Current approaches to disease severity and therapy effectiveness assessment in patients with inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a group of chronic recurrent disorders, Crohn’s disease and ulcerative colitis being its two major types. IBD patients require continuous lifetime monitoring of disease activity and effects of therapeutic interventions, achievement of stable remission being the goal of the current ‘treat-to-target’ strategy. This review considers a wide range of approaches applied for this purpose. Although ileocolonoscopy combined with histological evaluation and now employing modern endoscopic techniques is still regarded as the gold diagnostic standard, its inability of visualizing small intestine is a limitation. Alternative non-invasive techniques such as capsule endoscopy and, especially, cross-sectional imaging, comprising computed tomography enterography, magnetic resonance enterography, and intestinal ultrasound, are becoming increasingly popular. In addition, the use of molecular biomarkers detectable in human body fluids is a rapidly developing area, and recent rapid progress in gut microbiome research promises to add a new dimension to it. It is also anticipated that new approaches based upon multi-omics can identify new composite biomarkers useful for IBD monitoring. Artificial intelligence-driven integration of abundant information provided by various diagnostic and analytical modalities outlined in this review may help in transforming the current ‘one-size-fits-all’ treatment paradigm into a truly personalized model of IBD care.

Key Words: Ulcerative colitis; Crohn’s disease; Endoscopy; Cross-section imaging; Biomarkers; Gut microbiome; Precision medicine; Multi-omics; Artificial intelligence

Core Tip: Inflammatory bowel disease patients need continuous lifetime monitoring of disease activity and effects of therapeutic interventions. This review considers a wide range of approaches currently applied for this purpose. The reviewed modalities comprise clinical criteria, endoscopy, cross-sectional imaging, detection of biomarkers in body fluids and feces, gut microbiome analysis, and application of modern technologies, such as multi-omics and artificial intelligence. Artificial intelligence-driven integration of abundant information provided by a range of diagnostic and analytical approaches outlined in this review may help in transforming the current ‘one-size-fits-all’ inflammatory bowel disease treatment concept into a truly personalized model of disease care.

INTRODUCTION

Inflammatory bowel disease (IBD) is a group of chronic recurrent inflammatory disorders affecting gastrointestinal tract, Crohn’s disease (CD) and ulcerative colitis (UC) being its two major types[1,2]. The pathogenesis of these conditions is extremely complex and involves interplay between host genetics, immunity, gut microbiome, and environmental factors[3]. IBD is currently regarded as a global disease, remaining highly prevalent in western countries for decades and now demonstrating rapidly growing incidence in newly industrialized countries and regions[4,5]. Recent estimates of its global prevalence vary between 3.8 million[6] and 6.8 million[7] IBD cases, which usually require prolonged expensive treatment. It is inevitable that this scale of the problem gives rise to the growing cost of IBD care, with the annual direct healthcare cost per person averaging $12000 for CD and $9000 for UC in high-income regions[8]. Indirect costs, mostly related to the loss of productivity of the affected individuals further contribute to the financial burden[8]. As IBD is a progressive condition that often leads to irreversible gut damage and disability, patients suffering from it require continuous lifetime monitoring of inflammation activity, effects of therapeutic interventions, and overall disease impact on patient’s wellbeing. The combination of these variables can provide an estimate of disease severity[9] and thus help making IBD care sustainable. It is, however, obvious that the task of measuring IBD severity is highly challenging because multiple factors contribute to the outcome of the disease[9]. This review presents an attempt to consider the existing approaches to evaluating IBD severity, which is directly related to assessing IBD therapy efficiency.

NATURAL COURSE OF IBD, INFLAMMATION ACTIVITY, TREATMENT EFFECTS, AND DISEASE SEVERITY

The complexity of IBD pathogenesis is notorious, but the key stages of its natural course that are usually affected by a multitude of therapeutic treatments can be easily defined. Figure 1 presents a simple scheme showing the main phases of IBD development together with typical therapy outcomes. These phases, which are briefly outlined below, need to be taken into account for determining specific monitoring requirements and selecting appropriate analytical approaches at each timepoint.

Figure 1 Main phases of inflammatory bowel disease development and typical therapy outcomes. IBD: Inflammatory bowel disease.

Predisposition to IBD and asymptomatic pre-disease phase

It is now evident that the probability of developing IBD may be elevated in genetically predisposed individuals. Genome-wide association studies have identified at least 320 genetic loci associated with CD and UC[10]. Some of these gene variants were shown to influence IBD-related biological phenomena and metabolic pathways. They include nucleotide-binding oligomerization domain-containing protein 2 involved in bacterial sensing, autophagy-related 16-like 1 and immunity-related GTPase family M protein 1 that are related to autophagy, X-box binding protein 1 protecting from endoplasmic reticulum stress, interleukin 23 receptor promoting the T helper 17 cell immune response, and inflammation-modulating vitamin D receptor[10-13]. Moreover, epigenetic mechanisms including DNA methylation, histone modifications, expression of non-coding RNAs, and chromatin remodelling can affect susceptibility to developing intestinal inflammation[11,14].

However, not only host genetic background and epigenetic modifications define the predisposition to IBD. Recent studies indicate that gut microbiome changes may precede IBD onset for many years[15]. In their 2021 paper, Galipeau et al[16] described microbiota alterations increasing faecal proteolytic activity in clinically healthy individuals who later developed UC. Likewise, gut microbiome shifts associated with future onset of CD were later demonstrated by the same Canadian group[17]. While the effect of gut microbiome emerges as a major influence in modulating future IBD risk, this connection inevitably highlights the role of environmental exposures acting both at the level of host organism per se and as factors modifying human microbiota composition[5,18]. The connection between environment and gut microbiome formation in young children was the focus of the “hygiene hypothesis”[19] postulating that limited contact with a diverse range of microorganisms early in life may interfere with the ability to establish a mutualistic relationship between the microbiota and the host, which is crucially important for host immune development[20]. This can partially explain a reduced risk of IBD observed in rural populations compared to the urban ones[21]. It is also apparent that the role of environment in defining predisposition to IBD is not limited by interactions with the microbiome. Early life events, such as in utero exposures to antibiotics or maternal smoking were shown to increase IBD risk, whereas breastfeeding is a potent protective factor. The identified environmental risk factors are discussed in recent reviews[5,18].

It may be difficult to identify a distinct borderline between the predisposition to IBD and the asymptomatic preclinical phase of the disease. Nevertheless, it appears that the disease is initiated only when homeostatic mechanisms acting in the gut start undergoing alterations that compromise finely balanced cellular systems and corresponding metabolic and signalling pathways. Intestinal mucosa is the primary target of IBD, and the dysregulation of interactions between immune cells and intestinal epithelium typically triggers disease onset[3,22], rapidly leading to symptomatic manifestations. One highly important pathogenetic mechanism involved at early stages of IBD is the loss of integrity of the intestinal barrier normally limiting interactions between microbiome-related luminal factors and the mucosal immune system[23,24]. Significantly increased intestinal permeability in first-degree relatives of CD patients was first described almost 40 years ago[25], and it was recently shown that this initially asymptomatic abnormality may precede CD diagnosis by up to 3 years[26]. The intestinal epithelium constituting the physical component of the barrier is overlayed by the mucus produced by epithelial goblet cells. This continuous mucus layer, structure of which is different in the small intestine and the colon, serves as the first line of defense preventing direct contacts between gut microbiota and the epithelium[27,28]. Intestinal mucus layer alterations were observed in both CD and UC patients[29] therefore it can be assumed that early stages of these alterations precede epithelial barrier impairment that then triggers immune response development and, eventually, the onset of symptomatic disease[23].

The borderline phase of predisposition and pre-disease is especially important in the context of this review as its timely detection can offer better chances of IBD interception (i.e. prevention of disease progression to the symptomatic phase)[11]. The main challenge here is the absence of either clinical manifestations or structural changes that could be visualized. The choice of existing diagnostic/monitoring approaches suitable for this phase is limited with the use of molecular markers (encompassing genetic predisposition, gut microbiome shifts, and initial stages of intestinal barrier impairment) and individual history of environmental exposures for distinguishing between IBD risk and pre-disease groups. Interestingly, the development of an integrative risk score for future risk of developing CD in healthy first-degree relatives of patients has recently been described[30]. It is, however, obvious that reliably predicting future disease severity at such an early time point is hardly possible.

Active IBD, its treatment, temporary remissions, relapses, and stable remission

The question of IBD severity immediately comes out with the onset of symptomatic disease. Diverse clinical manifestations are well characterised for both CD and UC, however disease course and treatment response for individual patients are highly variable[1,2]. It is especially important to determine predictive factors allowing to early identify and distinguish severe and indolent disease since therapeutic strategy choice strongly depends on IBD severity[31]. Timely efficacious therapy, especially the use of biologics, is indispensable for severe cases, whereas patients with indolent disease may require a slower therapy escalation to avoid potential overtreatment[31]. Recent clinical studies indicate that early prediction of IBD severity may be achievable[32-35].

It is important to note that IBD management following disease onset starts from applying non-invasive therapeutic modalities that in most cases leads to clinical remission that can be temporary or stable (Figure 1). Temporary clinical remission of IBD often reflects the discordance between the disappearance of clinical symptoms and persistence of residual disease activity in terms of molecular, biochemical, and morphological changes that may later progress and cause IBD relapse[31]. In some cases, however, stable remission accompanied by complete mucosal healing can be achieved. Traditional approaches to IBD treatment were predominantly focused on symptom elimination, but the introduction of the current ‘treat-to-target’ concept[36] better addresses disease severity and considerably improves IBD treatment efficiency. The most recent update of this concept defined clinical remission, endoscopic healing, quality of life restoration, and the absence of disability as the most important long-term targets; symptomatic relief and normalization of serum and fecal biomarker levels are regarded as short-term targets[37]. While these targets look realistic, it is also accepted that complete transmural healing in CD and histologically confirmed healing in UC should be assessed as well as measures of remission depth and stability[37].

Active CD and UC are associated with typical structural changes[1,2,38] that can be visualized using a wide range of instrumental diagnostic techniques, whereas molecular and metabolic changes can be quantified and monitored by measuring a wide range of biomarkers in body fluids and excretions. The existing diagnostic and monitoring techniques are addressed in the next section of this review.

Later stages of IBD: Complete remission, complications, surgery, and quality of life

The achievement of complete remission is obviously the “holy grail” outcome for IBD clinical management that always requires effective maintenance therapy using advanced drugs (primarily biologics). Despite the availability of an expanding range of treatments, the average rate of stable remissions at 12 months remains below 40%[39]. Regretfully, therapy-associated immunosuppression is always a concern, as well as high drug costs[31], therefore all opportunities for de-escalating doses of advanced drugs are actively explored[31,40]. In this situation it is becoming increasingly clear that efficient de-escalation strategies may be developed only alongside the introduction of individually tailored IBD therapy. For this reason, it is especially important to stress the importance of tight disease control by applying non-invasive monitoring methods[31,41,42] that are considered later in this review.

The majority of IBD patients develop new disease flares and complications at some point following initially successful therapy, which eventually becomes ineffective (Figure 1). Then treatment schemes are usually revised, and it is essential to define the most informative and reliable endpoints for disease modification and progression prevention. These endpoints worked out by the international SPIRIT initiative[43] are presented in Table 1. Table 1 also shows a range of serious IBD complications that produce a huge negative impact on the quality of life of IBD sufferers, often result in life-changing surgical interventions and considerably increase colorectal cancer (CRC) development risk. Advanced IBD is always a severe disease, therefore its tight control is rarely possible. However, patients with complicated CD and UC certainly require intense personalized monitoring employing the whole range of diagnostic and analytical techniques described in the next section of the review.

Table 1 Endpoints for measuring disease modification and disease progression prevention according to the SPIRIT consensus[43].

Disease stage	Disease impact, measuring tools and timing
Early impact on health-related quality of patient’s life (patient-reported)	Health-related quality of life
	Tools: Questionnaires IBDQ-36 and SF-36
	Disability
	Tool: IBD disability index
	Fecal incontinence
	Tool: Jorge and Wexner (Cleveland) score
	Time point: 6-12 months
Mid-term complications	Bowel damage in CD
	Tool: Lémann index
	Time point: 12-24 months
	IBD-related surgery
	Tool for UC: Any colectomy
	Tools for CD: CD-related surgery; endoscopic balloon dilation; perianal surgery
	Time point: 24-36 months
	IBD-related hospitalizations
	Tool: Number of hospitalizations + cumulative hospital length of stay
	Time point: 12-24 months
	Disease extension in UC
	Tool: Macroscopic proximal disease extension (excluding pancolitis patients)
	Time point: 2-5 years
	Extraintestinal manifestations (all considered together)
	Time point: 12-36 months
	Permanent stoma
	Short bowel syndrome
Long-term complications	Dysplasia or cancer (all considered together)
	Time point: 5 years
	Mortality
	Tool: Both IBD-related and non-IBD-related mortality
	Time point: 5 years

IBDQ-36: The 36-item inflammatory bowel disease questionnaire; SF 36: Short form-36 health survey; IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis.

DIAGNOSTIC AND ANALYTICAL TOOLS APPLIED FOR ASSESSING IBD SEVERITY

In IBD patients the fact of UC or CD diagnosis immediately brings about the necessity of starting intense proactive monitoring. The arsenal of monitoring procedures is already impressively diverse. Many of them are well established and widely used, but rapid scientific and technological progress results in the proliferation of numerous new concepts, techniques and instruments. In accordance with the complexity of IBD pathogenesis and diversity of disease manifestations some modalities are preferable for either UC or CD, and the choice of methods often depends on specific timepoints in the natural course of the disease. The existing range of approaches to IBD activity and severity monitoring is presented in Figure 2.

Figure 2 The existing range of approaches to inflammatory bowel disease severity monitoring (the key modalities used in active inflammatory bowel disease are framed). POC: Point-of-care; IBD: Inflammatory bowel disease; HRQoL: Health-related quality of life; CT: Computed tomography; MR: Magnetic resonance.

Clinical criteria based on patient’s medical history, symptoms, and physical assessment

Symptom resolution was traditionally regarded as the key therapeutic endpoint in IBD management[31]. Numerous clinical scoring systems exist, among which there are several widely employed scores, including Harvey Bradshaw Index, CD Activity Index, and Perianal Disease Activity Index used in CD, as well as the partial Mayo score, the Simple Clinical Colitis Activity Index, and the Paediatric UC Activity Index that are used in UC[31,44-46]. Most of these scores produced by physicians were in use since the last century, but recently there was an opinion shift in favour of measures based on patients’ perceptions of their illness, i.e. ‘patient reported outcomes’ (PRO)[36]. Several PRO-based scores have been developed[47-50]; however, it is also evident that IBD usually has a considerable negative impact on patients’ health-related quality of life (HRQoL)[51]. Indeed, while clinical scores primarily reflect IBD activity, especially inflammation intensity, the addition of the HRQoL component much better characterizes disease severity. Therefore, multiple IBD-specific HRQoL instruments have been developed and validated, including the 32-item IBD questionnaire, the 36-item IBD questionnaire, the short IBD questionnaire, and the 9-item IBD questionnaire[52]. Among them, the 32-item IBD questionnaire appeared to be the most reliable and widely used[52,53]. Despite the emergence of PRO-based scores and questionnaires incorporating the HRQoL component, it was well understood that the development of new instruments assessing and predicting the overall severity of illness was a very important, albeit challenging, task. The three main domains relevant to the evaluation of IBD severity were defined by Peyrin-Biroulet et al[54] as follows: (1) Impact of disease on the patient: Clinical symptoms, patient-reported outcomes, quality of life, and disability; (2) Inflammatory burden: Extent, location, and severity of bowel involvement at a given time; and (3) Disease course, including structural damage. The disease severity index developed for IBD[55] was based on these criteria, but it should be noted that this combined index does not exclusively reflect PRO-generated observations supplemented by HRQoL information, but also includes results of endoscopy and laboratory tests[55], which will be considered later. Nevertheless, it has recently been shown that the disease severity index is strongly associated with psychological distress and impaired HRQoL[56].

Although the abovementioned clinical tools for IBD activity/severity monitoring are employed with varying degrees of success, this area remains highly fluid, and the introduction of new approaches is always expected. As healthcare systems often face financial problems, and IBD monitoring is costly[8], the employment of telemedicine has been proposed as an attractive option, potentially providing an efficient and equitable use of limited resources[57-59]. Digital health technologies can assist in overcoming the physical and time limitations of traditional face-to-face appointments through remote monitoring of disease activity/severity, facilitating access to healthcare providers via mobile technologies, and stimulate patient participation through individualized alerts and action plans[57-59]. Although this rapidly developing area has already demonstrated its potential during the coronavirus disease 2019 pandemic[58], further research is required for precisely identifying its place in IBD management.

Instrumental visualization of pathological changes

Conventional endoscopy: Endoscopic evaluation or ileocolonoscopy is regarded as the cornerstone in the diagnosis and management of IBD, and it is generally accepted that the achievement of endoscopic healing is associated with improved long-term outcomes in CD and long-term steroid-free clinical remissions with decreased risks of colectomy and dysplasia in UC[60-62]. Traditional ileocolonoscopy or white light endoscopy (WLE) accompanied by biopsy sample collection is in clinical use for many decades, and its limitations are well known. Although ileocolonoscopy is a safe procedure with a low rate of adverse effects in IBD patients[63], it remains an invasive manipulation requiring effective bowel preparation[64]. Moreover, WLE cannot reliably assess the persistence of histopathological inflammation in the mucosa without microscopic analysis of multiple biopsy samples[65,66]. Indeed, a minimum of two biopsies from each of five main colon segments (cecum-ascending, transverse, descending, sigmoid, and rectum) as well as from the terminal ileum should be analyzed. Additional biopsy samples should be taken from the most severely affected areas found at endoscopy[66]. It is, therefore, not surprising that considerable efforts directed on the improvement of endoscopic image quality and interpretation resulted in the emergence of a range of modern versions of the technique, which are briefly characterized in Table 2 that summarizes recent publications[60,62,67-70]. Briefly, it is evident that the new endoscopic tools are superior compared to conventional WLE in assessing IBD activity and severity. Virtual electronic chromoendoscopy (VEC) has already become a valuable instrument in clinical practice for grading disease activity and predicting possible outcomes. VEC is currently better validated for clinical use, however confocal laser endomicroscopy and endocytoscopy provide high-resolution imaging of intestinal barrier structure and may become indispensable instruments for reliably assessing mucosal or endoscopic healing[60,62,68,71]. The combination of the new endoscopic techniques also facilitates the detection of inflammation-associated dysplasia, and fluorescence molecular endoscopy enhances the detection of precancerous and neoplastic lesions[70].

Table 2 Endoscopic techniques used for inflammatory bowel disease detection and monitoring.

Endoscopic technique	Technique versions	Main advantages	Main disadvantages
Standard white light endoscopy		Widely used, regarded as the easiest option, being the standard endoscopy technique. Short examination time. This is a relatively low-cost option	Not always reflects histopathological IBD activity. Does not allow microvascular characterization
Chromoendoscopy	Dye-based chromoendoscopy)	Enhances mucosal visualization using dyes	Poorly studied in the context of IBD
	Virtual electronic chromoendoscopy	Employs optical filters and digital programs to improve visualization of glandular patterns and vascularization. Correlates with histopathological IBD activity. Short examination time. This is a widely available and relatively low-cost option	Highly trained personnel needed for applying currently available scores. Requires more prognostic validation
Optical magnification (high definition) endoscopy		Magnification adjustment allows maintaining image quality even at high zoom levels. The technique is easy to use. This is a relatively low-cost option	Does not permit efficiently examining the whole colonic surface
Ultra magnification endoscopy	Confocal laser endomicroscopy	Integrating laser scanning microscopy into an endoscope provides high-resolution histopathological imaging in vivo and allows intestinal barrier assessment	These techniques do not permit efficiently examining the whole colonic surface. Long duration of the examination. Highly trained personnel needed
	Endocytoscopy	The ultra-high magnification combined with the use of a mucolytic agent enhancing the penetration of a topical contrast agent provides highly accurate images in vivo. Intestinal barrier assessment possible
	Fluorescence molecular endoscopy	Targeted fluorescent probes permit to enhance the contrast between normal and diseased tissue
	Near-infrared fluorescence imaging	The use of near-infrared probes allows achieving deeper tissue penetration and improve signal-to-background ratio

IBD: Inflammatory bowel disease.

The interpretation of endoscopic findings is always a complex task, and a number of scoring systems are currently in use (Buda et al[62]). The most popular validated scoring systems for WLE include the CD endoscopic index of severity, the Simple Endoscopic Index for CD, the Mayo clinic endoscopy subscore, and UC endoscopic index of severity. However, these indices are difficult to apply in clinical practice as their calculation is complex and reliability is doubtful[72]. Amongst scores devised using advanced endoscopic techniques, the Paddington International virtual ChromoendoScopy ScOre was validated for UC, and results look encouraging[73]. Nevertheless, the required high standards of consistent interpretation of endoscopic images, diagnostic accuracy, reliable evaluation of disease activity/severity, and clinical outcomes are still difficult to achieve. The emergence of artificial intelligence (AI) as a powerful new tool addressing these challenges, especially on the basis of endoscopic image analysis[74-76], is highly promising, and recent studies already demonstrate its potential. Using endocytoscopy, Maeda et al[77] devised a computer-aided diagnosis system that allowed fully automated identification of persisting inflammation in UC patients. Iacucci et al[78] developed a VEC-based AI system able to generate the Paddington International virtual ChromoendoScopy ScOre score to distinguish between active disease and remission and predict clinical outcomes in UC. AI has also been shown to improve the performance of WLE in terms of correct Mayo clinic endoscopy subscore assignment, assisting in clinical relapse risk stratification in patients with UC[79].

Capsule endoscopy: While conventional ileocolonoscopy remains the gold standard for evaluating colonic mucosal inflammation, it is unable to assess the small intestine proximal to the terminal ileum, which is often affected by CD, especially in pediatric patients[80]. Examination of the entire length of the small bowel in CD patients is required because its results may define disease prognosis and therapy choice[81]. The introduction of non-invasive wireless or video capsule endoscopy (VCE) in 2000[82] revolutionized the imaging, diagnosis, and monitoring of diseases of the small intestine, especially CD. This ingestible capsule equipped with high-resolution video cameras was initially designed for enabling real-time video imaging of the small intestinal mucosa with simultaneous recording of the obtained images. Technology advancement resulted in the development of new versions of the method that permit non-invasive visualization of the colonic mucosa and pan-enteric VCE[83-85]. It should, however, be noted that for the latter two procedures a demanding bowel preparation protocol is mandatory[85]. In any case, bowel preparation is essential to provide colon cleanliness, reduce transit time and decrease capsule retention risk[86]. It is also important to mention that in healthy individuals the median small intestine transit time was found to be almost 200 minutes[87], median colon transit time being slightly longer[86], and these values might widely vary in IBD patients. Therefore, the volume of the imaging information generated by VCE during the prolonged recording time can be enormous and challenging for manual reviewing.

The indications for applying VCE in the context of IBD are as follows: (1) To investigate patients when CD is suspected, but both upper endoscopy and ileocolonoscopy findings are normal; (2) To assess small intestine involvement and disease activity/severity in patients with confirmed CD; (3) To detect postoperative CD recurrence in the small intestine; and (4) To monitor disease activity/severity and mucosal healing in the colon of patients with UC or colonic CD[83]. Already accumulated clinical experience has proven VCE as a very useful diagnostic/monitoring modality, however it is understood that it may not be suitable for all patients, especially those suffering from CD. CD patients with advanced disease often develop severe stenosis in the small intestine, which can cause capsule retention, the main potential adverse effect of the procedure[88]. The use of small dissolvable patency capsules for assessing intestinal patency may be essential to minimize the risk of video capsule retention, but VCE should not be recommended to CD patients with severe stenosis[89].

Pan-enteric VCE now permits assessing the entire intestinal surface and is comparable to conventional WLE in terms of diagnostic performance[84,90], however the standardization of VCE scoring systems is still difficult. The Lewis score, the Capsule Endoscopy CD Activity Index, and PillCam Crohn’s^TM capsule score were developed for CD[85,90]. These scores allow for the standardization of result reporting in CD cases. The Capsule Scoring of UC is currently the only VCE-based score used to assess inflammation in UC patients[90].

Finally, it should be noted that opportunities of incorporating AI in assisting endoscopists in analyzing numerous VCE-generated images and standardizing the results are being actively explored[91,92]. It is, however, obvious that many potential challenges remain to be addressed, and one of the most recent clinical studies reported by Brodersen et al[93] provided a set of interesting results. The AI-assisted analysis of 131 CD patients showed that the AI-driven system reduced the total number of images acceptable for review by 97.1%. That reduced the initial review time to a median of less than 4 minutes while maintaining high diagnostic accuracy for CD and IBD[93]. These impressive results confirm the potential of AI-assisted VCE, but further research and validation are needed for its full integration into clinical routines.

Cross-sectional imaging: Computed tomography enterography (CTE), magnetic resonance enterography (MRE), and intestinal ultrasound (IUS) are the key non-invasive techniques providing cross-sectional gut imaging and employed for clinically assessing different aspects of IBD[94]. CTE and MRE have emerged as the most effective radiological methods providing excellent spatial and temporal resolution, especially for small intestine imaging in CD[95]. These techniques complement ileocolonoscopy and permit visualizing intramural and proximal small intestine inflammation in up to 50% of CD patients with normal endoscopy results[95]. Regretfully, CTE is associated with radiation exposure that may potentially harm younger patients, who are often in need to undergo frequent disease re-assessments[96]. For this reason, its use in clinical practice is now restricted, and CTE is mainly employed in emergency settings. MRE and IUS are currently regarded as the main cross-sectional imaging options for routine clinical use. These techniques are considered in more detail below.

One obvious advantage of the use of ultrasound is its suitability for point-of-care testing that does not require bowel preparation. IUS is a non-invasive, patient-friendly and sustainable technology that allows assessing both the small intestine and the colon, which is especially important for CD patients[97]. From this point of view, MRE is less convenient since it requires the use of clinic-based stationary scanning systems. In addition, a demanding bowel preparation procedure is necessary for an informative MRE scan. Patients should drink 1.0 L to 1.6 L of an oral contrast that distends the bowel to facilitate interrogation of the intestinal wall and surrounding tissues, and this procedure may not be well tolerated by some of them[97,98].

IUS and MRE can reliably evaluate several parameters of intestinal inflammation, first of all IUS-determined bowel wall thickness, which increases as a direct consequence of intestinal wall inflammation, especially in CD[96]. The most common bowel wall thickness cut-off utilized as a threshold for IBD presence is over 3 mm, however it is not perfectly specific for IBD and may result from other pathological conditions[98,99]. On MRE, enhanced T2 (transverse relaxation time) signal caused by mural oedema is a highly specific sign of disease activity, usually indicating severe inflammation[94,98]. Other CD-associated phenomena that include neoangiogenesis, hypervascularity, and deep ulceration are also detectable by MRE[94,98,100] and, to some extent, by IUS[94,98].

Whereas it is generally accepted that cross-sectional imaging is necessary for the evaluation of the small intestine in CD patients, endoscopy remains preferable for visualizing UC-associated changes. Nevertheless, it has been demonstrated that IUS can also be successfully used for assessing UC activity/severity as a rapid, efficient, non-invasive, and relatively cheap alternative to endoscopy[101].

It is evident that cross-sectional imaging techniques can be used for assessing IBD activity/severity in different circumstances, including evaluation of therapy effects and guiding clinical decisions. Hence, various scoring systems were developed and validated for both MRE[94,97,98,102] and IUS[94,97,103]. Amongst MRE-based scores for CD, the best validated is magnetic resonance index of activity, but the London and the Clermont scores are also in use[94,97]. IUS-based scores for CD include International Bowel Ultrasound Segmental Activity Score, bowel ultrasound score, and simple ultrasound score for CD[97,103]. IUS scores for UC comprise the Milan ultrasound criteria and the UC-IUS index that remain to be fully validated[94,103]. The introduction of cross-sectional imaging resulted in the emergence of the concept of transmural healing as an important additional target for IBD treatment that complements endoscopic healing discussed above. Using only cross-sectional imaging techniques, Kucharzik et al[97] proposed a range of diagnostic algorithms encompassing: (1) Detection and confirmation of IBD in patients with uncertain diagnosis; (2) Non-invasive monitoring of IBD activity/severity using MRE or IUS for CD and IUS for UC; and (3) Detection of CD complications by MRE or IUS. Undoubtedly, the assessment of IBD therapy efficiency can be easily incorporated into this framework.

It has been convincingly demonstrated that non-invasive cross-sectional imaging techniques are better tolerated than ileocolonoscopy and allow examining the entire small intestine, permitting to assess the full thickness of the intestinal wall and to detect extra-enteric complications[94]. Both MRE and IUS were shown to be suitable for diagnosing and staging CD. More expensive MRE had a higher accuracy[104], however most patients preferred the experience of undergoing IUS rather than MRE[105]. Thus, the availability of alternative cross-sectional techniques provides clinicians with a wider range of diagnostic options, especially for CD patients.

CTE, MRE, and IUS imaging systems generate large volumes of data that require processing and interpretation, which may be performed by AI. It is anticipated that AI use will improve diagnostic accuracy, provide automatic assessment of disease activity, and help predicting clinical outcomes, leading to more personalized IBD management. However, considerable variability of currently available datasets, differences in imaging protocols, and the need for external validation in different population constitute significant challenges requiring further investigation[106].

Laboratory or point-of-care tests for gut inflammation activity and microbiome shifts

Histological analysis of gut mucosal biopsy samples: Mucosal healing is the main therapy target in IBD, and it can be defined as the combination of complete endoscopic and histological remission[107]. Evaluation of endoscopic and transmural healing in IBD patients has been discussed above, and neither of these optimistic conclusions can guarantee the absence of microscopically detectable areas of inflammation[107,108]. It is, however, evident that the role of histological analysis in confirming mucosal healing tends to differ in UC and CD. In UC inflammation is continuously spread throughout the colorectum, while CD is characterized by a discontinuous, ‘patchy’ inflammation pattern that may involve the whole gastrointestinal tract[107]. The latter feature of CD often makes reliable confirmation of histological healing problematic. At the same time, it has been shown that the examination of histologic remission in UC may improve the accuracy and precision of treatment decisions, serving as a predictor of improved clinical outcomes[109,110]. The International Organisation of IBD has proposed the following histological treatment targets for both UC and CD: (1) Disappearance of neutrophils (in both the crypts and the lamina propria); (2) Decrease of plasma cell infiltration and disappearance of basal plasmacytosis; and (3) Reduction of eosinophil infiltration to normal value[66]. It is presumed that these microscopic parameters should be evaluated using sections prepared from multiple biopsy samples collected during colonoscopy. As histological examination of IBD activity had become a generally accepted diagnostic practice many decades ago, a number of histological scoring systems (about 30 for UC and 13 for CD) have been developed, both to differentiate between the active and quiescent disease and to estimate therapy efficiency[107]. The most widely used scoring systems comprise the Geboes score, the Robarts histopathology index, and the Nancy histopathology index. All of them are based on assessing such histopathological features as chronic inflammation, neutrophilic inflammation, and surface epithelial injury[66,107,108,110]. As a rule, the proposed scoring systems are subjective and excessively complex to be used in routine clinical practice. For this reason, simplified scores, which employ the evaluation of neutrophils and their mucosal localization were also introduced[66]. It should also be noted that a few AI-based models providing automatic image analysis have been developed for standardizing histological assessment of biopsy samples. Recent studies in this field usually addressed UC, either targeting automated detection of neutrophils to estimate disease activity[111] or grade inflammatory activity[112,113]. Another AI-driven model was designed to accurately assess the presence of basal plasmocytosis in biopsy samples of both UC and CD patients with the purpose of facilitating the differential diagnosis between the two conditions[114]. It should, however, be concluded that, despite impressive recent progress in the histological diagnosis and monitoring of IBD, the concept of histological mucosal healing still needs further improvement, primarily in terms of standardization.

Biomarker detection in body fluids, feces or colonic mucus: The use of biomarkers for disease diagnosis, monitoring, and different aspects of patient management has now become an important element of clinical medicine. One of the most laconic definitions of a clinical biomarker introduced in 2017 by Aronson and Ferner[115] defines it as “a biological observation that substitutes for and ideally predicts a clinically relevant endpoint or intermediate outcome that is more difficult to observe”. Laboratory testing for biomarkers present in the serum or feces is a well-established approach to evaluate disease activity/severity in IBD patients[116,117], however the introduction of new advanced drugs and the concept of therapy personalization are now transforming traditional rules[118]. Only a few extensively studied inflammation biomarkers are routinely used in clinical practice for evaluating IBD activity/severity. They comprise calprotectin and lactoferrin, neutrophil-associated proteins that are stable and can be quantified in feces, as well as liver-derived C-reactive protein (CRP) detectable in the serum[116,117]. Recent guidelines of the American Gastroenterological Association recommend employing non-invasive biomarkers in monitoring and management of IBD patients. Specifically, fecal calprotectin, fecal lactoferrin, and serum CRP are recommended for UC[119], whereas only fecal calprotectin and serum CRP are advised for CD[120]. However, these markers are not IBD-specific and only reflect inflammation activity, like many other potential biomarkers that were proposed for IBD diagnosis and monitoring (Table 3). It should be noted that most of the biomarkers listed in Table 3 showed initial promise but were not found to be suitable for clinical use. Therefore, composite biomarkers, i.e., combinations of several biomarkers attracted attention of investigators. D’Haens et al[121] have developed an index for disease activity monitoring in CD patients, which is based on measuring serum levels of 13 proteins (Endoscopic Mucosal Healing Index or Endoscopic Healing Index). The American Gastroenterological Association considered the Endoscopic Healing Index for potential use in CD, but eventually it was not approved[120]. Studies on possible use of either circulating or fecal microRNAs as composite biomarkers are going on, however results of these studies need confirmation and validation[116]. Also, combined measurement of calprotectin and eosinophil-derived neurotoxin in non-invasively collected colorectal mucus showed an early promise[122]. Finally, Zhuang et al[123] have recently reported a simple ingestible pill-based biosensor device that detects reactive oxygen species and can potentially be used for IBD monitoring. However, fecal calprotectin remains the most popular biomarker used in clinical practice since it correlates well with gut inflammation activity and is resistant to degradation[46]. It is also clear that the emerging trend towards personalizing IBD therapy cannot be based on the non-specific calprotectin and most probably requires novel combinations of complementing biomarkers that can be obtained through application of modern analytical technologies that will be briefly discussed below.

Table 3 Serum and fecal biomarkers investigated in the context of inflammatory bowel disease according to recent publications[46,116,117,121,122].

Serum biomarkers	Fecal (or colorectal mucus) biomarkers
C-reactive protein1	Fecal calprotectin
Angiopoietin 11	Fecal lactoferrin
Angiopoietin 21	Fecal protein S100A12
Serum amyloid A11	Fecal protein - high mobility group 1
Interleukin 71	Neopterin
Extracellular matrix metalloproteinase inducer1	Polymorphonuclear neutrophil elastase
Matrix metalloproteinase 11	Fecal hemoglobin
Matrix metalloproteinase 21	α1-antitrypsin
Matrix metalloproteinase 31	Human neutrophil peptides
Matrix metalloproteinase 91	Neutrophil gelatinase-associated lipocalin
Transforming growth factor α1	Chitinase 3-like-1
Carcinoembryonic antigen-related cell adhesion molecule 11	Matrix metalloproteinase 9
Vascular cell adhesion molecule 11	Lysozyme
Serum calprotectin	M2-pyruvate kinase
Serum protein S100A12	Myeloperoxidase
Neopterin	Eosinophil cationic protein
Endothelin	Human β-defensin 2
Interleukin-6, interleukin-8, interleukin-17	β-glucuronidase
Soluble tumor necrosis factor receptor 1	Osteoprotegerin
Soluble interleukin-2 receptor	Lipocalin-2/neutrophil gelatinase-associated lipocalin
Perinuclear anti-neutrophil cytoplasmic antibodies	Colorectal mucus calprotectin
Anti-Saccharomyces cerevisiae antibodies	Colorectal mucus eosinophil-derived neurotoxin
Anti-mannobioside carbohydrate antibodies	MicroRNAs (MiR-16, MiR-21, MiR-223, MiR-1246)
Anti-laminaribioside carbohydrate antibodies
Anti-chitobioside carbohydrate antibodies
Anti-laminarin antibodies
Anti-chitin antibodies
Anti-flagellin CBir1 antibodies
Antibodies against the outer-membrane porin C of Escherichia coli
Antibodies against a Pseudomonas fluorescence-associated sequence l2
Serum leucine-rich glycoprotein
Micro RNAs (MiR-16, MiR-21, MiR-155, MiR-223, MiR-320a)

¹Components of Endoscopic Healing Index[118].

Gut microbiome-associated biomarker analysis: It has already been mentioned that gut microbiome changes provoking dysbiosis often precede IBD onset[15-17]. Dysbiosis is now believed to be one of the key factors in IBD pathogenesis[124,125]. The distinct features of dysbiosis in IBD patients is butyrate-producing bacteria depletion, alongside an increase in sulfate-reducing bacteria[125]. The loss of bacteria producing short-chain fatty acids, especially Faecalibacterium prausnitzii, impairs the intestinal epithelial barrier, increases its permeability, and facilitates bacterial translocation across the intestinal epithelium[126]. The expansion of sulfate-reducing bacteria stimulates sulfate conversion to hydrogen sulfide, which inhibits butyrate utilization and impairs immune responses[126]. It has been shown that the microbiome composition in IBD patients considerably differs from that of healthy individuals[127]. IBD is associated with a reduced diversity of intestinal microflora combined with a decrease in Furmicutes (e.g. Faecalibacterium prausnitzii and Roseburia hominis) and an increase in Enterobacteriaceae[128]. Dysbiosis was identified as a predictive factor in CD, with the presence of Clostridia, including the genus Faecalibacterium decreased in both patients with active disease and those in remission. In contrast, the presence of the genus Bacteroides increased during the active phase of the disease, whereas the genus Bifidobacterium appeared to be depleted during the active phase of CD, but increased in remission[129]. Samples taken from asymptomatic CD patients in the period preceding disease flare showed reduced abundance of some Furmicutes, such as Christensenellaceae, whereas other members of this phylum, such as Gemellaceae were increased[130]. Escherichia coli and genera Lactobacillus and Coprococcus were also associated with poor prognosis in CD patients[131]. Furthermore, the presence of Faecalibacterium prausnitzii and Roseburia hominis showed an inverse correlation with disease activity in UC patients[132]. UC activity also correlated with the presence of Peptostreptococcus anaerobius and with Proteobacteria, Shigella, and Escherichia[133]. Fecal bacteriome normalization after successful treatment of IBD flares was repeatedly described[134-136], thus highlighting this phenomenon as a potential indicator of disease treatment efficiency. It should not be forgotten that gut microbiome is not restricted by bacteria, but also comprises archaea, fungi, and viruses. Sokol et al[137] reported fungal microbiota shifts in IBD patients, with an increased Basidiomycota/Ascomycota ratio, a decreased proportion of Saccharomyces cerevisiae and an increased proportion of Candida albicans. It also appeared that CD-specific gut environment favoured fungi at the expense of bacteria. Gut virome may be an important factor in IBD pathogenesis as well, however this area requires further exploration[128].

Although the ongoing accumulation of data linking gut dysbiosis with both IBD activity and responses to therapeutic treatments is impressive, the available body of information is highly heterogeneous and very difficult to interpret. One problem is that it remains unclear whether dysbiosis instigates a proinflammatory state or the inflammatory environment accompanied by intestinal barrier dysfunction may lead to dysbiosis[128]. Whereas the importance of microbiome shifts for assessing IBD severity and treatment effects is evident, reliable interpretation of these changes in terms of their clinical significance remains a serious challenge. One apparent drawback is the current impossibility of obtaining representative samples that would reflect both longitudinal and cross-sectional heterogeneity of the microbiota throughout the gut[27,28,138,139]. Indeed, it is well known that easily obtainable fecal samples are the most popular material used in gut microbiome studies[140]. However, it is evident that IBD-related shifts in gut microbiota composition primarily occur within mucus overlaying intestinal mucosa[27,28,138,139]. Therefore, results of intestinal microbiota studies based on the analysis of stool samples are inevitably biased. The importance of intestinal and colorectal mucus as a uniquely informative biological material is now well understood[28], but its efficient collection remains problematic. The sampling methods currently used for gut microbiome investigations have been reviewed by Tang et al[140], but none of them seems to be perfect. It is, however, anticipated that the existing uncertainties will be solved by introducing modern research tools briefly considered below.

Modern analytical approaches under investigation

Precision medicine, multi-omics, bioinformatics, and AI: The necessity of IBD therapy personalization has already been highlighted in this review. This important task is in line with the concept of precision medicine widely used from the beginning of this century. According to the definition given by the United States National Human Genome Research Institute, “precision medicine (generally considered analogous to personalized medicine or individualized medicine) is an innovative approach that uses information about an individual’s genomic, environmental, and lifestyle information to guide decisions related to their medical management. The goal of precision medicine is to provide a more precise approach for the prevention, diagnosis, and treatment of disease”[141]. In the context of IBD precision medicine is regarded as “a population-based approach to managing IBD by integrating environmental, genomic, epigenomic, transcriptomic, proteomic, and metabolomic factors”[142]. The emergence of multi-omics technologies, comprising and combining data obtained through genomics, metagenomics, transcriptomics, proteomics, and metabolomics promises to provide better understanding of IBD molecular characteristics in their integrity[143,144]. It is anticipated that by integrating multiple omics layers it may be possible to predict IBD development risk[145] as well as identify and characterize IBD patient subpopulations both in terms of clinical phenotypes, such as disease activity/severity[143,146], and responsiveness to specific therapeutic schemes defining disease prognosis[143,146,147]. Designs of multi-omics approaches to IBD vary, and huge amounts of data generated by this research result in a plethora of potentially useful but still preliminary conclusions on newly identified composite biomarkers or pathogenetically important metabolic cascades. This situation can be illustrated by some recent studies that were either focused on gut bacteriome, using metagenomic, metatranscriptomic, and metabolomic analyses[148-150] or addressed host tissues (blood or biopsy samples)[144] and even single host cells[151]. In addition, combined analyses of mucosal quantitative microbiome profiling and host genotyping, epigenomics and transcriptomics are believed to be informative for prognostic assessment and relapse prediction in pediatric UC[147]. The limits of the present review do not allow discussing findings of these studies in detail; however, it is apparent that their immediate direct incorporation in clinical practice is impossible without employing reliable systems able to integrate and interpret enormous amounts of bioinformatics data generated by modern analytical techniques. It is becoming evident that only AI can potentially provide real-time automatic processing of abundant and complex multi-omics results[143,152]. In addition, it is anticipated that AI will enable integrating not only multi-omics data, but also results of endoscopic and histological investigations, thus leading to “endo-histo-omics” approach, harmoniously fusing endoscopic, histologic and molecular data[152]. Furthermore, the feasibility of incorporating AI in assessing IBD activity/severity by cross-sectional imaging has already been proven[74], and this information could also be incorporated in AI-driven analysis. All this innovation can potentially transform the current “one-size-fits-all” treatment paradigm into a truly personalized model of IBD care[148]. Multiple applications of AI-assisted technologies in IBD management are considered in detail by several recent reviews[74,143,152,153].

Nevertheless, it should be emphasized that all enticing applications of AI, highlighted above, remain to be validated through large-scale randomized controlled trials. Similar concerns exist about the reliability and reproducibility of the proposed AI models, as well as questions of cost-efficiency and potential ethical and regulatory challenges[152]. It is currently believed that in the short-term efforts should be focused on improving the diagnostic accuracy of AI-assisted techniques and their integration into routine clinical workflows. This can lead to developing predictive models for disease outcomes, including responses to applied treatments, and eventually advancing precision medicine through AI-driven multimodal data integration[152].

Assessment of mid-term and long-term IBD outcomes and disease impact on patients

Possible IBD outcomes and complications have already been briefly considered in the beginning of this review, and the SPIRIT-IBD guidelines[43,154] that specify the set of clinical endpoints defining therapeutic goals and aiming to minimise disease impact on the patient’s life are presented in Table 1. It should, however, be admitted that IBD patients often develop complications that require surgical interventions. Moreover, increased CRC risk is a well-known feature of the disease. Despite directly resulting from IBD, these late consequences are pathogenetically distinct and deserve to be considered as a separate group of disorders beyond the main framework of IBD activity/severity assessment (Figure 2).

IBD complications: Different characteristics of inflammation in UC and CD define the obvious differences in complications observed in these conditions. Overall, between 20% and 25% of UC patients may develop severe exacerbations of the disease (acute severe UC) requiring hospitalization and, in cases of drug therapy failure, colectomy[155]. Severe bowel damage in CD patients is usually manifested by the development of transmural inflammation of the bowel wall that may result in either stricturing fibrosis[156,157] or penetrating complications (the formation of fistules[158] as well as intra-abdominal and anorectal abscesses[159]). Fibrosis (or fibrostenosis), which results from the excessive production of extracellular matrix components driven by chronic inflammation and eventually causes strictures, is a typical complication of CD. Intestinal fibrosis pathogenesis is thoroughly considered elsewhere[156,157]. Strictures observed in CD patients typically occur in the ileum and the ileo-colonic region, but they can appear at any site throughout the gastrointestinal tract[156]. Fibrosis-associated colonic strictures may also be found in patients with UC[157].

The peculiarities of UC and CD complications dictate the necessity of being selective in choosing disease assessment approaches in different groups of patients. The severity of complications clearly prompts the initial use of objective clinical symptoms and patient-reported outcomes discussed earlier in this review. The early assessment of patients with suspected acute severe UC also includes blood examination, abdominal X-ray and cross-sectional imaging (emergency CTE), stool sample analysis (to exclude intestinal infection, especially Clostridium difficile), and sigmoidoscopy with biopsy to rule out cytomegalovirus infection[155,160]. Further management of these patients is described elsewhere[155,160].

The key element of assessing CD cases with suspected strictures, fistules, and abscesses is the use of cross-sectional imaging modalities, in particular MRE and IUS[97,161], however the use of CTE is also advocated by some authors[161]. Perianal fistulizing CD is an especially challenging subtype of the disease[162] that requires special diagnostic approaches. Magnetic resonance imaging appears to be highly efficacious in its diagnosis and staging[97,163,164], however endo-anal ultrasound[165], and recto-sigmoidoscopy[163] can also be considered.

Post-operational control: Despite significant recent advances in drug therapy of IBD, 5%-10% of UC patients and 10%-30% of CD patients in Europe still require surgical interventions within five years following IBD diagnosis[166]. Total proctocolectomy with ileal pouch-anal anastomosis has become the surgical treatment of choice for many UC patients[167]. The most common complication of this procedure is the development of pouchitis[168,169], when inflammation spreads through the pouch reservoir. Limited treatment options include antibiotics, probiotics, and biologics, but evaluations of disease activity/severity and therapy effect constitute an important element of the management of these patients[170]. The approaches to scoring pouchitis activity/severity are based on combining clinical, endoscopic, and histological items[170]. The existing scoring indices reviewed in more detail by Sedano et al[170] include pouchitis disease activity index, modified pouchitis disease activity index, and scoring systems combining endoscopic, clinical, and histological criteria. It was also reported that measuring fecal calprotectin and lactoferrin can be a useful addition to the existing indices of pouchitis activity[171]. Other complications observed after ileal pouch-anal anastomosis are fibrosis-associated and comprise strictures (sometimes causing obstruction) and fistulae[168]. Monitoring of UC patients suffering from these complications is generally similar to that of post-surgery CD patients, which is briefly discussed below.

Nearly 50% of patients with CD require surgical resection within the first 10 years of disease due to complications such as strictures, fistulae, abscesses or disease refractory to drug therapy[172,173]. Postoperative CD recurrence assessment is traditionally based on employing endoscopy, which is recommended at 6-12 months after surgery[174]. The existing endoscopic scores for postoperative CD activity/severity, including the Rutgeerts and modified Rutgeerts scores, postoperative Crohn’s endoscopic recurrence index, REMIND score, simple endoscopic score for CD, and the CD endoscopic index of severity have recently been compared by Hanzel et al[175] and found to be reliable for assessing CD activity in the neoterminal ileum, but suboptimal for evaluation in the anastomosis or distal colonic segment. Noninvasive methods, such as the use of biomarkers, especially fecal calprotectin, and cross-sectional imaging have also been tested for post-operational monitoring of CD patients, however the utility of these approaches remains to be validated[173]. In some especially severe cases of CD, proctocolectomy with end ileostomy may be best for the patient in order to remove all lesions and at-risk tissue[176], but management details of such cases are beyond the scope of this review.

Neoplasia development risk: Elevated risk of neoplasia development is another problem that is closely related to long-term monitoring of IBD patients. Indeed, it is well known that patients with long-standing UC and CD have an approximately 2-3-fold increased risk of CRC[176]. The peculiarity of IBD-associated carcinogenesis seems to be related to the initial emergence within chronically inflamed mucosa of relatively large areas of dysplasia that may undergo neoplastic transformation[176,177]. Dysplasia surveillance in IBD patients is primarily based on the use of endoscopy and multiple biopsies, and the advantages of using high definition WLE, chromoendoscopy or VEC were noted[178,179]. Fluorescence molecular endoscopy is another modern technique deserving attention in this context[69,70]. Today endoscopy appears to be the most potent instrument used for IBD-related CRC surveillance, however non-invasive cancer biomarkers detectable in blood and feces also present an interesting option. Although numerous potential CRC biomarkers are currently known[180], individual biomarker performance for detecting IBD-associated CRC remains unconvincing, especially given that haemoglobin detection in stool samples widely employed for CRC detection in other populations[180] cannot be used when the presence of blood in stool is one of the most common IBD symptoms. The promise of using AI- integrated multi-omics is certainly interesting[177], but it also needs further development.

Finally, it should be noted that perianal CD is associated with an increased risk of anal cancer development[181]. Although squamous-cell anal cancer is a relatively rare condition, it should not be overlooked, regular clinical examination and cross-sectional imaging being diagnostic techniques of choice[181].

CONCLUSION

Complex multifactorial pathogenesis of IBD involves interplay between host’s genetic predisposition, epigenomic modifications, host immunity interactions with altered gut microbiome, and environmental influences. Upon IBD onset, patients need life-time monitoring of disease activity/severity and effectiveness of applied therapy, achievement of stable remission being the goal of the currently adopted ‘treat-to-target’ strategy. Current approaches to IBD monitoring comprise such principal modalities as traditional assessment of clinical disease manifestations, instrumental visualization of IBD-related pathological changes, laboratory or point-of-care tests for gut inflammation, and modern analytical approaches, including multi-omics and AI. Rapid technical progress has permitted significant improvement of endoscopic and cross-sectional imaging, methods of molecular biomarker detection, and gut microbiome composition analysis. It is also anticipated that AI-assisted multi-omics can identify new composite biomarkers useful for IBD monitoring and disease activity/severity assessment. The combination of all these approaches already allows us to generate enormous amounts of potentially useful diagnostic results that need to be carefully prepared and analysed to be valid. AI-driven integration of abundant information provided by the diagnostic and analytical modalities outlined in this review may help in transforming the current ‘one-size-fits-all’ disease treatment paradigm into a truly personalized model of IBD care.