Systemic inflammatory markers in gastric ulcer: Leveraging routine blood tests

Abstract

Gastric ulcer (GU) represents a clinically significant manifestation of peptic ulcer disease, driven by a complex interplay of microbial, environmental, and immune-inflammatory factors. A recent cross-sectional study by Shen et al systematically evaluated six complete blood count-derived inflammatory indices: Neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammatory response index (SIRI), and aggregate index of systemic inflammation and demonstrated their positive associations with GU prevalence, identifying SIRI as the strongest predictor. This editorial contextualizes these findings within the broader literature, clarifies that these indices reflect systemic rather than GU-specific inflammation, highlights methodological strengths and major limitations, and proposes a conceptual clinical algorithm for integrating SIRI into GU risk assessment. Future multicenter studies incorporating Helicobacter pylori infection, non-steroidal anti-inflammatory drug exposure, and prospective design are essential to validate and translate these findings into clinical practice.

Key Words: Gastric ulcer; Peptic ulcer disease; Systemic inflammatory response index; Neutrophil-to-lymphocyte ratio; Inflammation; Biomarkers

Core Tip: This editorial provides a critical analysis and appraisal of Shen et al’s study, which links six complete blood count-derived inflammatory indices (systemic inflammation markers) with gastric ulcer (GU) and demonstrates that systemic inflammatory response index (SIRI) exhibits the highest predictive value (area under the curve = 0.868) among these indices. While these inexpensive and accessible markers particularly SIRI may serve as practical tools for GU risk stratification, the editorial introduces a refined clinical framework for their application in this context and emphasizes the essential need for confirmation in prospective multicenter studies that account for Helicobacter pylori and non-steroidal anti-inflammatory drug confounders.

INTRODUCTION

Gastric ulcer (GU) remains a prevalent and clinically significant subtype of peptic ulcer disease (PUD), affecting up to 10% of the global population over a lifetime and approximately 2.5%-6% of Chinese adults[1,2]. Despite advances in endoscopic diagnosis and pharmacologic therapy, GU continues to impose a substantial clinical and economic burden due to complications such as bleeding, perforation, and gastric outlet obstruction, all of which contribute to impaired quality of life and increased mortality[3]. The pathogenesis of GU is multifactorial, driven by a complex interplay of host, microbial, and environmental factors. Chronic inflammation and immune dysregulation play central roles, characterized by activation of nuclear factor kappa-B-dependent inflammatory pathways, infiltration of proinflammatory leukocytes particularly neutrophils and monocytes into the gastric mucosa, and compromised mucosal repair mechanisms that together lead to epithelial disruption and ulcer formation[4-6]. In addition to these inflammatory processes, Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drug (NSAID) exposure remain the two most important risk factors, acting synergistically to amplify mucosal damage through cytokine production, oxidative stress, and prostaglandin inhibition[7,8].

Over the past decade, there has been growing recognition of the role of systemic inflammation in both gastrointestinal and extra-gastrointestinal diseases. Complete blood count (CBC)-derived indices such as the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), and aggregate index of systemic inflammation (AISI) have emerged as simple, cost-effective, and non-invasive biomarkers for evaluating systemic inflammatory and immune responses[9]. These indices integrate cellular components of innate and adaptive immunity, thereby reflecting the overall balance between proinflammatory and regulatory processes. Although these indices are not disease-specific, their elevation has been associated with a wide range of pathological conditions, including cardiovascular diseases, metabolic disorders, malignancies, and autoimmune diseases[6,10]. For instance, Wang et al[5] demonstrated that higher levels of SII, SIRI, and NLR were associated with metabolic dysfunction-associated steatotic liver disease[5], while Huang et al[6] reported similar associations between these indices and adverse outcomes in heart failure.

Within the field of gastroenterology, CBC-derived inflammatory markers have shown particular promise as prognostic tools in gastric malignancy and ulcerative diseases. In gastric cancer, several studies have confirmed the prognostic superiority of SIRI over traditional indices such as NLR and PLR, underscoring its ability to integrate neutrophil, monocyte, and lymphocyte dynamics as a composite indicator of tumor-associated inflammation[7,8,11]. Similarly, Atay et al[12] and Tanrikulu et al[13] demonstrated that elevated NLR and PLR values predict disease severity and complications in patients with PUD, suggesting that systemic inflammatory responses play a pivotal role even in benign gastric pathology. However, the majority of these studies included mixed cohorts of gastric and duodenal ulcers, limiting their applicability to GU-specific inflammatory mechanisms.

Against this background, Shen et al[10] conducted a cross-sectional study specifically evaluating the relationship between six CBC-derived inflammatory indices (NLR, MLR, PLR, SII, SIRI, and AISI) and GU, providing comparative insights into their diagnostic performance and clinical relevance. By focusing exclusively on patients with histopathologically confirmed GU and incorporating multivariate regression and receiver operating characteristic (ROC) analyses, this study fills a crucial knowledge gap in the literature. The findings not only demonstrate significant associations between systemic inflammatory indices and GU prevalence but also identify SIRI as the most robust predictor among the evaluated markers. This editorial aims to contextualize Shen et al’s findings within the broader scope of inflammation-driven gastric pathology, critically evaluate the methodological strengths and limitations of the study, and propose directions for translating CBC-derived indices into clinical practice for GU management[10].

METHODOLOGY

Shen et al[10] conducted a cross-sectional study at the Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, between 2023 and 2024, enrolling consecutive patients who underwent upper gastrointestinal endoscopy. The study population included 166 GU patients (diagnosed by both endoscopic and histopathological confirmation by two independent specialists) and 77 controls (individuals without endoscopic or pathological evidence of ulcers), after excluding 10 participants with missing laboratory data (serum creatinine or blood urea nitrogen) from an initial sample of 253 individuals[10]. Eligibility criteria included age ≥ 18 years and completion of upper gastrointestinal endoscopy, while exclusions included other organic gastrointestinal diseases, autoimmune disorders, malignancies, and severe hepatic or renal dysfunction ensuring the cohort was focused on primary GU and minimizing confounding by comorbidities[10].

CBC-derived inflammatory markers were calculated from fasting venous blood samples collected prior to endoscopy: NLR (neutrophil count/Lymphocyte count), MLR (monocyte count/Lymphocyte count), PLR (platelet count/Lymphocyte count), SIRI (neutrophil count × monocyte count/Lymphocyte count), SII (platelet count × neutrophil count/Lymphocyte count), and AISI (neutrophil count × platelet count × monocyte count/Lymphocyte count)[9,10,14-17]. Covariates, selected based on prior studies of GU and inflammatory markers, included demographic factors (age, gender, marital status), comorbidities (hypertension, diabetes, stroke), and laboratory parameters [serum creatinine, blood urea nitrogen, estimated glomerular filtration rate (eGFR) calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration equation][10,17-19].

Statistical analysis was comprehensive: Baseline characteristics were compared using independent t-tests (normal continuous variables), Mann-Whitney U tests (non-normal continuous variables), and χ² tests (categorical variables). Due to the skewed distribution of inflammatory markers, all were log₂-transformed before analysis. Multivariate logistic regression models were constructed with three tiers of adjustment (model 1: No adjustments; model 2: Adjusted for age, gender, marital status; model 3: Fully adjusted for model 2 variables plus comorbidities and laboratory parameters) to assess associations between markers and GU[10]. ROC curve analysis was used to evaluate predictive ability, with pairwise Delong tests comparing area under the curve (AUC) values. Additionally, least absolute shrinkage and selection operator (LASSO) regression (using the λ + 1 SE rule) and stepwise regression (slentry = 0.1, slstay = 0.05) were employed to identify the most impactful markers, with all analyses conducted using R software (v4.2.1) and a two-tailed P < 0.05 considered statistically significant[10]. This rigorous methodological approach including histopathological confirmation of GU, comprehensive covariate adjustment, and multiple statistical techniques to validate findings strengthens the reliability of the study’s results.

KEY FINDINGS

The study’s primary findings underscore the significant association between CBC-derived inflammatory markers and GU prevalence, with SIRI emerging as the most clinically relevant indicator. First, baseline characteristics revealed that GU patients were older (median age 65 years vs 49 years in controls), more likely to be male (73% vs 43%), and had higher rates of hypertension (43% vs 16%), diabetes (20% vs 3%), and stroke (8% vs 0%), as well as poorer renal function (eGFR < 90: 51% vs 25%) compared to controls[10]. Importantly, all six inflammatory markers were significantly higher in the GU group: Median NLR (3.64 vs 1.77), MLR (0.33 vs 0.18), PLR (151.5 vs 129.38), SIRI (1.7 vs 0.55), SII (710.16 vs 378.86), and AISI (332.51 vs 115.65)[10]. To enhance clarity and didactic value, the key statistical results from multivariate logistic regression and ROC analyses are summarized in Table 1.

Table 1 Summary of complete blood count-derived inflammatory markers in gastric ulcer.

Marker	GU median	Control median	Adjusted OR (95%CI)	P value	AUC
NLR	3.64	1.77	3.20 (1.85-5.56)	< 0.001	0.818
MLR	0.33	0.18	4.14 (2.31-7.44)	< 0.001	0.808
PLR	151.5	129.4	1.49 (1.04-2.12)	0.029	0.600
SII	710.2	378.9	1.83 (1.33-2.50)	< 0.001	0.768
SIRI	1.70	0.55	3.04 (1.94-4.77)	< 0.001	0.868
AISI	332.5	115.7	1.94 (1.45-2.57)	< 0.001	0.805

Adapted from Shen et al[10]. Citation: Shen Q, Sun ZH, Xu YM, Hu QB, Zhang WH, Huang SA. Associations between complete-blood-count-derived inflammatory markers and gastric ulcer: A cross-sectional study. World J Gastroenterol 2025; 31: 111298. ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. GU: Gastric ulcer; OR: Odds ratio; CI: Confidence interval; AUC: Area under the curve; NLR: Neutrophil-to-lymphocyte ratio; MLR: Monocyte-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; SII: Systemic immune-inflammation index; SIRI: Systemic inflammatory response index; AISI: Aggregate index of systemic inflammation.

Multivariate logistic regression confirmed that higher log₂-transformed levels of most markers were associated with increased GU prevalence across all models. Only log₂ PLR reached significance in the fully adjusted model [model 3 odds ratio = 1.49, 95% confidence interval (CI): 1.04-2.12, P = 0.029], suggesting its association with GU may be confounded by demographic or clinical factors[10].

ROC curve analysis further highlighted SIRI’s superior predictive ability: Log₂ SIRI had the highest AUC (0.868, 95%CI: 0.823-0.913), significantly exceeding the AUCs of log₂ NLR (0.818), log₂ MLR (0.808), log₂ PLR (0.600), log₂ SII (0.768), and log₂ AISI (0.805) (all P < 0.05 by Delong test)[10]. Finally, LASSO and stepwise regression consistently identified SIRI as the only CBC-derived marker with a non-zero coefficient (LASSO) and the only marker retained in the final model (stepwise regression), confirming its unique role in predicting GU[10]. Collectively, these findings demonstrate that CBC-derived inflammatory markers particularly SIRI are strongly associated with GU prevalence and offer clinical utility for identifying high-risk individuals.

CRITICAL APPRAISAL

The study by Shen et al[10] makes a valuable and timely contribution to understanding the role of systemic inflammation in the pathogenesis of GU. Its rigorous design featuring endoscopic and histopathologic confirmation of GU, multivariate adjustment for clinical parameters, and comprehensive comparative analysis of six CBC-derived inflammatory indices adds considerable methodological robustness. By focusing exclusively on GU rather than combining gastric and duodenal ulcer cohorts, Shen et al[10] address a long-standing gap in the literature. Earlier investigations, such as those by Atay et al[12] and Tanrikulu et al[13], evaluated NLR and PLR across mixed PUD populations, which limited their specificity to GU-associated inflammation[12,20]. The exclusive focus on GU in Shen et al’s cohort[10], drawn from patients with confirmed lesions, thus provides a more refined understanding of the inflammatory response associated with this condition.

Importantly, the finding that the SIRI demonstrated the highest predictive power among the six evaluated markers extends observations from other gastrointestinal and oncologic contexts. SIRI, which integrates neutrophil, monocyte, and lymphocyte counts into a composite index, captures the dynamic balance between innate and adaptive immunity. In gastric cancer, Wu and Zhao[8] reported that pretreatment SIRI outperformed both NLR and PLR in prognostic discrimination, while He et al[11] demonstrated that elevated SIRI independently predicted poor outcomes in early gastric cancer patients with pyloric stenosis. These parallels suggest that SIRI’s multidimensional nature may make it particularly effective in reflecting mucosal injury and systemic inflammatory activity, whether arising from malignant transformation or benign ulceration. Mechanistically, Shen et al[10] proposed that elevated neutrophil and monocyte counts promote oxidative stress and mucosal barrier disruption through reactive oxygen species and proinflammatory cytokines, while reduced lymphocyte levels impair immune regulation and tissue repair capacity[3,10,21,22]. This integrated immune signature, embodied by SIRI, provides a biologically coherent explanation for its superior performance compared to single-parameter indices.

Nonetheless, several limitations temper the interpretation of these findings. The single-center, cross-sectional design restricts generalizability, as the data were derived from a hospital-based cohort in Nanchang, Jiangxi Province, China, potentially introducing selection bias and limiting applicability to asymptomatic or geographically diverse populations[10]. Moreover, the cross-sectional nature of the study precludes causal inference whether elevated inflammatory indices precede ulcer formation or merely reflect ongoing mucosal injury remains uncertain. Similar issues of temporality have been noted in other cross-sectional analyses of inflammatory indices, such as the work of Xu et al[23] linking SII with hypertension risk.

A more critical methodological limitation lies in the lack of adjustment for H. pylori infection and NSAID use two well-established determinants of ulcer development. Both H. pylori infection and chronic NSAID exposure are known to alter systemic and mucosal inflammatory pathways, leading to increased neutrophil recruitment, cytokine production, and epithelial injury[4,13]. Their omission from the regression model may have confounded the observed associations between SIRI and GU, thereby weakening causal interpretation. Future studies incorporating these factors are therefore essential to validate the independent predictive capacity of SIRI and other indices.

Despite these constraints, the consistent finding that SIRI outperformed other CBC-derived markers suggests that it may capture broader systemic inflammatory dynamics relevant to GU pathogenesis. This finding has potential clinical implications. Beyond serving as a simple marker of disease presence, SIRI could evolve into a clinically useful adjunct for risk stratification, early detection, and monitoring of therapeutic response. For instance, elevated baseline SIRI might identify patients at higher risk for complications such as bleeding or perforation, while declining SIRI levels during therapy could reflect mucosal healing or successful H. pylori eradication, as observed with other inflammatory biomarkers in gastrointestinal disorders[11,24,25]. By translating statistical associations into a clinically applicable framework, Shen et al’s study lays the groundwork for future translational research aimed at integrating routine hematological indices into the diagnostic and prognostic evaluation of GU[10].

FUTURE PERSPECTIVES

Despite its limitations, the study by Shen et al[10] provides an important foundation for future investigations aimed at translating CBC-derived inflammatory indices into practical tools for GU management. Moving forward, research efforts should not only validate these findings but also establish frameworks for their clinical application. To this end, we propose a three-pronged approach encompassing an exploratory clinical application model, identification of patient subgroups most likely to benefit, and prioritized directions for future research.

First, a conceptual clinical application framework is warranted to guide the potential integration of SIRI into routine GU assessment. A stepwise approach could begin with the initial screening of patients presenting with upper abdominal discomfort or dyspeptic symptoms, where evaluation of CBC-derived indices particularly SIRI may help identify individuals at increased risk. In the subsequent stratification phase, patients with high SIRI values (e.g., > 1.5, based on Shen et al’s reported data[10]) could be prioritized for early endoscopic evaluation to rule out ulcerative lesions. Those with intermediate SIRI levels (1.0-1.5) might benefit from non-invasive H. pylori testing and closer follow-up within a three-month interval[26], while those with low SIRI values (< 1.0) may be suitable for conservative management and lifestyle modifications. Finally, serial SIRI monitoring during therapy such as proton pump inhibitor administration or H. pylori eradication could provide a dynamic means of assessing treatment response or predicting ulcer recurrence[13,25]. This algorithm is presented as a conceptual and exploratory model, intended to stimulate hypothesis-driven clinical research rather than define immediate diagnostic standards.

Second, specific patient subgroups may derive the greatest benefit from implementing CBC-derived inflammatory markers in GU management. Elderly individuals and those with chronic comorbidities such as diabetes mellitus and hypertension are at increased risk of mucosal injury and impaired healing, and therefore represent ideal candidates for inflammation-based risk assessment[1,2]. Likewise, patients with recurrent dyspepsia, prior ulcer history, or those requiring long-term NSAID therapy could be effectively stratified using SIRI-based evaluation to optimize the timing and necessity of endoscopic investigation[27]. By targeting these higher-risk populations, SIRI-guided approaches could enhance early detection while promoting more cost-effective allocation of clinical and diagnostic resources.

Third, to advance from association to application, several future research priorities must be addressed. Prospective, multicenter cohort studies are essential to validate whether elevated baseline SIRI predicts incident rather than prevalent GU, thereby clarifying its role as a predictive biomarker[8,10]. In addition, longitudinal investigations should examine the temporal dynamics of SIRI during ulcer treatment and convalescence, determining whether serial declines in SIRI correlate with mucosal healing and reduced recurrence rates[9]. Finally, integrative modeling that combines SIRI with established clinical variables including H. pylori infection status, NSAID exposure, and serum pepsinogen levels could generate a comprehensive, multifactorial risk score for GU screening and follow-up[7]. Such composite models, once validated, may offer clinicians a practical and non-invasive tool to guide patient triage, inform therapeutic decisions, and monitor outcomes.

Therefore, future research on CBC-derived inflammatory markers, and SIRI in particular, should aim to bridge the gap between statistical association and clinical applicability. Through algorithm development, subgroup targeting, and integrative modeling, these readily obtainable indices may eventually serve as inexpensive, accessible, and reliable tools for personalized GU risk assessment and management.

CONCLUSION

Shen et al’s study offers valuable insights into the systemic inflammatory landscape of GU[10]. Among six CBC-derived indices, SIRI demonstrated the strongest association with GU prevalence, reflecting its potential utility in clinical risk stratification. Nevertheless, these indices are systemic rather than disease-specific markers, and confounders such as H. pylori infection and NSAID use must be addressed in future work. The conceptual clinical framework proposed herein outlines possible pathways for integrating SIRI into GU diagnosis and monitoring, emphasizing the need for multicenter, longitudinal studies to validate predictive thresholds and establish causality.