Anti-reflux mucosectomy (ARMS) for refractory gastroesophageal reflux disease

Antireflux mucosectomy (ARMS) was first reported by Inoue et al. in 2014 as a new endoscopic treatment for refractory GERD. In 2003, Inoue et al. reported a patient with high-grade dysplasia (HGD) in a short segment of Barrett’s esophagus [10]. Ten years after endoscopic mucosal resection, the patient remained asymptomatic, without requiring PPI therapy. This case suggests that ARMS may be an effective antireflux endoscopic operation. Subsequently, Inoue et al. refined the method and applied it in a case series study published in 2014 that showed that ARMS could be effective in improving the symptoms and DeMeester score of GERD patients [11]. Since the advent of ARMS, there have been several prospective and retrospective studies to evaluate its efficacy.

With the development of endoscopic technology, an increasing number of GERD endoscopic therapy methods have been proposed. These methods can be broadly divided into four categories (Fig. 1) based on the remodeling of anti-reflux barrier mechanisms [12]. The first method is to inject the injectable agents into the esophagogastric junction to strengthen the anti-reflux barrier (involving Enteryx, the Gatekeeper reflux repair system, Durasphere, Plexiglas and a suturing device). The second method is the application of radiofrequency energy near the lower esophageal sphincter (LES) and the gastric cardia to improve its pressure (Stretta). The third method is endoscopic fundoplication aiming to reconstruct the LES (GERD-X, MUSE, Esophyx). The last is mucosal resection/ablation/constriction of the esophagogastric junction (EGJ) to achieve fundoplication. Due to its safety issues and poor efficacy, the first method is not currently available. For the second and third methods, the clinical application may be limited due to the need for special instruments. According to the ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease [1], data on the efficacy of radiofrequency energy (Stretta) as an anti-reflux procedure are inconsistent and highly variable, and it cannot be recommended as an alternative to medical or surgical anti-reflux therapies. The last method seems to be an effective, simple and well-tolerated endoscopic treatment strategy for refractory GERD [13]. The last method includes ARMS using endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR), banded anti-reflux mucosectomy (ARM‑b), anti-reflux mucosal ablation (ARMA), and peroral endoscopic cardial constriction (PECC).

The aim of anti-reflux mucosectomy (ARMS) is to rebuild the mucosal flap valve by submucosal fibrosis after mucosectomy at the esophagogastric junction (EGJ). According to past studies, the specific operations are different. Inoue et al. [11] reported their pilot study in 2014; 2 patients underwent total circumferential resection, and the subsequent 8 patients underwent crescentic ARMS conducted with the standardized techniques of endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD) (Fig. 2 [11]). Benias et al. [14] evaluated resection and plication (RAP) antireflux, which comprised semicircumferential mucosectomy along with full-thickness plication of the lower esophageal sphincter (LES) and cardia. Hu et al. [15] first reported peroral endoscopic cardial constriction (PECC) (Fig. 3 [15]) in gastroesophageal reflux disease. PECC is simple and easy to apply with a shorter operation time. However, the main factor influencing the efficacy was the depth of ligation. Patil et al. [16] reported ARMS using cap-assisted endoscopic mucosal resection (AMRS-C) (Fig. 4 [17]). Hedberg et al. [18] first reported the use of an antireflux mucosectomy band (ARM-b) (Fig. 5 [19]) in the treatment of refractory gastroesophageal reflux disease. Inoue et al. [20] reported antireflux mucosal ablation (ARMA) (Fig. 6 [20]). Mucosal ablation was performed using the triangle-tip knife J in spray coagulation mode after markings were placed around the cardia and a submucosal cushion was injected. The strength of ARMA is that it can be repeated regardless of the presence of fibrosis from previous therapies. ARMA can be performed in patients who have failed ARMS or who are hesitant to undergo laparoscopic antireflux surgery (LARS). In addition, ARMA does not require specific expensive devices. ARMA improves the flap valve grade and ultimately resolves the patient’s symptoms. The success of ARMS is likely related to its ability to cause submucosal fibrosis at the LES. ARMS prevents the frequent occurrence of transient lower esophageal relaxation (TLESR). Therefore, ARMS techniques are more widely used in anti-reflux endoscopic therapy for refractory gastroesophageal reflux disease.

The quantity of mucosa to be resected to induce appropriate scar formation is an extreme issue in this operation. A tight gastroesophageal junction will require endoscopic esophageal dilation. A relatively loose gastroesophageal junction may have no anti-reflux effect.

The complications of ARMS include immediate or delayed complications. Bleeding, perforation and infection are immediate complications. Of these, bleeding is more common. The most common delayed complication is esophageal stricture, in which the clinical manifestation is dysphagia. A systematic review and meta-analysis reported an 11.4% risk of dysphagia and a 5% risk of bleeding [13]. Mucosal resection, which involves more than three-quarters of the circumference of the squamous esophageal mucosa, might increase the risk of esophageal stricture [30]. According to Inoue, less squamous mucosa involvement in the resected area may decrease the risk of stricture. In addition, the rate of stenosis has significantly decreased by adopting butterfly-shaped resection, leaving the mucosa on both sides of the lesser and greater curves unresected rather than performing circumferential resection [31]. We should be able to individualize the length and quantity of resection to reduce the incidence of stenosis. Hedberg et al. [18] noted that the effect of gastric acid on scarification post-ARMS is another factor influencing the remodeling of the EGJ. This may result in a high incidence of stenosis when PPIs are discontinued immediately after the operation. It is suggested to keep taking PPIs for more than 2 weeks after the procedure to reduce inflammation and scarring and thereby the incidence of dysphagia. Most patients who have dysphagia or esophageal strictures post-ARMS may receive endoscopic balloon dilation to relieve symptoms. With the improvement of ARMS and well-experienced skills of endoscopists, the incidence of complications will decrease.

Up to now, the population of studies on ARMS is relatively limited. Most studies [11, 18‐20, 26, 27] excluded the patients who had a hiatal hernia longer than 2 cm (or Hill score > 3 or 4), while those are more likely to suffer from refractory esophagitis. Just a recently study [29] included the PPI-refractory GERD patients with a 3–5 cm hernia sac. As for the definition of refractory reflux esophagitis, there is no universal definition. Patients with refractory reflux included in the study were included according to different national standards. In addition, several studies [14, 18, 32] had no 24 h esophageal pH monitoring results neither pre-operation nor post-operation. Without pH-impedance recordings before the procedure, it was difficult to distinguish r-GERD patients from functional heartburn ones those did not need operation. For the same, there is no objective evidence for postoperative results without 24 h esophageal pH monitoring.

Currently, the number of studies on ARMS is relatively small. We need more large-sample research to evaluate the safety and efficacy of this procedure. Moreover, almost all the follow-up periods of the current studies range from several months to two years. The follow-up time needs to be prolonged to validate the long-term efficacy. More future prospective studies and comparisons to other treatments are needed.

ARMS seems to be an effective and well-tolerated endoscopic treatment strategy for refractory GERD. Due to its less invasive technique, it can fill the gap between acid inhibitors and laparoscopic fundoplication for the treatment of refractory GERD.