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

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

There is a known discrepancy between symptoms reporting and histological disease activity in patients with eosinophilic esophagitis (EoE) such that patients with EoE in histological remission may still report symptoms while patients with histologically active EoE may report few or no symptoms. Esophageal symptom-specific anxiety, hypervigilance, and adaptive behaviours at mealtime may affect dysphagia reporting in EoE but this has not been investigated.

Aims & Methods

We investigated the role of esophageal symptom-specific anxiety, hypervigilance, and adaptive behaviours at mealtime on dysphagia reporting in patients with EoE.
Consecutive adults (>18 years) with histologically active or inactive EoE (i.e., ≥15 or <15 eosinophils/high-power field) at their last upper endoscopy (EGD) were prospectively enrolled. For each patient, esophageal hypervigilance, anxiety, and adaptive behaviours were assessed prior to the EGD by a physician who was blind to patients’ treatment status and histological disease activity. Esophageal anxiety and hypervigilance were assessed using the validated Esophageal Hypervigilance and Anxiety Scale (EHAS) with a 30-day recall, while the validated Dysphagia Symptom Questionnaire (DSQ) and Dysphagia Symptom Score (DSS) were used for quantification of dysphagia. A structured interview (Pisa adaptation questionnaire, PiEAQ) was used for the assessment of adaptive behaviours (including: drinking water to push the bolus, lubricating food, chewing for long, and blending food) over the 30 days prior to the EGD. Kruskal-Wallis Rank Sum Test and Pearson’s Chi-squared were used for comparisons as appropriate. ROC curve analysis was used to calculate the diagnostic accuracy (AUC). Significance threshold was p<0.05.

Results

Seventy-one patients were included. Sixty-two percent (n=44) had histologically active EoE and 38% (n=27) were in histological remission. High anxiety, hypervigilance, and use of adaptive behaviours were found in 49.3%, 46.5%, and 56.3% of patients, respectively. Higher levels of anxiety were associated with an increased severity of dysphagia according to DSQ and DSS scores (p=0.02 and p=0.003, respectively), whereas this was not true for hypervigilance (p=0.79 and p=0.24, respectively). Adaptive behaviours were significantly more commonly used by histologically active EoE compared to EoE in remission (72.3% vs 29.6%, p<0.001). The DSQ and DSS scores of patients using any or a combination of adaptive behaviours were comparable to those of patients not using any adaptive behaviour at mealtime (p>0.1 for all comparisons), suggesting a marginal impact of adaptive behaviours on dysphagia reporting. Based on ROC curve analysis, the AUC of the DSQ for the assessment of histological disease activity was 0.72 (DeLong 95% CI, 0.60-0.83), while the AUC of the DSS was 0.69 (DeLong 95% CI, 0.56-0.82). Dysphagia reporting adjustments based on anxiety or hypervigilance sub-scores of the EHAS or on the presence of adaptive behaviours at mealtime did not modify the performance of the DSQ and DSS.

Conclusion

Esophageal anxiety, hypervigilance, and adaptive behaviours can be found in half of EoE patients regardless of histological disease activity. Esophageal anxiety contributes to dysphagia severity in patients with EoE, while hypervigilance does not. The use of adaptive behaviours is associated with histologically active EoE and represents a clinical marker of disease activity but does not affect dysphagia reporting.

		Patients with high esophageal anxiety (n=35)	Patients with low esophageal anxiety (n=36)	p value
Full population n=71 (EHAS subscore cut-off>8)	DSQ	3 [0-5]	2 [0-3]	p=0.02
	DSS	5 [0-6]	2 [0-3]	p=0.003
		Patients with high esophageal hypervigilance (n=33)	Patients with low esophageal hypervigilance (n=38)
Full population n=71 (EHAS subscore cut-off>11)	DSQ	2 [0-3]	2 [0-3]	p=0.79
	DSS	3 [0-6]	2 [0-4]	p=0.24

Introduction

Provocative maneuvers are increasingly being performed during esophageal high-resolution manometry (HRM) in an attempt to increase the yield of the test. Recently, straight leg raise maneuver (SLR) (i.e., wet swallow with raised straight legs in supine position) has been proposed as a novel provocative test to evaluate esophageal reflux barrier and contraction reserve (CR) (i.e., augmentation of the esophageal contractile vigor following multiple rapid swallows, MRS). The rationale is that SLR augments intra-abdominal pressure, which has been shown to augment the contractile vigor of the esophagus.

Aims & Methods

The primary aim of this study was to investigate the relationship between the CR after multiple rapid swallows (MRS) and contractile vigor following SLR (i.e., obstructive stress reserve, OSR) in patients with normal esophageal manometry compared to those with ineffective esophageal motility (IEM). The secondary aim was to assess the characteristics of OSR in patients referred for gastroesophageal reflux disease (GERD) symptoms with normal manometry compared to those with IEM.
Between Nov 2021-Sep 2022, consecutive patients reporting GERD symptoms who underwent high-resolution manometry (HRM) were enrolled in two different esophageal centers (Pisa and Milano). GERD symptoms, height, and weight were recorded for all patients. Distal contractile integral (DCI) was analyzed during single water swallows (SS) (10 × 5 mL), MRS (3 × 2 mL), and SLR (2x5 mL). Preserved esophageal CR was defined as MRS/SS ratio was >1. Preserved OSR was defined as SLR/SS ratio >1. Data comparisons were performed using the independent sample t-test or the chi-square test, as appropriate. Pearson's correlation coefficient was used to investigate the correlation between the DCI following MRS and DCI during SLR in patients with normal peristalsis (group Normal) and IEM (Group IEM).

Results

Table 1: High Resolution Manometry in patients with Normal HRM group and IEM group

	HRM normal (196)	IEM (46)	p
EGJ type 3	26	6	0.061
EGJ-CI	50.5±28.9	43.9±30.4	0.169
DCI mean (ss)	1622.5±935.9	449.3±451.3	<0.001
Ineffective (failed) mean	15 (5)	85 (35)	<0.001
DCI mean (MRS)	2103.4±1753.1	778.5±1124.8	<0.001
MRS/SS ratio	1.4±1.4	1.7±1.8	0.218
DCI mean (SLR)	3347.1±2456.5	1647.2±2521.8	<0.001
SLR/SS ratio	2.4±1.8	3±2.6	0.014

242 patients (145 female, mean age: 53.7±14.8 years) were enrolled. Heartburn was reported as the main symptom in 165/242 (68.2%) patients and mean BMI 23.5±6.3. Esophageal HRM was normal in 196/242 (81%) patients (122 female, mean age 54.6±14.7yrs and mean BMI 23.6±6.7) and IEM was detected in 46/242 (19%) patients (23 female; 52.9±15.4yrs and mean BMI 22.9±4.9) patients (p=NS). All detail of manometric tests was reported in Table 1.
Esophageal CR was observed during MRS in 110/196 (56.1%) in the normal HRM group and 25/46 (54.3%) (p=0.87) in the IEM group and OSR was seen in 131/196 (66.8%) and 31/46 (67.4%) (p>0.99) in IEM following SLR. The DCI response following MRS correlated with the DCI response following SLR. Pearson's correlation coefficient was 0.479 (p < 0.01).

Conclusion

Swallowing against the resistance of increased intra-abdominal pressure from SLR improves esophageal body peristaltic performance and predicts esophageal body CR. The DCI response following SLR in patients with GERD is comparable to the DCI response after SS and MRS.

Disclosure

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

Introduction

A great percentage of patients with typical reflux symptoms, after proper evaluation do not have Gastro-esophageal reflux disease (GERD) and diagnosed with Functional Heartburn (FH) or Reflux hypersensitivity (RH). Both are characterized by normal acid exposure time (AET) though RH shows a positive correlation of symptoms to reflux episodes and may be benefited by PPI. Differences in various manometric and pH-impedance metrics have been observed. Positivity of Symptomatic Index (SI) and/or Symptom associated Probability (SAP) is used for RH diagnosis though experts support that concordance of both should be adopted.

Aims & Methods

We assessed differences among patients with RH and FH as also among patients with RH and concordance of SI or SAP or not. Consecutive patients with typical reflux symptoms without previous GERD diagnosis, submitted simultaneously to Ph-Impedance off PPI and High Resolution Manometry were included. Self-response to PPI was evaluated. Patients showing SI and/or SAP positivity were considered having RH and further classified to definite RH if both SI/SAP were positive and indefinite if only one was positive.

Results

Totally 2659 patients (M/F: 35.6%/64.7%, mean age: 45 ±14) were included. Final diagnosis was; FH:21.8%, RH:29.3% (definite:14.3%/indefinite:15%), GERD:36% and inconclusive GERD:12.9%. Patients with RH showed increased mean Distal Contractile Interval (DCI), AET, number of reflux episodes and episodes with proximal extent. They also showed numerically but not statistical significantly increased rates of Lower Esophageal Sphincter (LES) hypotension, ineffective esophageal motility/absent peristalsis as also Esophago-gastric Junction (EGJ) anatomical type 2/3, Mean Nocturnal Baseline Impedance (MNBI) and PPI responsiveness in comparison to patients with FH. Patients with definite RH showed increased mean DCI, AET, total number of reflux episodes, refluxes with proximal extent and EGJ anatomical type 2/3 as also numerically but not statistical significantly increased rates of PPI responsiveness vs indefinite RH. Moreover they showed statistical significant increased rate of PPI response vs patients with Functional Heartburn (p=0.031). Table 1

Table 1

	Functional Heartburn	Reflux Hypersensitivity (RH)	p	Definite RH		Indefinite RH	p
Total AET	1.12±0.94	1.65±0.96	<0.001	1.36±1.09		1.85±1.13	<0.001
Total reflux number	26±19	42±24	<0.001	32±19		50±29	<0.001
number of episodes with proximal extent	13±12	24±17	<0.001	16.1±13.2		28.7±18.4	<0.001
MNBI (3cm)	2016.1±1066.2	1872.1±608.7	0.893	1959±1515		1774.7±498.9	0.483
Esophago-Gastric Junction (EGJ) type 2/3	20.9%	27.1%	0.043	22.9%		31.1%	<0.001
Mean DCI	1061.9±1039.6	904.9±898.3	0.015	921.3±900.8		925.6±887.9	0.947
LES hypotension	42.5%	47.2%	0.165	45.8%		47.9%	0.305
Diagnosis of ineffective esophageal motility/absent contractility	33.8%	38.2%	0.170	34.2%		38.6%	0.207
PPI responsiveness	(137/330) 41.5%	(223/468)47.6%	0.168	104/229 (45.4%)	119/239 (49.8%)		0.356

Numerical values expressed as mean ± SD. EGJ type 2: separation of LES to Crural Diaphragm (CD) 1-3 cm, type 3: separation of LES to CD >3cm

Conclusion

Patients with RH and SI/SAP concordance differ from patients without. Some PPI responsiveness is frequent among patients with RH as also with FH and cannot discriminate those entities clinically, though a difference is observed when adopting a more strict RH definition.

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