Fecal calprotectin (Fcal) and intestinal ultrasonography (IUS) could be used as noninvasive tools to monitor mucosal and transmural healing, respectively, in Crohn's disease (CD). We assessed the agreement between Fcal and IUS to detect active CD and investigated their complementary to predict long-term CD outcomes.

In this prospective study, we consecutively included CD patients with concomitant IUS and Fcal testing within 7 days. Patients were divided into 4 groups: Transmural healing (TH; both normal), IUS healing (Fcal > 100 µg/g but normal IUS), biochemical remission reflecting mucosal healing (MH; Fcal < 100 µg/g but abnormal IUS), and no healing (abnormal Fcal and IUS). The primary endpoint was active CD. The secondary endpoints were time to bowel damage progression, time to relapse-related drug discontinuation, and patients' acceptability (10-points acceptability numerical scale).

Among the included 112 patients, 44.6% (50/112), 12.5% (14/112),16.1% (18/112), and 26.8% (30/122) achieved TH, IUS healing, biochemical remission, and no healing, respectively. The agreement between IUS and Fcal to detect an active CD was poor (71.4%, κ-coefficient = 0.41 ± 0.09). Transmural healing was associated with a reduced risk of bowel damage progression compared to no healing (P < .0001) contrary to IUS healing (P = .15) or biochemical remission (P = .84). Transmural healing was associated with a lower risk of relapse-related drug discontinuation than MH (hazard ratio [HR] = 0.09 [0.02-0.45], P = .003), IUS healing (HR = 0.10 [0.02-0.60], P = .001), or no healing (HR = 0.09 [0.018-0.04], P = .002). IUS was better accepted than Fcal testing (9.6 ± 0.8 vs 7.9 ± 2.3; P < .0001, 10-points range-acceptability numerical scale).

Transmural healing, evaluated by the combination of noninvasive and well-accepted tools such as Fcal and IUS, is associated with improved long-term outcomes and could be used to monitor patients with CD in daily practice.

Mucosal healing in Crohn's disease (CD) has been established as a crucial target of treatment, leading to long term remission and decrease in complication rates. Endoscopy still serves as the gold standard for assessment, particularly in the small bowel where balloon or capsule enteroscopy is frequently needed. However, these modalities are often unavailable, expensive, and invasive, posing risks to patients. Consequently, the identification of accessible and reliable biomarkers, especially in small intestinal CD, remains a challenge. The study by Ohno et al, published in this issue, further illuminates this field. It confirms the potential role of fecal biomarker leucine-rich α2 glycoprotein (LRG) and validates findings from previous smaller trials. Comparing to other markers LRG showed a much higher predictive value for mucosal healing of the small bowel, making it a useful option for small intestinal CD follow up. In this editorial, we explore the optimal marker of inflammation or mucosal healing in CD, particularly in the small bowel. We provide an overview of available conventional biomarkers and introduce several novel biomarkers, including an update on emerging technologies and innovations.

Inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) are lifelong chronic, relapsing, and remitting conditions that culminate in disease progression in many patients. Effective management of CD and UC requires consideration of both short- and long-term treatment outcomes. Historically, short-term outcomes such as clinical and endoscopic remission and symptom relief have been evaluated in clinical trials. With the expansion of treatments targeting underlying disease pathophysiology, there is the opportunity to develop management strategies that improve disease control and patients' lives in both the short and the long term. Researchers have been examining novel outcomes for assessing the efficacy of CD and UC treatments that are important to patients, and also those that go beyond symptomatic improvements or clinical remission. These include new patient-reported outcomes for symptoms, as well as transmural/histological healing and disease clearance that can be more reflective of deeper remission states and disease modification. This review analyses published clinical studies involving patients with UC and CD treated with biologics or small molecule therapies. It highlights novel IBD endpoints employed in published clinical trials and discusses their likely value for assessing disease activity and disease modification, and as predictors of reduced risk of complications and morbidities.

Achieving deep remission, encompassing clinical, endoscopic, and biological remission, is the goal in managing Crohn's disease (CD). The role of histological remission (HR) remains unclear. This study aimed to examine the impact of histological inflammation on clinical relapse risk in CD and explore the relationship between histology, endoscopic scores, and biomarkers.

Patients from the prospective STORI (Stable Remission on Combined Therapy with Immunosuppressors) cohort underwent ileocolonoscopy with Crohn's Disease Endoscopic Index of Severity calculation and 2 biopsies from the most inflamed or previously inflamed areas. Histological scores (Robarts, Geboes, modified Geboes, Nancy, and IBD-DCA) were determined by 2 independent pathologists in a central reading process. Histological remission was defined by specific score thresholds. Clinical relapse, defined by Crohn's Disease Activity Index (CDAI) > 250 or a CDAI increase of 70 points over 2 weeks, was monitored for at least 1 year.

Out of 115 patients included in STORI, 160 biopsies (44 ileal and 116 colonic) from 76 patients were analyzed. Histological remission rates were 46% (Nancy), 55% (Robarts), 61% (Geboes), and 41% (IBD-DCA). During follow-up, 35 patients (46%) experienced a clinical relapse: 37% with HR and 56% without, based on the Nancy score. Among the mucosal healing subgroup (45 patients), 34% with HR, and 44% without relapsed (p = 0.18). Histological scores did not predict clinical relapse. Only fecal calprotectin was a significant predictor in multivariate analysis (p = 0.029).

Despite correlations with endoscopy and biomarkers, histological scores did not predict clinical relapse in CD patients in remission. Thus, these scores are not recommended for clinical practice to assess relapse risk in CD.

Healing in Crohn's disease is complex and difficult to measure due to incongruencies between clinical symptoms and disease states. Mucosal healing (MH) and transmural healing (TH) are increasingly used to measure clinical improvement in Crohn's disease, but definitions of MH and TH can vary across studies, and their relationship to long-term outcomes is not clear. To address this knowledge gap, we performed a systematic literature review (SLR) to examine studies measuring MH and TH in Crohn's disease.

Database records from 2012 to 2022 were searched for real-world evidence and interventional studies that reported the association of MH or TH with clinical, economic, or quality of life outcomes of adult patients with Crohn's disease.

A total of 46 studies were identified in the systematic literature review, representing a combined patient population of 5530. Outcomes of patients with MH were reported by 39 studies; of these, 14 used validated scales for endoscopic assessment. Thirteen studies reported outcomes of patients with TH. Among studies that examined the outcomes of patients with and without MH or TH, patients with healing generally experienced improved clinical outcomes and reduced healthcare resource utilization, including fewer hospitalizations and surgeries and improved rates of clinical remission. This was especially true for patients with TH.

Mucosal and transmural healing are associated with positive long-term outcomes for adult patients with Crohn's disease. The adoption of standardized measures and less invasive assessment tools will maximize the benefits of patient monitoring.

There is limited evidence that histologic remission improves outcomes in Crohn's disease (CD). We aimed to characterize a cohort of patients with CD in endoscopic remission and explore factors associated with subsequent loss of remission (LOR).

In total, 4474 patients were enrolled in TARGET-IBD, a longitudinal, observational cohort study. Patients with a normal steroid-free colonoscopy (index) were defined as "in endoscopic remission" and were followed for LOR, defined as presence of inflammation, erosion, ulceration, or stricturing on a subsequent colonoscopy or commencement of steroids. Histologic activity was dichotomized using standard of care reports for active inflammation. Unadjusted and multivariable-adjusted Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of LOR in relation to independent variables.

Of 658 patients with CD with steroid-free endoscopic remission, the majority were female (57%), white (83%), non-Hispanic (93%); 20% had ileal and 20% isolated colonic disease. Inflammatory (B1) disease was the most common phenotype (43%). Of these 658 patients, 257 (39%) had histologic inflammation on index colonoscopy. Histologic inflammation at index colonoscopy was associated with nearly twice the LOR risk (HR 1.96, 95% CI: 1.50-2.57) with median time to relapse of 1.20 years. Biologic use at index was associated with lower LOR risk (monotherapy, HR 0.61, 95% CI: 0.45-0.82; combination therapy, HR 0.43, 95% CI: 0.28-0.66).

Active histologic inflammation despite endoscopic remission, and lack of biologic use were independently associated with risk of subsequent LOR, providing evidence that histologic remission may impart improved outcomes in patients with CD.

Endoscopic healing (EH) is a key therapeutic target in Crohn's disease (CD). Proximal small bowel (SB) lesions in patients with CD are associated with a significant risk of strictures and bowel resection. Assessing SB in patients with CD is necessary because of its significant therapeutic implications. The advent of biologic therapies, including infliximab, ustekinumab, and vedolizumab, has significantly altered CD treatment. However, data on the efficacy of biologics in achieving EH, specifically in the proximal SB of patients with CD, remain limited.

To assess the effectiveness of biologics for EH in patients with jejunal and/or proximal ileal CD.

Between 2017 and 2023, we retrospectively included 110 consecutive patients with isolated proximal SB CD, identified through baseline balloon-assisted enteroscopy. These patients completed 1-year of treatment with infliximab, ustekinumab, or vedolizumab, and underwent a second balloon-assisted enteroscopy at 1 year. Complete EH was defined as a modified Simple Endoscopic Score for CD (SES-CD) of < 3, while EH of the jejunum and proximal ileum was defined as a segmental modified SES-CD of 0.

In total, 64 patients were treated with infliximab, 28 with ustekinumab, and 18 with vedolizumab. The complete EH rate at 1 year was 20.9% (23/110), with 29.6% (19/64) for infliximab, 10.7% (3/28) for ustekinumab, and 5.5% (1/18) for vedolizumab. The median modified SES-CD significantly decreased compared to baseline [5 (2-8) vs 8 (6-9), P < 0.001]. The jejunal and proximal ileal EH rates at 1 year were 30.8% (12/39) and 15.5% (16/103), respectively. Multiple logistic regression analysis showed that stricturing or penetrating disease [odds ratio (OR) = 0.261, 95%CI: 0.087-0.778, P = 0.016], prior exposure to biologics (OR = 0.080, 95%CI: 0.010-0.674, P = 0.020), and moderate-to-severe endoscopic disease (OR = 0.277, 95%CI: 0.093-0.829, P = 0.022) were associated with a lower likelihood of achieving EH at 1 year.

Only 20.9% of patients with isolated proximal SB CD achieved complete EH after 1 year of biologic therapy.

We evaluated the association of achieving endoscopic outcomes at week 12 of induction with improvements in clinical outcomes and quality of life (QoL) at week 52 of maintenance in patients with moderately to severely active Crohn's disease (CD) treated with upadacitinib (UPA).

This post hoc analysis evaluated data from 2 phase 3 induction trials (NCT03345836 and NCT03345849) and 1 maintenance (NCT03345823) trial. Clinical responders to 12-week induction therapy with UPA who also received 52-week maintenance treatment with UPA were included. Endoscopic response, remission, healing, and ulcer-free endoscopy were assessed at week 12. Meaningful improvements in clinical and QoL outcomes were evaluated at week 52.

A significantly greater proportion of patients who achieved an endoscopic response at the end of induction, compared with patients who did not, attained Crohn's Disease Activity Index (CDAI) remission (52.0% vs 34.6%; P ≤ .01), corticosteroid-free CDAI remission (50.0% vs 30.9%), Inflammatory Bowel Disease Questionnaire remission (52.6% vs 30.3%), and meaningful improvements in Functional Assessment of Chronic Illness Therapy-Fatigue response (46.7% vs 25.9%), overall work impairment (47.1% vs 26.5%), and daily activity impairment (53.3% vs 34.1%) (all P < .05) at week 52. Similar findings were observed for patients who achieved endoscopic remission, endoscopic healing, and ulcer-free endoscopy at the end of induction vs those who did not.

Early improvement in endoscopic outcomes after UPA induction treatment was associated with long-term meaningful improvements in clinical outcomes and QoL in patients with CD.

U-EXCEED induction trial (NCT03345836), U-EXCEL induction trial (NCT03345849), and U-ENDURE maintenance trial (NCT03345823).

Endoscopic remission has emerged as an important treatment target in Crohn's disease (CD) and has been associated with improvement in long-term outcomes. We examined the relationship between achievement of endoscopic remission and hospitalizations using pooled data from 52-week Phase III maintenance trials of risankizumab and upadacitinib in patients with moderate-to-severe active CD.

Included patients received maintenance therapy after achieving a clinical response following a 12-week induction with risankizumab or upadacitinib. Endoscopic remission was defined as a Simple Endoscopic Score for Crohn's Disease (SES-CD) of no greater than 4, with at least a 2-point reduction vs induction baseline and no subscore greater than 1. All subsequent hospitalization events were recorded until completion of the maintenance trial or discontinuation. Exposure-adjusted negative binomial regression models were estimated to assess the relationship between post-induction endoscopic remission and long-term hospitalization, controlling for demographics, clinical variables, and treatment arm.

Post-induction hospitalization rates were lower in patients who achieved endoscopic remission at the end of the induction period. In multivariable models, post-induction endoscopic remission was independently associated with incidence rate ratios of 0.45 (95% confidence interval [CI], 0.22-0.95, p = 0.036) and 0.71 (95% CI, 0.44-1.14, p = 0.156) for long-term disease-related and all-cause hospitalizations, respectively.

Week 12 endoscopic remission is independently associated with a reduction in 52-week disease-related hospitalizations. However, achieving this stringent endpoint within 12 weeks of therapy may be challenging. Endoscopic response may be a more realistic early endoscopic target in the post-induction timeframe. Additional research is needed to evaluate early achievement of alternative endoscopic endpoints in CD.

A treat-to-target strategy for inflammatory bowel disease (IBD) recommends iterative treatment adjustments to achieve clinical and endoscopic remission. In asymptomatic patients with ongoing endoscopic activity, the risk/benefit balance of this approach is unclear, particularly with prior exposure to advanced therapies.

Using the RAND/University of California Los Angeles Appropriateness Method, 9 IBD specialists rated appropriateness of changing therapy in 126 scenarios of asymptomatic patients with ulcerative colitis and Crohn's disease and active endoscopic disease. Disease extent and behavior, prior treatment, prior complications, and recent disease progression were considered, as were factors that might influence decision-making, including age and pregnancy. Ratings were collected through anonymous survey, discussed at an in-person meeting, and finalized in a second anonymous survey.

Panelists rated change in therapy as appropriate (i.e., expected benefit sufficiently outweighs potential harms from continuing therapy) in 96/126 scenarios, generally in patients with progressive, complicated, and/or extensive disease, while changing therapy was rated uncertain in 27 scenarios of mild and/or stable disease. Changing therapy was rated inappropriate in ulcerative colitis patients with mild and stable disease previously exposed to ≥3 therapies or with improved endoscopic activity, and in Crohn's disease patients with only scattered aphthous ulcers. The validated threshold for disagreement was not crossed for any scenario. Patient age older than 65 years and a plan for pregnancy in the next year might influence decision-making in some settings.

Appropriateness ratings can help guide clinical decision-making about changing therapy to achieve endoscopic remission in asymptomatic patients with IBD until data from ongoing randomized studies are available.

Capsule endoscopy has been proven as an efficient and accurate tool in the diagnosing and monitoring patients with inflammatory bowel disease, especially Crohn's disease (CD). The current European Crohn's and Colitis Organization guidelines recommend small bowel disease assessment in newly diagnosed CD, wherein small bowel capsule endoscopy (SBCE) is of prime importance. SBCE plays an essential role in assessing mucosal healing in patients with CD, serving as a monitoring tool in a treat to target strategy, and is capable of identifying high-risk patients for future flares.

In phase 3 induction (ADVANCE and MOTIVATE) and maintenance (FORTIFY) trials, risankizumab was shown to benefit symptom and endoscopic defined outcomes in patients with Crohn's disease (CD). We examined the effects of risankizumab on the incidence of CD-related hospitalizations in these studies.

Patients with active CD were randomized to intravenous (IV) risankizumab 600 or 1200 mg, or placebo at weeks 0, 4, and 8 in the 12-week induction studies. Clinical responders were rerandomized to maintenance with subcutaneous (SC) risankizumab 180 or 360 mg or placebo every 8 weeks for 52 weeks. Incidence of CD-related hospitalizations was compared between groups, expressed as proportions with an event during induction and event/100 person-years (PYs) during maintenance. An integrated analysis incorporated exposure time and occurrence of CD-related hospitalizations in induction and maintenance periods for labeled doses.

The incidence of CD-related hospitalizations was lower (3.2% or 1.9% vs 11.6%; P < .01) in the risankizumab IV 600- and 1200-mg groups vs placebo IV during induction. Through 52 weeks, the incidence rate per 100 PYs of CD-related hospitalizations was similar among treatment groups, with few events reported (n = 5-9 per group). In the integrated analysis, a lower incidence rate per 100 PYs of CD-related hospitalizations was observed in the risankizumab-treated groups (600 mg IV/360 mg SC: 9.6; 600 mg IV/180 mg SC: 7.9) vs placebo (40.0, P < .001).

Risankizumab treatment resulted in reduced rates of CD-related hospitalization with treatment effect observed within 12 weeks of randomization.

Transmural healing, including as assessed by magnetic resonance enterography (MRE) has been associated with long-term favorable outcomes in Crohn's Disease (CD), but data concerning MRE improvement and normalization with therapy are sparse. We performed a prospective longitudinal study utilizing the recently developed pediatric MRE-based multi-item measure of inflammation (PICMI) to examine the efficacy of adalimumab (ADA) and immunomodulator (IM) in attaining improvement of transmural inflammation of the small intestine.

Pediatric patients with CD involving small bowel and initiating ADA or IM were prospectively enrolled and followed with repeat MRE at 1 year. A single radiologist provided global assessment (RGA) and scored PICMI items (wall thickness, wall diffusion restriction, mural ulcers, comb sign, mesenteric edema) blinded to clinical information and to the timing of MRE. The primary outcome was mild improvement in PICMI at one year without a change in therapy.

Sixty-two eligible patients were enrolled, 26 receiving ADA and 36 IM. On intent to treat basis, a decline in PICMI score of >20 points without change of therapy was observed more frequently in ADA versus IM-treated patients (54% vs 31%, P = .01). By RGA, 71% improved with ADA vs 42% with IM (P = .03). MRE normalization was rare with both treatments (9% vs 6%, P = .62). A change in PICMI of >20 points was confirmed as the best cut off for MRE improvement as assessed by RGA also for the small bowel.

ADA therapy was associated with objective improvement in MRE findings of inflammation more frequently than IM. The low rate of MRE normalization suggests that this is not yet a realistic target with existing therapies.

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) characterised by endoscopic inflammation, progressive bowel damage and gastrointestinal lesions. Although treatment strategies for CD have traditionally focused on a stepwise pharmacological approach to achieve clinical remission or symptom resolution, these treatment goals correlate poorly with disease activity. Thus, achieving full clinical remission and full endoscopic healing alone may be insufficient, as patients may remain at risk of inflammatory complications. Individualised 'treat-to-target' (T2T) pharmacological and treatment approaches represent a promising strategy for improving endoscopic remission and symptom resolution among patients with CD. The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) and STRIDE-II guidelines, launched in 2013 and later renewed, identified individualised targets for a T2T therapeutic approach for patients with IBD. These guidelines facilitate the individualisation of target treatment goals through evidence-based, long-term (health-related quality of life, absence of disability, endoscopic healing) and intermediate/short-term (abdominal pain, stool frequency, normalisation of biomarker levels) treatment targets, allowing patients and clinicians to consider the risk-to-benefit balance of goals and selected therapeutic strategies. This article aims to summarise the STRIDE-II guidelines and provide intellectual guidance for healthcare professionals to apply the STRIDE-II principles to current clinical practice in the United Kingdom (UK). Management recommendations for primary and secondary first-line non-responders are provided, along with suggestions for utilising the endoscopic outcomes scoring system in UK clinical practice.

Crohn's disease (CD) is a chronic inflammatory bowel disease affecting the entire gastrointestinal tract with a progressive and relapsing course. Achieving mucosal healing has emerged as a critical therapeutic goal, as it is associated with sustained clinical remission, reduced hospitalizations, and fewer surgery rates. Therefore, targeting mucosal healing is essential for long-term control in CD.

This review evaluates the efficacy of novel biologic therapies and small molecules in inducing mucosal healing, specifically targeting pathways like IL-12/23, IL-23, α4β7 integrins, Janus kinase 1 (JAK1), and sphingosine-1-phosphate receptor (S1PR) in adults (≥18 years) with moderate-to-severe CD. The rationale for selecting these specific pathways is their central role in modulating key inflammatory processes implicated in CD pathogenesis. We compare these therapies with placebo for both induction and maintenance of remission, based on a PubMed literature review for published articles and ClinicalTrials.gov for ongoing trials.

Upadacitinib and anti-IL23p19 agents (risankizumab, guselkumab and mirikizumab) are promising advanced non-TNF-targeting therapies for inducing endoscopic remission and mucosal healing but further studies are needed to integrate mucosal healing into a broader definition of endoscopic response, with a unified and precise definition.

Introduction: Acute severe ulcerative colitis (ASUC) represents a life-threatening medical emergency. One-third of ASUC patients are steroid non-responders. Our study aimed to create a new ASUC algorithm to predict corticosteroid response in the early course of the disease. Materials and Methods: A cross-sectional study included 103 patients with ASUC (65 male, 38 female). We calculated the serum CRP to 25-hydroxy 25 OH vitamin D ratio at admission. Logistic regression determined patients' response to glucocorticoids, depending on the CRP/25 OH vitamin D ratio value. Results and Discussion: Significant differences were observed in the CRP/25 OH vitamin D ratio at admission between glucocorticoid responders and non-responders (p = 0.001). A negative correlation was found between glucocorticoid response and CRP/25 OH vitamin D levels (Spearman's rho = -0.338, p < 0.01). Logistic regression revealed a significant association (p = 0.003) with a model chi-square value of 11.131 (p = 0.001). ROC curve analysis showed an AUC of 0.696 (p = 0.001), indicating moderate discriminatory ability. To achieve 91% sensitivity, the CRP/25 OH vitamin D ratio must be less than 3.985 to predict a complete glucocorticoid response. Conclusions: The serum CRP to 25 OH vitamin D ratio on the first day of hospital admission can potentially determine the response to glucocorticoids in patients with ASUC and significantly affect the mortality of these patients.

Intestinal ultrasound (IUS) is becoming a standard assessment tool in Crohn's disease (CD), but limited data exist on its ability to predict long-term objective outcomes. Therefore, we aimed to investigate the predictive value of IUS findings for long-term transmural healing (TH) and mucosal healing (MH) in CD.

We prospectively included consecutive CD patients with active endoscopic disease and bowel wall thickness (BWT) >3.0 mm, initiating infliximab. Intestinal ultrasound parameters (ie, BWT, inflammatory mesenteric fat [i-fat], bowel blood flow and stratification) and International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) were collected at baseline, after 14 to 26 weeks (visit 1, postinduction) and 44 to 56 weeks (visit 2). Transmural healing (normalization of all IUS parameters) and MH (SES-CD ≤2) were assessed at visit 2.

One hundred twenty-nine patients were evaluated. At visit 2, 38.0% and 48.1% of patients achieved TH and MH, respectively. All the IUS parameters and IBUS-SAS showed improvement at visit 1 and visit 2 compared with the baseline (all P < .001). Multivariable analysis found that presence of i-fat at baseline (odds ratio [OR], 0.57; P = .008) and greater postinduction BWT (OR, 0.24; P < .001) were negative predictors for TH, while higher baseline (OR, 0.98; P = .013) and postinduction (OR, 0.94; P < .001) IBUS-SAS predicted negatively for MH. Postinduction BWT <4.5mm best predicted TH (AUC 0.85; P < .001), while postinduction IBUS-SAS <25.0 best predicted MH (AUC 0.82; P < .001). Moreover, colonic disease was associated with higher risk of TH (OR, 2.55; P = .027), and disease duration >24 months with lower risk of MH (OR, 0.27; P = .006).

Baseline and postinduction IUS findings reliably predict long-term TH and MH in patients with CD receiving infliximab.

The role of ustekinumab therapeutic drug monitoring in patients with Crohn's disease (CD) remains ambiguous. Examination of the association serum ustekinumab concentrations and endoscopic outcomes has yielded inconsistent results. Our study examined whether serum ustekinumab concentrations were associated with endoscopic healing in patients with moderate-to-severe CD.

This was a cross-sectional study of adult patients with CD on maintenance ustekinumab. Patients were included if they had serum ustekinumab concentrations and endoscopic evaluation taken within 4 months of each other. Endoscopic healing was defined as absence of ulceration on endoscopy or Simplified Endoscopic Score for Crohn's disease (SES-CD) < 3. Quartile analysis of drug levels was performed, and receiver operating characteristic curve was calculated. Multivariate logistic regression assessed for the probability of endoscopic healing based on serum ustekinumab concentration.

Seventy-four patients were included in the final analysis. The mean serum ustekinumab concentration of the population was 6.10 mcg/mL. Serum ustekinumab concentration did not predict endoscopic remission based on either the absence of ulceration or SES-CD < 3. There was no difference in the frequency of ulceration at increasing serum ustekinumab concentrations. There was no threshold serum ustekinumab concentration associated with the absence of ulceration (area under the curve [AUC] = 0.50) or SES-CD < 3 (AUC = 0.49).

Our study found no association between serum ustekinumab concentrations and endoscopic remission in patients with CD. Exploration of mechanisms accounting for this lack of association is warranted.

We evaluated the association between endoscopic outcomes following risankizumab induction and subsequent rates of hospitalization and surgery through 52 weeks of risankizumab (both doses) maintenance therapy in patients with Crohn's disease (CD).

Patients with moderately to severely active CD and clinical response to 12-week risankizumab induction were rerandomized to continued therapy or drug withdrawal in the phase 3 FORTIFY maintenance trial. Incidence rates (events/100 person-years) of CD-related hospitalization and surgery, and the composite of both, through 52 weeks of maintenance were compared between patients achieving vs not achieving predefined endoscopic outcomes following induction.

Patients who achieved vs did not achieve endoscopic response or remission, or absence of ulcers (ulcer-free endoscopy) after induction had reduced rates of CD-related hospitalization through 52 weeks of risankizumab maintenance (endoscopic response, 1.7 vs 7.9/100 person-years; endoscopic remission, 1.2 vs 6.9/100 person-years; ulcer-free endoscopy, 1.5 vs 6.4/100 person-years; all P < .05). No CD-related surgeries were observed through 52 weeks of risankizumab maintenance among patients who achieved vs did not achieve endoscopic outcomes following induction (endoscopic response, 0 vs 3.2/100 person-years; endoscopic remission, 0 vs 2.6/100 person-years; ulcer-free endoscopy, 0 vs 2.4/100 person-years; all P = .025). In contrast, patients who received placebo during maintenance had statistically similar rates of CD-related hospitalizations and surgeries regardless of achievement of endoscopic outcomes after induction.

Patients achieving endoscopic outcomes following risankizumab induction experienced less CD-related hospitalizations and surgeries through 52 weeks of maintenance when continuing active therapy. Early treatment success may predict favorable long-term outcomes of disease.

ADVANCE (NCT03105128); MOTIVATE (NCT03104413) and FORTIFY (NCT03105102).

To compare the recently proposed Capsule Endoscopy-Crohn's Disease index (CE-CD) to pre-existing capsule endoscopy (CE) scores, to measure its precision and accuracy to predict adverse clinical outcomes in children with Crohn's disease (CD).

Children with CD who underwent CE at diagnosis and had, at least, 1-year follow-up postprocedure were selected. Capsule study was viewed and the different indices were independently scored by two trained paediatric gastroenterologists. The relationship between pre-existing scores and CE-CD was assessed by linear regression analysis. Clinical outcomes prediction assessment was based on receiver operating characteristics curves, survival analysis and Cox regression. Finally, interobserver agreement was measured.

Fifty-nine patients were finally included. CE-CD showed a strong positive correlation with the Lewis score (ρ = 0.947) and the Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) (ρ = 0.982). Both CE-CD and CECDAI were significant predictors of treatment escalation (hazard ratio 1.07 and 1.09, respectively, with both p-values < 0.01). However, no score predicted risk of hospital admission, surgery or clinical/endoscopic relapse. The presence of moderate-to-severe small bowel (SB) inflammation, defined as a score of ≥9 on CE-CD, provided a hazard ratio of treatment escalation of 2.6 (95% confidence interval: 1.3-5.3). This cut-off provided the optimal sensitivity/specificity pair: 48.4%/89.3%. No interobserver misclassification among inflammation categories given by CE-CD were observed (kappa 100%).

CE-CD is a useful tool to document SB inflammation in children with CD. It correlates strongly with classical scores, can better predict need for treatment escalation and shows good interobserver agreement.

We assessed Modified Multiplier Simple Endoscopic Score for Crohn's Disease (MM-SES-CD) and Simple Endoscopic Score for Crohn's Disease (SES-CD) thresholds that are best associated with low likelihood of long-term disease progression.

Data from 61 patients with early Crohn's disease (CD) who participated in the CALM long-term extension study were used as the derivation cohort and validated using the McMaster inflammatory bowel disease database (n = 99). The primary outcome was disease progression (new internal fistula/abscess, stricture, perianal fistula or abscess, CD-related hospitalization or surgery) since the end of the CALM trial. Optimal MM-SES-CD and SES-CD thresholds were determined using the maximum Youden index. Receiver operating characteristic curve analyses compared threshold scores of remission definitions on disease progression.

In the derivation cohort, based on the maximum Youden index, the optimal thresholds associated with a low likelihood of disease progression were MM-SES-CD <22.5 and SES-CD <4. A significantly greater proportion of patients with a MM-SES-CD ≥22.5 had disease progression as compared with patients in the derivation cohort with MM-SES-CD <22.5 (10/17 [58.8%] vs 3/44 [6.8%]; P < .001). Similarly, a significantly greater number of patients with SES-CD ≥ 4 had disease progression compared with those with a SES-CD <4 (11/25 [44.0%] vs 2/36 [5.6%]; P < .001). Compared with other clinical or endoscopic remission definitions, which demonstrated poor to fair accuracy, MM-SES-CD <22.5 performed the best for predicting disease progression (area under the curve = 0.81; 95% confidence interval, 0.68-0.94; P < .001). These thresholds were confirmed in the validation cohort.

Achievement of MM-SES-CD <22.5 or SES-CD <4 in patients with ileocolonic or colonic CD is associated with low risk of disease progression and may be suitable targets in clinical trials and practice for endoscopic healing.

It is uncertain whether a treat-to-target approach could be an effective strategy for improving outcomes in children with Crohn's disease (CD). Previously, we reported mucosal healing (MH) and deep remission rates throughout the intestinal tract by performing 3 pan-enteric capsule assessments and using a treat-to-target strategy over 52 weeks in children with CD. This report describes the outcomes of this approach at 104 weeks.

Children with known CD who completed the 52-week protocol repeated pan-enteric capsule endoscopy (PCE) at 104 weeks. Results at weeks 52 and 104 were compared, and long-term outcomes between patients, with and without MH, were calculated using an intention-to-treat analysis of clinical relapse, need for steroids, treatment escalation, hospitalization, and surgery.

Of the previous study cohort of 48 patients, 46 (96%) were available for this extension study (28 [61%] of 46 with MH and 18 [39%] of 46 without MH at 52 weeks). When evaluated at 104 weeks, MH was maintained in 93% of patients with MH at 52 weeks. In the intention-to-treat analysis, complete MH at 52 weeks was associated with reduced risk of steroid use (log-rank P < .0001), treatment escalation (log-rank P < .0001), hospitalization (log-rank P < .0001), and clinical relapse (log-rank P < .0001).

When a PCE-based, treat-to-target strategy is employed, MH is sustainable (93%) over a 1-year period and is correlated with improved patient outcomes, including reduced need for steroids, treatment escalation, hospitalization, and clinical relapses at 104 weeks.ClinicalTrials.gov number: NCT03161886.

Data on infliximab efficacy in bio-exposed patients with ulcerative colitis (UC) are limited.

To evaluate infliximab effectiveness and its predictors in UC patients with prior exposure to subcutaneous (SC) anti-TNF agent.

In this multicenter retrospective study (8 centers), we included all consecutive UC patients with prior exposure to subcutaneous anti-TNF, starting infliximab for symptomatic UC, excluding acute severe colitis. Corticosteroid-free clinical remission (CFREM) was assessed at week 14 (W14) and W52 while endoscopic improvement (CFREM + endoscopic Mayo score≤1) was evaluated at W14.

Overall, 104 patients were included (pancolitis=54.8%, primary failure to subcutaneous anti-TNF=57.4%, concomitant immunosuppressant=53.8%, median partial Mayo score at baseline=7[5-8]). The rate of CFREM was 33.6% (35/104) at W14 and 40.4% (42/104) at W52. At W14, endoscopic improvement was achieved in 29.8%(31/104). In multivariable analysis, concomitant immunosuppressant was associated with higher rate of CFREM at W14(OR=2.83[1.06-7.54], p = 0.037) and W52(OR=2.68[1.16-6.22];p = 0.021), while primary failure to a previous subcutaneous anti-TNF agent led to lower rate of CFREM at W14 (OR=0.37[0.14-0.98], p = 0.046). After a median follow-up of 20.9 months[11.7-33.7]), 50.0%(52/104) patients had discontinued infliximab.

Infliximab is an effective option in UC patients previously exposed to prior subcutaneous anti-TNF agent and should be used with concomitant immunosuppressant.

Endoscopy is still the gold, standard for assessing disease activity in Crohn's disease (CD). Its invasiveness, poor acceptability, and cost limit its use in the era of tight control and treat-to-target management. Fecal calprotectin (FC) and intestinal ultrasound (IUS) are non-invasive alternatives to colonoscopy to assess disease activity. We aimed to evaluate the performance of IUS and FC to assess mucosal healing in CD.

All consecutive CD patients who underwent colonoscopy for mucosal healing assessment and IUS and/or FC within four weeks between September 2019 and April 2022 were included in a prospective cohort. The bowel-wall thickness (BWT) and color Doppler signal (CDS) were assessed for each segment. Endoscopic remission was defined by a CDEIS score < 3.

In total, 153 patients were included, of whom 122 showed endoscopic mucosal healing. Eighty-two (53.6 %) were female, the median was age 36 years (IQR, 28-46), and the median disease duration was 10 years (IQR, 4-19). The sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) of a BWT < 3 mm to predict endoscopic mucosal healing were 56 %, 88 %, 95 %, and 36 %, respectively (patients misclassified as mucosal healing, 2.5 %). The best FC threshold (< 92.9 µg/g) provided similar results: 77 %, 89 %, 96 %, and 67 %, respectively (patients misclassified, 2.2 %). The association of an FC < 250 µg/g with a BWT < 3 mm and the absence of CDS increased the Sp and PPV: Se 58 %, Sp 95 %, PPV 97 %, VPN 43 %; patients misclassified, 1.3 %.

Noninvasive evaluation of mucosal healing by IUS or calprotectin efficiently identifies patients with CD who have achieved endoscopic mucosal healing.

Transmural healing (TH) has emerged as a potential treatment goal for Crohn's disease (CD). However, further research is needed to confirm its benefits and risk factors associated with TH remain unclear.

We aimed to assess the value of TH based on magnetic resonance enterography (MRE) in Chinese CD patients regarding the long-term outcomes and its associated factors.

Retrospective, observational cohort study.

Patients with CD diagnosed by colonoscopy and MRE examination between 2015 and 2022 were included. All patients were evaluated with endoscopy together with MRE within 6-12 months after baseline and followed up for at least 6 months after evaluation. The primary endpoint was the occurrence of major outcomes during the follow-up, including drug escalation, hospitalization, and surgery. The cumulative probabilities of major outcomes were calculated using Kaplan-Meier survival curves. Logistic regression analyses were used to predict TH within 6-12 months after baseline.

A total of 175 patients were included in the study. Of these, 69 (39.4%) patients achieved mucosal healing (MH), but only 34 (19.4%) of them achieved TH. The median follow-up duration was 17.4 months (interquartile range, 11.6-25.5), and major outcomes occurred in 58.3% of patients. A lower occurrence rate of major outcomes was noted in patients who achieved TH than in those who achieved MH only (p = 0.012). The baseline lymphocyte/C-reactive protein ratio (LCR) [odds ratio (OR), 1.60; 95% confidence interval (CI), 1.02-2.50; p = 0.039] and bowel wall thickness (BWT) (OR, 0.72; 95% CI, 0.59-0.90; p = 0.003) were independent predictors associated with TH. According to multivariate Cox regression analysis, low LCR [hazard ratio (HR), 2.34; 95% CI, 1.51-3.64; p < 0.001], and no healing (HR, 5.45; 95% CI, 2.28-13.00; p < 0.001) were associated with an increased risk of major outcomes.

Patients with CD who achieved TH showed improved prognosis compared to those who achieved MH only. Baseline LCR and BWT might predict TH.

Inflammatory bowel disease (IBD) is a chronic relapsing disease of the gastrointestinal (GI) system that includes two groups, Crohn's disease (CD) and ulcerative colitis (UC). To cope with these two classes of IBD, the investigation of pathogenic mechanisms and the discovery of new diagnostic and therapeutic approaches are crucial. Long non-coding RNAs (lncRNAs) which are non-coding RNAs with a length of longer than 200 nucleotides have indicated significant association with the pathology of IBD and strong potential to be used as accurate biomarkers in diagnosing and predicting responses to the IBD treatment. In the current review, we aim to investigate the role of lncRNAs in the pathology and development of IBD. We first describe recent advances in research on dysregulated lncRNAs in the pathogenesis of IBD from the perspective of epithelial barrier function, intestinal immunity, mitochondrial function, and intestinal autophagy. Then, we highlight the possible translational role of lncRNAs as therapeutic targets, diagnostic biomarkers, and predictors of therapeutic response in colon tissues and plasma samples. Finally, we discuss the potential of extracellular vesicles and their lncRNA cargo in the pathophysiology, diagnosis, and treatment of IBD.

Crohn's disease and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by a progressive nature of the disease resulting in subsequent intestinal damage, limited efficacy of current treatments and suboptimal disease management and a significant burden for patients.

The IBD-PODCAST study aims to estimate the proportion of Crohn's disease and UC patients with suboptimal disease control (SDC) in a real-world setting.

A non-interventional and cross-sectional study was conducted across 103 sites in 10 countries (Austria, Belgium, Canada, Germany, Greece, Italy, Portugal, Spain, Turkey, and UK). Criteria for SDC were based on STRIDE-II criteria and adapted by an expert panel.

2185 patients (Crohn's disease: n = 1,108, UC: n = 1077) with a mean (SD) age of 44.0 (14.8) years and mean (SD) disease duration of 12.4 (9.2) years were included (52.2% male). Ileal involvement was present in 39.1% of Crohn's disease patients, 35.3% of UC patients had extensive colitis. 77.3% of Crohn's disease and 65.3% of UC patients were on targeted immunomodulators and, according to STRIDE-II-based treatment phases, 85.6% of Crohn's disease and 85.4% of UC patients were assigned to the long-term treatment phase. SDC was detected in 52.2% of Crohn's disease and 44.3% of UC patients predominantly due to impaired quality of life (QoL), clinically significant extraintestinal manifestations, steroid overuse, signs of active inflammation in UC and Crohn's disease, and active fistulas in Crohn's disease. More than one criterion was seen in 37% of patients with SDC. Opportunities for on-label treatment optimization were observed in 49% of Crohn's disease and 61% of UC patients on advanced therapy.

The high percentage of SDC in this global, real-world cohort suggests a large disease burden and high unmet medical need in IBD patients. Future analysis should focus on monitoring and responding to SDC in this cohort and on patients' QoL.

Mucosal healing (MH) has become a perspective treatment target in patients with Crohn's disease (CD). Data about the impact of MH on long-term outcome in pediatric patients are still scarce.

Seventy-six pediatric patients with CD were evaluated retrospectively (2000-2015) in a tertiary care center. Based on MH achievement, they were divided into two groups (MH, N.=17; and No MH, N.=59). The primary endpoint was to assess the association of MH and the need for CD-related hospitalizations or surgery in pediatric patients with CD.

The number of hospitalized patients was 24% in the MH group and 42% in the No MH group (P=0.26). The total number of CD-related hospitalizations was not significant between the MH group and the No MH group (5 vs. 41, P=0.15). The time to the first hospitalization was 24 months in MH and 21 months in No MH (P>0.99). About 24% of the patients in the MH group and 39% patients in the No MH group underwent CD-related operation (P=0.39). Time to the first operation was 43 months for MH and 19 months for the No MH group (P=0.13). The follow-up period was 91 months in the MH group and 80 months in the No MH group (P=0.74). The use of infliximab was positively associated with MH (P=0.002).

MH was not associated with fewer CD-related hospitalizations or operations in pediatric patients with CD during seven years of follow-up.

Background: Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and Ulcerative colitis (UC). The main goal of treatment is to obtain mucosal healing via endoscopy. More recently, intestinal ultrasounds, along with biochemical markers, have been increasingly popular as point-of-care testing to monitor treatment response. This systemic review and meta-analysis aimed to assess the diagnostic test performance of ultrasonography and biochemical markers (C-reactive protein and fecal calprotectin) compared with endoscopy for detecting inflammation in IBD. Methods: A comprehensive literature search was conducted using PubMed Medline, EMBASE, ScienceDirect, and CINAHL from 1 January 2018 to 1 January 2024. The included studies were prospective and retrospective observational studies, clinical trials, and cross-sectional studies investigating the diagnostic sensitivity and specificity of ultrasonography, biochemical markers, and endoscopy. Studies were selected based on the Preferred Reporting Items for Systematic Review and Meta-analysis Statement (PRISMA). Results: Of the 1035 studies retrieved, 16 met the inclusion criteria, and most of the included studies were prospective observational studies. Diagnostic test accuracy was conducted, and the pooled sensitivity and specificity of all the studies revealed that ultrasonography has the highest pooled sensitivity, at 85% (95% CI, 78 to 91%), and specificity, at 92% (95% CI, 86 to 96%), as compared with biochemical markers and endoscopy. More specifically, biochemical markers had a pooled sensitivity and specificity of 85% (95% CI, 81 to 87%) and 61% (95% CI, 58 to 64%), respectively, and endoscopy had 60% (95% CI, 52 to 68%) and 82% (95% CI, 76 to 87%), respectively. However, the results also show substantial heterogeneity in the studies because of various populations, protocols, and outcomes in the studies included. This was especially noted in the assessment of biochemical markers, in which a metaregression was performed showing a nonsignificant p-value of 0.8856 for the coefficient. Conclusions: IUS was found to have the highest pooled sensitivity and specificity of all the included studies for diagnosing inflammation in patients with CD and UC, and this, coupled with biochemical markers, can improve diagnostic utility.

Increasing evidence supports the use of transmural remission as a treatment target in Crohn's disease (CD), but it is seldom achieved in clinical practice. Tight monitoring of inflammation using fecal calprotectin with reactive treatment escalation may potentially improve these results.

To evaluate if treatment escalation based on fecal calprotectin can improve the rates of transmural remission in CD. The influence of the timing of intervention on this strategy was also evaluated.

Retrospective cohort study including 256 CD patients with 2 consecutive assessments by MRI-enterography and colonoscopy and with regular monitoring using fecal calprotectin. For each occurrence of an elevated fecal calprotectin (≥250 μg/g), we evaluated whether a reactive adjustment of medical treatment was performed. The ratio of treatment escalation/elevated fecal calprotectin was correlated with the chances of reaching transmural remission. Early disease was defined as disease duration <18 months without previous exposure to immunomodulators and biologics.

After a median follow-up of 2 years (IQR 1-4), 61 patients (23.8%) reached transmural remission. Ratios of escalation ≥50% resulted in higher rates of transmural remission (34.2% vs. 15.1%, p < 0.001). The effect was more pronounced in patients with early disease (50.0% vs. 12.0%, p = 0.003). In multivariate analysis, a treatment escalation ratio ≥50% (OR 3.46, 95% CI 1.67-7.17, p = 0.001) and early disease intervention (OR 3.24, 95% CI 1.12-9.34, p = 0.030) were independent predictors of achieving transmural remission.

Tight-monitoring and reactive treatment escalation increase the rates of transmural remission in CD. Intervention in early disease further improves these results.

Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies.

PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228).

Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight).

Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease.

Wellcome and PredictImmune Ltd.

Endoscopic mucosal healing serves as a critical predictor for achieving long-term remission in Crohn's disease treatment. Recent data indicate that the effectiveness of healing varies based on the location of gastrointestinal inflammation. Additionally, reports suggest that antitumor necrosis factor-α (anti-TNF-α) agents exhibit reduced efficacy in treating small intestinal inflammation compared to colorectal inflammation. Conversely, limited research exists regarding the impact of the anti-IL12/23 agent ustekinumab (UST) on small intestinal inflammation. This study aimed to compare the effects of anti-TNF-α agents and UST on small intestinal inflammation using propensity score analysis.

This retrospective observational study involved 70 patients with Crohn's disease who had inflammation in the small intestine and had initiated treatment with either anti-TNF agents or UST between March 2015 and August 2021. Endoscopic findings were evaluated before treatment commencement and at 1-2 years post-treatment initiation. The propensity score was employed to compare the efficacy of TNF agents and UST on small bowel inflammation.

Ustekinumab exhibited greater improvement in the small intestinal endoscopy score than anti-TNF-α antibodies according to the propensity score analysis (inverse probability weighting; P = .0448). However, no significant disparity was observed in the overall improvement of endoscopic scores between UST and anti-TNF-α antibodies (P = .5938).

This study suggests that UST might be more effective than anti-TNF-α agents in treating small intestinal inflammation in Crohn's disease.