Fecal calprotectin and endoscopic scores: The cornerstones in clinical practice for evaluating mucosal healing in inflammatory bowel disease

Managing inflammatory bowel disease(IBD)is becoming increasingly complex and personalized,considering the advent of new advanced therapies with distinct mechanisms of action.Achieving mucosal healing(MH)is a pivotal therapeutic goal in IBD management and can prevent IBD progression and reduce flares,hospitalization,surgery,intestinal damage,and colorectal cancer.Employing proactive disease and therapy assessment is essential to achieve better control of intestinal inflammation,even if subclinical,to alter the natural course of IBD.Periodic monitoring of fecal calprotectin(FC)levels and interval endoscopic evaluations are cornerstones for evaluating response/remission to advanced therapies targeting IBD,assessing MH,and detecting subclinical recurrence.Here,we comment on the article by Ishida et al Moreover,this editorial aimed to review the role of FC and endoscopic scores in predicting MH in patients with IBD.Furthermore,we intend to present some evidence on the role of these markers in future targets,such as histological and transmural healing.Additional prospective multicenter studies with a stricter MH criterion,standardized endoscopic and histopathological analyses,and virtual chromoscopy,potentially including artificial intelligence and other biomarkers,are desired.

Mucosal healing and inflammatory bowel disease:Therapeutic implications and new targets

Mucosal healing(MH)is vital in maintaining homeostasis within the gut and protecting against injury and infections.Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair.However,when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results,particularly inflammatory bowel disease(IBD).Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions,with the mechanisms of regulation just beginning to be understood.Consequently,there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes,so tissue damage in the gastrointestinal tract of patients,even those in clinical remission,persists.With increased understanding of the molecular mechanisms of IBD and MH,tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing response.In this review,we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.

Systemic interleukin-9 in inflammatory bowel disease: Association with mucosal healing in ulcerative colitis

To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODSSerum IL9 as well as other cytokines (IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn’s disease (CD) and 74 with ulcerative colitis (UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn’s Disease Activity Index (CDAI) and the Mayo Scoring System (MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex xMAP® technology. High-sensitive C-reactive protein concentrations (hsCRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTSSystemic IL9 was significantly lower in healthy individuals [9 pg/mL (95%CI: 8.2-10)] than in patients with inflammatory bowel disease (IBD): both inactive [14.3 pg/mL (11.9-19.9)] and active [27.6 pg/mL (24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/mL (23.4-32.2)] and in active UC [32.7 pg/mL (27-38.9)] compared to inactive diseases [15.9 pg/mL (10.8-23.4) in CD and 19.4 pg/mL (13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI (ρ = 0.32, P = 0.003) and MDAI (ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC (ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing (MH), IL9 had an accuracy superior to hsCRP and IL6 [97% (P < 0.0001), 67% (P = 0.071), and 55% (P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/mL (24.4-37.5) vs 21.88 pg/mL (18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations (ρ = -0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A in both active and inactive CD.CONCLUSIONThe systemic IL9 level is higher in IBD and corresponds with endoscopic inflammation, suggesting its possible application as a negative marker of mucosal healing in UC.

Prognosis of ulcerative colitis differs between patients with complete and partial mucosal healing, which can be predicted from the platelet count

AIM: To determine the difference in clinical outcome between ulcerative colitis (UC) patients with Mayo endoscopic subscore (MES) 0 and those with MES 1.

Thalidomide induces mucosal healing in Crohn's disease: Case report

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract that is defi ned by relapsing and remitting episodes. Tumor necrosis factor alpha (TNF-α) appears to play a central role in the pathophysiology of the disease. Standard therapies for inflammatory bowel disease fail to induce remission in about 30% of patients. Biological therapies have been associated with an increased incidence of infections, especially infection by Mycobacterium tuberculosis (Mtb). Thalidomide is an oral immunomodulatory agent with anti-TNF-α properties. Recent studies have suggested that thalidomide is effective in refractory luminal and fistulizing Crohn's disease. Thalidomide costimulates T lymphocytes, with greater effect on CD8+ than on CD4+ T cells, which contributes to the protective immune response to Mtb infection. We present a case of Crohn's disease with gastric, ileal, colon and rectum involvement as well as steroid dependency, which progressed with loss of response to infliximabafter three years of therapy. The thorax computed tomography scan demonstrated a pulmonary nodule suspected to be Mtb infection. The patient was started on thalidomide therapy and exhibited an excellent response.

Trefoil factor-3 is not a useful marker of mucosal healing in Crohn's disease treated with anti-TNF-α antibodies

AIMTo evaluate whether repeated serum measurements of trefoil factor-3 (TFF-3) can reliably reflect mucosal healing (MH) in Crohn&#x02019;s disease (CD) patients treated with anti-tumor necrosis factor-&#x003b1; (anti-TNF-&#x003b1;) antibodies.METHODSSerum TFF-3 was measured before and after anti-TNF-&#x003b1; induction therapy in 30 CD patients. The results were related to clinical, biochemical and endoscopic parameters. MH was defined as a &#x02265; 50% decrease in Simple Endoscopic Score for Crohn&#x02019;s disease (SES-CD).RESULTSSES-CD correlated significantly with CD clinical activity and several standard biochemical parameters (albumin, leukocyte and platelet counts, C-reactive protein, erythrocyte sedimentation rate, fibrinogen). In contrast, SES-CD did not correlate with TFF-3 (P = 0.54). Moreover, TFF-3 levels did not change significantly after therapy irrespectively of whether the patients achieved MH or not. Likewise, TFF-3 did not correlate with changes in fecal calprotectin, which has been proposed as another biochemical marker of mucosal damage in CD.CONCLUSIONSerum TFF-3 is not a convenient and reliable surrogate marker of MH during therapy with TNF-&#x003b1; antagonists in CD.

Fecal calprotectin measurement is a marker of shortterm clinical outcome and presence of mucosal healing in patients with inflammatory bowel disease

AIM To evaluate the utility of fecal calprotectin(FC) in predicting relapse and endoscopic activity during follow-up in an inflammatory bowel disease(IBD) cohort.METHODS All FC measurements that were obtained during a 3-year period from patients with inflammatory bowel disease in clinical remission were identified. Data regarding the short-term(6 mo) course of the disease were extracted from the medical files. Exclusion criteria were defined as:(1) An established flare of the disease at the time of FC measurement,(2) Loss to follow up within 6 mo from baseline FC measurement, and,(3) Insufficient data on file. Statistical analysis was performed to evaluate whether baseline FC measurement could predict the short term clinical relapse and/or the presence of mucosal healing.RESULTS We included 149 [Crohn's disease(CD) = 113, Ulcerative colitis(UC) = 36, male = 77] IBD patients in our study. Within the determined 6-month period post-FC measurement, 47(31.5%) had a disease flare. Among 76 patients who underwent endoscopy, 39(51.3%) had mucosal healing. Baseline FC concentrations were significantly higher in those who had clinical relapse compared to those who remained in remission during follow up(481.0 μg/g, 286.0-600.0 vs 89.0, 36.0-180.8, P < 0.001). The significant predictive value of baseline median with IQR FC for clinical relapse was confirmed by multivariate Cox analysis [HR for 100μg/g: 1.75(95%CI: 1.28-2.39), P = 0.001]. Furthermore, lower FC baseline values significantly correlated to the presence of mucosal healing in endoscopy(69.0 μg/g, 30.0-128.0 vs 481.0, 278.0-600.0, in those with mucosal inflammation, median with IQR, P < 0.001). We were able to extract cut-off values for FC concentration with a high sensitivity and specificity for predicting clinical relapse(261 μg/g with AUC = 0.901, sensitivity 87.2%, specificity 85.3%, P < 0.001) or mucosal healing(174 μg/g with AUC = 0.956, sensitivity 91.9%, specificity 87.2%, P < 0.001). FC was better than CRP in predicting either outcome; nevertheless, having a pathological CRP(> 5 mg/L) in addition to the cutoffs for FC, significantly enhanced the specificity for predicting clinical relapse(95.1% from 85.3%) or endoscopic activity(100% from 87.2%). CONCLUSION Serial FC measurements may be useful in monitoring IBD patients in remission, as FC appears to be a reliable predictor of short-term relapse and endoscopic activity.

Ulcerative colitis patients in clinical remission demonstrate correlations between fecal immunochemical test results, mucosal healing, and risk of relapse

AIM: To assess the risk of relapse in ulcerative colitis (UC) patients in clinical remission using mucosal status and fecal immunochemical test (FIT) results.METHODS: The clinical outcomes of 194 UC patients in clinical remission who underwent colonoscopy were based on evaluations of Mayo endoscopic subscores (MESs) and FIT results.RESULTS: Patients with an MES of 0 (n = 94, 48%) showed a ten-fold lower risk of relapse than those with an MES of 1-3 (n = 100, 52%) (HR = 0.10, 95%CI: 0.05-0.19). A negative FIT result (fecal hemoglobin concentrations &#x02264; 100 ng/mL) was predictive of patients with an MES of 0, with a sensitivity of 0.94 and a specific of 0.76. Moreover, patients with a negative FIT score had a six-fold lower risk of clinical relapse than those with a positive score (HR = 0.17, 95%CI: 0.10-0.28). Inclusion of the distinguishing parameter, sustaining clinical remission &#x0003e; 12 mo, resulted in an even stronger correlation between negative FIT results and an MES of 0 with respect to the risk of clinical relapse (HR = 0.11, 95%CI: 0.04-0.23).CONCLUSION: Negative FIT results one year or more after remission induction correlate with complete mucosal healing (MES 0) and better prognosis. Performing FIT one year after remission induction may be useful for evaluating relapse risk.

Surrogate markers of mucosal healing in inflammatory bowel disease:A systematic review

Mucosal healing(MH)has emerged as a key therapeutic target in inflammatory bowel disease(IBD),and achievement of this goal is documented by endoscopy with biopsy.However,colonoscopy is burdensome and invasive,and substitution with an accurate noninvasive biomarker is desirable.AIM To summarize published data regarding the performance of noninvasive biomarkers in assessing MH in IBD patients.METHODS We conducted a systematic review of studies that reported the performance of biomarkers in diagnosing MH in patients with IBD.The main outcome measure was to review the diagnostic accuracy of serum and fecal markers that showed promising utility in assessing MH.RESULTS We screened 1301 articles,retrieved 46 manuscripts and included 23 articles for full-text analysis.The majority of the included manuscripts referred to fecal markers(12/23),followed by circulatory markers(8/23);only 3/23 of the included manuscripts investigated combined markers(serum and/or fecal markers).Fecal calprotectin(FC)was the most investigated fecal marker for assessing MH.In ulcerative colitis,for cutoff levels ranging between 58 mcg/g and 490 mcg/g,the sensitivity was 89.7%-100%and the specificity was 62%-93.3%.For Crohn’s disease,the cutoff levels of FC ranged from 71 mcg/g to 918 mcg/g(sensitivity 50%-95.9%and specificity 52.3%-100%).The best performance for a serum marker was observed for the endoscopic healing index,which showed a comparable accuracy to the measurement of FC and a higher accuracy than the measurement of serum C-reactive protein.CONCLUSION Several promising biomarkers of MH are emerging but cannot yet substitute for endoscopy with biopsy due to issues with reproducibility and standardization assessing MH.In ulcerative colitis,for cutoff levels ranging between 58 mcg/g and 490 mcg/g,the sensitivity was 89.7%-100%and the specificity was 62%-93.3%.For Crohn’s disease,the cutoff levels of FC ranged from 71 mcg/g to 918 mcg/g(sensitivity 50%-95.9%and specificity 52.3%-100%).The best performance for a serum marker was observed for the endoscopic healing index,which showed a comparable accuracy to the measurement of FC and a higher accuracy than the measurement of serum C-reactive protein.CONCLUSION Several promising biomarkers of MH are emerging but cannot yet substitute for endoscopy with biopsy due to issues with reproducibility and standardization.

Frequency and prognostic role of mucosal healing in patients with Crohn's disease and ulcerative colitis after one-year of biological therapy

AIM: To assess the endoscopic activity before and after a one-year period of biological therapy and to evaluate the frequency of relapses and need for retreatment after stopping the biologicals in patients with Crohn&#x02019;s disease (CD) and ulcerative colitis (UC).

In vivo detection of mucosal healing-involved histiocytes by confocal laser endomicroscopy

Histiocytes have a pivotal role in wound repair and intestinal epithelial recovery-the most important goal to sustain gut functionality.Yet,an in vivo description of colonic histiocytes by confocal laser endomicroscopy(CLE) is missing.Here,we report the case of a 45-yearsold male patient who was referred to our clinic with weight loss and a history of two consecutive Clostridium difficile colitis episodes,the latter cured 3 wk before present admission.Stool microbiology was negative.Conventional colonoscopy showed atrophy and a light mucosal oedema in the distal colon.During on-going endoscopy,we performed a fluorescein-aided CLE which revealed large polygonal(histiocytes-like) cells with copious cytoplasm and large nuclei in the lamina propria of the sigmoid colon as well as regenerative epithelial changes.Histopathological assessment of biopsies from the same areas confirmed the endomicroscopical findings:Periodic acid-Schiff-and CD68-positive foamy histiocytes in the colonic lamina propria and an advanced epithelial recovery.Since stool microbiology was repeatedly negative and polymerase chain reaction-analysis from colonic biopsies could not detect any mRNA for Thropheryma whippleii and common pathogens,we interpreted this particular setting as a mucosal healing process after consecutive Clostridium difficile infections.In conclusion,by describing these colonic histiocytes,we highlight the clinical usefulness of CLE in describing the entity of histiocytes in vivo and in real-time during the process of post-infectious mucosal healing in the colon.

Mechanism of Acupuncture and Moxibustion on Promoting Mucosal Healing in Ulcerative Colitis

The latest guideline about ulcerative colitis(UC) clinical practice stresses that mucosal healing, rather than anti-inflammation, is the main target in UC clinical management. Current mucosal dysfunction mainly closely relates to the endoscopic intestinal wall(mechanical barrier) injury with the imbalance between intestinal epithelial cells(IECs) regeneration and death, as well as tight junction(TJ) dysfunction. It is suggested that biological barrier(gut microbiota), chemical barrier(mucus protein layer, MUC) and immune barrier(immune cells) all take part in the imbalance, leading to mechanical barrier injury. Lots of experimental studies reported that acupuncture and moxibustion on UC recovery by adjusting the gut microbiota, MUC and immune cells on multiple targets and pathways, which contributes to the balance of IEC regeneration and death, as well as TJ structure recovery in animals. Moreover, the validity and superiority of acupuncture and moxibustion were also demonstrated in clinic. This paper aims to review the achievements of acupuncture and moxibustion on mucosal healing and analyse the underlying mechanisms.

Disease clearance in ulcerative colitis:A new therapeutic target for the future

Advancements in murine modeling systems for ulcerative colitis have diversified our understanding of the pathophysiological factors involved in disease onset and progression.This has fueled the identification of molecular targets,resulting in a rapidly expanding therapeutic armamentarium.Subsequently,management strategies have evolved from symptomatic resolution to well-defined objective endpoints,including clinical remission,endoscopic remission and mucosal healing.While the incorporation of these assessment modalities has permitted targeted intervention in the context of a natural disease history and the prevention of complications,studies have consistently depicted discrepancies associated with ascertaining disease status through clinical and endoscopic measures.Current recommendations lack consideration of histological healing.The simultaneous achievement of clinical,endoscopic,and histologic remission has not been fully investigated.This has laid the groundwork for a novel therapeutic outcome termed disease clearance(DC).This article summarizes the concept of DC and its current evidence.

Navigating new horizons in inflammatory bowel disease:Integrative approaches and innovations

This editorial offers an updated synthesis of the major advancements in the management and treatment of inflammatory bowel disease(IBD),as documented in the World Journal of Gastroenterology between 2023 and early 2024.This editorial explores substantial developments across key research areas,such as intestinal microecology,computational drug discovery,dual biologic therapy,telemedicine,and the integration of lifestyle changes into patient care.Furthermore,the discussion of emerging topics,including bowel preparation in colonoscopy,the impact of the coronavirus disease 2019 pandemic,and the intersection between IBD and mental health,reflects a shift toward a more holistic approach to IBD research.By integrating these diverse areas of research,this editorial seeks to promote a holistic and multidisciplinary approach to IBD treatment,combining emerging technologies,personalized medicine,and conventional therapies to improve patient outcomes.

Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions in the colon

Epithelial-to-mesenchymal and mesenchymal-to-epi- thelial transitions are well established biological events which have an important role in not just normal tissue and organ development, but in the pathogenesis of diseases. Increasing evidence has established their presence in the human colon during colorectal carcinogenesis and cancer invasion, chronic inflammation-related fibrosis and in the course of mucosal healing. A large body of evidence supports the role for transforming growth factor-13 and its downstream Smad signaling, the phosphatidylinositol 3＇-kinase/Akt/mTOR axis, the Ras-mitogen-activated protein kinase/Snail/Slug and FOXC2 pathway, and Hedgehog signaling and microR- NAs in the development of colorectal cancers via epi- thelial-to-mesenchymal transition. C-met and Frizzled-7, among others, seem to be the principle effectors of mesenchymal-to-epithelial transition, hence have a role not just in mucosal regeneration but in the progression of colonic wall fibrosis. Here we discuss a role for these pathways in the initiation and development of the transition events. A better understanding of their induction and regulation may lead to the identification of pathways and factors that could be potent therapeu- tic targets. The inhibition of epithelial-to-mesenchymal transition using mTOR kinase inhibitors targeting theATP binding pocket and which inhibit both mTORC1 and mTORC2, RNA aptamers or peptide mimetics, such as a Wnt5A-mimetic, may all be useful in both cancer treatment and delaying fibrosis, while the induction of mesenchymal-to-epithelial transition in induced pluripotent stem cells may enhance epithelial healing in the case of severe mucosal damage. The preliminary results of the current studies are promising, but more clinical investigations are needed to develop new and safe therapeutic strategies for diseases of the colon.

Clinical relevance of endoscopic assessment of inflammation in ulcerative colitis: Can endoscopic evaluation predict outcomes?

Ulcerative colitis(UC) is a chronic inflammatory bowel condition characterised by a relapsing and remitting course. Symptom control has been the traditional mainstay of medical treatment. It is well known that histological inflammatory activity persists despite adequate symptom control and absence of endoscopic inflammation. Current evidence suggests that presence of histological inflammation poses a greater risk of disease relapse and subsequent colorectal cancer risk. New endoscopic technologies hold promise for developing endoscopic markers of mucosal inflammation. Achieving endoscopic and histological remission appears be the future aim of medical treatments for UC. This review article aims to evaluate the use of endoscopy as a tool in assessment of mucosal inflammation UC and its correlation with disease outcomes.

Interleukin-34 deficiency aggravates development of colitis and colitis-associated cancer in mice

BACKGROUND Although expression of interleukin(IL)-34 is upregulated in active ulcerative colitis(UC),the molecular function and underlying mechanism are largely unclear.AIM To investigate the function of IL-34 in acute colitis,in a wound healing model and in colitis-associated cancer in IL-34-deficient mice.METHODS Colitis was induced by administration of dextran sodium sulfate(DSS),and carcinogenesis was induced by azoxymethane(AOM).Whether the impact of IL-34 on colitis was dependent on macrophages was validated by depletion of macrophages in a murine model.The association between IL-34 expression and epithelial proliferation was studied in patients with active UC.RESULTS IL-34 deficiency aggravated murine colitis in acute colitis and in wound healing phase.The effect of IL-34 on experimental colitis was not dependent on macrophage differentiation and polarization.IL-34-deficient mice developed more tumors than wild-type mice following administration of AOM and DSS.No significant difference was shown in degree of cellular differentiation in tumors between wild-type and IL-34-deficient mice.IL-34 was dramatically increased in the active UC patients as previously reported.More importantly,expression of IL-34 was positively correlated with epithelial cell proliferation in patients with UC.CONCLUSION IL-34 deficiency exacerbates colonic inflammation and accelerates colitis-associated carcinogenesis in mice.It might be served as a potential therapeutic target in UC.

Controversies in the treatment of Crohn’s disease: The case for an accelerated step-up treatment approach

The ideal treatment strategy for Crohn’s disease (CD) remains uncertain, as does the optimal endpoint of therapy. Top-down versus step-up describes two different approaches: early use of immunomodulators and biological agents in the former versus initial treatment with steroids in the latter, with escalation to immunomodulators or biological drugs in patients proven to be steroid refractory or steroid dependent. Top-down therapy has been associated with higher rates of mucosal healing. If mucosal healing proves to be associated with better long-term outcomes, such as a decreased need for hospitalization and surgery, top-down therapy may be the better approach for many patients. The main concern with the top-down approach is the toxicity of the immunomodulators and biological agents, which have been linked with infectious complications as well as an increased risk of lymphoma. It is unlikely that one strategy will be best for all patients given the underlying heterogeneity of CD presentation and severity. Ultimately, we must weigh the safety and efficacy of the therapies with the risks of the disease itself. Unfortunately our ability to risk stratify patients at diagnosis remains rudimentary. The purpose of this paper is to review the data that supports or refutes the differing treatment paradigms in CD, and to provide a rationale for an approach, termed the "accelerated step-up" approach, which attempts to balance the risks and benefits of our currently available therapies with the risk of disease related complications as we understand them in 2008.

Inflammatory bowel disease:Therapeutic limitations and prospective of the stem cell therapy

Inflammatory bowel disease(IBD),consisting primarily of ulcerative colitis and Crohn’s disease,is a group of debilitating auto-immune disorders,which also increases the risk of colitis-associated cancer.However,due to the chronic nature of the disease and inconsistent treatment outcomes of current anti-IBD drugs(e.g.,approximately 30%non-responders to anti-TNFαagents),and related serious side effects,about half of all IBD patients(in millions)turn to alternative treatment options.In this regard,mucosal healing is gaining acceptance as a measure of disease activity in IBD patients as recent studies have correlated the success of mucosal healing with improved prognosis.However,despite the increasing clinical realization of the significance of the concept of mucosal healing,its regulation and means of therapeutic targeting remain largely unclear.Here,stemcell therapy,which uses hematopoietic stem cells or mesenchymal stem cells,remains a promising option.Stem cells are the pluripotent cells with ability to differentiate into the epithelial and/or immune-modulatory cells.The overreaching concept is that the stem cells can migrate to the damaged areas of the intestine to provide curative help in the mucosal healing process.Moreover,by differentiating into the mature intestinal epithelial cells,the stem cells also help in restoring the barrier integrity of the intestinal lining and hence prevent the immunomodulatory induction,the root cause of the IBD.In this article,we elaborate upon the current status of the clinical management of IBD and potential role of the stem cell therapy in improving IBD therapy and patient’s quality of life.

Evaluation of “top-down” treatment of early Crohn's disease by double balloon enteroscopy

AIM: To assess &#x0201c;top-down&#x0201d; treatment for deep remission of early moderate to severe Crohn&#x02019;s disease (CD) by double balloon enteroscopy.