Perspectives on the current pharmacological strategies for chronic and atrophic gastritis: can more be done?

KEYWORDS:

• Atrophic gastritis
• autoimmune gastritis
• chronic gastritis
• chronic gastritis treatment Helicobacter pylori

1. Introduction

Chronic gastritis (CG) is frequently encountered in gastroenterological clinical practice, which may raise concerns about patient care. Despite its significant prevalence and the availability of defined diagnostic criteria [1], the clinical scenario is often hindered by the heterogeneity of its clinical manifestations and variability in stewardship, both for general practitioners and gastroenterologists.

CG is defined as a long-lasting gastric mucosa inflammation characterized by the histological presence of mononuclear cells such as lymphocytes, histiocytes, plasma cells, and occasionally eosinophils [1,2]. The most common cause of CG is H.pylori infection [2,3], which is related to chronic active gastritis, characterized by mononuclear cell infiltration and the co-presence of an ‘active’ neutrophilic inflammation of varying degrees [1]. The long-lasting inflammation may progress to the loss of the gastric glands resulting in mucosal atrophy [4].

Autoimmunity is another common cause of chronic and atrophic gastritis, defined as a non-self-limiting chronic inflammatory condition affecting the oxyntic mucosa [5]. Unlike H.pylori-related gastritis, autoimmune gastritis (AIG) is restricted to the corpus and fundus glands of the stomach, sparing the antrum.

Glandular atrophy, irrespective of gastric localization, represents a turning point within the context of CG, being related to substantive structural and functional alterations in the gastric mucosa influencing disease progression and therapeutic strategies. Therefore, assessing the extension of CG mucosal damage (e.g. antrum-restricted, corpus-restricted, or pangastritis), the degree of inflammation and atrophy, and a careful evaluation of upper gastrointestinal (GI) symptoms are crucial points for the optimal care of patients.

This editorial aims to address criticism surrounding the management of chronic and atrophic gastritis and delineates the current therapeutic approaches.

2. Chronic gastritis: clinical considerations and therapeutic strategies

As stated before, the majority of CG, more than 90%, is secondary to H.pylori infection [3]. All H.pylori-infected patients harbor chronic active gastritis, which could be defined as a reversible inflammatory condition. Therefore, H.pylori treatment should be recommended as the main therapeutic strategy [6] to cure acute inflammation and eventually reduce the progression toward gastric precancerous [e.g. atrophy and intestinal metaplasia (IM)] and cancerous conditions [7,8]. However, among patients with advanced stages of atrophic gastritis (e.g. severe atrophic changes or IM in both antrum and corpus), the eradication of H.pylori infection does not necessarily avoid the gastric cancer risk [9]. Regular endoscopic and histological follow-up is recommended in these patients according to the European guidelines on managing gastric precancerous conditions [8]. We refer to recent European guidelines for the specific therapeutic regimens for H.pylori infection [6]. Generally, eradication therapy regimens consist of the combination of two or more antibiotics with proton pump inhibitors (PPIs), but recently potassium-competitive acid blockers (p-CAB) have been introduced in clinical practice [10]. However, the studies are heterogeneous, and a definitive combination of p-CAB and antibiotics has not yet been established.

The successful eradication of H.pylori infection leads to the resolution of polymorphonuclear neutrophil infiltration, whereas reducing lymphocytic inflammation may require more time or can persist in the long term. In fact, in clinical practice, the chronic inflammatory infiltrate may be indicative of past H.pylori-related CG. In such instances, if patients do not experience any upper GI symptoms [e.g. dyspepsia (post-prandial distress syndrome (PDS)/epigastric pain syndrome (EPS) and/or gastroesophageal reflux disease] medical treatment is not necessary. However, given the wide range in the prevalence of H.pylori infection around the world and the consequent heterogeneous prevalence of gastric cancer [11], some Asian countries suggest screening test for H.pylori infection even in asymptomatic people during medical checkup [12]. Furthermore, the common attitude to prescribe PPIs in asymptomatic or paucisymptomatic patients ‘just to cure’ CG is not supported by any evidence. We recommend referring to specific clinical guidelines for the appropriate use of PPIs in acid-related diseases [13,14].

Besides H.pylori-related CG, it is worth acknowledging the existence of other low-prevalence CG forms (<1%), including eosinophilic, lymphocytic, and collagenous gastritis [2]. These low-prevalence gastritis may have different clinical behaviors and treatments, and they may be associated with other GI conditions, including autoimmune diseases (e.g. celiac disease, autoimmune gastritis, microscopic colitis, Crohn’s disease, as well as H.pylori infection) [2,15–18]. Systemic and topical glucocorticoids, like budesonide, are the most common pharmacological treatment for eosinophilic gastritis [15]. The use of topical budesonide should be preferred to avoid systemic side effects, even if dose, duration, and formulation are not yet standardized [15]. The efficacy of some biological drugs, benralizumab (anti-IL5Rα), lirentelimab (anti-Siglec-8), and dupilumab (anti- IL-4/13) are currently under investigation [15].

On the other hand, lymphocytic and collagenous gastritis could have a self-limiting course or may resolve by treating the concomitant GI condition (e.g. H.pylori eradication, gluten-free diet in celiac patients) [16–18]. The uncertain etiopathogenetic profile of these CG hinders the implementation of specific etiology-based therapies. However, due to their low prevalence and absence of risk of cancer progression, the clinical impact of these entities remains poorly known. Therefore, therapeutic strategies should be tailored accordingly, emphasizing a personalized approach based on accurate patient upper GI symptoms assessment. Table 1 outlines practical therapeutic management and the histological definition of CG patients.

Table 1. Therapeutic strategies in chronic gastritis.

	High-prevalence		Low-prevalence
	Chronic active gastritis	Chronic non-active gastritis	Eosinophilic gastritis	Lymphocytic gastritis	Collagenous gastritis
Histological definition	Mononuclear cell infiltration associated with active PMN and H.pylori evidence	Mononuclear cell infiltration in the absence of PMN and H.pylori	Presence of ≥ 30 eosinophils per hpf in at least 5 hpf, or ≥ 50 eosinophils in at least 1 hpf	IELs infiltrating the superficial epithelium. The usual diagnostic threshold for the number of IELs is 20 IELs per 100 epithelial cells	Subepithelial collagenous band (≥10 µm in thickness), associated with loss or denudement of the superficial epithelium
Therapeutic strategies	H.pylori eradication	− Treating according to GI symptoms − No PPI for asymptomatic patients	− Systemic or topical glucocorticoids (budeosonide) (dose, duration, and formulation are not standardized)	− No specific pharmacological approach − If present treat the concomitant GI condition (i.e. H.pylori eradication, GFD in celiac patients)	− No specific pharmacological approach − If present treat the concomitant GI condition (i.e. H.pylori eradication, GFD in celiac patients)

Abbreviations: GI: gastrointestinal; hpf: high-power field; IELs: intraepithelial small lymphocytes; GFD: gluten-free diet; PMN: polymorphonuclear neutrophils; PPI: proton pump inhibitor.

3. Chronic atrophic gastritis: clinical considerations and therapeutic strategies

Chronic atrophic gastritis is a chronic inflammatory disorder characterized by the loss of gastric glands, that could be replaced by fibrosis, or most frequently by pseudopyloric or IM [19]. The etiology of chronic atrophic gastritis is still debated: it may occur as a long-term consequence of H.pylori infection or in the context of gastric autoimmunity. Currently, no specific pharmacological strategies are available for AIG. In AIG, despite the underlying immune-mediated mechanism attributed to autoreactive T helper cells and cytotoxic T cells targeting the H+/K+ ATPase on parietal cells [5], no therapy based on glucocorticoids or immunomodulators was demonstrated to be effective. A recent study on AIG patients showed that thymic-stromal-lymphopoietin and nicotinamide-phosphoribosyltransferase may be future therapeutic targets, and zinc-l-carnosine, which was used in the past for restoring gastric healing in peptic ulcer disease could have a role in damping mucosal inflammation [20].

Considering H.pylori-related chronic atrophic gastritis several studies demonstrated that curing infection could be beneficial on atrophy, both on the corpus and antrum, but not on IM, which is considered as the ‘point of no return’ [21,22]. All patients with chronic atrophic gastritis and H.pylori infection should receive eradication treatment. When atrophy involves the corpus mucosa, acid secretion is hampered leading to hypo- achlorhydria. Thus, in corpus atrophic patients, the common eradication regimens, using the combinations of PPI with two or more antibiotics, may be questionable because of the reduced or absent acid secretion. Thus, there is no clear evidence regarding the efficacy of these PPI-based H.pylori eradication strategies in corpus atrophic gastritis patients. Bismuth-based therapy might offer a possible therapeutic approach in cases of corpus atrophic gastritis. It was observed that bismuth salts could hinder the bacterium’s growth helping in eradicating it [23]. Currently, the efficacy of bismuth-based (quadruple) therapy, endorsed as a primary treatment option in European guidelines [6], may not be the same in the setting of corpus atrophic gastritis, where the usefulness of adding PPI has to be proven.

Patients with corpus atrophic gastritis, including AIG, may complain of a wide range of upper-GI symptoms ranging from PDS-like (post-prandial fullness and/or early satiety), EPS-like dyspepsia (epigastric pain and/or burning), typical (heartburn and/or regurgitation) and atypical (cough, non-cardiac chest pain, pharyngeal globe and dysphagia) gastroesophageal reflux symptoms [24–26]. Even if these symptoms are commonly treated with PPI in clinical practice, it was demonstrated through pH-impedance monitoring that symptoms in these patients are mainly related to nonacid reflux with neither rationale to prescribe nor benefit antisecretory drugs [26]. Assuming that upper-GI symptoms in chronic atrophic patients may be related to hypo- achlorhydria, the use of HCl substitutes to acidify gastric microenvironment has been proposed, but no placebo-controlled studies are available [27]. Considering other possible medical treatments (antiacids, prokinetics, or neuromodulators) aimed at relieving upper-GI symptoms, no ad hoc studies in chronic atrophic gastritis patients are available.

4. Expert opinion

There are no substantial updates in the pharmacological strategies for chronic and atrophic gastritis, with the treatment for H.pylori infection representing the primary approach to eradicate the infection and reduce the progression of inflammation toward precancerous and cancerous gastric conditions.

Therapeutic strategies should be tailored based on an accurate assessment of the patient’s upper GI symptoms. In asymptomatic or paucisymptomatic patients with chronic non-active gastritis, the use of PPIs should be avoided solely to ‘cure’ gastritis and the therapeutic strategies should be chosen according to the specific GI symptoms.

Among the low-prevalence forms of chronic gastritis, except for eosinophilic gastritis where budesonide could play a role as a possible pharmacological intervention, there are no specific treatments for lymphocytic and collagenous gastritis. However, managing the coexisting GI conditions may be beneficial.

Clinicians address two main issues during the therapeutic approach for atrophic gastritis patients: firstly, the eradication of H.pylori, may benefit from bismuth-containing regimens, although the efficacy of combining bismuth with PPIs requires further investigation; secondly, in symptomatic patients, even if complain of gastroesophageal reflux symptoms, the use of PPIs should be firmly discouraged.

The future agenda should include the definition of H.pylori therapeutic strategies tailored for atrophic gastritis (especially in corpus-restricted) patients, as well as optimizing symptom relief strategies in both chronic and atrophic gastritis.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Funding

This paper was not funded.