Non-invasive tools for inflammatory bowel disease: A systematic review and meta-analysis of biochemical markers and intestinal ultrasound compared to endoscopy

Despite endoscopy's gold standard status, non-invasive tools are revolutionizing Inflammatory Bowel Disease (IBD) management. This systematic review and meta-analysis compared the diagnostic accuracy of biochemical markers, intestinal ultrasound (US), and endoscopy in adults with IBD. This systematic review and meta-analysis aimed to compare the diagnostic accuracy of fecal calprotectin, C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), and bowel wall thickness measured by US with endoscopy in IBD patients. We searched electronic databases for most recent studies published between 2012 and 2023, identifying 25 studies comparing at least one non-invasive tool with endoscopy. We pooled sensitivity and specificity for relevant outcomes and conducted subgroup analyses to explore heterogeneity. 25 studies (n=5872 patients) met inclusion criteria. Fecal calprotectin emerged as a powerful diagnostic tool, with pooled sensitivity of 92.5% and specificity of 85.1% for IBD. But it’s performance was less consistent in differentiating active vs. inactive disease and predicting flares. Intestinal US proved reliable for diagnosis, particularly in Crohn's disease (pooled sensitivity 86.3%, specificity 78.9%), and showed promise in assessing activity and predicting treatment response. C-Reactive Protein and Erythrocyte Sedimentation Rate, though less accurate, provided additional information about disease status. Combining calprotectin and US further enhanced prediction accuracy, while decision tree analysis incorporating clinical data and both tools maximized prediction in ulcerative colitis. Non-invasive tools offer invaluable insights for IBD management, complementing and potentially reducing reliance on endoscopy. Standardizing methodologies and developing more specific markers, potentially aided by AI, holds immense potential for personalized, effective IBD care. This evolving landscape paves the way for a future where patients actively participate in their journey, empowered by the growing arsenal of non-invasive tools.


Introduction
Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, presents a significant global health burden with complex diagnosis and monitoring challenges [1] [2].The traditional gold standard for IBD assessment relies on invasive endoscopy, which, while highly accurate, carries inherent risks, discomfort, and cost limitations [3] [4].Consequently, the search for reliable non-invasive alternatives has gained considerable traction in recent years [5] [6].
Biochemical markers, readily obtained through blood or stool samples, have emerged as promising candidates for noninvasive IBD evaluation [7] [8].Fecal calprotectin, for instance, has demonstrated efficacy in differentiating IBD from functional bowel disorders and monitoring disease activity [2] [3].Similarly, emerging markers like C-reactive protein and erythrocyte sedimentation rate offer preliminary evidence for predicting treatment response and potential for flare-ups [8].However, while these markers provide valuable insights, their diagnostic accuracy often falls short of endoscopy, prompting exploration of additional non-invasive tools [3].
Intestinal ultrasound (US) has positioned itself as another promising alternative to endoscopy in IBD management [9] [10].Transabdominal US offers a readily accessible, radiation-free approach capable of visualizing bowel wall thickness, vascularization patterns, and presence of inflammatory infiltrates [9] [11].Studies have shown its effectiveness in differentiating IBD from healthy states and assessing disease activity, particularly in Crohn's disease [10] [12].However, despite its advantages, US interpretation relies heavily on operator expertise and lacks the detailed mucosal visualization of endoscopy, limiting its ability to detect subtle mucosal changes [9].Therefore, the need for a comprehensive comparative evaluation of these non-invasive approaches compared to the established gold standard of endoscopy remains evident.This systematic review and meta-analysis aims to bridge this gap by critically assessing the diagnostic accuracy, sensitivity, and specificity of biochemical markers and intestinal ultrasound in comparison to endoscopy for the diagnosis and assessment of activity in IBD patients.By synthesizing the existing literature and identifying the strengths and limitations of each approach, we hope to provide invaluable insights to guide clinical decision-making and pave the way for future optimization of non-invasive IBD management strategies.

Method
This systematic review and meta-analysis aimed to evaluate the diagnostic accuracy of non-invasive tools, including biochemical markers and intestinal ultrasound (US), compared to endoscopy in patients with Inflammatory Bowel Disease (IBD).The methods employed followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for comprehensive and transparent reporting.

Data Sources and Search Strategy
We conducted a comprehensive search across electronic databases (PubMed, Cochrane, Emabase, scopus and other databases) using pre-defined search terms related to IBD, biochemical markers, intestinal ultrasound, and endoscopy.Studies published in English between January 2012 to December 2023 were included.Studies in English comparing the diagnostic accuracy of biochemical markers, intestinal ultrasound, and endoscopy in adult IBD patients were included.
Review articles, case reports, and studies focused solely on pediatric populations were excluded.We excluded studies with solely non-IBD populations, case reports, narrative reviews, and those lacking data on diagnostic performance metrics (sensitivity, specificity, etc.) compared to endoscopy.

Inclusion and Exclusion Criteria
To ensure a comprehensive and relevant analysis of non-invasive tools for IBD assessment, we established specific criteria for study selection: (See Table 1).By applying these criteria, we aimed to select a comprehensive and relevant set of studies for our analysis, providing a robust and reliable assessment of the current landscape and future potential of non-invasive tools in IBD management.

Inclusion criteria Exclusion criteria
Original research articles or meta-analyses: We included studies investigating the diagnostic accuracy of biochemical markers, intestinal ultrasound, or both compared to endoscopy in IBD patients.Case reports, reviews, and studies not evaluating diagnostic accuracy were excluded.
Studies not comparing non-invasive tools with endoscopy: Studies solely focusing on non-invasive tools without comparing them to the gold standard were not included.
Published in English: Due to resource limitations, we focused on English language publications.-Studies using different methods for endoscopy (e.g., colonoscopy, ileoscopy) were included if the methodology was clearly described and consistent with established guidelines.
-The specific cut-off values used for defining positive and negative test results for each marker or ultrasound parameter were recorded and considered during data analysis.

Data extraction
From each included study, relevant data was extracted, including study design, patient population, type of biochemical marker, ultrasound parameters, endoscopic scoring system, diagnostic outcomes (sensitivity, specificity, accuracy), and potential sources of heterogeneity.

Ethical Approval and Quality Assessment
Data was collected and analyzed from existing studies; ethical approval from the ethics review board was obtained beforehand.Research conduct was transparent, and confidentiality protocols were adhered to throughout our study.The risk of bias assessment and quality check for each study were carried out using the adjusted Newcastle-Ottawa scale.

Statistical Analysis
This meta-analysis employed robust statistical tools to unveil the diagnostic accuracy of non-invasive IBD assessments compared to endoscopy.Random-effects models, accounting for expected study variations, estimated pooled sensitivity, specificity, PPV, and NPV for each tool relative to endoscopy.Cochran's Q test and I² statistic identified and quantified potential differences between studies.To delve deeper, we explored whether factors like IBD subtype, marker type, and ultrasound technique influenced accuracy through subgroup analyses.When appropriate, we investigated the influence of study characteristics on accuracy estimates through meta-regression.Robustness checks included excluding highbias studies, utilizing alternative statistical models, and addressing potential publication bias.

Study Selection
Two independent reviewers screened the retrieved records through title, abstract, and keyword analysis.Disagreements were resolved through discussion or by consulting a third reviewer.Full-text articles were retrieved for potential studies meeting the inclusion criteria.Following a thorough evaluation of methodology, data reporting, and quality assessment, 25 studies were ultimately deemed eligible for inclusion in the meta-analysis.This stringent selection process ensures the quality and reliability of the data analyzed in this meta-analysis.By adhering to clearly defined criteria and employing a systematic double-blind approach, we minimize bias and maximize the validity of our findings.

Study Characteristics
Our meta-analysis draws insights from 25 diverse studies illuminating IBD assessment.Fecal calprotectin (5 studies) reigns supreme in IBD detection, while ultrasound (5 studies) shines in Crohn's disease.C-Reactive Protein and Erythrocyte Sedimentation Rate (5 studies) offer additional clues.Most studies explored Crohn's (5) and Ulcerative Colitis (4), with fewer venturing into Indeterminate Colitis (1).Heterogeneity, a natural mist, pervades due to varying methodologies.Quality assessment reveals a spectrum of designs, with randomized controlled trials and cohort studies leading the way.Complete transparency reigns, with detailed study characteristics presented in supplementary tables.By exploring this diverse landscape, we gain a deeper understanding of non-invasive tools, paving the way for personalized IBD management.

Risk of Bias in Included Studies
While our meta-analysis unveils valuable insights into non-invasive IBD assessments, it is crucial to acknowledge the potential presence of bias, which can cast shadows on the results.Consequently, we meticulously evaluated each included study using established risk-of-bias assessment tools, revealing a spectrum of potential influences.While some studies exhibited commendable methodological rigor and minimal bias, others raised concerns about factors like participant selection, blinding strategies, and outcome reporting.To ensure transparency, a detailed bias assessment of each study is provided in the supplementary materials.

Synthesis of results
The extracted data will be analyzed and synthesized to address the primary and secondary objectives of the review.The results of the analysis will be presented in a clear and concise manner and utilizing tables to visually represent key findings.Subgroup analyses will be reported and discussed within the context of the overall findings.
This systematic review and meta-analysis delved into the promising realm of non-invasive tools for Inflammatory Bowel Disease (IBD) management, meticulously comparing the diagnostic accuracy of biochemical markers, intestinal ultrasound (US), and the established gold standard of endoscopy.We present key findings from relevant individual meta-analyses and studies to provide a comparative overview of the diagnostic accuracy of each approach.
Several studies analyzed the diagnostic accuracy of fecal calprotectin for differentiating IBD from non-IBD conditions.We pooled data from five high-quality studies using a random-effects model and calculated the overall sensitivity, specificity, and positive and negative predictive values (PPV and NPV).
These findings (See Table 2) suggest that fecal calprotectin demonstrates high sensitivity and specificity for diagnosing IBD, with excellent NPV and good PPV.However, it is important to note that these values may vary depending on the specific cut-off point used for calprotectin levels and the prevalence of IBD in the target population.Four studies evaluated the accuracy of bowel wall thickness measured by transabdominal ultrasound compared to endoscopy for assessing disease activity in Crohn's disease.Again, we employed.These results (See Table 3) indicate that bowel wall thickness measured by US has moderate to good discriminatory power for identifying active Crohn's disease compared to endoscopy.However, the sensitivity and specificity values suggest some overlap between active and inactive disease states, highlighting the need for further refinement of US parameters and integration with other markers for optimal assessment.
While fecal calprotectin emerged as the dominant non-invasive marker for IBD in the previous section, several studies investigated the diagnostic utility of other inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).Here, we delve into the meta-analytic findings for these markers compared to US and endoscopy.While calprotectin demonstrated the best performance in predicting disease flare, all other modalities showed lower accuracy.This suggests a need for further research on more specific and predictive non-invasive markers and combinations of tools for flare management.
The diagnostic utility of CRP and ESR may vary depending on the specific IBD subtype and disease severity.Combining these markers with clinical data and other non-invasive tools might improve their predictive capabilities.Future studies should investigate the potential role of CRP and ESR in monitoring response to treatment.

Subgroup Analysis of Heterogeneity in Non-Invasive IBD Assessment
Heterogeneity was observed in the diagnostic accuracy of non-invasive markers and ultrasound across included studies.
To explore potential sources of this variation, we conducted subgroup analyses based on:

IBD Subtype
Markers and US generally demonstrated higher sensitivity and specificity for Crohn's disease compared to ulcerative colitis, likely due to its more transmural involvement [10][13].Fecal calprotectin showed good accuracy for diagnosis and activity assessment, while US results were less consistent, highlighting the limitations of visualizing mucosal changes [2][3].Pooled data showed high sensitivity and specificity for IBD diagnosis but less reliable for distinguishing active vs. inactive disease and predicting flares.Variations in assay methods and cut-off values likely contributed to heterogeneity [7][9].Although these markers offered some insight into disease activity, their diagnostic accuracy compared to endoscopy remained limited, suggesting their primary role in monitoring disease course alongside other tools [8].
This parameter proved a reliable indicator of Crohn's disease activity, with some studies suggesting its utility for monitoring treatment response [11][12].Limited data showed promise for predicting response to anti-TNF therapy, warranting further investigation [14].Variations in US interpretation skills could contribute to heterogeneity, highlighting the need for standardization and training programs [15].While markers and ultrasound generally demonstrated higher diagnostic accuracy for Crohn's disease, their utility in Ulcerative Colitis (UC) remains less consistent.This section delves into the subgroup analysis of bowel wall thickness (BWT) measurement accuracy in relation to UC activity, exploring potential reasons for the observed heterogeneity [12][20].

Discussion
A total of 25 studies met the inclusion criteria for this systematic review and meta-analysis, encompassing diverse methodologies and populations.Table 8 provides a descriptive overview of these studies, categorized by the noninvasive modality they investigated: The sample sizes varied considerably across studies, ranging from individual case reports to large-scale meta-analyses.Some studies focused on specific IBD subtypes (e.g., Crohn's disease, ulcerative colitis), while others included mixed populations.A diverse range of non-invasive markers and ultrasound techniques were investigated, highlighting the need for standardization in future research.Several review articles and meta-analyses were included to provide context and comprehensive insights into the existing literature.
Fecal calprotectin and intestinal ultrasound demonstrate good accuracy for IBD diagnosis, with calprotectin superior for identifying active disease and predicting flares.(See Table 9) Ultrasound performs well in Crohn's disease and monitoring treatment response but offers limited mucosal visualization compared to endoscopy.

Limitations
While this meta-analysis illuminates the promising landscape of non-invasive IBD tools, limitations deserve consideration.Inter-study variability due to diverse methodologies and populations warrants caution.While addressed statistically, residual heterogeneity may linger.Publication bias remains a possibility, potentially skewing findings.Moreover, this analysis captures a snapshot in a rapidly evolving field.Novel markers and techniques may emerge, necessitating future updates.Importantly, non-invasive tools do not replace clinical expertise or the pivotal role of endoscopy in specific scenarios.Interpretation must occur within the broader clinical context.By acknowledging these limitations and fostering further research, we pave the way for even more accurate and clinically useful non-invasive tools, empowering both patients and clinicians to navigate IBD care with greater clarity and confidence.

Conclusion
This review maps the future of IBD assessment, where non-invasive tools rise as challengers to the endoscopy throne.Fecal calprotectin leads the charge, pinpointing IBD with remarkable accuracy.Intestinal ultrasound, meanwhile, visualizes disease activity, especially in Crohn's, and holds promise for monitoring and predicting response.Even markers like CRP and ESR, though less precise, offer valuable glimpses into disease status.But the true magic unfolds when these tools intertwine.Combining calprotectin and ultrasound enhances prediction, leading to better decisions.Decision trees further amplify this synergy, integrating data for personalized care.However, challenges remain.Standardization is key to ensuring accuracy across settings.And the future beckons with the development of even more specific markers.

Figure 1
Figure 1 PRISMA Flow Diagram exported from Covidence

Table 2
Diagnostic Accuracy of Fecal Calprotectin Compared to Endoscopy

Table 3
Diagnostic Accuracy of CRP and ESR Compared to EndoscopyBoth CRP and ESR exhibited moderate sensitivity and specificity for IBD diagnosis, falling short of the accuracy of fecal calprotectin.Their performance in differentiating active vs inactive disease was similarly modest, suggesting limitations in monitoring disease activity.These findings (See Table4) highlight the potential limitations of relying solely on CRP and ESR for IBD diagnosis and activity assessment.

Table 4
Comparison of CRP, ESR, and US with Endoscopy for Predicting Disease Flare

Table 5
Subgroup Analysis of Fecal Calprotectin Diagnostic Accuracy by IBD Subtype

Table 6
Subgroup Analysis of Bowel Wall Thickness Measurement Accuracy for Crohn's Disease Activity See Table5& 6) the influence of IBD subtype, marker type, and ultrasound technique on diagnostic accuracy.Standardization of methodologies and interpretation protocols is crucial for reducing heterogeneity and improving the reliability of non-invasive assessments.Future research should focus on optimizing specific markers and US techniques for different IBD subtypes and disease stages.

Table 7
Subgroup Analysis of Bowel Wall Thickness Measurement Accuracy for Ulcerative Colitis Activity

Table 8
Descriptive Summary of Included Studies

Table 9
Comparative Summary of Diagnostic Accuracy: Biomarkers, US, and Endoscopy in IBD