Drug treatment strategies for erosive esophagitis in adults: a narrative review

Abstract

Background and Objective

Erosive esophagitis (EE) is the second most common phenotype of gastroesophageal reflux disease (GERD). While proton pump inhibitors (PPIs) are considered the mainstay treatment for healing and maintaining remission of EE, a significant proportion of patients, particularly those with advanced grades, fail to respond adequately. This review provides an updated overview of the current pharmacological treatment options for EE.

Methods

An extensive electronic literature search was performed using PubMed database to identify relevant articles. The search included prospective clinical trials, observational trials, case-control studies, systematic reviews with or without meta-analysis, and narrative reviews describing pharmacological therapy for adult patients with EE. Articles were limited to English language publications. Search terms encompassed various treatment modalities including PPIs, potassium-competitive acid blockers (P-CABs), histamine 2 receptor antagonists (H2RAs), sucralfate, prokinetics, rebamipide and alginates.

Key Content and Findings

Research has shown varying effectiveness across different treatments for EE. While randomized controlled trials found alginates, sucralfate, and histamine-2 receptor antagonists to have limited healing efficacy, PPIs remain the most effective treatment, achieving healing rates of 75–95% after 8 weeks, though symptom resolution reaches about 60–85%. Among PPIs, esomeprazole shows slightly better healing outcomes compared to others. However, PPI effectiveness decreases in advanced EE cases [Los Angeles (LA) grades C/D], with healing rates dropping to 60–70%. More recently, P-CABs have demonstrated promising results, demonstrating healing rates non-inferior to PPIS but superior in patients with advanced EE or PPI-resistent EE. Given that most patients experience relapse upon discontinuation, maintaining PPI or PCAB therapy is crucial for preventing EE recurrence.

Conclusions

The future of EE management lies in a more personalized approach that takes into account disease severity, PPI response, and patient preferences. While PPIs remain the mainstay of treatment, P-CABs represent a promising new therapeutic option, particularly for severe and PPI-resistant cases. The addition of nighttime to bedtime H2RAs or use of double PPI dose may benefit refractory cases. Further studies are needed to directly compare PPIs and P-CABs in different EE grades and evaluate the value of adjunctive therapies.

Introduction

Gastroesophageal reflux disease (GERD) has been defined as symptoms or complications resulting from the reflux of gastric contents into the esophagus or beyond, into the larynx, oral cavity, and lungs (1). Cardinal symptoms of GERD are heartburn and regurgitation (2).

GERD can be subclassified into three different phenotypes: erosive esophagitis (EE), nonerosive reflux disease (NERD), and Barrett’s esophagus (BE) (3). Epidemiological studies have demonstrated that NERD is the most common presentation of GERD accounting for 70% of the patients (4). Whereas EE represents about one-third of the GERD patients and BE only 6–8% of the patients. However, there is a significant overlap in esophageal acid exposure (47.8%) between EE and NERD (5).

EE is defined endoscopically by visible mucosal breaks (>5 mm) in the distal esophagus resulting from the caustic chemical effect of refluxed gastric acid. The severity of EE is determined by the LA classification (LA grades B–D), where grade B is considered low-grade EE while grades C and D represent the more severe forms of EE (6). Grade A is considered inconclusive for GERD (Figure 1). However, one cannot predict the presence of esophagitis based on symptoms severity, frequency or duration of symptoms (3,7). Symptoms alone are not sensitive or specific for the diagnosis of GERD, or more specifically EE. The sensitivity and specificity of heartburn and regurgitation in diagnosing reflux disease are 30–76% and 62–96%, respectively (8,9). EE may be associated with several short and long-term complications, including esophageal ulcer and peptic stricture (10).

Figure 1.

Los Angeles classification of erosive esophagitis. Grade A is considered inconclusive for GERD. GERD, gastroesophageal reflux disease; LA, Los Angeles.

EE management is focused on symptom resolution, esophageal mucosal healing, maintenance of healed esophagitis, improvement of patient’s quality of life, and prevention of complications (11). Proton-pump inhibitors (PPIs) have been the mainstay treatment for EE. However, studies have demonstrated that healing rates with PPIs range from 75–95% and symptom resolution is lagging behind by 10–15%. Advance EE (LA grade C and D) remains an area of unmet need, due to limited healing rates of approximately 60–70% despite PPI once daily treatment and a high recurrence rate during maintenance treatment (about 40%) (12). Potassium-competitive acid blockers (P-CABs) demonstrated improved healing rates for all grades of EE but specifically grade C and D (13).

This review provides an up-to-date information about the current treatment strategies for EE, including medical, endoscopic and surgical. We present this article in accordance with the Narrative Review reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-168/rc).

Methods

An extensive electronic literature search was performed using PubMed database to identify relevant articles to be included in this review. An advanced strategy search was applied to identify prospective, randomized clinical trials, observational trials, case-control studies, systematic reviews with or without meta-analysis, and narrative reviews, describing pharmacological therapy for patients with EE. Included articles were in the English language, mainly in adults diagnosed with EE. Terms used in the search process included, ‘Erosive esophagitis’, ‘esophagitis’, ‘reflux esophagitis’, ‘proton-pump inhibitors’, ‘potassium competitive acid blockers’, ‘Histamine 2 receptor antagonists’, ‘histamine 2 receptor blockers’, ’sucralfate’, ‘baclofen’, ‘prokinetics’, ‘Rebamipide’ and ‘alginate’. We also checked references from extracted studies and international guidelines (Table 1).

Table 1. The search strategy summary.

Items	Specification
Date of search	First search: October 1, 2024; second search: January 5, 2025
Databases and other sources searched	PubMed database, reference lists of relevant articles, and international guidelines
Search terms used	‘Erosive esophagitis’, ‘esophagitis’, ‘reflux esophagitis’, ‘proton-pump inhibitors’, ‘potassium competitive acid blockers’, ‘Histamine 2 receptor antagonists’, ‘histamine 2 receptor blockers’, ‘sucralfate’, ‘baclofen’, ‘prokinetics’, ‘Rebamipide’, ‘alginate’
Timeframe	January 1990 to January 2025
Inclusion and exclusion criteria	Inclusion: English language, adult population, prospective randomized clinical trials, observational trials, case-control studies, systematic reviews with or without meta-analysis, and narrative reviews describing pharmacological therapy for patients with erosive esophagitis. Exclusion: non-English publications, pediatric studies, case reports, and opinion papers
Selection process	Two authors (F.S. and A.M.) independently screened titles and abstracts. Full-text articles were reviewed by all authors. Disagreements were resolved through discussion and consensus, with final decisions made by the senior author (R.F.)
Any additional considerations, if applicable	Reference lists of included studies and relevant international guidelines were also examined to identify additional articles that might have been missed in the electronic search

Results

Pharmacological treatments currently available for EE

Currently, there are various medical options for the treatment of patients with EE, which are mainly aimed at inhibiting gastric acid secretion and protecting esophageal mucosa.

Alginates (Gaviscon)

Gaviscon is an antacid that contains sodium alginate combined with antacids (calcium carbonate and sodium bicarbonate). Alginates are natural polysaccharide polymers extracted from marine brown algae (phacophycae) (14). Compared to antacids, alginates in contact with gastric secretions float as a raft over the surface of the gastric content in the upper part of the stomach, creating a mechanical-like barrier that prevents gastric refluxate from washing back into the esophagus (15). In addition, alginates have a buffering effect on the acid pocket in the proximal stomach after meals (16). It has been demonstrated in healthy volunteers that sodium alginate adheres to the esophageal mucosa for longer time than placebo or viscous slurry 10.4 vs. 1.1 vs. 3.6 minutes, respectively (17). In patients, sodium alginate adhered to the esophageal mucosa for longer than placebo 9.0 vs. 3.7 (P<0.01).

Antacids alone have been investigated in patients with EE. In a randomized controlled trial Graham et al. (18) compared liquid antacid (15 mL Maalox) to placebo, taken seven times daily, in 32 patients with EE. The authors demonstrated similar healing rates in both groups, concluding that there is no significant antacids effect on EE healing.

While simple antacids show limited efficacy for EE healing, alginate-based formulations may provide symptom relief through their unique raft-forming mechanism. The effect of combining alginate with antacids (Gaviscon double action liquid) vs. antacids alone was blindly tested in a crossover study of 10 patients with GERD (19). The aim of the study was to evaluate the effect of the two treatments in preventing postprandial acid reflux. Most of the participants (80%) had LA grade A or B. Distal esophageal acid exposure was statistically significant lower in the alginate group as compared to the antacid group (0.7% vs. 8%, P=0.001). However, despite the difference in the number of acid reflux events (8.7 vs. 12.4), it didn’t reach statistical significance (P=0.06). A recent randomized controlled trial assessed the efficacy and safety of the alginate-antacid combination as compared to placebo (20). About 50% of the participants (214/424) had low-grade EE (LA grades A–B). Overall, the clinical response that was assessed by the GERD-RDQ score was significantly greater in the alginate group than in the placebo group (3.2 vs. 2.2, respectively, P=0.001).

The aforementioned studies suggest that antacids alone or alginate + antacid may improve symptoms in patients with low grade EE but unlikely to provide esophageal healing. Gaviscon may also reduce esophageal acid exposure. Thus, the value of Gaviscon appears to be as an add-on therapy to antisecretory medications, like PPIs, in patients with refractory GERD.

Antisecretory agents

Three main classes of antisecretory medications are currently available for the treatment of EE patients including, histamine 2 receptor antagonists (H2RAs), proton pump inhibitors (PPIs), and P-CABs. All of them have been evaluated in patients with EE.

H2RAs

The first antisecretory class of drugs has been used for almost four decades for GERD. H2RAs act by direct competition at the histamine 2 receptor on the parietal cell’s basal membrane and thus inhibit histamine related acid secretion. The main drawback of H2RAs is the clinical tolerance or “tachyphylaxis” which develops shortly after starting the medication and thus limits their use in clinical practice (21). There are five types of H2RAs and they include cimetidine, ranitidine, famotidine, nizatidine, and roxatidine. Ranitidine was recently removed from the US market due to concerns about carcinogenic potential of the coating of the drug.

Studies in patients with EE had shown limited and unsatisfactory healing rates when H2RAs were administered alone. Cimetidine, the oldest molecule in this class, was investigated in several randomized controlled trials that were evaluating patients with EE (22). Healing rates were depending on the duration and dose of treatment as well as EE severity. A relatively high healing rate was noted in patients receiving high dose of cimetidine (up to 1,600 mg daily) for 12 weeks who also had law grades, (by Hetzel-Dent endoscopic scoring) of EE (85% for grade I, 70% for grade II and 50% for grade III). A multicenter study (23) evaluated the effectiveness of ranitidine 150 mg four times daily vs. cimetidine 800 mg twice daily in patients with EE. The study demonstrated healing rates of 71% in the ranitidine group and 49% in the cimetidine group (P<0.02). Simon et al. (24) conducted a randomized controlled trial in 368 EE patients assigned to receive famotidine in two doses (20 or 40 mg twice daily) vs. placebo for 6 and 12 weeks. The authors demonstrated a greater healing rate in the famotidine group at both 6 and 12 weeks than placebo (48% and 69% vs. 18% and 29%, respectively, P<0.01). A similar study that evaluated the effect of famotidine in two doses (20 and 40 mg twice daily) for 12 weeks in patients with varying degrees of EE severity have shown better endoscopic healing rate in the higher dose of famotidine at both 6 and 12 weeks (58% and 76%, respectively, P<0.05). Similarly, when comparing famotidine in different doses to ranitidine 150 mg twice daily in patients with documented EE, healing rates are almost similar for both treatments, 71% in the famotidine group and 68% in the ranitidine group (25). A randomized, double-blind trial compared nizatidine (300 mg twice daily) to placebo in patients with EE at 6 and 12 weeks (26). The healing rate of EE was higher in the nizatidine group vs. placebo at both 6 and 12 weeks of treatment (40% and 50% vs. 26% and 34%, respectively, P<0.05).

When comparing H2RAs to PPIs, Wang et al. (27) have shown superiority of PPIs over H2RA with significantly higher cumulative healing rates [1.59; 95% confidence interval (CI): 1.44–1.75] in all grades of EE irrespective of length or dose of treatment. Chiba et al. conducted a comprehensive meta-analysis comparing the efficacy of different drug classes in treating grade II to IV GERD. Their findings revealed that H2RAs were significantly less effective than PPIs in both healing erosive or ulcerative esophagitis and providing symptom relief. Specifically, H2RAs achieved a healing rate of 51.9%, markedly lower than the 83.6% healing rate observed with PPIs. Additionally, the speed of healing and symptom relief was quantifiably slower with H2RAs, highlighting PPIs as a more effective option for the management of moderate to severe erosive GERD (28).

Currently, H2RAs may be used in low grades of EE (grades A and B), especially in patients who are allergic to PPIs or prefer not to take them. They have no role in advance grading of EE (grades C and D). It has been shown that concomitant administration of H2RAs and PPIs enhance gastric acid suppression and improve esophageal acid control (29). Therefore, adding an H2RA at bedtime to a twice-daily PPI regimen is considered a therapeutic option for EE patients with refractory symptoms (30).

PPIs

PPIs revolutionized the treatment of EE due to their profound and consistent acid suppression (1,31,32). PPIs demonstrate a dose-response effect in patients with EE unlike in those with NERD (33). In addition to high healing rates that have not been seen with their predecessors the H2RAs, PPIs also provide a high rate of symptom control and prevention of GERD-related complications (11). Despite the published data regarding their many long-term side effects, PPIs are considered a safe class of drugs. Currently, there are six types of PPIs that are available in the market, including, omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole and dexlansoprazole.

Studies in patients with EE, treated with a PPI, showed healing rates ranging from 75% to 95% after 8 weeks of therapy, regardless of the PPI type (34,35). However, endoscopic healing of EE is not commonly accompanied by symptom improvement demonstrating a gap of up to 15% (36). Overall, the pooled symptomatic response rate in patients with EE receiving 4 weeks of standard-dose PPI is 56% (37,38). However, patients with more severe EE (grades C and D) have demonstrated lower healing rates as compared with those with less severe disease (grades A and B) (39). In one study (40) that included 1,284 patients with EE who were treated with two different PPIs (lansoprazole and omeprazole) once daily, 6.7% to 8.4%, respectively, of those with grade 2 EE failed to heal after 8 weeks of treatment, when compared with 11.3% to 14.7%, respectively, of those with grades 3 and 4.

Dexlansoprazole, a dual delayed-release formulation, was shown to be highly efficacious in patients with EE. In a phase 2, randomized, double-blind, placebo-controlled multicenter trial, patients underwent through 3 periods: screening, treatment (open-label healing phase, double-blind maintenance phase), and follow-up (41). Overall, 88% of the patients achieved complete mucosal healing after an 8-week open-label treatment with dexlansoprazole 60 mg. During the 16-week maintenance phase, 82% of the patients who received dexlansoprazole 30 mg and 58% of those who received placebo maintained esophageal mucosal healing (41).

Ilaprazole, a new PPI formulation, was compared to esomeprazole in a phase 3, randomized, double-blind, active controlled trial involving 537 patients with EE (42). After 8 weeks of treatment, the healing rates were similar in both groups, with 95% for ilaprazole 10 mg and 92.5% for esomeprazole 40 mg. Additionally, symptom improvement was comparable between the two groups (75.8% for ilaprazole and 76.7% for esomeprazole; P=0.8223), indicating that ilaprazole is as effective as esomeprazole in treating EE and improving associated symptoms.

A double-blind, multicenter study of 1,148 patients, demonstrated that a failure to achieve mucosal healing is higher in advance EE compared to mild-moderate EE, even after 8 weeks of PPI therapy (43). The study specifically compared esomeprazole (40 mg) with omeprazole (20 mg), finding that esomeprazole achieved an overall superior healing rates (92.2% vs. 89.8%, P=0.007). Notably, the difference was more pronounced in patients with moderate to severe EE (LA grade C or D), where esomeprazole showed significantly higher healing rates at week 4 (60.8% vs. 47.9%, P=0.02), while no significant difference was observed in milder EE cases (LA grade A or B). Both medications demonstrated comparable tolerability profiles and similar outcomes for secondary measures such as heartburn symptom assessments. A multicenter retrospective study in Japan found that the mean healing rate in EE was only 61.6%, with significantly higher failure rates in patients with advance EE (44).

Symptom control in EE is also challenging, as it is in patients with NERD. A systematic review found that while the healing rate after 12 weeks of PPI therapy was 83.6%, the heartburn-free proportion was only 77.4%, indicating that symptoms may persist even after mucosal healing (28).

Does the choice of PPI matter in the management of EE?

The EXPO study has shown the superiority of esomeprazole over pantoprazole in the healing and remission of EE (45,46). In the healing study, the efficacy of esomeprazole 40 mg and pantoprazole 40 mg was compared randomly in 3,170 EE patients (46). Esomeprazole was significantly better than pantoprazole in healing EE at both 4 and 6 weeks (81% vs. 75% and 96% vs. 92%, respectively; P<0.001). The maintenance study (esomeprazole 20 mg vs. pantoprazole 20 mg) has also shown higher endoscopic and symptomatic remission rates over 6 months in the esomeprazole group as compared with the pantoprazole group (87% vs. 75%, P<0.0001) (45). Furthermore, Labenz et al. (47) showed a different healing effect among the different PPIs in the treatment of EE patients. A hypothetical management model was generated, which included six studies comparing the efficacy of different PPIs (esomeprazole 40 mg, pantoprazole 40 mg, and lansoprazole 30 mg) in the acute or maintenance healing of EE, often 4–8 weeks and 6 months, respectively. The authors demonstrated that esomeprazole provided the highest healing rate when compared to lansoprazole (82.4–92.6% vs. 77.5–88.8%; respectively, P<0.01) or pantoprazole (95.5% vs. 92%; respectively, P<0.001). At 6 months, remission rates were significantly higher in the esomeprazole 20 mg group as compared to lansoprazole 15 mg (83–84.8% vs. 74–75.9%) or pantoprazole 20 mg (70.9% vs. 59.6%; P<0.0001).

A systematic review and meta-analysis that was performed by Edwards et al. (48) included 12 trials comparing five types of PPIs in different doses (esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 and 40 mg, pantoprazole 40 mg and rabeprazole 20 mg) used for the treatment of severe EE (LA grades C and D) for periods of 4 and 8 weeks. The authors found significantly higher healing rates when esomeprazole was used than the other PPIs at both 4 and 8 weeks [odds ratio (OR) 1.84, 95% credible interval (95% CrI): 1.50–2.22 vs. OR 1.91, 95% CrI: 1.13–2.88]. Similarly, a recent network meta-analysis included 25 randomized controlled trials (RCTs) which compared the effectiveness of all PPIs presently approved by the FDA and recommended for EE treatment including, esomeprazole 20 and 40 mg, dexlansoprazole 60 mg, pantoprazole 40 mg, lansoprazole 30 mg, rabeprazole 20 mg, and omeprazole 20 mg (31). Again, esomeprazole at a standard dose of 40 mg was the most potent among all other PPIs in achieving mucosal healing at 4 and 8 weeks [OR 1.46 (95% CI: 1.24–1.71) and OR 1.58 (95% CI: 1.29–1.92)], and in symptoms relief [1.29 (1.07–1.56)].

P-CABs

P-CABs have been approved for GERD patients in several countries around the world, including the US (49). They have a unique mechanism of action: potassium competitive and reversible ionic binding of the proton pump (50,51). P-CABs, unlike PPIs, demonstrate maximum effect on intragastric pH immediately after first dose administration (52). Overall P-CABs provide potent acid suppression, rapid and durable effect and flexibility of drug administration (not dependent on food).

The efficacy and safety of P-CABs in healing and maintaining EE healed have been investigated in multiple randomized controlled trials (Table 2).

Table 2. Randomized controlled trials comparing potassium competitive acid blockers with proton pump inhibitors in patients with erosive esophagitis.

Study	Year	No.	P-CAB (name and dose)	Duration (weeks)	Comparison (name and dose)	Duration (weeks)	Population	Symptom resolution rate	Healing rate	Maintenance rate
Ashida et al. (53)	2015	409	Vonoprazan	8	Lansoprazole	8	Erosive esophagitis	NA	99% for vonoprazan and 95.5% for lansoprazole	52 weeks vonoprazan 20 mg
Ashida et al. (54)	2016	732	Vonoprazan	8	Lansoprazole	8	Erosive esophagitis	NA	100%	20 or 40 mg
Ashida et al. (55)	2018	607	Vonoprazan 10 mg, 20 mg	24	Lansoprazole 15 mg	24	Maintenance of healing of EE	–	Rates of EE recurrence during the 24-week maintenance period were 16.8%, 5.1%, and 2.0% with lansoprazole 15 mg, vonoprazan 10 mg, and vonoprazan 20 mg, respectively	–
Oshima et al. (56)	2019	32	Vonoprazan	2	Lansoprazole	2	Erosive esophagitis	Vonoprazan (HR 3.58, 95% CI: 1.16–11.08, P<0.05 vs. lansoprazole)	NA	NA
Laine et al. (57)	2023	1,024	Vonoprazan	8	Lansoprazole	8	Erosive esophagitis		Lansoprazole 30 mg vs. vonoprazan 20 mg for 8 weeks healing rate 92.9% vs. 84.4%	Maintenance for 24 weeks vonoprazon 10 mg vonoprazan 20 mg and lansoprazole 30 mg
Sakurai et al. (58)	2015	20	Vonoprazan	1	Esomeprazole and rabeprazole	1	Healthy volunteers	NA	NA	Study assessed intragastric pH and demonstrated more potent acid suppression. The day 1 to day 7 ratio of 24-h pH 4 HTRs was >0.8 for vonoprazan, compared with 0.370 for esomeprazole and 0.393 for rabeprazole
Takeuchi et al. (59)	2020	30	Vonoprazan	2	Rabeprazole	2	Healthy volunteers	–	NA	24-hour intragastric pH monitoring - vonoprazan was more potent in maintaining pH >3 and pH >4
Xiao et al. (60)	2020	486	Vonoprazan	8	Lansoprazole	8	Erosive esophagitis	NA	92.4	No maintenance
Iwakiri et al. (61)	2017	19	Vonoprazan 20 mg	8	Lansoprazole 40 mg	8	Erosive esophagitis PPI resistant	NA	Healing rate in subjects with baseline EE grades A-D was 60.0% (3/5 patients) in the 20 mg group and 71.4% (5/7 patients) in the 40 mg
Lee et al. (62)	2019	302	Tegoprazan 302 mg, n=100; 100 mg, n=102) or esomeprazole (n=100)	8	Tegoprazan (50 mg, n=100; 100 mg, n=102) or esomeprazole (n=100)	8	Erosive esophagitis	NA	Tegoprazan (50 mg, n=100; 100 mg, n=102) or esomeprazole (n=100)
Hoshino et al. (63)	2017	24	Vonoprazan 20 mg	4+8	PPI refractory EE—all patients received vonoprazan	8	Refractory EE to PPI	NA	87.50%	76.20%
Chen et al. (64)	2022	238	Keverprazan	8	Lansoprazole	8	Refractory EE to PPI	NA	Healing rates at week 8 were 99.1% (110/111) and 92.7% (102/110) for keverprazan and lansoprazole respectively	–
Cho et al. (65)	2023	351	Tegoprazan 25 mg	24	Lansoprazole 15 mg	24	Healed erosive esophagitis	–	Remission rate after 24 weeks was 90.6% with tegoprazan and 89.5% with lansoprazole	–
Haruma et al. (66)	2023	208	Vonoprazan 20 mg	36	Lansoprazole 30 mg	36	Healed erosive esophagitis	NA	No safety issues with vonoprazan	–
Zhuang et al. (67)	2024	332	Fexuprazan 40 mg	8	Esomeprazole 40 mg	8	Erosive esophagitis	Equality	88.5% vs. 89%	–
Lee et al. (68)	2022	218	Fexuprazan 40 mg	8	Esomeprazole 40 mg	8	Erosive esophagitis	–	99.10%	99.10%
Okanobu et al. (69)	2021	73	Vonoprazan 20 mg	4	Vonoprazan 10 mg	4	Erosive esophagitis	–	Healing rates of the 20 and 10 mg groups were 94.6% and 94.4%, respectively	–
Xiao et al. (70)	2024	703	Vonoprazan 10 mg, 20 mg	24	Lansoprazole	24	Maintenance of healing of EE	-	EE recurrence was observed in 24/181 (13.3%) and 21/171 (12.3%) patients receiving vonoprazan 10 or 20 mg, respectively, and 47/184 (25.5%) patients receiving lansoprazole	–

EE, erosive esophagitis; PPI, proton pump inhibitor; NA, not applicable; HR, hazard ratio; CI, confidence interval.

Ashida et al. (54) conducted a randomized controlled trial of 409 patients with EE (LA grades A to D), comparing the efficacy and safety of vonoprazan 20 mg to lansoprazole 30mg daily, over a period of 8 weeks. Endoscopically conformed healing of EE was similar at 8 weeks in both groups (99.0% vs. 95.5%, respectively, P<0.0001). Moreover, long-term maintenance of healed EE’s has been assessed in 74.5% (305/409) of the patients who randomly received vonoprazan 10 or 20 mg daily for 52 weeks. Recurrence rates were similar in both vonoprazan groups (9.4% and 9.0%, respectively). Both medications (vonoprazan and lansoprazole) demonstrated similar tolerability and safety profile, suggesting that vonoprazan is non-inferior to lansoprazole in healing and maintaining EE healed. Another phase 3 randomized controlled trial performed by the same authors aimed to compare the maintenance effect of vonoprazan (10 and 20 mg daily) with lansoprazole (15 mg) once daily for 24 weeks (55). Again, vonoprazan in both doses was found to be non-inferior to lansoprazole in maintaining healed erosive esophagitis (94.9%, 98% and 83.2%, respectively, P<0.0001).

Another randomized controlled trial evaluated the rate of which vonoprazan 20 mg provides symptoms relief as compared to lansoprazole 30 mg given for 2 weeks to 32 patients with EE (56). The study showed that complete symptom resolution, as assessed by FSSG (Frequency Scale for the Symptoms of GERD) score, was significantly faster on day 1 in the vonoprazan group (31.3%) as compared to only 12.5% in the lansoprazole group (P= NS). After 2 weeks of treatment, the FSSG score for reflux and dyspepsia significantly improved on day 7 and 14 in the vonoprazan group, while for the lansoprazole group, the improvement was noticed only at day 14 (P<0.01 and P<0.001 vs. P<0.07 and P<0.01, respectively). Moreover, vonoprazan was significantly more effective than lansoprazole in relieving nocturnal symptoms (P<0.05). These findings suggest that vonoprazan provides faster effect on symptoms as compared with lansoprazole.

A recent prospective, observational study assessed the efficacy of vonoprazan in the treatment and maintenance of EE, NERD, and refractory GERD symptoms in 200 patients. Vonoprazan was given 20 mg daily for 4 weeks, followed by 10 mg daily for 24 weeks. The authors demonstrated that the highest symptom resolution rate after initial therapy was in the EE group, as assessed by FSSG score, as compared to NERD and the refractory group (−8±−2.9 vs. −6±−1.8 vs. −7.4±−1.3, respectively, P<0.001). At 24 weeks, this reduction in FSSG score was similarly noted in the three groups as compared to baseline (−7.5±−3.2 vs. −6.3±−1.3 vs. −7.6±−1.1, respectively, P<0.001) (71).

A systematic review and meta-analysis which compared the efficacy of vonoprazan with four types of PPIs (esomeprazole 20 mg, rabeprazole 20 mg, omeprazole 20 mg and lansoprazole 30 mg) for healing of GERD patients (72). The analysis showed a higher OR (2.29, CrI: 0.79–7.06) for vonoprazan in healing EE when compared to rabeprazole (2.4, CrI: 0.90–6.77). However, no difference was found when compared to other PPIs (esomeprazole, omeprazole, and lansoprazole).

In a recent randomized controlled trial, Laine et al. demonstrated that vonoprazan, was both non-inferior and superior to lansoprazole in the healing and maintenance of healed EE. The study revealed significant improvements in both the initial healing by week 8 and sustained healing at week 24, with vonoprazan performing particularly well in patients with severe EE (LA grades C and D) (Table 3). This research supports vonoprazan as a potent alternative to traditional PPIs, offering improved treatment outcomes for patients suffering from more severe forms of EE (57).

Table 3. Vonoprazan vs. lansoprazole for healing and maintenance of healing of erosive esophagitis (57) (permission file is not needed under an open access Creative Commons CC BY license).

Efficacy end point	Vonoprazan 20 mg (n=514)	Lansoprazole 30 mg (n=510)	Difference (95% CI)
Healing by week 8 (%)	92.9	84.6	8.3 (4.5–12.2)
24-hour heartburn-free days (%)	66.8	64.1	2.7 (−1.6 to 7.0)
Healing at week 2 in LA grade C/D (%)	70.2	52.6	17.6 (7.4–27.4)
Onset of sustained resolution of heartburn by day 3, n (%)	177 (34.4)	164 (32.2)	2.3 (−3.5 to 8.0)
Healing by week 8 in LA grade C/D (%)	91.7	72.0	19.6 (11.8–27.6)
Healing at week 8 (%)	74.3	68.2	6.1 (0.5–11.6)

CI, confidence interval; LA, Los Angeles.

Another P-CAB, tegoprazan, currently approved in South Korea for GERD, gastric ulcer, and H. pylori eradication, was compared in a randomized controlled trial to esomeprazole in 302 patients with EE (LA grades A to D). Patients were randomly assigned to either tegoprazan 50 or 100 mg daily vs. esomeprazole 40 mg daily for 4 or 8 weeks. The authors demonstrated that tegoprazan, in both doses, was as effective as esomeprazole in healing EE (cumulative healing rate of 98.9% at 8 weeks) and in symptom resolution as assessed by GERD-HRQOL score (−8.1 vs. −7.3 vs. −7.1, respectively, P<0.0001). In addition, a similar safety profile with no severe adverse events was reported in both treatment arms (62).

It is important to note that many of the aforementioned studies were designed to demonstrate non-inferiority of the P-CAB when compared to PPI. In addition, most of the studies were conducted in Asia where EE, especially advanced EE (C and D), is less common than in westernized population, resulting in patient population that included very few patients with severe EE.

Esophageal mucosal protection

Rebamipide

Rebamipide is a mucosal protective agent that was developed in Japan in 1989 and is mainly used for the treatment of peptic ulcers (73). Rebamipide mechanism of actions includes activation of prostaglandin and growth factors pathways, scavenging oxygen free radicals and inhibition of inflammatory cytokines and chemokines pathways (74-76). In a randomized multicenter study, EE patients either received esomeprazole 40 mg alone or esomeprazole plus rebamipide 300 mg, for 4 weeks (77). The main finding of the study was that combination therapy with esomeprazole and rebamipide was more effective in decreasing symptoms among EE patients, compared to the esomeprazole alone group (the mean decreases in the total symptom scores were estimated to be –18.1±13.8 and –15.1±11.9, respectively, P=0.011). Furthermore, one open label randomized study from Japan has shown that treatment of lansoprazole 15 mg plus rebamipide 300 mg was superior to lansoprazole alone in the prevention of symptoms recurrence among patients with EE, over 12 months follow-up (77). Still, data regarding the role of rebamipide in the treatment armamentarium of EE management is very scares and limited to Japan and some Asian countries. Presently, more studies are needed to determine its value in patients with EE.

Sucralfate

Sucralfate is composed of sucrose sulfate and aluminum hydroxide that was developed to treat peptic ulcers (78). The main mechanisms of actions of sucralfate that may protect esophageal mucosa include adhering to ulcer surface, inhibition of pepsin activity, activation of prostaglandin pathways as well as the activation of tissue growth factor and repair processes (79). The effect of sucralfate in peptic ulcer treatment is well established, whereas data to support its efficiency in GERD and specifically in EE is scarce. A double-blind placebo-controlled trial evaluated the efficacy of sucralfate as compared to placebo in preventing recurrent erosive esophagitis (80). Overall, 184 EE patients (Savary grade 1 and 2) were included. All patients had healed EE before being randomized to sucralfate or placebo. After 6 months, there was a significant reduction in the endoscopic relapse rate of EE, 31% in the sucralfate group vs. 65% in the placebo group, P<0.001. A meta-analysis included 4 GERD trials restricted to patients with EE treated with sucralfate and aimed to determine the healing rates of EE grades II to IV (28). The authors determined that the mean overall healing proportion for sucralfate was 39.2%±22.4% (95% CI: 3.6–74.8). Notably, the CI is very wide, indicating inconsistent results. In addition, this meta-analysis is limited by small number of studies. Finally, a small randomized controlled study included 7 patients who received omeprazole 40 mg twice a day as compared to 8 patients who received sucralfate plus omeprazole 40 mg twice a day, found that sucralfate may decrease the development of strictures in patients with severe EE (81). Overall, the published data on the role of sucralfate in managing EE alone or in combination with a PPI is very limited and thus its routine use in this patient population is not recommended.

Prokinetics

The role of prokinetics in treating patients with GERD is controversial. One study comparing pantoprazole alone vs. pantoprazole plus mosapride in 68 patients with GERD found that the combination of pantoprazole and mosapride significantly improved symptom scores in patients with erosive GERD compared to pantoprazole alone. The study demonstrated that while both treatments were effective in managing GERD symptoms, the addition of mosapride to pantoprazole therapy offered a clear advantage in symptom relief (69.7% vs. 89.2%, respectively, P=0.11), despite showing no significant difference in the endoscopic healing of EE (54.5% vs. 70.5%, respectively, P=0.44) (82). Similar randomized controlled trial comparing the efficacy of mosapride plus omeprazole vs. omeprazole alone in NERD and EE patients, demonstrated no significant difference between the two treatment groups (P=0.49). A meta-analysis of 12 randomized controlled trials, included 2,403 patients with GERD and demonstrated that prokinetics have no significant effect in symptom-control when added to PPI therapy (83). Furthermore, the study has shown that the combined therapy did not increase healing of EE or improve esophageal dysmotility, but patients treated with prokinetics were significantly more likely to experience adverse effects. Thus, utilization of prokinetics alone or in combination with a PPI in patients with EE is not recommended. However, the value of this class of drugs in patients with gastroparesis and EE remains to be elucidated.

Refractory EE

Healing rates of EE achieved by PPI therapy can vary from 60% to almost 100%, depending on disease severity. Between 6–15% of all EE patients will fail to respond to once-daily PPI after 8 weeks of treatment (84). It has been demonstrated that EE healing rates tend to be lower in LA grades C and D (70% and 60%, respectively) (85,86). The underlying mechanism for treatment failure is unknown but has been suggested to be due to nocturnal acid breakthrough or patients who are CYP2C19 extensive metabolizers (87,88). Patients with PPI-resistant EE report having low quality of life, sleep disorders, and a more severe disease course (89,90).

Patients who failed the first course of treatment may benefit from an additional one, suggesting that higher EE grades (C and D) may need a longer duration to achieve mucosal healing (91). Furthermore, doubling the PPI dose may also increase the healing rates of patients with severe EE.

P-CABs have been shown to be superior to the currently available PPIs in treating PPI-refractory EE patients. Yamashita et al. (92) assessed the effect of vonoprazan on eight EE patients refractory to standard-dose PPI given for 8 weeks. All patients were CYP2C19 extensive metabolizers and negative for H. pylori infection. A 24-hour impedance-pH monitoring was performed before and after treatment with vonoprazan 20 mg daily for 4 weeks. The authors demonstrated a significant increase in daytime esophageal pH >4 post-initiation of vonoprazan treatment (after switching from PPI to vonoprazan) compared to pre-treatment (88.5% vs. 23.7%, P=0.014). Nighttime esophageal pH >4 was also higher post-treatment compared to pre-treatment, but did not reach statistical significance (69.3% vs. 44.3%, P=0.058).

Another randomized, double-blind, controlled trial evaluated the effect of vonoprazan at two doses (20 and 40 mg) in 19 PPI-refractory EE patients (61). Patients were randomly assigned to either 20 or 40 mg vonoprazan daily for 8 weeks. The primary outcome was the percentage of total time esophageal pH >4 over 24 hours, and secondary outcome was EE healing rate. Both groups showed a clear increase in the percentage of time with esophageal pH >4 compared to baseline (100% vs. 69.9% for the 20 mg group and 96.4% vs. 73.2% for the 40 mg group, respectively), but these increases did not reach statistical significance. As for the healing rate, the 40 mg group demonstrated a higher healing rate compared to the 20 mg group (71.4% vs. 60.0%, respectively). In addition, the higher the EE grade (LA grades C and D), the lower the healing rate, irrespective of the dose (50.0–66.7%).

Interestingly, Hoshino et al. (63) investigated the efficacy of vonoprazan 20 mg for healing PPI-refractory EE given for 4 weeks, followed by vonoprazan 10 mg for an additional 4 weeks as short-term maintenance therapy. At 4 weeks, 21/24 (87.9%) of patients achieved esophageal mucosal healing. At 8 weeks, the healing rate was maintained in 76.2% of the patients.

Maintenance treatment of EE

Maintenance therapy has a special significance among patients with EE particularly in those with advanced EE (LA-C and D) due to the high relapse rate of both mucosal inflammation and symptoms. The American college of gastroenterology (ACG) recommends PPI once daily for 8 weeks for patients with grade A and B EE. A longer period of treatment or maintenance therapy with PPI is recommended for patients with grade C and D EE (1). Maintenance treatment is commonly given for 6 months after complete healing of EE has been achieved, although in some studies it was extended to 12 months (93). Carlsson et al. have demonstrated in a prospective trial that when stopping omeprazole therapy after 4 weeks of treatment, 90% of EE patients have experienced symptoms relapse, compared to 75% of the NERD patients (94). Moreover, one meta-analysis by Chiba et al., that included 7,635 GERD patients, has found that most EE patients (83%) have experienced symptoms recurrence within a year after discontinuing the initial treatment (28). However, a significant recurrence rate occurs shortly after PPIs cessation in 70–80% of patients (95). Thus, maintenance therapy is necessary for most patients who initially achieved endoscopic mucosal healing on a standard PPI dose for 8 weeks (96,97). Kinoshita et al. evaluated rabeprazole’s efficacy and safety as maintenance therapy in 517 patients with refractory EE to standard PPI therapy (98). Patients were randomly assigned to receive either rabeprazole 10 mg once daily or twice daily for 52 weeks. The authors showed a significantly higher recurrence rate in the once-daily group as compared to the twice-daily group (63.2% vs. 26.1%, respectively, P<0.001). A twice-daily regimen was more effective, particularly for more severe EE grades (LA grades B–D).

The EXPO study assessed maintenance therapy (esomeprazole 20 mg vs. pantoprazole 20 mg) among patients with healed EE. Although most patients achieved symptoms relief and healing after initial treatment, high proportions of those patients developed symptoms recurrence and esophageal inflammation after 6 months while on PPI treatment (16% relapse in LA-C and 41% in LA-D) (28). A recent multi-center prospective observational study from Japan that followed GERD patients, has found that those with advanced EE frequently experience symptoms relapse upon PPI discontinuation and are more prone to esophageal mucosal complications (45) Furthermore, Isshi et al. reported that 42% of severe EE patients failed to achieve mucosal healing after a mean of 13 months of PPI treatment (99).

As with PPIs, P-CABs have been assessed for the maintenance therapy of healed EE. In an open-label prospective study, Mizuno et al. (100) evaluated the efficacy of vonoprazan in maintaining healed EE in 52 patients with PPI-refractory EE. After EE healing was achieved, vonoprazan 10 mg was given for 24 weeks. The authors demonstrated a significantly high maintenance rate (86%) and a significant decrease in symptom scores as assessed by the Frequency Scale for Symptoms of GERD (FSSG) and Gastrointestinal Symptom Rating Scale (GSRS) (−4.8±0.6, P<0.001). Similarly, another study evaluated the long-term (52 weeks) efficacy of vonoprazan 10 mg in the maintenance of healed EE (101). The study showed a significantly high maintenance rate (93.8%), and no difference in symptom scores was observed compared with the start of maintenance therapy.

In summary, maintenance therapy in advanced EE grades is necessary since a substantial proportion of those patients will experience symptoms and/or mucosal inflammation relapse. Notably, symptoms recurrence may happen also during maintenance therapy, regardless of the severity of esophageal inflammation (102).

EE and esophageal dysmotility

Systemic sclerosis (scleroderma) is a connective tissue disorder that involves the gastrointestinal tract, including the esophagus (103-105). Scleroderma leads to esophageal smooth muscle atrophy and extensive esophageal fibrosis, resulting in profound effect on motility. Patient may develop overtime absent contractility in the smooth muscle part of the esophagus and hypotensive lower esophageal sphincter. Symptoms include, dysphagia, heartburn, regurgitations, chest pain, and weight loss (105,106). EE is a common finding in scleroderma and has been reported in up to 65% of patients with esophageal symptoms and its severity and chronicity predispose patients to peptic stricture and BE (107,108). Hendel et al. showed that omeprazole was efficacious in controlling symptoms and reduce EE severity in scleroderma patients. However, healing of EE was not achieved in half of the cases (109). One study showed that lansoprazole 30 mg was effective in controlling GERD symptoms in scleroderma patients during 6 months of treatment (110). Muro et al. studied the efficacy of rabeprazole 10 mg in scleroderma patients with GERD symptoms and EE by using a validated questionnaire (FSSG). The authors found that rabeprazole significantly reduced GERD symptoms severity after 4 and 8 weeks of treatment but provided no report about healing (111). Although the medical literature is scarce, patients with scleroderma and EE commonly need more than once a day PPI to control symptoms and heal EE (112-115).

The abnormal esophageal motility in scleroderma further contributes to the pathophysiology of GERD and severity of EE in these patients, constituting a potential treatment target. Prokinetic drugs such as metoclopramide, erythromycin, and cisapride have been investigated in scleroderma patients (116-120). These studies have yielded mixed results and suffered from limitations, including small sample sizes, short-term follow-up, and different endpoints. Nevertheless, prokinetics are still used in some cases in clinical practice to help control symptoms, while awareness of their cardiovascular and neurological adverse events is crucial.

Grande et al. (118) investigated the effectiveness of metoclopramide and domperidone on esophageal motor activity and acid reflux in patients with reflux esophagitis. Despite both drugs significantly increasing lower esophageal sphincter pressure for up to 120 minutes, they failed to improve esophageal motility or reduce esophageal acid exposure when compared to placebo. This randomized, double-blind, placebo-controlled study highlights the challenges of treating EE with prokinetic agents alone, suggesting that enhancing LES pressure alone may not suffice in managing the complex motility and acid reflux issues associated with scleroderma.

In summary, the evidence supporting the use of PPIs and prokinetic agents in scleroderma patients with GERD and EE is limited and inconsistent. While PPIs appear to provide a better healing rate and symptom control the role of prokinetics alone appears to be very limited. Further research with larger sample sizes, longer follow-up periods, and standardized endpoints is needed to better understand the role of these therapies in managing GERD and EE in scleroderma patients.

Expert opinion

The pharmacological treatment of EE has evolved significantly over the past few decades, with PPIs the current mainstay of treatment. However, the suboptimal response rates, particularly in advanced grades of EE and the discrepancies between EE healing and symptoms response, underscore the need for alternative and more effective therapeutic strategies. Combination therapies with prokinetics and mucosal protectants have not markedly improved healing or symptoms control.

PCABs, on the other hand, represent a promising new class of antisecretory agents that have demonstrated efficacy, which is better than PPIs in healing EE, especially in grades C and D. Their rapid onset of action and ability to maintain intragastric pH >4 over a longer duration make them also an attractive option for patients with PPI-resistant EE. As more clinical data on the long-term safety and efficacy of P-CABs become available, they may challenge the dominance of PPIs in the management of EE.

Tailoring treatment regimens based on EE severity and PPI response is crucial for optimizing clinical outcomes. For patients with mild-to-moderate EE who respond adequately to PPIs, maintenance therapy with the lowest effective dose of a PPI should be considered to prevent relapse. In contrast, advanced grades of EE may require double dose PPI or switching to a P-CAB for improved symptom control and mucosal healing.

The role of adjunctive therapies in EE management remains unclear. While the addition of nighttime histamine-2 receptor antagonists to PPI therapy may benefit some refractory cases, the evidence for prokinetics, alginates, and sucralfate is limited and inconsistent. Further studies are needed to evaluate the efficacy and safety of these adjunctive therapies in well-defined patient populations.

Conclusions

In conclusion, the future of EE management lies in a more personalized approach that takes into account disease severity, PPI response, and patient preferences. The introduction of P-CABs has expanded the therapeutic armamentarium of EE, offering hope for patients who failed to respond adequately to PPI therapy. P-CABs are likely to become the leaders of the EE market in the future, although the timeline is currently unknown.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.