IBD is a chronic, nonspecific inflammatory condition of the gastrointestinal tract that includes both UC and CD. UC typically presents with continuous lesions that extend from the proximal colon to the rectum and are confined to the mucosal layer. In contrast, CD can affect any part of the gastrointestinal tract, with inflammation often involving the entire bowel wall and manifesting in a patchy, segmental pattern. Both diseases share primary clinical manifestations, including recurrent abdominal pain, diarrhea, abdominal masses, mucus and bloody stools, intestinal obstruction, perforation, and weight loss. These symptoms fluctuate between episodes of relapse and remission. The exact etiology of IBD remains unclear; however, it is likely influenced by a combination of genetic, immune, environmental, and microbial factors (1). In recent years, the global incidence of inflammatory bowel disease (IBD) has been rising, with a prevalence exceeding 0.3% in North America, Oceania, and much of Europe. Currently, more than 10 million people worldwide are affected by IBD, which places a significant burden on healthcare systems and the global economy (2, 3). Although most patients achieve long-term symptom control through medication, these treatments often fail to fully suppress intestinal inflammation and are associated with various complications that substantially impact patients’ quality of life. At present, no effective cure exists for the disease (4). Furthermore, IBD is the third most significant risk factor for colorectal cancer (CRC). Studies indicate that approximately 18% of CRC cases occur in patients with IBD who have had the disease for fewer than eight years (5). With the evolving treatment paradigm for inflammatory bowel disease (IBD), achieving symptom relief and endoscopic remission has become a key therapeutic goal, which is associated with improved patient prognosis. Endoscopic cross-sectional imaging offers an accurate assessment of current intestinal inflammation and is essential for diagnosing IBD, evaluating disease severity, monitoring treatment response, and predicting relapse. However, both endoscopy and histopathology are invasive procedures that necessitate repeated colonoscopies, pathology reviews, and imaging assessments. These interventions can be costly, time-consuming, and may be hindered by low patient compliance (6). In addition, approximately one-third of patients in remission from UC experience gastrointestinal symptoms, such as abdominal pain and diarrhea, due to visceral hypersensitivity, despite the absence of disease activity on endoscopy (7). Consequently, there is an urgent need to identify non-invasive and easily accessible biomarkers for monitoring disease severity and tailoring therapeutic interventions. While white blood cell count (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fecal calreticulin (FC) have been proposed as clinical markers for assessing disease severity, their accuracy remains limited (8). Among the currently available markers, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are the most commonly used; however, they may occasionally remain normal in the presence of active inflammation (9), and their sensitivity and specificity are limited. Studies have demonstrated that the sensitivity and specificity of laboratory markers used to assess UC range from 50% to 60%, thereby limiting their clinical utility (10). In contrast, other markers, such as fecal calprotectin and lactoferrin, exhibit higher sensitivity and specificity. A meta-analysis conducted by Rokkas et al (11) reported that fecal calprotectin reflected a sensitivity of 82.4% and a specificity of 72.1% in relation to endoscopic activity in CD, with an area under the ROC curve of 0.84. Despite these promising results, fecal calprotectin has not yet achieved widespread availability due to the technical demands of the assay and its associated high costs. This situation underscores the necessity for a simpler, more user-friendly, effective, and cost-efficient biomarker capable of differentiating between quiescent and active disease states in inflammatory bowel disease (IBD), assessing mucosal recovery, predicting disease recurrence, and evaluating treatment response. They are useful in assessing the severity of many chronic diseases such as COPD (12)、hepatic encopresis (13)、rheumatoid arthritis (14)、glomerulonephritis (15) and many inflammatory disorders. Torun et al (16) observed that in patients with active ulcerative colitis (UC), elevated neutrophil-to-lymphocyte ratio (NLR) was correlated with leukocyte counts and erythrocyte sedimentation rate (ESR). Additionally, in patients with active UC, the NLR decreased significantly following the resolution of intestinal inflammation. Although numerous studies have demonstrated the potential value of peripheral blood NLR, platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in assessing the severity and progression of inflammatory bowel disease (IBD), their clinical utility remains controversial due to variations in demographic characteristics, study design, and sample size. In Cherfane’s retrospective case-control study (17), NLR effectively differentiated between active UC and controls, but not between active and inactive UC. Therefore, we conducted this meta-analysis to summarize the available evidence and explore the clinical value of peripheral serum inflammatory markers—NLR, PLR, and LMR—in patients with IBD.

The protocol has been registered in the International Prospective Register of Systematic Reviews data base (PROSPERO: CRD42024608118).

Inflammatory bowel disease encompassing UC and CD, is a chronic inflammatory condition affecting the colorectal region, characterized by alternating periods of activity and remission. The assessment of disease activity and the prediction of treatment outcomes have become essential components of personalized management for patients with UC. Evaluating the activity of UC and CD involves a combination of clinical signs, laboratory indices, endoscopy, and histopathology. Currently, disease surveillance methods predominantly rely on colonoscopy, which is invasive, uncomfortable, time-consuming, and costly. This reliance may hinder patient compliance, and colonoscopy has been ranked as the least acceptable disease surveillance test among patients with CD (40, 41). Simple, non-invasive biomarkers are essential for mitigating the risks associated with invasive diagnostic procedures. Biomarkers previously studied for predicting inflammatory bowel disease (IBD) activity include serum markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), as well as fecal markers like calprotectin and lactoferrin. While CRP and ESR demonstrate high sensitivity in detecting IBD activity, their specificity is relatively low; these markers can be elevated not only due to IBD but also as a result of other extraintestinal inflammatory processes. Furthermore, genetic variability among individuals contributes to differences in CRP production, complicating accurate differentiation (42). The ESR is utilized less frequently than CRP due to its slower response to fluctuations in disease activity (43). Levels of the fecal marker calprotectin are proportional to neutrophil migration through the inflamed intestinal wall into the mucosa, and studies have demonstrated a correlation between calprotectin levels and endoscopic activity in patients with CD (44). Levels of fecal markers may be influenced by gut microbiota, as microbial diversity and quantity can affect marker expression and detection. Their routine use is further limited by high costs, lengthy sample processing times, and the challenges associated with fecal sample collection, which render them accessible to only a small proportion of patients with CD. Increasing evidence suggests that the pathology of IBD largely involves the progression of immunological lesions characterized by significant cellular infiltration, primarily by neutrophils, lymphocytes, macrophages, and plasma cells. Various systemic inflammatory markers, including the NLR, PLR, and LMR, derived from complete blood counts, have been reported as diagnostic and predictive indicators for IBD. While these markers are less costly and more easily accessible, their accuracy remains controversial. In response to this issue, we conducted a meta-analysis to evaluate the predictive value of peripheral blood inflammatory markers (NLR, PLR, and LMR) for IBD activity. The results showed that the level of NLR was significantly expressed in both UC and CD patients compared with the healthy population: (1) Compared with healthy individuals, the NLR levels of IBD patients were significantly elevated. The serum NLR level of IBD patients during the active phase was significantly higher than that during the remission phase. (2) The severity of IBD patients was positively correlated with the NLR and PLR levels. (3) There were no significant differences in serum LMR and LMR levels between IBD patients and healthy individuals, but the serum LMR level during the active phase of IBD patients was significantly lower than that during the remission phase. Finally, our study structure showed that NLR had better accuracy in diagnosing IBD AUC[ES=0.72,95%CI(0.69,0.75),P < 0.001].To address the high heterogeneity observed in the analyses, we conducted subgroup analyses and univariate/multivariate meta-regression analyses, which indicated that differences in study type and diagnostic criteria may contribute to this variability. The final results indicate that peripheral serum biomarkers such as the NLR and the PLR can serve as effective markers for predicting the activity of IBD. However, LMR levels did not demonstrate statistically significant differences between IBD patients and healthy individuals, nor among varying severities of IBD. Furthermore, LMR levels were significantly lower during the active phase of IBD compared to the remission phase, which introduces uncertainty and controversy regarding the predictive capability of LMR given these conflicting and non-significant results. These discrepancies may arise from limitations in the number of available studies; specifically, six studies reported differences in LMR levels between active and remission phases in IBD patients, while only two studies addressed the remaining two results. This limitation may have affected the outcomes of data pooling. We hope that future high-quality studies will further explore LMR levels at different stages of IBD, and we will continue to monitor research developments in this field.

The NLR was first identified as a marker of systemic inflammation in 2001 and has since been extensively studied in both malignant and non-malignant diseases (45). The NLR combines neutrophil and lymphocyte counts to provide a comprehensive view of the body’s immune-inflammatory status. Neutrophils are the first immune cells recruited to sites of inflammation, serving as the primary defense against pathogenic microorganisms and playing a crucial role in the innate immune system. In mucosal colon biopsies, the presence of neutrophils is associated with an increased risk of IBD recurrence and a poorer prognosis. Neutrophils are recruited from the circulatory system to areas of intestinal inflammation, where they eliminate pathogens by promoting inflammation through direct phagocytosis or by releasing NETs. These mechanisms contribute to mucosal healing and the resolution of inflammation (46, 47). Excessive neutrophil extracellular traps (NETs) can secrete inflammatory cytokines such as IL-1β and TNF-α, which amplify the inflammatory cascade and significantly contribute to the dysregulation of the immune-inflammatory response in the intestinal mucosa of patients with UC. Angelidou et al. (48) demonstrated that the activation of the REDD1/autophagy/NETs/IL-1β signaling pathway, which produces IL-1β, plays a crucial role in mediating intestinal inflammation and mucosal damage in UC. Furthermore, patients with IBD exhibit elevated levels of TNF-α, IL-1β, IL-16, and interferon-γ (IFN-γ) compared to healthy individuals (49, 50). When neutrophils (NEUs) are exposed to antigens, specific antigens bind to the ‘Fcγ receptor I/specific immunoglobulin G complex’ formed on the surface of sensitized NEUs. This binding stimulates the release of pro-inflammatory cytokines, such as TNF-α, which activates the protein kinase and NF-κB pathways. Ultimately, this activation leads to cellular differentiation, proliferation, and an increased production of pro-inflammatory cytokines, contributing to mucosal barrier defects in patients with UC (51, 52). The primary pathways for IL-1β production include the neutrophil serine protease pathway and the inflammasome-dependent caspase-1 pathway. In UC, IL-1β is produced both in the bloodstream and locally within the inflamed intestinal tract, contributing to tissue damage and inflammation (53). Conversely, neutrophils become “over-activated” in this pathological state. The increased expression of the anti-apoptotic protein A1 delays or reduces neutrophil apoptosis, significantly prolonging their lifespan and enhancing their activation. This over-activation results in the release of protein particles and reactive oxygen species, which disrupt the integrity of tight and adherens junctions, leading to dysfunction of the intestinal epithelial barrier. Such dysfunction further exacerbates tissue damage and results in typical UC mucosal manifestations, including cryptitis, mucosal erosion, and ulcer formation (54, 55). In addition, neutrophils upregulate pro-inflammatory chemokines, such as C-X-C motif chemokine ligand (CXCL) 1 (CXCL1), CXCL3, and CXCL8, which perpetuate the inflammatory cycle in colitis (56). CD inflammation can affect the entire intestinal tract, with the distal ileum being the most commonly involved site. Elevated levels of TNF-α, IL-1β, and IL-6 are also observed in patients with CD (57). TNF-α enhances the immune response of Th17 cells and promotes the secretion of cytokines such as interferon-γ (IFN-γ), while IL-6 facilitates the differentiation of Th17 cells, further mediating the destructive inflammatory response (58). The inflammatory response in Crohn’s disease (CD) is primarily sustained by the migration of Th17 lymphocytes and regulatory T (Treg) cells to the site of inflammation, mediated through interactions with integrins, such as α4β7 integrin, and other adhesion molecules, including leukocyte MacCAM-1 (59). Lymphocytes are crucial for antimicrobial defense and also play significant roles in organ development, tissue protection, regeneration, and mucosal homeostasis. Although these cells are components of the adaptive immune system, they originate from the same lymphoid progenitor cell population as other lymphocytes (60). Furthermore, lymphocytes are instrumental in the early phases of the immune response and in maintaining intestinal mucosal homeostasis by rapidly responding to cytokines and other signals produced by surrounding cells (61). Studies on Crohn’s disease and ulcerative colitis have identified lymphocyte dysfunction and abnormalities at both peripheral and mucosal levels, primarily characterized by a diminished response to mitogenic phytohemagglutinin and a tendency towards reduced absolute lymphocyte counts (31). The low lymphocyte counts observed in patients with active ulcerative colitis may stem from various factors, including mucosal lymphocyte infiltration, autoimmune-related apoptosis, malnutrition, and colonic bleeding or leakage. Platelets, which are essential for coagulation, are among the first cells recruited to the vascular endothelium at infection sites during both acute and chronic inflammation. They facilitate the recruitment of inflammatory cells by adhering to the endothelium or subendothelial space, regulating cell adhesion and extravasation, and activating monocytes, neutrophils, and endothelial cells. Furthermore, platelets synthesize and release substantial amounts of pro-inflammatory cytokines and chemokines (28, 62). During acute inflammation, cytokines such as IL-6 stimulate platelet differentiation, resulting in the release of activated platelets that contribute to both inflammation and thrombosis (30). Inflammatory mediators are released following intestinal microthrombosis in patients with IBD. Elevated platelet counts and activated platelets can trigger a series of inflammatory responses by increasing vascular permeability and promoting leukocyte migration, which exacerbates ischemia in the intestinal mucosa and may lead to irreversible intestinal damage (27). Additionally, platelets contain IL-8, which induces neutrophil aggregation and the release of superoxide; this process is mediated by adhesion molecules, resulting in platelet-neutrophil aggregation (30). Maugeri (63) found that platelets activate neutrophils through the release of HMGB1-containing platelet microparticles, which promotes the formation of an extracellular trapping network of neutrophils. Furthermore, monocytes can differentiate into macrophages and dendritic cells within tissues. In patients with active inflammatory bowel disease (IBD), elevated platelet counts result partly from an intestinal inflammatory response that promotes platelet maturation in the bone marrow. Concurrently, inflammatory factors drive continuous platelet consumption, which further stimulates platelet production and raises peripheral blood platelet counts. During inflammation, pro-inflammatory cytokines and chemokines stimulate monocyte production in the bone marrow and recruit these cells to sites of inflammation, where they differentiate into tissue-resident macrophages and dendritic cells. Consequently, sustained monocyte activation and a defective innate immune response play crucial roles in the pathogenesis of IBD (64). A substantial body of research indicates that elevated neutrophil and platelet counts, along with reduced lymphocyte counts, reflect the intensity of immunoinflammation in UC. Notably, elevated neutrophil levels can be observed even during clinical remission, provided that other infectious factors affecting leukocyte subtypes are excluded. Crispino et al. (65) reported that the NLR can be utilized in clinical practice to predict the response to anti-TNF-α therapy in patients with CD. Additionally, a recent study found that NLR and PLR levels can predict mucosal healing and the outcomes of anti-TNF-α monotherapy in patients with UC. These findings suggest that these markers could enhance the management of IBD in clinical settings (66).

This study represents the first meta-analysis to evaluate the predictive value of peripheral serum biomarkers, specifically the NLR, PLR, LMR, for Inflammatory Bowel Disease (IBD). The literature search conducted was comprehensive, and the statistical analysis applied was rigorous. However, our study is limited by a high degree of heterogeneity in the results. To address this limitation, we employed subgroup analysis and regression analysis to identify the sources of heterogeneity. The findings suggest that variations in study types and diagnostic criteria may contribute to this heterogeneity. (1) There were discrepancies in the definitions and assessment criteria for IBD activity among the original studies included. Currently, various tools are utilized in both clinical practice and research to define disease activity, and a globally accepted gold standard does not exist. The studies incorporated in this meta-analysis utilized diverse scoring systems, including the Mayo score, Lichtiger index, Pediatric Ulcerative Colitis Activity Index (PUCAI), Pediatric Crohn’s Disease Activity Index (PCDAI), Truelove & Witts criteria, Rachmilewitz index, and the Modified Truelove & Witts Severity Index (MTWSI).The clinical, endoscopic, and laboratory indicators included in each scale vary, as do the weighting and scoring criteria for the same indicators (such as the frequency of bloody stools and endoscopic findings) across different scales. Furthermore, these scales exhibit inconsistent definitions of remission and severity. For instance, a patient classified as ‘moderately active’ by the Mayo score may be categorized as ‘mild’ or ‘severe’ when evaluated using the Lichtiger Index or Rachmilewitz Index. This ‘tool diversity’ in defining and assessing disease activity leads to substantial differences in the inclusion criteria for study populations. Despite the significant heterogeneity observed in the studies, we found that all 23 included studies demonstrated that the NLR and PLR during the active phase were higher than those during the remission phase, or that NLR and PLR in IBD patients were elevated compared to healthy individuals (as illustrated in Figures 2 , 4 , which show no cross-quadrant studies). This indicates that heterogeneity primarily affects the magnitude of the effect size rather than the direction of the conclusion. (2) The heterogeneity observed in this study may also be partially attributed to differences in the types of study designs included (prospective cohort studies versus retrospective cohort studies). Prospective studies, which adhere to predefined protocols, standardized data collection, and active follow-up, can more reliably assess baseline disease activity, control for confounding factors, and reduce bias. In contrast, retrospective studies rely on historical medical records and often encounter issues such as missing critical data, insufficient standardization, and incomplete follow-up, which directly impact the reliability and comparability of study results, thereby contributing to heterogeneity in meta-analyses.(3)There are notable differences in the cutoff values for NLR, PLR, and LMR across various regions. The observed range for NLR is between 1.91 and 3.6, while the range for PLR spans from 132.88 to 191.22. Studies employing lower cutoff values may categorize a greater proportion of patients into the ‘high exposure’ group, which could result in variations in the actual severity and composition of the ‘high NLR, PLR’ population across different studies. Furthermore, some studies did not specify their cutoff values. Given the limited number of studies and the fact that, although a few reported extreme values, most cutoff values were relatively concentrated within a specific range, we were unable to conduct subgroup analyses on cutoff values. Considering these factors, we anticipate that future high-quality prospective studies will further assess the predictive efficacy of NLR, PLR, and LMR for Inflammatory Bowel Disease (IBD), standardize diagnostic criteria, and narrow the range of cutoff values to mitigate bias.

In conclusion, we believe that NLR and PLR can be used as auxiliary indicators for clinical diagnosis of IBD and for assessing the activity of IBD. These indicators are simple to obtain, inexpensive, practical, have low operational difficulty, and have high patient compliance and clinical application value. Considering that LMR showed conflicting or insignificant results in several comparisons, LMR may not be a reliable independent marker. We still need more high-quality studies for further verification, which also provides a research direction for our subsequent studies.