Add-on multiple submucosal injections of the RNA oligonucleotide GUT-1 to anti-TNF antibody treatment in patients with moderate-to-severe ulcerative colitis: an open-label, proof-of concept study.

BACKGROUND: Carbohydrate sulfotransferase 15 (CHST15) is an enzyme biosynthesizing matrix glycosaminoglycan that modulates tissue remodeling. We evaluated the efficacy of add-on submucosal injections of GUT-1, the RNA oligonucleotide inhibitor of CHST15, to ongoing anti-tumor necrosis factor (TNF) antibody treatment in patients with moderate-to-severe ulcerative colitis (UC). METHODS: This was an open-label study of 250 nM of GUT-1 by endoscopic submucosal injections at weeks 0, 2, 4 in five UC patients who lost response during maintenance treatment to anti-TNF antibodies. The primary endpoint was the rate of endoscopic improvement at week 6 and secondary endpoints included the rates of clinical remission by modified Mayo Score (mMS). Patients received follow-up observation with continuous maintenance treatment by the same anti-TNF antibody till the time of clinical recurrence or for overall 52 weeks. RESULTS: At week 6, rates of endoscopic improvement and clinical remission were 80% (n = 4/5) and 60% (n = 3/5), respectively. The mean Endoscopy Subscore was reduced from 2.4 (95%CI: 1.7 to 3.1) at baseline, to 1.0 (95%CI: 0.1 to 1.9) at week 6. The mean mMS was reduced from 7.8 (95%CI: 6.2 to 9.4) to 1.3 (95%CI: 2.9 to 4.3). GUT-1 was well tolerated. Three patients did not show clinical recurrence for 52 weeks. All three corticosteroid-dependent patients showed no corticosteroid exposure for at least 24 weeks after achieving clinical remission. Multiple dosing was also well tolerated. CONCLUSIONS: Add-on multiple injections of GUT-1 to ongoing anti-TNF antibody was able to induce rapid and durable clinical responses in UC patients who lost response to anti-TNF therapy. TRIAL REGISTRATION: Clinical trial Registration Number (Japan): UMIN000020900.

Achievement of Clinical, Endoscopic, and Histological Outcomes in Patients with Ulcerative Colitis Treated with Etrasimod, and Association with Faecal Calprotectin and C-reactive Protein: Results From the Phase 2 OASIS Trial.

BACKGROUND AND AIMS: Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This post-hoc analysis of the phase 2 OASIS trial [NCT02447302] evaluated its efficacy for endoscopic improvement-histologic remission [EIHR] and assessed correlation between faecal calprotectin [FCP] and C-reactive protein [CRP] levels with efficacy outcomes. METHODS: In total, 156 adults with moderately to severely active UC received once-daily etrasimod (1 mg [n = 52]; 2 mg [n = 50]) or placebo [n = 54] for 12 weeks. Clinical, endoscopic, and histologic variables were evaluated at baseline and Week 12. EIHR was defined as achievement of endoscopic improvement [endoscopic subscore ≤ 1, without friability] and histologic remission [Geboes score < 2.0]. Outcomes included the relationships between FCP and CRP concentration and clinical, endoscopic, and histologic variables. RESULTS: Achievement of EIHR was significantly higher in patients who received etrasimod 2 mg versus placebo [19.5% vs 4.1%; Mantel-Haenszel estimated difference, 15.4%; p = 0.010]. In the etrasimod 2 mg group, median FCP and CRP levels at Week 12 were significantly lower in patients who achieved clinical remission, endoscopic improvement, histologic remission, and EIHR versus patients who did not [all p < 0.05]. An FCP concentration cutoff of 250 µg/g achieved optimum sensitivity and specificity for efficacy, including EIHR [0.857 and 0.786, respectively; κ coefficient, 0.3584]. Higher proportions of patients with FCP ≤ 250 µg/g achieved efficacy outcomes at Week 12 versus patients with FCP > 250 µg/g. CONCLUSIONS: Etrasimod was effective for inducing EIHR in patients with UC. FCP and CRP may be useful, noninvasive biomarkers to monitor treatment response. CLINICALTRIALS.GOV NUMBER: NCT02447302.

A combination of bowel wall thickness and submucosa index is useful for estimating endoscopic improvement in ulcerative colitis: external validation of the Kyorin Ultrasound Criterion.

BACKGROUND: Endoscopic improvement (EI; a Mayo endoscopic subscore of 0 or 1) is considered a therapeutic target in ulcerative colitis (UC) treatment. The potential to estimate EI non-invasively is an advantage of intestinal ultrasound (IUS). In a previous study, we developed a new sonographic parameter, the submucosa index (SMI), calculated as the ratio of the submucosal thickness to bowel wall thickness (BWT), and reported that combining BWT and SMI results in a practical and promising criterion for estimating EI without color Doppler assessment. This study aimed to validate the EI estimation ability of our B mode-based criterion, the 'Kyorin Ultrasound Criterion for UC' (KUC-UC; BWT < 3.8 mm and SMI < 50%), using an external cohort. METHODS: Patients with UC who underwent IUS and colonoscopy within 15 days without a treatment change between examinations were included. IUS findings, including BWT, SMI, and modified Limberg score for vascularity of the colon, were assessed. RESULTS: Forty-four test pairs of IUS and colonoscopy examinations in a total of 122 colonic segments were analyzed. The KUC-UC showed positive predictive value (PPV) of 94.6% and negative predictive value (NPV) of 80.0% for EI. In comparison, PPV and NPV were 85.4% and 79.0%, respectively, for the common criterion BWT of < 3 mm, and 83.0% and 82.7% for the validated Milan Ultrasound Criteria (a score of ≤ 6.2). CONCLUSIONS: External validation showed that the KUC-UC using only B mode findings without complicated calculations is a feasible and accurate sonographic criterion for estimating the EI of UC.

Predicting Endoscopic Improvement in Ulcerative Colitis Using the Ulcerative Colitis Severity Index.

INTRODUCTION: We developed and internally validated a prognostic scoring index for ulcerative colitis (UC) patients that includes baseline patient-reported outcomes (PROs), biomarkers, endoscopy, and histology for achieving 1-year endoscopic improvement (EI). METHODS: This post hoc analysis included 644 patients treated with ustekinumab induction therapy. Data were randomly split to obtain a 70% training and 30% testing cohort. Multivariate analyses assessed baseline variables and those with P < .05 were assigned weights based on their relative prognostic value from logistic regression modeling for predicting 1-year EI (Mayo endoscopic score ≤1). A cutoff was obtained by calculating the maximum Youden index and validated in the testing cohort. RESULTS: Prior biologic failure, albumin <40 g/L, C-reactive protein >5 mg/L, Mayo stool frequency subscore, endoscopic erosions/ulcerations, and chronic histologic structural/architectural changes demonstrated significant associations with 1-year EI and were included in the final model. The Ulcerative Colitis Severity Index (UCSI) had acceptable discriminative ability for 1-year EI in the training (area under the curve [AUC], 0.78; 95% confidence interval, 0.70-0.86) and testing cohort (AUC, 0.76; 95% CI, 0.68-0.85). Compared with the UCSI, the Mayo Clinic score demonstrated poor accuracy (AUC, 0.49; 95% CI, 0.40-0.58) for predicting 1-year EI (P = .0006). The UCSI predicted 1-year endoscopic healing (Mayo endoscopic score = 0), clinical remission (total Mayo Clinic score ≤2 and no subscore >1), partial Mayo score remission <2, and 2-item Patient-Reported Outcome score (Mayo stool frequency and rectal bleeding subscore = 0) with significantly greater accuracy compared with the Mayo Clinic score. DISCUSSION: The UCSI is an internally validated prognostic scoring tool that accurately predicts 1-year EI at baseline among moderate-to-severe UC patients initiating therapy. Further validation with additional datasets is needed.

ENTERPRET: A Randomized Controlled Trial of Vedolizumab Dose Optimization in Patients With Ulcerative Colitis Who Have Early Nonresponse.

BACKGROUND & AIMS: Patients with ulcerative colitis (UC) may experience nonresponse to biologics, possibly as a result of low drug exposure. This trial assessed the efficacy of dose optimization in patients with UC who have early nonresponse to vedolizumab and high drug clearance. METHODS: ENTERPRET was a phase 4, open-label, randomized, controlled trial that included patients with moderate to severe UC who had high drug clearance at week 5 (serum concentration, <50 µg/mL) and nonresponse to standard vedolizumab treatment at week 6. At week 6, eligible patients were randomized 1:1 to receive standard dosing (300 mg every 8 weeks) or dose-optimized vedolizumab (600 mg at week 6, then 300 mg every 4 weeks; or 600 mg at week 6, then 600 mg every 4 weeks [based on week 5 serum concentration]). The primary end point was endoscopic improvement at week 30. RESULTS: Of 278 enrolled patients, 132 (47.5%) had a clinical response at week 6. From week 6, 108 patients received standard (n = 53) or dose-optimized vedolizumab (n = 55); among patients with nonresponse at week 6, 86.5% had high drug clearance. At week 30, 10 patients (18.9%) who received standard vedolizumab had endoscopic improvement vs 8 patients (14.5%) who received dose-optimized vedolizumab. Five patients (9.4%) who received standard vedolizumab had clinical remission at week 30 vs 5 patients (9.1%) who received dose-optimized vedolizumab; clinical response was observed in 17 (32.1%) and 17 patients (30.9%), respectively. Safety event rates were similar among treatment groups. CONCLUSIONS: In patients with early nonresponse and high drug clearance, vedolizumab dose optimization is probably not required. A proportion of patients benefited from continued treatment irrespective of the dose received. CLINICALTRIALS: gov: NCT03029143.

Systemic immune-inflammation index as a potential biomarker to monitor ulcerative colitis.

OBJECTIVE: The treat-to-target strategy is recommended by Selecting Therapeutic Targets in Inflammatory Bowel Disease II (STRIDE-II) for treating ulcerative colitis (UC), and monitoring remission status is crucial during this management. The systemic immune-inflammation index (SII), defined as platelet * neutrophil/lymphocyte, is a complete blood count-based index reflecting the balance of immune and inflammatory status. This study aims to investigate the feasibility of SII for diagnosing UC and monitoring UC disease activity. METHODS: This study retrospectively analyzed patients with UC and controls. Relationships between SII and Mayo clinical score, Mayo Endoscopic Score (MES), and Nancy Histological Index (NHI) were evaluated. RESULTS: 167 patients with UC and 106 controls were included. SII significantly increased in patients with UC and was closely correlated with the Mayo clinical score, MES, and NHI. SII diagnosed UC with a cut-off value of 619.1 × 109/L (area under the curve = 0.861, p < 0.0001, sensitivity 79.64%, specificity 77.36%), evaluated clinical remission status with a cut-off value of 1068 × 109/L (area under the curve = 0.691, p < 0.05, sensitivity 55.71%, specificity 81.48%), endoscopic improvement with a cut-off value of 981.3 × 109/L (area under the curve = 0.819, p < 0.0001, sensitivity 65.22%, specificity 89.66%), and histological healing with a cut-off value of 689.3 × 109/L (area under the curve = 0.898, p < 0.0001, sensitivity 88.89%, specificity 95.83%). CONCLUSION: SII is a potential biomarker for diagnosing UC and monitoring UC disease severity, especially in evaluating mucosal and histological healing during the long-term management in treat-to-target strategy. However, further research is needed to confirm its usefulness and optimize its clinical application.

Researchers studied an index calculated from a blood test, named the "systemic immune-inflammation index" (SII), to see if it can identify and track the activity of a bowel condition called ulcerative colitis (UC).They reviewed health records of UC patients and compared them to people without this condition. They specifically checked if the SII test's results aligned with other common tests that show the severity of UC.People with UC tended to have higher SII results. The SII test results were consistent with other tests for UC. Specific scores from the SII test, like 619.1 × 10⁹/L, can indicate someone might have UC. What's more, this test can give clues about inflammation in the bowel, saving some from more invasive tests like a colonoscopy or biopsy.The SII test could be a promising way for doctors to diagnose UC and gauge its activity without needing more intrusive tests. However, more studies are required to fully trust this approach.

Matching-Adjusted Indirect Comparison Between Risankizumab and Ustekinumab for Induction and Maintenance Treatment of Moderately to Severely Active Crohn's Disease.

INTRODUCTION: Risankizumab (RZB) and ustekinumab (UST), interleukin (IL)-23 and IL-12/23 inhibitors, respectively, are approved treatments for moderately to severely active Crohn's disease (CD); direct comparison between the two is ongoing. We indirectly compared efficacy of RZB versus UST using data from phase 3 trials (RZB: NCT03104413; NCT03105128; NCT03105102; UST: NCT01369329; NCT01369342; NCT01369355). METHODS: Matching-adjusted indirect comparison was conducted using individual patient-level data from RZB trials and published aggregated data from UST trials. During induction, patients received RZB 600 mg intravenous (IV) at weeks 0, 4, and 8 or a single dose of UST 6 mg/kg IV at week 0. During maintenance, patients received RZB 180 or 360 mg subcutaneous (SC) or UST 90 mg SC every 8 or 12 weeks to 52 weeks. Outcomes included proportion of patients achieving Crohn's Disease Activity Index (CDAI) response (decrease of ≥ 100 points or total score < 150) or remission (CDAI ≤ 150) and endoscopic improvement (measured by the Simple Endoscopic Score in CD [SES-CD]; response, ≥ 50% reduction from baseline; remission, SES-CD ≤ 2) following induction/baseline. RESULTS: Higher proportions of patients achieved clinical and endoscopic outcomes with RZB vs. UST induction treatment, resulting in significantly (p ≤ 0.05) greater percent differences (95% confidence intervals) between groups for CDAI remission (15% [5%, 25%]) and endoscopic response (26% [13%, 40%]) and remission (9% [0%, 19%]). Following maintenance, rates of CDAI remission were similar (range - 0.3% to - 5.0%) for RZB vs. UST. Differences for endoscopic response and remission ranged from 9.3% to 27.7% and 11.6% to 12.5%, respectively; differences were significant (p < 0.05) for endoscopic response for both doses of RZB compared to UST 12-week dosing. CONCLUSIONS: This indirect comparison demonstrated higher rates of clinical and endoscopic outcomes during induction for RZB compared to UST; CDAI remission following maintenance was comparable. Direct comparisons of RZB and UST are warranted to validate these findings.

Using individual patient-level data from risankizumab and aggregated data from ustekinumab phase 3 Crohn's disease trials, we indirectly compared efficacy of risankizumab and ustekinumab to determine whether rates of improvement in disease symptoms (clinical) and endoscopic outcomes differed between treatments. Findings showed that clinical and endoscopic outcomes were more frequently achieved for patients receiving risankizumab versus ustekinumab after induction, while most maintenance outcomes were comparable.

Delayed Ustekinumab Responders in Ulcerative Colitis Have Greater Inflammatory Burden but Similar Outcomes as Early Responders.

BACKGROUND & AIMS: Differences in 1-year outcomes among early compared with delayed responders to vedolizumab have been shown in ulcerative colitis. However, it is unclear whether similar differences exist with ustekinumab, and what factors differentiate delayed responders from nonresponders. METHODS: This study was a post hoc analysis of patient-level data from the UNIFI clinical trial. Ustekinumab-treated patients with clinical response, defined as a reduction in total Mayo score of 30% or more and 3 or more points from baseline with a reduction in their rectal bleeding subscore of 1 or more or a rectal bleeding subscore of 1 or less, at week 8 were deemed early responders and their outcomes were compared with delayed responders (week 8 nonresponders who subsequently responded at week 16). The primary outcome assessed was 1-year clinical remission, defined as a total Mayo score of 2 or less and no subscore greater than 1. RESULTS: We included 642 ustekinumab-treated patients, including 321 (50%) early responders, 115 (17.9%) delayed responders, and 205 (32.1%) nonresponders. No differences were observed for 1-year clinical remission among early vs delayed responders (132 of 321 [41.1%] vs 40 of 115 [34.8%]; P = .233), or for other outcomes assessed regardless of induction dose. Compared with early responders, delayed responders had more severe baseline Mayo endoscopic disease (88 of 115 [76.5%] vs 206 of 321 [64.2%]; P = .015) and abnormal baseline C-reactive protein level greater than 3 mg/L (83 of 115 [72.2%] vs 183 of 321 [57%]; P = .004). Compared with nonresponders, delayed responders had a significant decrease in C-reactive protein level (F-value [degrees of freedom, mean squares] [4, 844]; P < .0001) and fecal calprotectin level (F[4, 818]; P < .0001) through week 16. CONCLUSIONS: Compared with early ustekinumab responders, delayed responders had a greater inflammatory burden at baseline. Early and delayed responders had similar 1-year outcomes. Biomarker decline observed in delayed responders can help differentiate them from nonresponders.

Early-Phase Partial Mayo Score following Golimumab Treatment Is Associated with Endoscopic Improvement at 1 Year in Ulcerative Colitis: A post hoc Analysis of PURSUIT-J Randomized Controlled Trial.

Introduction: Golimumab (GLM) is an anti-tumor necrosis factor-alpha antibody therapy for moderately to severely active ulcerative colitis (UC). Endoscopic improvement is considered one of UC treatment's main goals, and earlier prediction of future endoscopic improvement has clinical implications. We retrospectively analyzed data from the PURSUIT-J, a phase III randomized controlled trial evaluating the efficacy of GLM in the maintenance phase, to find predictors for endoscopic improvement after 60 weeks of GLM treatment. Methods: Ninety-two patients who had completed the maintenance phase of the PURSUIT-J were divided into two groups: those with mucosal healing (MH: Mayo endoscopic subscore of 0 or 1) and those without MH at week 60 (non-MHs). Multivariate logistic regression analysis was conducted using baseline data in the induction phase to determine predictive factors for MHs compared to non-MHs. Results: Twenty-nine patients were classified as MHs and 63 as non-MHs. The multivariate logistic regression analysis showed that the odds ratio for partial Mayo (pMayo) score was highest in MHs (1.87 [95% CI: 1.18-2.98]) at baseline in the induction phase. The receiver operating characteristic analysis to determine the timing of predictions of MHs using pMayo showed that an area under the curve reached 0.8 at week 14 after the first GLM administration. Discussion/Conclusion: pMayo scores at week 14 of GLM treatment are associated with MH at week 60. These results suggest the timing when a clinical decision to continue GLM based on the patient-reported outcomes and the physician's general assessment could be considered.

Modeling Endoscopic Improvement after Induction Treatment With Mesalamine in Patients With Mild-to-Moderate Ulcerative Colitis.

BACKGROUND & AIMS: Endoscopic improvement is an important treatment target for mild-to-moderate ulcerative colitis (UC). However, early endoscopic evaluation is not always feasible. We aimed to develop a clinical decision support tool to discriminate patients who have achieved endoscopic improvement from those with more severe inflammation following mesalamine induction therapy. METHODS: We performed a post-hoc analysis of data from a phase 3 non-inferiority trial of 726 adults with mild-to-moderate UC treated with mesalamine. Multivariable logistic regression modeling determined associations between candidate variables and endoscopic improvement (Mayo endoscopic subscore=0-1 according to blinded central reading) at Week 8. Internal model validation was performed using bootstrap resampling. A clinical decision support tool was developed to stratify patients into low, intermediate, and high probability groups for endoscopic improvement. RESULTS: Variables associated with endoscopic improvement at Week 8 included 50% reduction in fecal calprotectin from baseline (odds ratio [OR] 2.64, 95% CI:, 1.81, 3.85), reduction in rectal bleeding (OR 1.79 per point reduction, 95% CI: 1.35, 2.39), and improvement in physician global assessment (OR 2.32 per point improvement, 95% CI: 1.88, 2.85). The baseline Geboes score (OR 0.74 per grade, 95% CI: 0.65, 0.85) and prolonged disease duration (OR 0.95 per year, 95% CI: 0.92, 0.98) were negatively associated with endoscopic improvement. This model strongly discriminated endoscopic improvement in the development dataset (area under the curve [AUC] 0.84, 95% CI: 0.81, 0.87) and during validation (AUC 0.83). CONCLUSIONS: We developed and validated a clinical decision support tool that has good discriminative performance for induction of endoscopic improvement in patients with mild-to-moderate UC treated with mesalamine. ClinicalTrials.gov Registration: NCT01903252.

Combination Therapy With Ustekinumab Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis in Patients With Refractory Ulcerative Colitis.

There are currently no reports on the efficacy and safety of combination therapy with ustekinumab (UST) plus intensive granulocyte and monocyte adsorptive apheresis (GMA) for the treatment of refractory ulcerative colitis (UC). We retrospectively evaluated the 10-week effectiveness of combination therapy with UST plus intensive GMA on refractory UC patients including two corticosteroid (CS)-dependent patients, two CS-refractory patients and one patient with loss of response to tacrolimus. Four patients were administered initial combination therapy of UST (6 mg/kg UST followed by subcutaneous injections of 90 mg UST every 8 weeks) plus intensive GMA. Of the four patients who received this combination therapy, two (50%) achieved clinical remission at 10 weeks. The rate of patients achieving endoscopic improvement (endoscopy subscore ≤ 1) at 10 weeks was 50%. In all cases, CSs were discontinued within 10 weeks. No adverse events were observed. Combination therapy with UST plus intensive GMA is helpful to reduce clinical disease activities in refractory UC patients and appears well tolerated.

Histologic Outcomes With Vedolizumab Versus Adalimumab in Ulcerative Colitis: Results From An Efficacy and Safety Study of Vedolizumab Intravenous Compared to Adalimumab Subcutaneous in Participants With Ulcerative Colitis (VARSITY).

BACKGROUND AND AIMS: VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis) showed superior clinical remission and endoscopic improvement in ulcerative colitis with vedolizumab vs adalimumab. This analysis compared histologic outcomes. METHODS: Patients in VARSITY were randomized 1:1 to maintenance with vedolizumab IV 300 mg every 8 weeks or adalimumab SC 40 mg every 2 weeks (both following standard induction). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52. RESULTS: In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Mean baseline histologic disease activity was similar between vedolizumab and adalimumab groups. Vedolizumab induced greater histologic remission than adalimumab at week 14 (Geboes: 16.7% vs 7.3%, Δ9.4% [95% confidence interval {CI}, 4.9%-13.9%], P < .0001; RHI: 25.6% vs 16.1%, Δ9.5% [95% CI, 3.8%-15.2%], P = .0011) and week 52 (Geboes: 29.2% vs 8.3%, Δ20.9% [95% CI, 15.6%-26.2%], P < .0001; RHI: 37.6% vs 19.9%, Δ17.6% [95% CI, 11.3%-23.8%], P < .0001) overall and in both anti-tumor necrosis factor (TNF)-naïve and -failure subgroups. Results were similar for minimal histologic disease activity. Histologic outcomes were generally better in anti-TNF-naïve vs -failure patients. At week 52, rates of mucosal healing (composite end point of histologic plus endoscopic improvement) were also higher with vedolizumab than adalimumab (Geboes: 25.6% vs 6.7%; RHI: 30.5% vs 14.5%). CONCLUSIONS: Higher rates of histologic remission, minimal histologic disease activity, and combined histologic plus endoscopic outcomes were observed with vedolizumab than with adalimumab in ulcerative colitis in both anti-TNF-naïve and -failure subgroups. REGISTRATION: ClinicalTrials.gov NCT02497469; EudraCT 2015-000939-33.

Epithelial Cell Biomarkers Are Predictive of Response to Biologic Agents in Crohn's Disease.

BACKGROUND: Therapeutic efficacy of biologics has remained at about 50% for 2 decades. In Crohn's disease (CD) patients, we examined the predictive value of an epithelial cell biomarker, ileal microvillar length (MVL), for clinical response to ustekinumab (UST) and vedolizumab (VDZ) and its relationship to another biomarker, intestinal epithelial cell (IEC) pyroptosis, with respect to response to VDZ. METHOD: Ileal biopsies from the UNITI-2 randomized controlled trial were analyzed for MVL as a predictor of clinical response to UST. In a 5-center academic retrospective cohort of CD patients, ileal MVL was analyzed to determine its predictive value for response to VDZ. Correlation between ileal MVL and IEC pyroptosis was determined, and the discriminant ability of the combination of 2 biomarkers to VDZ was examined. RESULTS: Clinical response in UST was significantly higher than placebo (65% vs 39%; P = 0.03), with patients with normal MVL (>1.7 µm) having the greatest therapeutic effect: 85% vs 20% (P = 0.02). For VDZ, clinical response with MVL of 1.35 to 1.55 µm was 82% vs 44% (<1.35 µm) and 40% (>1.55 µm; P = 0.038). There was no correlation between ileal MVL and IEC pyroptosis. The combination criteria of ileal pyroptosis <14 positive cells/1000 IECs or MVL of 1.35 to 1.55 µm could identify 84% of responders and 67% of nonresponders (P = 0.001). CONCLUSION: Ileal MVL was predictive of response to UST and VDZ in prospective and retrospective CD cohorts. It was independent of ileal IEC pyroptosis, and combination of the 2 biomarkers enhanced the discriminate ability of responders from nonresponders to VDZ.

Mucosal Biomarker of Innate Immune Activation Predicts Response to Vedolizumab in Crohn's Disease.

OBJECTIVE: Mucosal barrier dysfunction plays a crucial role in intestinal inflammation in Crohn's disease (CD). Intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was recently found to be a cause of this barrier defect. The aim of this study was to determine the predictive value of pretreatment ileal biopsy pyroptosis as a biomarker for clinical response to vedolizumab in CD. DESIGN: Crohn's disease patients ranging 18 to 80 years old from 5 IBD centers with pre-vedolizumab ileal biopsies during colonoscopy were enrolled. Biopsies were stained for activated caspases, and levels of ileal IEC pyroptosis levels were quantified. The primary outcome was clinical response 6 months after therapy, defined as a reduction of Harvey-Bradshaw Index (HBI) of ≥5 points from baseline. Secondary outcomes included clinical remission, defined as HBI <5, and endoscopic improvement, as measured by the Simple Endoscopic Score for Crohn's Disease (SES-CD). RESULTS: One hundred CD patients (45 male, 55 female), median age 47 (19, 78) years, were included; clinical response rate was 60%, and clinical remission was 36%. The response rate in patients with ileal pyroptosis <14 positive cells per 1000 IECs was significantly higher than those above the threshold: 89% (25 of 28) vs 49% (35 of 72), odds ratio (OR) 8.8 (95% CI, 2.3-48.6; P < 0.001). Corresponding remission rates were 54% (15 of 28) vs 29% (21 of 72; OR 2.8 [1.03-7.59; P = 0.036]). For endoscopic improvement, ileal pyroptosis of 22 positive cells per 1000 IECs was the optimal threshold that determines the magnitude SES-CD change. CONCLUSIONS: Ileal biopsy IEC pyroptosis was predictive of clinical response and endoscopic improvement to vedolizmab in CD patients.

Mejoría mucosa endoscópica en pacientes con enfermedad inflamatoria intestinal / Endoscopic mucosal improvememt in patients with inflammatory bowel disease

La curación mucosa endoscópica en enfermedad inflamatoria intestinal se asocia con remisión clínica sostenida, reducción de hospitalizaciones y cirugía, pero lograrlo es difícil, según la literatura. Por ello evaluamos la mejoría mucosa endoscópica en nuestros pacientes. Objetivo: Evaluar la mejoría mucosa endoscópica en pacientes con enfermedad inflamatoria intestinal. Métodos: estudio multicéntrico, descriptivo, transversal. Incluyó 24 pacientes entre 17 y 73 años. Para evaluar respuesta a tratamiento se realizó colonoscopia, utilizando clasificaciones endoscópicas de Mayo para colitis ulcerosa, Score simplificado para enfermedad de Crohn y Rutgeerts para recurrencia post operatoria, considerando curación endoscópica grado 0 en todas las escalas y mejoría cuando disminuyó un grado en relación al estudio previo. Resultados: colitis ulcerosa: 12 pacientes, 10 recibían aminosalicilatos y 2 terapia biológica. De ellos, 3 tuvieron curación endoscópica y 8 mejoría. De estos, 6 recibían aminosalicilatos y 2 Infliximab. Hubo 1 paciente con aminosalicilatos sin mejoría. Enfermedad de Crohn: 12 pacientes, 7 con aminosalicilatos, 2 con biológicos, 2 con biológicos e inmunomoduladores y 1 con biológicos y aminosalicilatos. De ellos, 4 tuvieron mejoría, 6 mantuvieron igual afectación y 2 curación con aminosalicilatos. Conclusiones: Se observó un alto porcentaje (70,8%) de curación y mejoría endoscópica, asociado a adherencia y optimización del tratamiento.

Introduction: endoscopic mucosal healing in inflammatory bowel disease has been associated with sustained clinical remission and hospitalizations and surgery reduction, but it has been difficult to achieve, according to the literature. So, we decided to assess improvement in endoscopic mucosal in our inflammatory bowel disease patients. Purpose: endoscopic mucosal assess improvement in patients with inflammatory bowel disease. Methods: multicenter, descriptive and transversal. We included 24 patients with IBD between 17-73 years. Control colonoscopy was performed to evaluate the response to treatment using endoscopic Mayo Score for ulcerative colitis, Simplified Score for Crohn’s disease and postoperative recurrence was evaluated with Rutgeerts Index endoscopic healing was considered when the patient had grade 0 at all scales and improvement when they had one point less in the endoscopy scale in decreased relation to the previous study. Results: ulcerative colitis: 12 patients, 10 received aminosalicylates and 2 biological therapy. The group receiving aminosalicylates, 3 had endoscopic healing, there was endoscopic improvement in 8 of which 6 are aminosalicylates and 2 Infliximab. There was one patient with no improvement aminosalicylates. Crohn’s Disease: 12 patients, 7 with aminosalicylates, 2 biological therapy alone, 2 with biological and immunomodulatory and 1 with biological and aminosalicylates. Of which 4 had endoscopic improvement, 12 stayed the same degree of involvement and 2 with aminosalicylates was endoscopic healing. Conclusions: There was a high percentage (70.8%) of healing and endoscopic improvement associated with adherence and treatment optimization.