Reconceptualization of immune checkpoint inhibitor-associated gastritis

Abstract

In recent years, with the extensive application of immunotherapy in clinical practice, it has achieved encouraging therapeutic effects. While enhancing clinical efficacy, however, it can also cause autoimmune damage, triggering immune-related adverse events (irAEs). Reports of immunotherapy-induced gastritis have been increasing annually, but due to its atypical clinical symptoms, early diag-nosis poses a certain challenge. Furthermore, it can lead to severe complications such as gastric bleeding, elevating the risk of adverse outcomes for solid tumor patients if immunotherapy is interrupted. Therefore, gaining a thorough under-standing of the pathogenesis, clinical manifestations, diagnostic criteria, and treatment of immune-related gastritis is of utmost importance for early identification, diagnosis, and treatment. Additionally, the treatment of immune-related gastritis should be personalized according to the specific condition of each patient. For patients with grade 2-3 irAEs, restarting immune checkpoint inhibitors (ICIs) therapy may be considered when symptoms subside to grade 0-1. When restarting ICIs therapy, it is often recommended to use different types of ICIs. For grade 4 irAEs, permanent discontinuation of the medication is necessary.

Key Words: Programmed cell death receptor-1; Programmed cell death-ligand 1; Cytotoxic T lymphocyte-associated antigen 4; Immune-related adverse events; Immune-related gastritis

Core Tip: With the widespread application of immunotherapy, the incidence of immune-related gastritis has increased than before. However, the diagnosis of immune-related gastritis is somewhat challenging due to its atypical clinical symptoms and lack of specific findings in serological tests. Although endoscopy and histopathological examination are valuable for immune-related gastritis diagnosis, differential diagnosis for different diseases (such as autoimmune gastritis) is still necessary. The treatment of immune-related gastritis should be individualized based on the patient's specific situation. The occurrence and management of immune-related adverse events (irAEs), as well as whether to continue treatment with immune checkpoint inhibitors (ICIs) after resolution, are major challenges in clinical practice. Studies have shown that for patients with grade 2-3 irAEs, ICI treatment can be considered for reinitiation when symptoms regress to grade 0-1, preferably using a different class of ICIs. For grade 4 irAEs, ICIs should be permanently discontinued.

INTRODUCTION

In this editorial, we commented on the article by Lin et al[1]. In recent years, immunotherapy has become a hot topic in the research and treatment of malignant tumors. The activation of signaling pathways related to immune checkpoint molecules programmed cell death receptor-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) can inhibit the activation of T lymphocytes. Therefore, tumor cells can achieve immune escape by activating these signaling pathways. Immune checkpoint inhibitors (ICIs) are a class of anti-tumor drugs with immunosuppressive effects, which can activate T lymphocytes to exert anti-tumor effects. However, despite the killing effect on tumor cells, ICIs also affect multiple body organs, causing autoimmune damage, known as immune-related adverse events (irAEs)[2]. Various sites and frequencies of irAEs have been reported[3], and gastrointestinal irAEs are frequent adverse reactions. Research has reported that the irAEs-induced gastrointestinal toxicity is dose-dependent on ICI drugs[4], with CTLA-4 inducing a higher incidence of gastrointestinal adverse reactions than PD-1 and programmed cell death-ligand 1 (PD-L1) ICIs[5].

Currently, there are few reports on immune therapy-induced gastritis[6]. However, it can lead to serious complications such as gastric bleeding. Immune therapy-related gastritis was first reported in 2017[7]. In recent years, as the clinical application of ICIs and the approval of indications increase, more and more reports on immune therapy-related gastritis have been revealed. With its atypical clinical symptoms, early diagnosis of immune-related gastritis remains challenging. In this article by Lin et al[1], the pathogenesis, clinical manifestations, diagnostic criteria, and treatment of immune-related gastritis were detailed investigated, with emphasis on the importance of early recognition, diagnosis, and treatment for immune-related gastritis. This study may provide new insights and ideas for future clinical practice work.

IMMUNE-RELATED GASTRITIS

It has been shown[8] that the onset time of immune-related gastritis ranges from 2 weeks to 156 weeks, with a median onset time of approximately 29.3 weeks. Compared to common immune-related enteritis, immune-related gastritis is a relatively rare adverse reaction[9]. Immune combination therapy has been evidenced to improve clinical outcomes[10], which, however, can increase the incidence of irAEs accordingly at the same time. irAEs are a common reason for treatment interruption, with an interruption rate of immune therapy ranging from 3% to 25%. Immune therapy-caused gastrointestinal toxicity is the main reason for the interruption of ICI therapy[11].

CLINICAL MANIFESTATIONS OF IMMUNE-RELATED GASTRITIS

Immune-related gastritis is commonly characterized by symptoms including diarrhea, sometimes accompanied by abdominal pain, nausea, vomiting, rectal bleeding, and fever. Moreover, severe complications (such as intestinal obstruction and intestinal perforation) may also occur[5]. Additionally, immune-related gastritis may also be accompanied by various extraintestinal manifestations, such as joint pain, endocrine abnormalities, and skin damage. A previous study[1] has pointed out that immune-related gastritis has diverse clinical manifestations, and its onset time may be delayed or masked due to previous treatments, or may even be overlooked when coexisting with extraintestinal manifestations. Therefore, it remains challenging to diagnose immune-related gastritis in clinical practice[12]. Woodford et al[7] have found through a literature review that epigastric pain is the most common adverse reaction of immune-related gastritis, often accompanied by anorexia, nausea, and vomiting. Therefore, for patients receiving long-term immunotherapy, early vigilance is needed for the occurrence of immune-related gastritis if gastric discomfort symptoms (such as nausea and vomiting) recur frequently.

LABORATORY TESTS AND CLINICAL EXAMINATION OF IMMUNE-ASSOCIATED GASTRITIS

The author found that the vast majority of patients with immune-related gastritis showed no notable clinical significance of laboratory test results. Only a few patients may exhibit abnormalities (such as elevated C-reactive protein, anemia, hypoalbuminemia), and a very small number of patients may have positive autoimmune antibodies (such as antineutrophil cytoplasmic antibody). Abdominal computed tomography scans suggest that only a few patients have thickening or no obvious characteristic signs of gastric wall edema[13]. As proposed by Lin et al[1], gastroscopy is an important means of diagnosing immune-related gastritis, with endoscopic histological features including isolated erythema, erythema combined with erosion, polyps, ulcers, and folds[14]. However, some patients with immune-related gastritis may not exhibit obvious endoscopic manifestations. Therefore, for patients suspected of having immune-related gastritis, endoscopic pathological tissue biopsy is recommended[15-17] to avoid misdiagnosis. Meanwhile, differentiating it from autoimmune gastritis, Helicobacter pylori gastritis, and cytomegalovirus gastritis is also necessary. Therefore, immune-related gastritis should be dragonized by combining the patient's clinical manifestations, endoscopic features, and histopathological examination results[18].

TREATMENT OF IMMUNE-RELATED GASTRITIS

Immune-related gastritis should be treated individually based on the patient's condition. Observation therapy can be adopted for patients without obvious symptoms, whereas for those with severe symptoms, immediate cessation of immunotherapy is necessary[19]. Glucocorticoids have demonstrated crucial roles in the treatment and management of immune-related gastritis, with some patients experiencing rapid symptom improvement after a few days of glucocorticoid therapy[10]. However, studies have found[20] that among patients with irAEs requiring high-dose glucocorticoid therapy, 30% of patients still cannot achieve complete relief and require additional immunosuppressive therapy. For some patients, even with longer periods of steroid pulse therapy at the beginning of high-dose glucocorticoid treatment, they will not benefit from the treatment if there is no symptom relief and ultimately require infliximab treatment to benefit.

The author[1] has cited numerous trial results regarding the re-use of immunosuppressants after the occurrence of irAEs. However, there is still controversy regarding the re-use of ICIs in patients who have experienced irAEs. irAEs may not occur again in some patients who have experienced irAEs after reinitiating immunotherapy, or the severity of the induced irAEs upon re-initiation is milder. Dolladille et al[21] have found that 1/4 to 1/3 of patients who experienced irAEs for the first time and stopped ICI treatment experience irAE recurrence when receiving previous ICI treatment again. Therefore, whether to continue ICI treatment after irAE relief has become a major challenge in clinical immunotherapy. A previous study[22] has shown that for patients with grade 2-3 irAEs, when symptoms subside to grade 0-1, reinitiating ICI treatment can be considered, and different categories of ICIs are often recommended; for grade 4 irAEs, ICI treatment should be permanently discontinued.

CONCLUSION

ICIs have been proven to exert potent anti-tumor effects on the treatment of various cancers. Currently, with the widespread use of immunotherapy, the overall incidence of irAEs is ever-increasing, together with an increased incidence of immune-related gastritis than before, which may lead to serious issues. Moreover, the diagnosis of immune-related gastritis is somewhat challenging due to its varying onset time, atypical clinical symptoms, and the lack of specific findings in serological tests. Although endoscopy and histopathological examination are valuable for immune-related gastritis diagnosis, differentiation from other diseases (such as autoimmune gastritis) is still necessary. At present, the mechanism of immune-related gastritis is not fully understood. Some scholars hold the view that its mechanism may be related to ICIs increasing T cell activation and proliferation, thereby enhancing autoimmunity. Given the common histological feature of immune-related gastritis being increased CD8 (+) T cells and decreased CD4 (+) T cells, it's hypothesized that T cells may attack gastric epithelial cell antigens, ultimately causing immune-related gastritis. The treatment of immune-related gastritis should be individualized based on the patient's specific condition. For mild cases, close observation or the use of mucosal protective drugs may be sufficient. However, in most cases, early treatment with glucocorticoids can quickly and effectively relieve symptoms and reduce the recurrence rate of immune-related gastritis. Patients with long-term use of steroids should be closely monitored for adverse reactions. Despite the crucial role of glucocorticoids currently in immune-related gastritis treatment, combination therapy with immunosuppressants may be necessary for patients with poor response to steroid treatment. Whether to continue ICI treatment after the occurrence, development, and resolution of irAEs has become a major clinical challenge. However, studies have shown that for patients with grade 2-3 irAEs, ICI treatment can be considered for restarting when symptoms have improved to grade 0-1, and ICIs of different categories are recommended for restarting treatment. For grade 4 irAEs, ICIs should be permanently discontinued.

ACKNOWLEDGEMENTS

The authors acknowledge and appreciate our colleagues for their valuable suggestions and assistance for this editorial.