INTRODUCTION
Crohn’ disease (CD) is a chronic inflammatory condition that affects the gastrointestinal tract, most commonly the terminal ileum and proximal colon. The incidence of CD has rapidly increased in parallel with human civilization and population growth, with the highest incidence observed in Western regions[1]. The patchy nature of transmural inflammation is a well-known characteristic of CD. This chronic inflammation involves the entire intestinal wall, leading to recurrent intestinal damage and subsequent repair, characterized by a progressive and destructive nature, which can potentially result in irreversible structural bowel damage and disability[2]. Given the transmural characteristics of CD, fistulas, abscesses, and strictures frequently complicate the disease course. Extraintestinal manifestations, predominantly involving the joints, skin, and eyes, may be present in as many as 50% of patients[1].
Compared with endoscopic healing alone, transmural healing was found to be associated with superior outcomes in patients with CD, including reduced rates of hospital admission, therapy escalation, and surgery[3]. Thus, accurate assessment of inflammatory activity is a key element in the management of CD and therapeutic efficacy monitoring. Owing to the incomplete understanding of the etiology and pathogenesis of CD, a comprehensive evaluation encompassing clinical examinations, biochemical assessment, stool analyses, endoscopic examinations, cross-sectional imaging, and histological investigations is needed for the diagnosis of this disease. Upon diagnosis, complimentary investigations should focus on markers of disease activity.
In clinical practice, the diagnosis of CD is strongly indicated by the combination of clinical symptoms and endoscopic findings, while biopsy-based histopathology often lack supportive evidence for this diagnosis, which is commonly observed during the initial assessment of CD. Recently, Lee et al[4] examined the difference between endoscopic and histopathologic assessment of ileal CD. The protocolized biopsies were taken consecutively from the ulcer edge, 7 mm and 14 mm away from the ulcer edge, in patients with discrete ileal ulcers. These findings revealed the poor endoscopic-histologic correlation between mucosal inflammation and disease activity in patients with ileal CD. Thus, the method by which to incorporate histologic disease activity into the treatment paradigm remains unclear. Further research is needed to optimize biopsy protocols and histologic assessments for CD.
DIAGNOSTIC MODALITIES FOR CROHN’S DISEASE
Colonoscopy is commonly employed for the diagnosis of CD and evaluation of treatment efficacy. However, it only allows visualization of the terminal ileum rather than the entire small intestine. Additionally, it is unable to detect extraluminal complications and may fail to assess the complete extent of small intestinal disease. This incomplete examination could lead to an underestimation of disease activity. The advent of double-balloon enteroscopy marked a revolutionary breakthrough for deep enteroscopy. The diagnostic yield of balloon enteroscopy in suspected cases of CD has been reported to range from 44% to 100%. Motorized spiral enteroscopy and single-balloon enteroscopy demonstrate comparable technical success rates and diagnostic yields when evaluating the small bowel in suspected cases of CD. However, motorized spiral enteroscopy outperforms single-balloon enteroscopy in terms of achieving deeper small bowel evaluation with complete coverage and greater depth of insertion within a shorter timeframe[5]. The current situation, however, poses a challenge for accurate histopathological assessment and deep remission of CD when the disease is confined to the small intestine. When CD is confined to the small intestine, evaluating deep remission presents a significant challenge. A pilot study evaluated the effectiveness of endoscopic ultrasound (EUS) during double-balloon enteroscopy in distinguishing small bowel CD patients in endoscopic remission from those with active disease. Eighty-two patients (21 females and 61 males) were stratified into groups of endoscopic remission and endoscopic activity on the basis of the segmental simple endoscopic score for CD. The use of an ultrasonic catheter probe during EUS in double-balloon enteroscopy proves to be effective for assessing both mucosal and transmural healing in patients with small bowel CD. The active CD patients had significantly greater total wall thickness and submucosal thickness of the small intestine than the remission CD patients did. The cut-off values of 2.65 mm for total wall thickness and 0.95 mm for submucosal thickness can aid in the differentiation of active small-bowel CD from inactive disease (sensitivity of 91.5%, specificity of 80.8% and sensitivity of 70.2%, specificity of 88.6%, respectively)[6]. Additionally, shear wave elastography is a widely utilized noninvasive ultrasonic technique for the quantitative assessment of tissue elasticity. The elasticity of various types of active perianal fistulas in CD patients was evaluated via EUS in conjunction with shear wave elastography, which revealed that the elastic modulus of the high-activity anal fistula group was significantly lower than that of the low-activity anal fistula group, providing a superior method for detecting and quantifying the activity of perianal fistulas, monitoring fibrosis in CD-related intestinal stenosis, and differentiating between inflammatory and fibrotic stenosis in CD patients[7].
Noninvasive evaluation and quantification of the relative degree of inflammation and/or fibrosis play crucial roles in the treatment of CD, enabling the selection of optimal treatments for individual patients and the assessment of treatment response. Cross-sectional imaging techniques, such as computed tomography enterography (CTE), magnetic resonance (MR) enterography, and bowel ultrasound, are used to assess small bowel CD and CD-related complications[8]. CTE, which involves thin section scanning with multiplanar reconstruction, has emerged as a valuable diagnostic modality for imaging the small bowel wall. The exceptional spatial resolution and multiplanar imaging capability of CTE can assist in delineating subtle changes in segmental mural hyperenhancement, wall thickening, and mural stratification; mesenteric findings such as an engorged vasa recta (“comb sign”); and increased attenuation in mesenteric fat, which is a potential radiologic marker of inflammation activity[8]. CTE can detect all lesions beyond the strictures as well as areas on the distal side of the strictures that cannot be passed with the enteroscope[9]. A combination of fecal calprotectin level measurement and CTE appears to be an effective approach for monitoring disease activity in patients with small intestinal CD, including those with strictures that are not accessible via conventional endoscopy[10].
As a noninvasive imaging modality, MR enterography (MRE) has played an increasing important role in the assessment of CD in clinical practice. According to the MRE diagnostic results, the arterial phase predominantly presented high signal intensity, and the venous phase mainly presented low signal intensity or isointensity. MRE presented an accuracy of 93.75%, sensitivity of 97.37%, and specificity of 80.00% in diagnosing CD[9]. The MR index of activity (MaRIA) is used to evaluate four parameters: Wall thickness, relative contrast enhancement, edema, and ulcers. The simplified MaRIA employs dichotomized scoring for the parameters (wall thickness > 3 mm, presence of edema, fat stranding, and ulceration). For the evaluation of luminal disease activity in CD, the evaluated MRE indices showed moderate-to-large responsiveness, and simplified MaRIA may be preferable because of its responsiveness and nonreliance on gadolinium administration[11]. Bowel ultrasonography serves as a noninvasive diagnostic tool for assessing bowel activity in CD patients in terms of complications and postoperative recurrence and monitoring the response to medical therapy, which is particularly valuable for monitoring the improvement or resolution of bowel activity induced by biological therapies in CD patients[12]. It reliably identifies postoperative recurrence and complications and provides a means to monitor disease progression[13]. Some studies have revealed that oral 67 Ga scintigraphy has similar accuracy and agreement to colonoscopy in the identification of inflammatory activity in patients with CD. This new approach may be useful and less invasive for long-term follow-up[14]. Positron emission tomography combined with MRE constitutes an outstanding noninvasive diagnostic modality. Both MR parameters and positron emission tomography findings provide high accuracy in detecting inflamed segments[15].
Cross-sectional imaging has emerged as a suitable and efficient diagnostic modality for patients with CD. However, to date, there is no consensus guidance on reporting the findings of cross-sectional imaging. A recent study evaluated the diagnostic accuracy of disease location and activity in various cross-sectional imaging modalities, including B-mode intestinal ultrasound, CTE and MRE, for CD[16]. These findings indicate that MRE is more sensitive for detecting small bowel CD, whereas B-mode intestinal ultrasound is more effective for identifying terminal ileal CD. Additionally, the international bowel ultrasound segmental activity score has potential for accurately defining CD activity[16]. The European Crohn’s and Colitis Organization and the European Society of Gastroenterology and Abdominal Radiology have delineated various core elements required for reporting the findings of cross-sectional imaging for inflammatory bowel disease (IBD). These recommendations would facilitate comparisons across various reports and enhance communication among the diverse specialties involved in IBD management[17].
A systematic review was recently conducted, encompassing a total of 29 original histopathological scoring systems for the assessment of inflammation and/or fibrosis in patients with CD[18]. The methodological quality and operating properties of these scoring systems (validity, reliability, responsiveness and feasibility) were thoroughly evaluated, aiming to identify the most reliable and accurate scores applicable for clinical research and clinical practice settings[18]. They suggested that the most reproduced transmural histopathological scores were the scores for inflammation only (namely, its AIS component)[18] and for both inflammation and fibrosis[19,20] because of their ease of application in clinical studies. The high methodological quality of the studies (75%, 80%, and 77.5%, respectively) and adequate operating properties (validity, reliability, and responsiveness)[18]. However, assessments utilizing existing histological disease severity scoring systems for CD depend on highly trained experts and necessitate considerable time and effort. This approach has notable limitations, including the variability inherent in human evaluations and the intrinsic constraints of these scoring systems, such as limited dynamic range and inadequate sensitivity to clinically significant therapeutic effects. Artificial intelligence and machine learning technologies are capable of effectively addressing these limitations, and the applications in gastroenterology are expanding rapidly. Deep learning models based on the Global Histologic Disease Activity Score are effective at distinguishing the presence and absence of microscopic CD disease activity[21]. Fecal calprotectin has emerged as a well-validated, noninvasive biomarker that enables the assessment of gut inflammation. Fecal calprotectin levels are significantly correlated with clinical or endoscopic disease activity in patients with CD. Elucidating the regulatory mechanisms and biological functions of calprotectin in the gastrointestinal tract may pave the way for innovative diagnostic approaches and therapeutic strategies for IBDs[22].
Most existing histopathological scoring systems for CD were developed as a part of cross-clinical-endoscopic-imaging-pathological correlation studies. However, there is no universally accepted transmural histological grading system for CD that can be considered the best choice for assessing the severity of intestinal fibrosis or inflammation. The comprehensive evaluation of each measurement instrument is essential in clinical practice, encompassing a meticulous examination of the included items and domains, assessment forms, and operational properties of the scoring system. The coexistence of varying degrees of inflammation and fibrosis within the same lesion poses challenges in their differentiation, particularly in terms of fibrosis detection. The most prominent histological change in Crohn’s fibrostenosing bowel strictures is characterized by smooth muscle hyperplasia/hypertrophy, whereas fibrosis is less significant. The “inflammation-smooth muscle hyperplasia axis” may be the most important factor in the pathogenesis of CD[23].
