Ongoing need for biomarkers to predict disease activity in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic disease that severely affects patients’ quality of life and is associated with an increased risk of colorectal carcinoma. The advent of new therapies has improved the management of patients with IBD; however, there remains a substantial need to identify factors that can predict disease relapse and guide therapy. For decades, the follow-up of patients with IBD has relied on regular endoscopist surveillance depending on clinical symptoms, despite the well-known discrepancy among clinical, endoscopic, and histopathological findings. Although fecal calprotectin has emerged as a useful and reliable marker of disease activity, there remains a considerable need to identify more accurate and prognostic biomarkers. In this editorial, we comment on the article by Chen et al published in the recent issue of the World Journal of Gastroenterology and review recent advances in the diagnosis and management of IBD.

Key Words: Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Biomarkers; Relapse; Calprotectin; Oncostatin M; Micro-RNA; Artificial intelligence; Therapeutic drug monitoring

Core Tip: Inflammatory bowel disease is a severe, relapsing inflammatory disease, and early detection and treatment can help improve patient outcomes. Although endoscopic and histopathological scores remain the most reliable markers for predicting disease relapse, they are invasive, and there is a clear need to identify biomarkers that enable a noninvasive and practical approach to disease diagnosis and treatment. Although fecal calprotectin has emerged as the most useful biomarker, there remains a substantial need to improve its accuracy. Novel technologies, including the various omics approaches and several emerging biomarkers, promise to advance the diagnosis and management of inflammatory bowel disease in the near future, further supported by the development of artificial intelligence-based strategies.

This editorial refers to “Role of leucine-rich α-2-glycoprotein in Taiwanese patients with inflammatory bowel disease as a predictive biomarker for endoscopic activity” by Chen et al, 2026; https://doi.org/10.3748/wjg.v32.i3.114677.

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INTRODUCTION

The term inflammatory bowel disease (IBD) encompasses two disorders, namely Crohn’s disease (CD) and ulcerative colitis (UC). Both are chronic immune-mediated inflammatory conditions characterized by alternating periods of remission and relapse that severely impair patients’ quality of life and carry a long-term risk of colorectal cancer development. Although IBD was described by Morgagni in the 18^th century, its etiology remains unknown[1]. It appears that several environmental factors can trigger the disease in genetically predisposed individuals; however, the underlying mechanisms are not yet fully understood, and therefore, prevention is not currently possible.

Diagnosis is based on a combination of clinical, radiological, endoscopic, and pathological findings, and several indices and scores have been proposed to diagnose IBD and assess disease activity and relapse. However, the correlation among these measures is far from perfect, although it is well known that disease recurrence is associated with progressive bowel damage, an increased risk of hospitalization and surgery, and impaired quality of life.

Endoscopic mucosal healing is one of the strongest predictors of sustained remission in IBD and is a key therapeutic target in current guidelines[2,3]. Patients achieving complete mucosal healing experience significantly lower relapse rates compared with those with residual endoscopic inflammation. In UC, histologic remission has emerged as an additional prognostic factor. Persistent microscopic inflammation, even in the presence of endoscopic remission, has been consistently associated with a higher risk of relapse[4]. Despite their strong predictive value, endoscopic and histologic assessments are invasive, not devoid of risks for patients, and impractical for frequent monitoring.

There is a clear need to identify sensitive, specific, and cost-effective biomarkers for IBD that can be obtained using noninvasive techniques and predict response to therapy with the shortest possible turnaround time and sufficient robustness for use in everyday practice. For this reason, there is a growing interest in identifying reliable biomarkers that allow early identification of patients at risk of relapse. This has become a central yet unsolved objective in modern IBD management, particularly within treat-to-target and tight-control strategies aimed at limiting disease progression and improving the long-term outcomes of patients with IBD through early intervention during flares[5]. The report by Chen et al[6] published in a recent issue of the World Journal of Gastroenterology emphasizes the predictive role of leucine-rich α-2-glycoprotein in a Taiwanese cohort of patients with IBD, with promising results.

CURRENT BIOMARKERS

Serum biomarkers

Serum inflammatory markers, particularly C-reactive protein (CRP) and erythrocyte sedimentation rate, are widely used because of their low cost and accessibility. Nevertheless, their ability to predict relapse is limited by suboptimal sensitivity and specificity. It has been reported that up to 50% of patients with active UC can have normal CRP levels, a fact that has been attributed to genetic polymorphisms. As a result, serum biomarkers alone are insufficient for reliable relapse prediction but may provide complementary information when combined with fecal or endoscopic markers[7]. Nevertheless, CRP levels remain crucial for diagnosing acute severe UC, as levels > 30 mg/L in the setting of bloody diarrhea and more than six stools per day identify patients who require intensive therapy according to the European Crohn’s and Colitis Organisation guidelines, and increasing CRP levels during therapy predict a high risk of requiring a colectomy[8].

Fecal biomarkers

Fecal biomarkers are considered the most clinically relevant noninvasive indicators of intestinal inflammation. Among them, fecal calprotectin (FC) is the best-validated biomarker for predicting relapse in IBD. Calprotectin (CP) is a member of the family of calcium-binding S100 leukocyte proteins and is composed of two monomers, S100A8 and S100A9. CP is present in the cytosol of neutrophils, and normal FC levels range from 10 mg/g to 50 mg/g. It has been shown that FC concentrations closely correlate with endoscopic and histological activity of IBD[9]. Multiple prospective studies and meta-analyses have shown that elevated FC levels in patients in clinical remission are strongly associated with an increased risk of relapse within the following months[10]. Although optimal cutoff values vary, FC levels above 150-250 μg/g are commonly associated with a higher probability of disease recurrence. Serial measurements further enhance predictive accuracy by identifying rising trends that often precede clinical relapse[11].

Fecal lactoferrin, another marker of neutrophilic inflammation, has also demonstrated value in relapse prediction, with performance comparable to that of FC in some studies. However, its use is less widespread owing to the small number of validation studies and its limited availability in routine practice[12].

NOVEL AND EMERGING BIOMARKERS

Serum biomarkers

Oncostatin M: Oncostatin M (OMS) is a member of the interleukin-6 cytokine family and is involved in signaling through the Janus kinase-signal transducer and activator of transcription and phosphatidylinositol 3-kinase-protein kinase B pathways. OMS has been proposed as an inflammatory activator and driver of IBD chronicity after being identified as one of the most highly expressed cytokines in the inflamed mucosa of patients with IBD. Studies have shown that increased OMS levels can predict relapse with higher sensitivity than FC. It can be used alone or in combination with FC[13,14].

Glycome profiling: Compared to healthy subjects, patients with IBD show decreased galactosylation and alterations in glycan complexity[15]. Serum glycomic signatures identified using ultra-high-performance liquid chromatography have been used to predict therapeutic response in patients with IBD[16]. However, these markers remain largely confined to research settings owing to biological variability, the lack of standardized assays, and uncertain clinical utility.

Proteins and metabolites: Many studies have analyzed the profiles of proteins and metabolites in patients with IBD and compared them with those of healthy subjects to define the risk of disease development and progression[17]. Recent reports have also shown that these different profiles can influence the response to biological therapies.

Antibodies against the yeast Saccharomyces cerevisiae have been proposed as useful biomarkers for the diagnosis of CD, especially when combined with antineutrophil cytoplasmic antibodies[18]; however, their role in predicting flares and relapse remains unclear[19].

Genetic variants: Although genetic polymorphisms have been linked to IBD development, therapy response, and adverse effects, they have not yet entered clinical practice[20,21].

Fecal biomarkers

Fecal myeloperoxidase: Fecal myeloperoxidase has been proposed as a biomarker for IBD, mainly for patients with UC. Recent reviews suggest that fecal myeloperoxidase can improve the diagnostic accuracy of FC for IBD and also predict poorer outcomes[22,23].

Fecal OSM: As already mentioned for serum, fecal OSM can also be used to increase the diagnostic accuracy of CP for IBD and to predict therapeutic response. Combined serum and fecal measurements can achieve sensitivities of more than 91%[24].

Micro-RNAs

The potential use of microRNAs (miRNAs) as noninvasive disease biomarkers was described more than a decade ago. miRNAs are small, single-stranded noncoding RNA molecules that regulate gene expression by binding to the untranslated region of messenger RNA. They have been widely explored in cancer and inflammatory disorders, but in IBD, results have been variable, and there is still no clear candidate for clinical use[25]. Serum miR-21 and miR-223 have been proposed as candidates in UC and CD[26]; however, the lack of consistency among studies, small sample sizes, and the lack of standardization hamper their widespread clinical use. Fecal miRNAs are also promising, and miR-223 has shown a very good correlation with endoscopic relapse[27] and has been validated in independent cohorts. Fecal miRNAs appear more promising than serum miRNAs for future clinical use. Other omics approaches, such as proteomics, metabolomics, and genomics, are also being explored as potential biomarkers. While these approaches may ultimately enable personalized risk stratification, they currently lack sufficient validation for routine clinical use[28].

Therapeutic drug monitoring

In patients treated with biologic therapies, therapeutic drug monitoring has become an important tool for predicting loss of response and relapse. Low trough levels of biologic agents and the presence of anti-drug antibodies are associated with an increased risk of disease recurrence[29]. Proactive therapeutic drug monitoring strategies may allow early treatment optimization, thereby reducing relapse rates and improving long-term outcomes.

Artificial intelligence

Artificial intelligence (AI) is revolutionizing the field of medicine. In IBD, AI can improve the interpretation of endoscopic and histopathological scores[30]. It is expected that these AI tools will incorporate much more information to personalize therapies and predict outcomes. In this regard, a recent report by Hirten et al[31] proposed that the information gathered by wearable health devices can predict relapses up to 7 weeks in advance. These devices are easy to use and, when combined with AI algorithms, can become useful tools for the early management of relapses; however, they still require validation in larger patient cohorts.

Precision medicine

Precision medicine is one of the main challenges in IBD research. The main objective of precision medicine is to bridge the gap between the mechanistic knowledge about the disease and the prediction of disease outcomes and response to therapy. Precision medicine integrates several areas of disease knowledge, including genetics, proteomics, and metabolomics, among others. A recent review by Syed et al[32] highlights the four main objectives of precision medicine in IBD. This review underscores the value of biosamples and the data derived from them, as integrating this information is key to biomarker development and validation. This growing body of knowledge will influence not only diagnosis but also disease management, including personalized therapy guided by multiomics approaches[33] and precision nutrition[34]. AI is expected to become the most important tool for integrating this wealth of information into the clinical management of patients with IBD[35]. In addition, the widespread use of wearable devices may facilitate individualized and remote monitoring of patients with IBD in the context of personalized medicine, and these devices hold great promise for the near future[31,36].

CONCLUSION

FC remains the most practical and well-validated biomarker for predicting relapse in IBD, particularly when used longitudinally. Endoscopic and histologic remission continue to provide robust prognostic information but are limited by their invasiveness and cost. Therapeutic drug monitoring adds important predictive value in patients receiving biologic therapies. Future relapse prediction is likely to rely on an integrated approach combining clinical assessment with biochemical, endoscopic, and emerging molecular biomarkers to support personalized disease management, likely with the aid of new AI tools.