PWPM had a higher AET (p<0.001), total reflux events (p < 0.001), and lower MNBI (p < 0.001) on MII-pH; lower EGJCI, and higher prevalence of hiatal hernia (p<0.001) on HRM; higher Milan SCORE (p < 0.001), and higher Lyon Score (p<0.01) compared to negative PWPM. See Table 1.

	Negative PWPM 96h (15)	Positive PWPM 96h (36)	P
PPI response (VAS)	59 (39, 69)	59 (39, 69)	0.014
Hiatal Hernia	0 (0%)	18 (50%)	<0.001
EGJ-CI	63 (46, 87)	20 (11, 30)	<0.001
MILAN SCORE	48 (42, 53)	196 (173, 234)	<0.001
AET (MIIpH)	1.60 (1.10, 2.90)	5.20 (3.75, 5.85)	<0.001
N REFLUX	25 (19, 29)	44 (36, 54)	<0.001
Symptom Index (+)	0 (0%)	10 (28%)	0.024
MNBI	2871 (2269, 3165)	1055 (910, 1247)	<0.001
LYON SCORE	1.00 (0.00, 2.00)	5.00 (3.00, 6.00)	<0.001

ROC analysis showed that MNBI is the strongest predictor of GERD (AUC 1.0), followed by the Milan (AUC 0.99, Sens 100%, Spec 93%) and Lyon Scores (AUC 0.97, Sens 80%, Spec 100%), total number of reflux events (AUC 0.9, Sens 86%, Spec 93%)
A subgroup of 13 patients (7 female) with an AET<4% but MNBI values <1500 Ohms on MII-pH, all (100%) were confirmed as having GERD on 96h PWPM.

Conclusion

We demonstrate that a low MNBI value on MII-pH is the strongest predicting factor of conclusive GERD diagnosis in patients with borderline or normal AET values. A sub-group of patients with AET <4% but very low MNBI (<1500 Ohms) on MII-pH showed conclusive GERD during subsequent 96 hour PWPM, establishing its longitudinal role in confirming reflux disease.

Disclosure

Conference Speech: Reckitt Benckiser; Malesci; Dr Falk, PharmaLine, AlfaSigma, Sanofi-Genzyme.
Advisory Board: Dr Falk; Astra Zeneca; Sanofi Genzyme, AlfaSigma
Research grant: Dr Falk; Sanofi Genzyme

Introduction

Up to 40% of patients with heartburn (HB) do not respond to proton pump inhibitors (PPI). In absence of objective gastroesophageal reflux disease (GERD) evidence, functional esophageal disorders (FEDs) defined by Rome IV criteria, such as functional heartburn (FH) and reflux hypersensitivity (RH), represent a possible cause. Paroxetine may have a therapeutic role in these conditions. We investigated the efficacy of paroxetine in patients with FH and RH.

Aims & Methods

We investigated the efficacy of paroxetine in patients with FH and RH.
We enrolled consecutive outpatients with negative endoscopy and PPI-refractory HB who were treated with paroxetine following a diagnosis of FH or RH on pH-impedance monitoring (MII-pH) performed off therapy at Pisa University Hospital. Demographics, symptoms, PPI response rates, paroxetine dose and response, and MII-pH findings were recorded. Patients were classified, according to Rome IV criteria, into group A (FH) and group B (RH). All patients received either paroxetine 10mg or 20mg daily according to individual HB response.
An adequate response to SSRI was defined as HB relief >60% on a VAS questionnaire. In addition, anxiety levels were assessed using the corresponding items of Hospital Anxiety and Depression Scale (HADS) questionnaire at baseline and after 8 weeks.

Results

57 patients were included (44 F), median age 53 years (40-62) mean BMI 24 (22-26), of these, 42 had FH and 15 had RH. The groups were comparable in age, sex distribution, BMI, and symptoms. Table 1 reports clinical data.
On MII-pH, RH patients had higher total, recumbent and upright AET, higher number of total refluxes, and lower values of MNBI (p<0.001 for all) and PSPW (p<0.05) compared to FH. Table 1 reports MII-pH details. FH showed higher anxiety scores at baseline compared to RH (all p<0.001). Although FH more frequently required a higher dose of paroxetine to achieve symptoms relief (p<0.001), response to paroxetine was comparable between FH vs RH (69% vs 53%, respectively) (p=0.4). SSRI outcomes has been evaluated by means of HADS questionnaire (anxiety) that changed from a 16 (IQR 13.2, 17.8) to 9 (IQR 7, 10) in FH patients and from 11 (IQR 9.5, 12) to 6 (IQR 5, 8) in RH patients. At least 37/42 (88%) of patients with FH required standard dose of paroxetine compared to 12/15 (80%) of patients with RH who required only 10mg of paroxetine to reach symptomatic relief.
On ROC curve analysis, anxiety scores at baseline predicted the dose of paroxetine required for HB control in patients with FH and RH, with an area under the curve of 0.84 (CI, 0.71-0.96).

Table 1: demographic, clinical and pH-imopedance findings

	Functional Heartburn (42 pts)	Reflux Hypersensitivity (15 pts)	P
Female (%)	35 (83%)	9 (60%)	0.082
BMI (median, IQR)	24 (21, 26)	24 (23, 26)	>0.9
Age (median, IQR)	53 (39, 61)	49 (42, 62)	0.4
Total AET (median, IQR)	0.2 (0.1, 0.8)	1.4 (0.9, 2)	<0.001
Reflux events (median, IQR)	18 (12, 27)	38 (32, 40)	<0.001
MNBI (median, IQR)	3617 (3040, 3945)	2670 (2447, 2882)	<0.001
PSPW-index (median, IQR)	72 (66, 77)	64 (63, 66)	0.004
SI/SAP positivity	0	15 (100%)	N/A
PPI Response rate, VAS	10% (10, 30)	40% (40, 50)	<0.001

Conclusion

Baseline anxiety scores predict whether patients with FH or RH will respond to low dose (10mg) or high-dose (20mg) paroxetine. These results suggest that patients with FH or RH who have high anxiety scores, should be treated with paroxetine 20mg, while 10mg could be adequate for patients with low anxiety levels at baseline.

Disclosure

Conference Speech: Reckitt Benckiser; Malesci; Sofar; Alfa-Sigma;
Dr Falk; Cadigroup; Sanofi Genzyme.
Advisory: Astra-Zeneca

Introduction

Gastroesophageal reflux disease (GERD) patients with atypical symptoms represents a diagnostic and therapeutic challenge. In particular, the diagnosis of GERD is often suspected by ENT surgeons according to laryngoscopic findings, but their sensitivity and specificity for diagnosis is low. The aim of this study was to assess the prevalence of GERD in patients with atypical symptoms undergoing laryngoscopic examination and pH monitoring.

Aims & Methods

We retrospectively evaluated patients with atypical symptoms with or without typical symptoms associated referred to Gastroenterology Units of six tertiary Italian centres between January and December 2020. Of 477 patients, we enrolled 277 patients who underwent both 24 hours pH-impedance monitoring off-therapy and laryngoscopy. Diagnosis of GERD was made according to Lyon Consensus, and we considered the novel impedance metrics (baseline impedance and post reflux swallow-induced peristaltic wave index) when pH-impedance monitoring was inconclusive in order to add confidence to diagnosis of GERD. Three patients with hypersensitive esophagus were excluded.

Results

The most common atypical symptom was cough (90/274). Laryngoscopic examination showed pathological findings in 195 patients (71.2%), and the most frequent feature detected was posterior laryngitis (77.4%). GERD was diagnosed in 80/274 patients (29.2%) on pH impedance monitoring. Upper endoscopy was made in 269 patients and 5 of them had B grade esophagitis. The prevalence of GERD diagnosis in patients with or without positive laryngoscopy examination was not statistically significant (p=0.075). No difference in the number of proximal refluxes was observed in patients with positive or negative laryngoscopy (65/195, 33.3% vs 19/79, 24.1%; p= 0.133). Sensitivity and specificity of laryngoscopy in diagnosing GERD is 78.8% and 32.0% respectively (PPV= 32.3%; NVP= 28.4%).

Conclusion

Laryngoscopic examination has a poor specificity in diagnosing GERD in patients with atypical symptoms. This study may underline that pathological laryngoscopy findings could only pose a suspect of an underlying GERD, but its diagnosis would still need to be confirmed by impedance-pH monitoring, even in patients with atypical symptoms.

Introduction

High resolution manometry (HRM) currently has a marginal role in the diagnosis of gastroesophageal reflux disease (GERD) except for the correct placement of pH-impedance (MII-pH) probes. However, a Manometric Score for Gerd Probability (i.e., the Milan Score) has been recently developed to predict a diagnosis of GERD based on HRM findings prior to pH monitoring studies.

Aims & Methods

In this study, we performed the external validation of the Milan Score in a high-volume tertiary referral center. HRM and MII-pH tracings of consecutive patients reporting GERD symptoms between 2019-2022 were retrospectively reviewed. Clinical, MII-pH, and HRM data were recorded for all patients. Patients with achalasia, body mass index>35 Kg/m^2, previous esophageal surgery, paraesophageal hiatal hernia, eosinophilic esophagitis and scleroderma were excluded. To calculate the Milan Score score, data on diagnosis of ineffective esophageal motility (IEM) according to Chicago Classification v4.0, esophagogastric junction contractile integral (EGJ-CI), EGJ morphology (i.e., type I, II or III), intraesophageal pressure (IEP) during reference ID and straight-leg raise (SLR) pressures were collected. A SLR maneuver was considered positive if >11mmHg. The Milan Score was calculated using the nomogram published in the Milan Score paper (United European Gastroenterology Journal 2024 [1]). Wilcoxon rank sum test, Pearson's chi-squared test and Fisher's exact test were used for comparison. ROC curve analysis was used to calculate the diagnostic accuracy (AUC) of the MSGP score.

Results

Of the 86 included patients, 36 (41.8%) had conclusive GERD based on acid exposure time (AET) > 6%, while 50 (58.2%) had AET<6%. Patients with AET>6% and AET< 6% were comparable in terms of age, weight, regurgitation, chest pain, dysphagia, erosive esophagitis, and HRM diagnosis. Patients with AET>6% more frequently had heartburn (p=0.009), EGJ type 3, MNBI < 1500 Ohms (p< 0.001) and positive symptoms index and symptoms association probability (p=0.007). The median Milan Score was 78 (IQR, 54-132) in patients with AET<6% and 164 (IQR, 125-198) in patients with AET>6% group. Based on ROC curve analysis, a Milan Score higher than 103 was associated with a diagnosis of conclusive GERD (i.e., AET>6%) with AUC of 0.78, with 70% specificity and 80% sensitivity.

Conclusion

The Milan Score has good performance in the diagnosis of GERD upon HRM recording, prior to MII-pH in patients reporting GERD symptoms. The Milan Score proved external validity and can be used as a screening test for GERD in patients undergoing HRM.

Characteristic	AET ≤6%, n = 50 (58%)​	AET>6%, n = 36 (42%)	p-value​​​​​
Ineffective esophageal motility	5 / 50 (10%)	5 / 35 (14%)	0.24
SLR >11mmHg	13/50 (26.0%)	26/36 (72.2%)	<0.001
EGJ-Contractile Index (CI)	42 (28, 55)	27 (13, 42)	0.015
Positive SI/SAP	2 / 50 (4.0%)	9 / 36 (25%)
EGJ type			0.005
1	26 / 50 (52%)	14 / 36 (39%)
2	20 / 50 (40%)	9 / 36 (25%)
3	4 / 50 (8.0%)	13 / 36 (36%)
Total Milan Score​​​​​	78 (54, 132)	164 (125, 198)	<0.001

References

[1] Siboni, S., Sozzi, M., Kristo, I., Boveri, S., Rogers, B. D., De Bortoli, N., Hobson, A., Louie, B. E., Lee, Y. Y., Tolone, S., Marabotto, E., Visaggi, P., Haworth, J., Ivy, M. L., Greenan, G., Masuda, T., Penagini, R., Barcella, B., Coletta, M., Theodorou, D., … Gyawali, C. P. (2024). The Milan score: A novel manometric tool for a more efficient diagnosis of gastro-esophageal reflux disease. United European gastroenterology journal, 10.1002/ueg2.12565. Advance online publication. https://doi.org/10.1002/ueg2.12565

Introduction

The number of gastroesophageal reflux disease (GERD) patients that do not improve sufficiently by standard treatment is relatively high. Multichannel intraluminal impedance and pH monitoring (MII-pH) is the gold standard for diagnosing GERD, and it can be useful for selecting secondary treatment. However, in some cases, secondary treatments are not remarkably effective even when selected based on the diagnosis. On the other hand, the clinical value of the symptom–reflux association (SRA) obtained using MII-pH remains unknown.

Aims & Methods

The current study aimed to investigate the effect of SRA on the efficacy of secondary treatment in refractory true GERD.
This study included patients who underwent MII-pH monitoring for evaluating proton pump inhibitor (PPI)- or potassium-competitive acid blocker (P-CAB)-refractory GERD symptoms and who were diagnosed with abnormal acid reflux (acid exposure time > 6%). Patients with a positive symptom index (SI) and symptom association probability (SAP) on the MII-pH monitoring were included in the SRA-positive group and the remaining ones in the SRA-negative group. The differences in the subsequent treatment efficacy between the two groups were retrospectively analyzed. Treatment efficacy was evaluated using the Frequency Scale for the Symptoms of GERD (FSSG) questionnaire.

Results

Of the 192 patients with PPI-/PCAB-refractory GERD, 41 (21.4%) were diagnosed with abnormal acid reflux. Among them, 30 (7 in the SRA-positive group and 23 in the SRA-negative group) underwent symptom assessments before and after treatment. The SRA-positive group had a significantly greater symptom improvement after treatment compared with the SRA-negative group (FSSG score changes: −13.0 ± 6.5 vs −5.4 ± 8.2, p = 0.016).

Conclusion

SRA evaluation is effective in predicting secondary treatment outcomes in patients with abnormal acid reflux.