A systematic review of gastritis as an immune-related adverse event in clinical interventions

ABSTRACT

Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment, and the associated immune-related adverse events (irAEs) have garnered significant attention, yet reports on associated immune related gastritis are limited. The diagnosis of immune related gastritis remains predominantly exclusionary, meanwhile its management diverges significantly from that of conventional gastritis. Current guidelines lack standardized grading criteria, and substantial data from large-scale, tertiary clinical studies are absent, therefore we conducted a systematic review of Medline, Web of Science, and Embase databases, identifying 31 articles from 2017 to December 31, 2023, involving 258 patients. Clinical manifestations included epigastric pain (53.1%), mucosal erythema (56.1%), and lymphocyte infiltration (48.6%). Corticosteroid therapy was common (94.7%), with 86.7% experiencing post-treatment improvement. 80% of patients can be diagnosed through endoscopy and pathology, while the remaining 20% may require PET-CT. Hormonal therapy is favored but diverges from standard management. Accurate diagnosis is crucial in managing immune related gastritis effectively.

Introduction

Since the approval of Ipilimumab as the first immune checkpoint inhibitor (ICI) for advanced melanoma patients by the FDA in 2011¹, there has been a growing application of ICIs in clinical settings. Inhibitors targeting Programmed Cell Death Protein 1 (PD-1), Programmed Cell Death Protein-ligand 1 (PD-L1), and Cytotoxic T-lymphocyte-associated Antigen 4 (CTLA-4) have significantly transformed the therapeutic landscape of malignancies.² However, the toxicities associated with ICIs span multiple systems, including the skin, gastrointestinal tract, endocrine system, respiratory system, heart, kidneys, eyes, and nervous system.³

Combining ICIs therapies in the treatment of malignant tumors enhances tumor regression more rapidly and thoroughly,^4,5 but it also comes with an increased risk of side effects.⁶ Immune-related adverse events (irAEs) often result from the activation of self-reactive T cells, leading to damage to host tissues.⁷ Immune related gastritis was initially reported in 2017, followed by several case reports. However, there is a scarcity of comprehensive articles detailing its characteristics, making clinical diagnosis challenging. This paper conducts a systematic review of immune related gastritis to explore its clinical features and significance.

Methods

The objective of this systematic review is to investigate the clinical characteristics and treatment modalities of immune related gastritis, strictly adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. The search was conducted on Medline, Web of Science, and Embase databases, encompassing literature published from January 1, 2017, to December 31, 2023, in order to identify relevant publications on immune related gastritis. Our search strategy included key terms such as immune checkpoint inhibitors, immune-related adverse events, and gastritis.

The inclusion criteria are outlined as follows:

1) Case reports or case series reporting immune related gastritis induced by ICIs in patients with solid tumors.

2) Case reports contain detailed patient information, including the type of ICIs used, diagnostic and treatment processes, management of adverse reactions, and patient prognosis.

3) Exclusion of articles related to nursing care.

In addition to case reports, other types of studies meeting the inclusion criteria were considered. Three independent reviewers assessed the eligibility criteria for these studies. The primary author (FS) downloaded the full text of all eligible articles and conducted data extraction. All authors engaged in collective discussions to reach a unanimous consensus on the final inclusion of literature.

Given that the included studies primarily consist of case reports of rare events, we did not employ additional research quality assessment criteria, nor did we assess the risk of bias. As the systematic review was not pre-registered, there was no predefined analysis plan conducted. It’s essential to acknowledge the limitations associated with the absence of further quality assessment and the lack of a pre-registered analysis plan in the course of this systematic review. Future research efforts may consider addressing these aspects for a more comprehensive evaluation.

The overarching goal of this systematic review is to comprehensively understand the characteristics of immune related gastritis and its association with ICIs therapy. By undertaking this review, we aim to furnish clinical practitioners and researchers with extensive information regarding this rare adverse effect. This, in turn, will facilitate improved management and prevention strategies for immune related gastritis. The synthesis of available evidence will contribute to a more nuanced understanding of the interplay between immune checkpoint inhibitors and immune related gastritis, ultimately enhancing the knowledge base for clinicians and researchers in this field.

Results

To document our current understanding of gastritis as a rare side effect of ICIs therapy, we conducted a systematic review of literature from major medical databases up to December 31, 2023. A total of 14 articles were retrieved from the Web of Science database, 49 from the Medline database, and 160 from the Embase database. Following the inclusion criteria, a total of 31 articles were identified (Figure 1). Supplementary Figure s1 displays the PRISMA 2020 flow diagram outlining the selection process.

Figure 1.

PRISMA flow diagram for the systematic review.

Among the studies included, a total of 258 patients were reported to have undergone treatment in various countries, including France (n = 124), the United States (n = 95), Japan (n = 28), China (n = 2), Australia (n = 2), Denmark (n = 1), Italy (n = 1), Canada (n = 1), Germany (n = 1), Spain (n = 1), Belgium (n = 1), and Israel (n = 1). Of these, 24 were case reports or case series (Table 1), and 7 were observational studies (Table 2). Table 1 summarizes the key characteristics of patients in the 24 case reports and case series, while Table 2 outlines the most significant findings from retrospective studies. Due to partial incompleteness and heterogeneity in clinical data, a retrospective diagnostic assessment could not be conducted. Consequently, we relied on the individual authors’ assessments of immune related gastritis for further analysis.

Table 1.

Summary of the studies reporting on individual.

No. (ref)	Sex	Age(y)	Types of tumor	Drug	Duration(m)	Symptom	Gastroscope	Pathology	CMV	H.pylori	Apoptosis	Treatment	Result	Relieving-time(d)
18	M	52	Metastatic cancer	Nivolumab	7	Anorexia,nausea	Diffuse erythematous swelling of the gastric mucosa	Infiltration of lymphocytes and neutrophils	−	−	−	Methylprednisolone (1.0 mg/kg/day)	Improvement	30
29	F	57	Metastatic cancer	Toripalimab	13	Abdominal-pain	Localized mucosal erosion	Weak positive expression of CD4 and strong positive expression of CD8	−	−	−	Termination of ICIS	Improvement	136
310	M	78	Bladder cancer	Pembrolizumab	9.8	Asymptomatic	Longitudinal gastric ulcer	Infiltration of neutrophils and eosinophils, crypt abscess formation	ND	−	−	Termination of ICIS	Improvement	60
411	M	68	Squamous lung cancer	Pembrolizumab	6	Anorexia, abdominal-pain	Superior gastric erosion, mottled erythema near the pylorus ring	Predominant lymphocytic infiltration	−	−	−	Methylprednisolone (1.0 mg/kg/day)	Improvement	15
512	F	16	Melanoma	Nivolumab	4.2	Anorexia,nausea,abdominal-pain	Mucosa displaying erythematous patches	Neutrophilic inflammation, crypt abscesses	−	−	−	Infliximab (5 mg/kg/day)	Improvement	28
613	M	54	Non-small cell lung cancer	Sintilimab	5.6	Abdominal-pain	Diffuse gastric mucosal congestion, spontaneous bleeding	Neutrophil infiltration	−	−	−	Methylprednisolone	Improvement	20
714	M	71	Adenocarcinoma of the lungs	Pembrolizumab	13.3	Anorexia, Abdominal-pain	Multiple erosions in the gastric antrum	Lymphocyte infiltration	−	−	−	Termination of ICIS	Improvement	7
815	F	76	Melanoma	Nivolumab	10	Anorexia,nausea,abdominal-pain	Mucosal edema and scattered erosions	Severe infiltration of inflammatory cells within the submucosal layer	−	−	−	Prednisone tablets (30 mg/day)	Improvement	ND
916	M	71	Melanoma	Nivolumab	3	Anorexia,nausea	Diffuse mucosal erythema with associated epithelial shedding in the stomach	Eosinophilic infiltration and cystic dilatation of glandular structures	ND	ND	−	Prednisolone (0.33 mg/kg/day)	Improvement	30
1017	F	61	Ovarian carcinoma	Pembrolizumab	4	Anorexia,nausea,abdominal-pain, weight loss	Complete sloughing of gastric mucosa	Inflammatory infiltration, granulation tissue, complete absence of gastric mucosal glands	−	−	−	Corticosteroid therapy	Improvement	56
1118	M	Fifties	Non-small cell lung cancer	Atelizumab	2.8	Nausea,abdominal-pain	Diffuse mucosal erosion and erythema of the stomach	Infiltration of inflammatory cells	ND	−	−	Prednisone tablets (30 mg/day)	Improvement	45
1219	M	75	Melanoma	Pembrolizumab	13.3	Nausea,abdominal-pain	Diffuse mucosal erythema	Infiltration of eosinophils, crypt abscesses	−	−	−	Prednisone tablets (0.5 mg/kg/day)	Improvement	ND
1320	F	61	Adenocarcinoma of the lungs	Pembrolizumab	9.1	Abdominal-pain	Gastric mucosal erythema and edema	Mildly proliferative epithelium	ND	ND	−	Corticosteroid therapy	Improvement	7
1421	M	44	Melanoma	Pembrolizumab	1	Anorexia	Esophageal hiatal hernia	Lymphocyte infiltration	ND	−	−	PPI	No improvement	ND
1522	F	54	Non-small cell lung cancer	Pembrolizumab	4.2	Anorexia,nausea,abdominal-pain	Mucosal diffuse congestion	Epithelial glandular loss	−	−	−	Methylprednisolone (200 mg/day)	Improvement	120
1623	F	47	Melanoma	Ipilimumab/Nivolumab	ND	ND	ND	ND	ND	ND	ND	Methylprednisolone (60 mg/day)	Improvement	ND
1724	M	83	Melanoma	Nivolumab	5.6	Anorexia,nausea	Gastric body erythema, mucosal edema	Infiltration of inflammatory cells	−	ND	−	Methylprednisolone (40 mg/day)	Improvement	14
1825	F	36	Breast carcinoma.	Pembrolizumab	10	Weight loss	Mucosal erythema, desquamation	Chronic active gastritis	ND	ND	−	Vedolizumab	Improvement	60
1926	F	67	Melanoma	Pembrolizumab	69	Anorexia, abdominal-pain	Mucosal erythema with diffuse erosion	Infiltration of lymphocytes and neutrophils	ND	−	−	Methylprednisolone (32 mg/day)	Improvement	60
2027	F	53	Endometrialcarcinoma	Nivolumab	36	Anorexia, abdominal-pain	Diffuse mucosal erosion of the stomach	Infiltration of lymphocytes, crypt abscesses	−	−	−	Prednisone tablets(2 mg/kg/day)	Improvement	7
2128	F	75	Melanoma	Ipilimumab/Nivolumab	2	Anorexia, nausea	Diffuse mucosal erosion of the stomach	Infiltration of inflammatory cells	ND	+	−	Prednisone tablets (1.0 mg/kg/day)	Improvement	20
2229	F	76	Cervical Cancer	Pembrolizumab	12	Nausea and vomiting blood	Diffuse Hemorrhagic Gastritis	Infiltration of neutrophil			−	Prednisone tablets	Improvement	56
2330	F	71	Lung carcinoma	Pembrolizumab	2.1	Abdominal-pain	No apparent abnormalities observed	Infiltration of neutrophils and eosinophils	−	−	−	Prednisone tablets (1.0 mg/kg/day)	Improvement	28
24	M	50	Melanoma	Ipilimumab/Nivolumab	2.8	Anorexia,nausea	Diffuse mucosal erosion of the stomach	Infiltration of inflammatory cells	ND	ND	−	Prednisone tablets (1.0 mg/kg/day)	Improvement	365
2531	M	84	Melanoma	Nivolumab	0.2	Anorexia,nausea	Mucosal erythema, edema, and reticular erosions	Infiltration of inflammatory cells within the submucosal layer	−	−	−	Methylprednisolone (0.5 mg/kg/day)	Improvement	A few days
26	F	75	Melanoma	Pembrolizumab	9.3	Anorexia,nausea	Mucosal erythema, edema, and reticular erosions	Infiltration of inflammatory cells within the submucosal layer	−	−	−	Methylprednisolone (0.5 mg/kg/day)	Improvement	A few days
27	F	65	Lung carcinoma	Pembrolizumab	3.5	Anorexia,nausea	Mucosal erythema, edema, and reticular erosions	Infiltration of inflammatory cells within the submucosal layer	−	−	−	Prednisone tablets (0.5 mg/kg/day)	Improvement	14
28	M	62	Gastric carcinoma	Nivolumab	5.6	Anorexia,nausea	Mucosal erythema, edema, and reticular erosions	Infiltration of inflammatory cells within the submucosal layer	−	+	−	Prednisone tablets (0.5 mg/kg/day)	Improvement	A few days

Ref, references; M, male; F, female, CMV, cytomegalovirus;H.pylori, helicobacter pylori; ND, not described; PPI, proton pump inhibitor; y, years old; m, months; d,days.

Table 2.

Primary characteristics of studies included in the scope of assessment.

Authors ref year country	No. of patients	Drug	Median time to onset (m)	Treatment	Median time in relieving (d)	Discoveries of importance
Zhang et al.32 2020 USA	29	ND	ND	Corticosteroid therapy (n = 26), Infliximab (n = 13)	ND	Patients subjected to a therapeutic regimen involving concurrent administration of anti-CTLA-4 and anti-PD-1/PD-L1 inhibitors demonstrate an elevated propensity for the development of immune-related gastritis. The application of endoscopic biopsy to discern immune-related gastritis yields a sensitivity rate of 56%. Furthermore, it is observed that 44% of individuals afflicted with diarrhea manifest concurrent engagement of both upper and lower gastrointestinal tissues.
Collins et al.33 2017 France	4	ND	4.4(0.9-7.4)	Ceased medication and none underwent treatment with corticosteroid therapy.	94.5(64-302)	The gastroscopic examination reveals pronounced pathological alterations in the gastric mucosa, characterized by the presence of necrotic regions accompanied by an expansion of the lamina propria due to infiltration by lymphoplasmacytic cells.
Johncilla et al.34 2020 USA	12	Nivolumab (n = 1), Pembrolizumab (n = 3), Ipilimumab (n = 1), Nivolumab + Ipilimumab (n = 5), Pembrolizumab + Ipilimumab (n = 1); Nivolumab + LAG-3 Inhibitor (n = 1)。	ND	Corticosteroid therapy (n = 10), Infliximab (n = 2)	ND	The presence of heightened intraepithelial lymphocytic infiltration, along with conspicuous apoptotic bodies, contributes significantly to the indicative features for diagnosing immune-related gastritis. Patients exhibiting severe gastric involvement or a focal enhancement pattern may potentially possess genetic polymorphisms associated with susceptibility to inflammatory bowel diseases.
Tang et al.35 2019 USA	60	ND	3(1-8)	Corticosteroid therapy (n = 25), Infliximab (n = 14)	77(33-123)	The majority of patients experiencing upper gastrointestinal adverse events exhibit responsiveness to PPIs and/or H2 receptor antagonists. Hence, these classes of medications should be regarded as the primary therapeutic approach.
de Malet et al.36 2019 France	80	CTLA-4 inhibitor (n = 5), Nivolumab (n = 11), Pembrolizumab (n = 16), combination therapy(n = 8)	1.3	ND	90	Stratification should be based on the patient’s primary symptoms. Patients undergoing a secondary course of immunosuppressive agents are more inclined to experience milder forms of immune-related gastritis.
Noriko Hayama et al.37 2020 Japan	14	Pembrolizumab (n = 7), Nivolumab (n = 6), Atezolizumab (n = 1)	4.9	PPI (n = 1), Corticosteroid therapy (n = 11), Infliximab (n = 1)	ND	The immunohistochemical findings of immune-related gastritis are reported for the first time.
Clément Bresteau et al.38 2023 France	40	CTLA-4 inhibitor (n = 10), PD(L)1 inhibitor(n = 24)	3.4	Corticosteroid therapy(n = 34). infliximab following insufficient response to corticosteroids(n = 8)	2.8	Upper gastrointestinal (GI) and lower GI-irAEs exhibit similar endoscopic and histological phenotypes, and demonstrate comparable responses to corticosteroids and infliximab.

Ref, references; ND, not described; PPI, proton pump inhibitor.;LAG-3, Lymphocyte-activation gene 3;CTLA-4, Cytotoxic T-lymphocyte-associated Antigen 4; m, months; d, days.

Combining the findings from case reports, case series, and studies by Collins, Johncilla, Noriko, and Clément, we observed that 53.1% of patients were male, while 46.9% were female. Melanoma constituted 56.1% of the cases, non-small cell lung cancer represented 17.3%, and other cancer types were observed in the remaining patients. The onset of symptoms varied from a few days to one month, with a median time of 5.6 months.

Common symptoms included nausea and vomiting in 54% of patients, abdominal pain in 53.1%, anorexia in 40.8%, weight loss in 30%, and diarrhea in 30%. Notably, one patient exhibited no apparent gastritis symptoms. During gastroscopy, mucosal erythema was observed in 56.1% of patients, mucosal ulceration in 31.6%, and 6 patients had normal gastroscopic findings. Pathological examinations revealed lymphocyte infiltration in 67.1% of patients, including 8 with plasma cell infiltration and 5 with CD8+ lymphocyte infiltration (Figure 2).

Figure 2.

Symptoms (a), endoscopic findings (b), and pathological results (c) of immune related gastritis.

Symptom improvement occurred in 9.6% of patients only after discontinuation, while 84.0% received corticosteroid therapy, with symptom improvement observed in 87.2%. Eight patients experienced symptom improvement with the use of infliximab, and one patient showed improvement with vedolizumab. The median time to symptom relief was 28 days.

Discussion

Pathophysiological mechanisms underlying ICI-related gastritis and classical autoimmune gastritis

The current understanding of the mechanisms underlying immune related gastritis remains incomplete. CTLA-4 and PD-1/PD-L1 play distinct roles in immune regulation. CTLA-4 serves as a decoy receptor for B7–1 and B7–2, reducing the activation of resting T cells and potentially interfering with T cell stimulation occurring in inflammatory tissues.³⁹ CTLA-4 is highly expressed on regulatory T cells (Tregs), where it can physically remove B7 from the membrane of antigen-presenting cells (APCs) by binding to activated B7 on APCs.⁴⁰ PD-1, upon binding with its ligand PD-L1 or PD-L2, directly inhibits TCR and CD28 signal transduction by activating SHP-2 phosphatase. PD-1 inhibitors may diminish the immunosuppressive function of Tregs, enhancing the activity of CD8+ T cells, thereby leading to the occurrence of gastritis.^41,42 Research by Ferrian et al. has indicated that the pathological features of immune gastritis include severe mucosal damage, interferon-γ production by gastric epithelial cells, and mixed inflammation involving infiltration of CD8+ and CD4+ T cells, accompanied by reduced expression of granule enzyme B and FOXP3.⁴³ Autoimmune gastritis (AIG) is an organ-specific disorder characterized by the progressive destruction of oxyntic glands, driven by partly elucidated immunological mechanisms. The disease onset is indicated by the presence of circulating parietal cell antibodies (PCAs) targeting the H+/K+ ATPase and antibodies against intrinsic factors (IFAs). The mucosal inflammatory infiltrate, composed of T and B lymphocytes and macrophages, leads to the destruction of native gastric glands, including both parietal and zymogenic cells. This results in intestinal metaplasia or atrophy, intrinsic factor deficiency, and reduced hydrochloric acid production. Subsequently, these changes lead to hypergastrinemia, decreased serum levels of pepsinogen I (PG-I), and enterochromaffin-like cell (ECL) hyperplasia⁴⁴ (Figure 3).

Figure 3.

(a) the oxyntic mucosa consists of many cells, including chief cells, mucous neck cells, enterochromaffin-like (ECL) cells and parietal cells. The gastric proton pump, H+/K+ ATPase, on parietal cells is the major target autoantigen recognized by anti-parietal cell antibodies (PCAs). PCA targets both the α-subunits and β-subunits of the proton pump. Anti-intrinsic factor antibodies (IFAs) are also found in patients with AIG. A number of pro-inflammatory cytokines are produced by activated autoreactive T cells, amplifying the immune response and favoring parietal cell apoptosis, through a fas–fas ligand (FasL) and perforin – granzyme mechanism. The consequent extensive tissue remodeling, possibly sustained by gastric myofibroblasts and conspicuous eosinophil infiltration, can lead to the atrophy of the oxyntic mucosa. (b) PD-L1 is a ligand of PD-1 and is associated with immune suppression. The expression of PD-L1 by tumor cells can lead to T cell evasion, enabling immune escape. Anti-CTLA-4 antibodies activate anti- tumor immunity, while LAG-3 inhibits activated T cells, terminating signal transduction after binding to class II MHC molecules and class I MHC molecules, leading to a decline in immune response. (c) A hypothesis linking microbiota to T-cell response, intestinal inflammation and antitumor response.

Timing and prevalence of immune-related gastritis

In our literature review, the median onset of immune-related gastritis was 5.6 months after starting immunosuppressive therapy. Ipilimumab treatment was associated with the highest incidence of this condition,⁴⁵ with a median onset of 60 days for immune related colitis (interquartile range: 28–88 days).⁴⁶ Immune related hepatitis typically occurs 3–14 weeks after therapy begins,⁴⁷ possibly due to the lower presence of lymphoid follicles in the gastric mucosa.⁴⁸ Despite gastrointestinal toxicity being the second most common irAEs after cutaneous toxicity, immune-related gastritis is often overlooked due to the high incidence of immune enteritis. Therefore, increased attention and monitoring for immune-related gastritis are essential, especially for patients on immunosuppressive therapy like Ipilimumab.

Clinical manifestations of immune-related gastritis and AIG

Among patients undergoing ICIs treatment, the occurrence of upper gastrointestinal symptoms such as abdominal pain, nausea, and vomiting is relatively common.⁴⁹ Literature review indicates that over half of the patients experience symptoms of nausea, vomiting, and abdominal pain, with some patients additionally presenting symptoms like fever, hematemesis, and melena. While a minority of patients may exhibit no overt symptoms, a proactive clarification of the diagnosis of immune related gastritis is essential based on examination findings.¹⁰ Therefore, for patients undergoing ICIs treatment, particularly those manifesting upper gastrointestinal symptoms, close monitoring of symptoms and timely relevant examinations are imperative to definitively establish the diagnosis of immune related gastritis.⁵⁰ However, anemia, regardless of type, is a hallmark of AIG and frequently prompts its diagnosis. Pernicious anemia, a subtype of megaloblastic anemia, is distinguished by vitamin B12 deficiency, macro-ovalocytes, anisocytosis, hyper-segmented neutrophils, and, occasionally, pancytopenia.⁵¹

Endoscopic and histological characteristics of immune-related gastritis

The typical endoscopic manifestations of immune related gastritis include erythema, loss of vascular pattern, vascular ulceration, and ulcers.¹⁴ immune related gastritis patterns encompass chronic active gastritis, lymphocytic gastritis, focal enhanced gastritis, and adenitis.⁵² Chronic active gastritis is the most common form, characterized by increased infiltration of lamina propria lymphoplasmacytes, increased neutrophils within the epithelium, with or without neutrophilic gland abscesses.³⁴ Histologically, features include inflammatory cell infiltration, abscess formation, granulomas, increased plasma cells, and atypical glands. Endoscopic ultrasound findings comprise thickening or blurring of the gastric wall and increased blood flow.⁹ Histological findings in AIG include the loss of native oxyntic glands, accompanied by a mononuclear infiltrate and replacement by fibrous tissue characterized by micro-scarring and inflammation.⁵³

Zhang and Neyaz’s research demonstrated that the duodenal mucosa exhibited architectural alterations, such as villous blunting, which were not present in the colon or stomach. Biopsies from both the duodenal and colonic mucosa frequently revealed diffuse intraepithelial lymphocytosis, whereas gastric intraepithelial lymphocytes were confined to regions of periglandular inflammation. Notably, apoptotic activity was predominantly observed in the colon, whereas granulomas were specifically localized to the upper gastrointestinal tract, with a predominant occurrence in the stomach³²

Gonzalez and colleagues’ study suggests that clinical history, lack of prominent intraepithelial lymphocytes, and crypt rupture may aid in distinguishing immune related gastritis from other causes of gastritis such as drug reactions, inflammatory gastritis, graft-versus-host disease, cytomegalovirus infection, and autoimmune gastritis.⁴⁹ Furthermore, the research indicates that clinical manifestations of gastritis may lack specificity, but histologically, a substantial amount of cell apoptosis is observed, best visualized through anti-Caspase-3 immunohistochemistry. These histopathological features contribute to a histological differentiation of immune related gastritis from other forms of gastritis and provide crucial information for optimal therapeutic decision-making.⁵⁴

In a cohort of cases with confirmed immune related gastritis through histological examination, it has been observed that 20% of patients exhibit a normal endoscopic appearance of immune related gastritis.⁵⁵ In light of this observation, PET-CT emerges as a valuable adjunctive tool.⁵⁶ By observing the metabolic status of the gastric wall, PET-CT can indicate the likelihood of immune related gastritis, facilitating timely therapeutic interventions.⁵⁷ A retrospective analysis study, involving 46 patients, observed the staging and response of patients before and after treatment through PET-CT imaging. In this analysis, 28 patients (61%) exhibited a total of 43 cases of immune-mediated gastritis on 18F-FDG PET-CT. Furthermore, 10 patients (22%) presented simultaneous immune-related adverse reactions involving at least two different tissues on the same imaging (n = 4) or subsequent PET/CT scans (n = 6). This suggests that PET-CT holds significant clinical relevance in the diagnosis of immune related gastritis.⁵⁸

Differential diagnosis process

In clinical practice, differentiation between immune related gastritis and Helicobacter pylori (H. pylori) infection as well as cytomegalovirus (CMV) infection is necessary.⁵⁹ While immune related gastritis differs immunologically from H. pylori gastritis, there are morphological similarities, adding to the diagnostic challenges.⁶⁰ Simultaneously, in patients undergoing immune checkpoint inhibitor therapy, CMV may experience reactivation or primary infection.⁶¹ Viral gastritis is sometimes difficult to distinguish from immune related gastritis based on symptoms and endoscopy, and the former contraindicates corticosteroid therapy.⁶² Typically, glucocorticoids can alleviate immune related gastritis symptoms and aid in tissue healing, further substantiating the association between immune related gastritis and immune system dysregulation.⁶³ Therefore, before diagnosing immune related gastritis, breath tests and CMV antigen detection should be performed to rule out the possibility of H. pylori and CMV infections. Additionally, differentiation of immune related gastritis from other differential diseases, including radiation gastritis, drug-induced gastritis, and Zollinger-Ellison syndrome, is essential.⁶⁴ Based on histological diagnosis and clinical course, consideration should also be given to excluding the possibility of proliferative malignant diseases, such as malignancies or lymphomas (Figure 4).

Figure 4.

Decision-making framework for diagnosis of immune-related gastritis.

Treatments for immune-related gastritis and AIG

The latest guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) do not delineate a specific classification system tailored exclusively for immune related gastritis along with its corresponding therapeutic modalities. Instead, immune-related gastrointestinal diseases are collectively addressed, with a primary focus on categorizing enteritis and elucidating treatment approaches.^65,66 We contend that establishing standardized classification systems and treatment protocols for immune related gastritis is imperative.⁶⁷ In the majority of reports, it is recommended that patients refrain from reinitiating ICIs therapy after developing immune related gastritis. However, publicly available data on recurrence rates remain insufficient.⁶⁸ Micronutrient supplementation is the mainstay of therapy for patients with AIG. According to a position paper dealing with AIG, the use of proton pump inhibitors should be discouraged, as evidence for their efficacy in AIG is lacking and they can theoretically worsen ECL cell hyperplasia.

Outcomes of immune-related gastritis and AIG

Through literature review, we can ascertain that the average time to relief for immune related gastritis after aggressive treatment is 48 days, with a remarkable improvement rate of 96.3%, and a mortality rate of 3.7%. Among immune checkpoint inhibitor-related toxic reactions, myocarditis is considered to carry the highest risk of mortality, with reported death rates of 10% to 17% for pneumonia, hepatitis, myositis, nephritis, neurologic, and hematologic toxic reactions. In contrast, the mortality rates for hypophysitis, adrenal insufficiency, and colitis are lower at 2%, 3.7%, and 5%.⁶⁹ This underscores the critical importance of timely diagnosis and treatment for immune related gastritis, reflecting that proactive interventions can significantly enhance treatment outcomes for patients. There is currently no evidence to suggest that immune-related gastritis affects cancer progression. Conversely, according to a large study examining the natural history of AIG, mild atrophy progresses to severe atrophy in all patients within a median of 3 years from the time of diagnosis.⁷⁰ The incidence of polyps, GNETs and adenocarcinoma is significantly increased in patients with AIG.⁷¹ Massironi and Gallo’s study confirms that type I gNENs represent a non-negligible complication in patients with AIG and that they are related to hypergastrinemia.⁷²

Limitations

There are some limitations in this review. Firstly, the review was conducted using only case reports and case series, which are descriptive studies providing lower quality evidence. Future research should focus on basic and prospective controlled clinical studies to elucidate the molecular mechanisms of immune-related gastritis and to assess its treatment. Secondly, certain cases lacked comprehensive medical records, missing critical data such as biopsy findings as well as differential diagnoses like H. pylori infection and drug-induced gastritis, and specifics regarding the dosage and duration of corticosteroids therapy.

Summary

In conclusion, the widespread use of ICIs introduces various irAEs, including immune-related gastritis, which is challenging to distinguish from typical gastritis due to its nonspecific symptoms. For mild cases (Grades I and II), symptomatic treatment is usually sufficient, but more severe cases (Grades III and higher) require corticosteroids as the primary treatment. Accurate diagnosis is crucial, achieved through timely endoscopic examination and biopsy, confirming about 80% of cases. However, an additional 20% of cases may need further imaging like PET-CT. Managing immune-related gastritis demands a multidisciplinary approach, involving specialists across oncology, gastroenterology, radiology, and pathology. Current guidelines need to be refined to better specify the diagnostic and treatment protocols for immune-related gastritis.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Biography

Jun Zhao, Medical doctor, chief physician, and master’s supervisor, Director of Oncology Department of Changzhi People’s Hospital, Executive Director of Cancer Center of Changzhi People’s Hospital, Chairman of Changzhi Cancer Prevention Association.

Funding Statement

This case report was supported by grants from Changzhi People’s Hospital Innovative Research Program [2022A055]. Changzhi People’s Hospital [2022A055].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

1.Design: JZ, FS, X-LZ and Y-YD. 2. Manuscript writing: FS and JZ. 3. Data extraction :FS,W-XF, and YZ. 4. Manuscript revision: JZ, FS, X-LZ, Y-YD,W-LL and W-QH. 5. Final approval of the manuscript: JZ and W-QH. All authors contributed to the final manuscript. The author(s) read and approved the final manuscript.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2408852