Malignant neoplasm of the stomach is one of the most common cancers worldwide, affecting over 20,000 patients yearly in the USA. The average 5-year survival rate is less than 20%, underlining the importance of the disease (1, 2). This poor prognosis can be improved by early diagnosis. If the tumor is detected and treated before reaching the muscular layer of the stomach (T1), the 5-year survival rate can be up to 90% (3).

A significant decline in incidence and mortality can be observed over the past few decades (4), which can be attributed to the recognition of certain causative factors, decreased incidence of Helicobacter pylori infection, and decreased use of tobacco and dietary salt (2, 5). While the overall rate of gastric cancer has been declining, the distribution of its subtype was changing neoplasms of the cardia and gastro-esophagal junction became more frequent, and an unexplained increased incidence among younger than 50 years of age, particularly in females, could be observed (5–8).

Despite the effective H. pylori eradication strategies, gastric cancer remains the fifth most common cancer worldwide (9), highlighting the possibility of further etiological factors. Besides H. pylori, autoimmune gastritis is another common cause of gastric cancer, reflecting 7.8%–19.5% of the cases, and thought to be another possible cause of the rising incidence of gastric cancer in females younger than 50 years of age (5, 7, 10).

The incidence of autoimmune gastritis and generally autoimmune diseases has increased in the past few decades (11–13). Several previous studies have described the potential association of autoimmunity and gastric cancer (14, 15), but up to date, data have been controversial regarding cause-effect relationships and underlying pathomechanism. Our study aims to provide a comprehensive summary of the potential association between autoimmune disorders and the incidence of gastric cancer in the form of a meta-analysis and systematic review.

This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement (16). The protocol of this analysis was registered on the PROSPERO International Prospective Register of Systematic Reviews in advance (CRD42021262875). We did not deviate from the protocol.

This meta-analysis, including data of 499,427 patients collected from 43 studies, was conducted to understand the relationship between autoimmunity and gastric cancer. Based on our results, the incidence of gastric cancer significantly increased in patients with pernicious anemia, Graves’ disease, dermatomyositis, diabetes mellitus type I, inflammatory myopathies, and systemic lupus erythematosus.

In line with our results, the literature suggests that patients with dermatomyositis, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, or diabetes mellitus type I may have an increased risk for developing multiple cancers (29–34). Positive associations have been observed between various gastrointestinal tumors and rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, celiac disease, idiopathic inflammatory myositis, and systemic sclerosis (35–39).

A recent meta-analysis described a correlation between autoimmune disorders and increased risk of gastric cancer (40). Song et al. concluded that patients with dermatomyositis, pernicious anemia, Addison’s disease, dermatitis herpetiformis, IgG4-related disease, primary biliary cirrhosis, diabetes mellitus type I, systemic lupus erythematosus, and Graves’ disease had elevated risk for developing gastric neoplasms.

Pernicious anemia has been demonstrated as a risk factor for gastric cancer (41) since it correlates with autoimmune gastritis and results from gastric mucosal damage. This pathomechanism has been modeled in mice and has suggested an association between autoimmunity and carcinogenesis (14). Autoimmune thyroiditis, diabetes mellitus type I, vitiligo, and Addison disease are frequently associated with pernicious anemia.

An increase in the incidence of autoimmune diseases has been observed recently parallelly with the increasing incidence of cancers. The autoimmune inflammation often correlates with the tumorous disorder of the affected organ. This phenomenon is most conspicuous in people below 50 years of age, and it affects females more considering the development of gastric cancer (7, 8).

Although autoimmune processes can play a significant role in developing different cancers, the exact pathomechanisms remain unclear. Several common factors can be identified, such as immunosuppression/dysregulation, infections, dietary habits, environmental factor, and chronic inflammation. These factors can induce chronic cell damage and can trigger either autoimmune conditions or cancer (12). Autoimmune disorders may lead to antigen specificity-driven tissue damage causing chronic inflammation, whose role in carcinogenesis is well known and precedes the tumor formation in time (42).

Regarding the strengths of our meta-analysis, we included a large number of cohort studies. Many of our analytical results proved to be significant. This comprehensive work contains wide coverage of AI disorders from 15 different countries and four continents of the currently available literature so far. Following the PRISMA Statement and a rigorous methodology, the quality is secured. The key questions of this study were not widely investigated recently; thus, most of our findings are novel.

The formerly mentioned meta-analysis (40) discussing the question of interest had several limitations. Compared with that work, a more general search key was used in our study, which allowed us to find a higher number of relevant records. Our search was conducted in four databases compared with the two in the previous work, which also contributed to the identification of further eligible studies. They calculate pooled relative risk ratios (RR) with 95% CI; however, hazard ratios, SIRs, RRs, and standardized mortality rates were pooled into RR. Statistical analysis of our study is also more coherent as only SIR-s were calculated consistently (43, 44).

However, our analysis has some limitations, which should be considered for a correct interpretation. Firstly, other risk factors for gastric cancer, such as H. pylori infection status, smoking, dietary habits, obesity, occupational exposure to dust, high-temperature particulates, and metals such as chromium VI, gastric surgery (by-pass), and Epstein-Barr infection could be present that were not measured or reported. We also did not have information about drugs taken for autoimmune disorders, so how it may affect the outcome is unknown. However, according to 10 included articles, the mean time interval from the diagnosis of AI disorder to the diagnosis of cancer is 2–7.4 years. Although, the mentioned time intervals refer to the development of any type of cancer in general, not only to gastric cancer.

The diagnosis of AI diseases in countries could be different, which could create significant heterogeneity in some of the analyses. The presence of ascertainment cannot be ruled out, since people with an autoimmune disease are subjected to medical examinations more frequently, than the general population, which may lead to a greater number of cancer diagnoses. The low number of enrolled studies regarding certain autoimmune disorders, which could not be meta-analyzed, is also a further limitation. The risk of bias assessment deemed in case of multiple domains as not low overall risk of bias too.

Subgroup analyses regarding the type of gastric cancer could not be performed, because there were no details available on histological type, or location of cancer. However, Ji et al. described that a few autoimmune diseases is an important risk factor for gastric cancer, mainly for corpus cancer (22). Sensitivity analysis was carried out to define the strength of confounding factors, such as H. pylori infection, which results suggest the examined association is unlikely to be solely because of confounding.

Most of the included studies originate from either North Europe (where incidence of autoimmunity could be higher compared with other populations) or Asia (where H. pylori infection and/or gastric cancer could be more prevalent). To address this problem, we performed subgroup analyses based on low- or high-incidence countries of gastric cancer. The results of the subgroup analysis reassert our main results, namely pernicious anemia, diabetes mellitus type I, Graves’ disease, and autoimmune vasculitis were associated with gastric cancer in low-incidence countries.

Our meta-analysis of 39 articles concludes that pernicious anemia, Graves’ disease, dermatomyositis, diabetes mellitus type I, inflammatory myopathies, and systemic lupus erythematosus are associated with higher incidence rates of gastric cancer. For clinical practice, close gastroenterological follow-up or routinely performed gastroscopy and application of other diagnostic measures may be cost-effective and clinically helpful for patients diagnosed with these six autoimmune diseases. Based on the importance of the problem, conducting further clinical trials on this topic is essential.

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

NZ: conceptualization, project administration, formal analysis, and writing—original draft. EO: conceptualization, methodology, and statistical analysis. PH: conceptualization and writing—review and editing. SV: conceptualization, data curation, and writing—review and editing. NV: conceptualization, data curation, and writing—review and editing. SK: conceptualization, methodology, and writing—review and editing. LF: conceptualization, visualization, and writing—review and editing. LS: conceptualization, methodology, visualization, and writing—original draft. JC: conceptualization, supervision, and writing—original draft. All authors have participated sufficiently to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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