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Background and aimsThe NASH Clinical Research Network histologic scoring system, the gold-standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS).Approach and resultsFour liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80-0.85) and interrater (0.60-0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68-0.79), including those extending scores from 0-2 to 0-4. Steatosis measures (interrater ICCs, 0.72-0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory-Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70-0.87.ConclusionsAfter extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.

Background and aimsDespite increasing interest in histologic remission as a treatment target in ulcerative colitis (UC), the accuracy of histologic findings in left colon in detecting pancolonic histologic remission is unknown.MethodsIn a retrospective cohort study of patients with endoscopically active pancolitis undergoing treat-to-target interventions, we evaluated the diagnostic accuracy of left-sided (distal to splenic flexure) histologic and endoscopic findings on colonoscopy for detecting histologic and endoscopic healing elsewhere in the colon.ResultsOf 86 patients with moderate to severely active pancolitis who underwent 2 consecutive colonoscopies during treat-to-target interventions, 38% and 51% achieved histologic and endoscopic remission, respectively. Substantial agreement (kappa, 0.67; 95% confidence interval (CI), 0.51-0.83) was observed in histologic findings between left and right colon on follow-up colonoscopy. Histologic, and endoscopic, findings in left colon showed excellent accuracy in detecting pancolonic histologic remission (area under the curve (AUC), 0.96 [95% CI, 0.93-1.0]; misclassification rate, 5.9%), histologic normalization (AUC, 1.0, 0%), endoscopic improvement (AUC, 0.95 [0.96-1.0], 3.5%) and endoscopic remission (AUC, 0.98 [0.96-1.00], 5.8%), respectively.ConclusionsIn patients with active pancolitis undergoing treat-to-target interventions, histologic and endoscopic findings in the left colon on colonoscopy have excellent accuracy for detecting pancolonic histologic remission, histologic normalization, endoscopic improvement, and endoscopic remission. Flexible sigmoidoscopy may suffice for monitoring histologic and endoscopic activity in patients with pancolitis.

Immune checkpoint inhibitor-associated colitis (ICIC) affects approximately 15% of cancer patients treated with immunotherapy. Although histological evaluation is potentially valuable for both the diagnosis of ICIC and evaluation of disease activity, use in clinical practice is heterogeneous. We aimed to develop expert recommendations to standardize histological assessment of disease activity in patients with ICIC. Using the modified Research and Development/University of California Los Angeles (RAND/UCLA) appropriateness methodology, an international panel of 11 pathologists rated the appropriateness of 99 statements on a 9-point Likert scale during two rounds of anonymous voting. Results were discussed between rounds using moderated videoconferences. There are currently no disease-specific instruments for assessing histological features of ICIC. The panel considered that colonoscopy with at least three biopsies per segment from a total of at least five segments, including both endoscopically normal and inflamed areas, was appropriate for tissue acquisition. They agreed that biopsies should be oriented such that the long axis of the colonic crypts is visualized and should be stained with hematoxylin and eosin. Histological items that the panel voted were appropriate to evaluate in ICIC included the degree of structural/architectural change, chronic inflammatory infiltrate, lamina propria and intraepithelial neutrophils, crypt abscesses and destruction, erosions/ulcerations, apoptosis, surface intraepithelial lymphocytosis, and subepithelial collagen thickness. The appropriateness of routine immunohistochemistry was uncertain. These expert recommendations will help standardize assessment of histological activity in patients with ICIC. The panel also identified the development and validation of an ICIC-specific histological index as a research priority.

Background & aimsThe IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients with Crohn's disease. Here, we report the final results of IM-UNITI LTE through 5 years.MethodsPatients completing safety and efficacy evaluations at week 44 of the maintenance study were eligible to participate in the LTE and continue the treatment they were receiving. Unblinding occurred after completion of maintenance study analyses (August 2015), and patients receiving placebo were discontinued from the study after unblinding. No dose adjustment occurred in the LTE. Efficacy assessments were conducted every 12 weeks until unblinding and at dosing visits thereafter through week 252. Serum ustekinumab concentrations and antidrug antibodies were evaluated through weeks 252 and 272, respectively.ResultsUsing an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. Corresponding remission rates among patients who entered the LTE were 54.9% and 45.2%. Overall, adverse event rates (per 100 patient-years) from maintenance week 0 through the final visit generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4). Serum ustekinumab concentrations were maintained throughout the LTE. Antidrug antibodies occurred in 5.8% of patients who received ustekinumab during induction and maintenance and continued in the LTE.ConclusionsPatients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

BackgroundCertolizumab pegol (CZP) is effective for moderately to severely active Crohn's disease (CD). Higher plasma concentrations are associated with better outcomes and increased drug clearance is the driver of subtherapeutic CZP concentrations.ObjectiveWe aimed to develop a prediction model incorporating predicted CZP clearance and patient variables to allow estimation of the probability for remission prior to initiating therapy.MethodsA population pharmacokinetic model estimated baseline CZP clearance in patients with CD from nine phase II and III trials. Multivariable prediction models were developed and validated using the PRECiSE 1 and PRECiSE 2 datasets to identify candidate predictors for a composite remission outcome (Crohn's Disease Activity Index ≤ 150 and fecal calprotectin concentration ≤ 250 μg/g) at Weeks 6 or 26. An online clinical decision support tool (CDST) was developed.ResultsBaseline predicted CZP clearance ≥ 0.5 L/day was associated with subtherapeutic Week 6 CZP plasma concentrations. Baseline weight (odds ratio [OR] 1.04; 95% confidence interval [CI] 1.02-1.07), calculated CZP clearance (OR 0.92; 95% CI 0.87-0.96), hematocrit (OR 2.55; 95% CI 1.43-4.54), and fecal calprotectin (OR 0.66; 95% CI 0.54-0.80) were associated with Week 6 remission (p ≤ 0.0015 for all predictors). Baseline weight (OR 1.04; 95% CI 1.02-1.07), calculated CZP clearance (OR 0.93; 95% CI 0.88-0.97), and Patient-Reported Outcome-2 (PRO2) (OR 0.93; 95% CI 0.87-0.99) were associated with Week 26 remission (p ≤ 0.033 for all predictors).ConclusionsPatients who are predicted to have accelerated baseline CZP clearance are at risk of subtherapeutic CZP concentrations. Patient-level probabilities for a composite remission outcome can be predicted for patients with CD by entering commonly available patient- and disease-related factors into an online CDST ( https://premedibd.com ) incorporating predicted CZP clearance.

Background and aimsImmunogenicity with formation of anti-drug antibodies (ADA) to biologics is an important reason for treatment failure in inflammatory bowel disease (IBD). Our aim was to assess the rate of ADA, the effect of combination therapy with immunomodulators on ADA and the influence of ADA on efficacy and safety of biologics for IBD treatment.MethodsMEDLINE, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to April 2020 for trials of biologics that assessed immunogenicity. The overall certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). The primary outcome was rate of ADA. Secondary outcomes included efficacy and safety outcomes among patients with detectable versus undetectable ADA. For dichotomous outcomes, pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated.ResultsData from 68 studies were analyzed and 33 studies (5850 patients) were included in the meta-analysis. Pooled ADA rates for biologic monotherapy were 28.0% for infliximab, 7.5% for adalimumab, 3.8% for golimumab, 10.9% for certolizumab, 6.2% for ustekinumab and 16.0% for natalizumab. Pooled ADA rates were 8.4% for vedolizumab and 5.0% for etrolizumab for combo- and monotherapy combined. In all biologics, ADA rates were underestimated by use of drug-sensitive ADA assays and higher dose and/or frequency. ADA rate was significantly reduced in patients treated with combination therapy for infliximab (RR 0.52; 95% CI 0.44-0.62), adalimumab (RR 0.31; 95% CI 0.14-0.69), golimumab (RR 0.29; 95% CI 0.10-0.83), certolizumab pegol (RR 0.30; 95% CI 0.14-0.67) and natalizumab (RR 0.20; 95% CI 0.11-0. 39). ADA to infliximab were associated with lower clinical response rates (RR 0.75; 95% CI 0.61-0.91) and higher rates of infusion reactions (RR 2.36; 95% CI 1.85-3.01).ConclusionsDifferences in analytical methods to detect ADA hamper comparison of true ADA rates across biologics in IBD. Use of combination therapy with immunomodulators appeared to reduce ADA positivity for most biologics. For infliximab, ADA were associated with reduced drug efficacy and increased adverse events.

Background & aimsWe conducted a systematic review with meta-analysis to estimate rates and trends of colectomy in patients with ulcerative colitis (UC), and of primary and re-resection in patients with Crohn's disease (CD), focusing on contemporary risks.MethodsThrough a systematic review until September 3, 2019, we identified population-based cohort studies that reported patient-level cumulative risk of surgery in patients with UC and CD. We evaluated overall and contemporary risk (after 2000) of surgery and analyzed time trends through mixed-effects meta-regression.ResultsIn patients with UC (26 studies), the overall 1-, 5-, and 10-year risks of colectomy was 4.0% (95% CI, 3.3-5.0), 8.8% (95% CI, 7.7-10.0), and 13.3% (95% CI, 11.3-15.5), respectively, with a decrease in risk over time (P < .001). Corresponding contemporary risks were 2.8% (95% CI, 2.0-3.9), 7.0% (95% CI, 5.7-8.6), and 9.6% (95% CI, 6.3-14.2), respectively. In patients with CD (22 studies), the overall 1-, 5-, and 10-year risk of surgery was 18.7% (95% CI, 15.0-23.0), 28.0% (95% CI, 24.0-32.4), and 39.5% (95% CI, 33.3-46.2), respectively, with a decrease in risk over time (P < .001). Corresponding contemporary risks were 12.3% (95% CI, 10.8-14.0), 18.0% (95% CI, 15.4-21.0), and 26.2% (95% CI, 23.4-29.4), respectively. In a meta-analysis of 8 studies in patients with CD with prior resection, the cumulative risk of a second resection at 5 and 10 years after the first resection was 17.7% (95% CI, 13.5-22.9) and 31.3% (95% CI, 24.1-39.6), respectively.ConclusionsPatient-level risks of surgery have decreased significantly over time, with a 5-year cumulative risk of surgery of 7.0% in UC and 18.0% in CD in contemporary cohorts. This decrease may be related to early detection and/or better treatment.

Background & aimsWe created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC).MethodsWe performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December 2017.ResultsAbsence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27-32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy.ConclusionsWe used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718.

Background & aimsClinical remission, defined by a composite of patient reported outcomes and Mayo endoscopy subscore (MES) 0 or 1 is a recommended treatment target in patients with ulcerative colitis (UC). We estimated whether incorporating more rigorous remission definitions, of endoscopic remission (MES 0) and histologic remission, affects risk of relapse.MethodsThrough a systematic review, we identified cohort studies in adults with UC in clinical remission that reported a minimum 12-month risk of clinical relapse, based on MES (0 vs 1) and/or histologic disease activity, in patients with endoscopic remission. Using random effects meta-analysis, we calculated relative and absolute risk of clinical relapse in patients with UC achieving different treatment targets.ResultsIn a meta-analysis of 17 studies that included 2608 patients with UC in clinical remission, compared to patients achieving MES 1, patients achieving MES 0 had a 52% lower risk of clinical relapse (relative risk, 0.48; 95% CI, 0.37-0.62). The median 12-month risk of clinical relapse in patients with MES 1 was 28.7%; the estimated annual risk of clinical relapse in patients with MES 0 was 13.7% (95% CI, 10.6-17.9). In a meta-analysis of 10 studies in patients in endoscopic remission (MES 0), patients who achieved histologic remission had a 63% lower risk of clinical relapse vs patients with persistent histologic activity (relative risk, 0.37; 95% CI, 0.24-0.56). Estimated annual risk of clinical relapse in who achieved achieving histologic remission was 5.0% (95% CI, 3.3-7.7).ConclusionsIn a systematic review and meta-analysis of patients with UC in clinical remission, we observed that patients achieving more rigorous treatment endpoints (endoscopic and histologic remission) have a substantially lower risk of clinical relapse compared with patients achieving clinical remission.

Background & aimsWith several options available for patients with moderate-severe ulcerative colitis (UC), rapidity of symptom resolution could be an important differentiator. We compared the efficacy and speed of onset of action of infliximab vs golimumab induction therapy using patient-level data from phase 3 trials (ACT-1, ACT-2, and PURSUIT-SC).MethodsWe compared differences in proportions of patients who achieved the composite outcome of a rectal bleeding score=0 and stool frequency score ≤1 (patient-reported outcome 2 remission) at weeks 2 and 6 of treatment with standard-dose infliximab vs golimumab using logistic generalized estimating equation. Overall efficacy for inducing clinical remission (Mayo clinic score

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 subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12. Methods Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism. Results In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission [ p  < 0.05] in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p  = 0.033; experienced: 18.9% vs 13.2%, p  = 0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [ N  = 90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p  = 0.030], but not clinical remission [9.8% vs 3.4%, p  = 0.248], with etrasimod vs placebo. Conclusions Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo. ClinicalTrials.gov NCT03945188; NCT03996369 [ABSTRACT FROM AUTHOR]

Background and Aims Quality of life in patients with active Crohn's disease may be significantly reduced. We evaluated the effects of upadacitinib induction and maintenance therapy on fatigue, quality of life, and work productivity in the phase 3 trials U-EXCEL, U-EXCEED, and U-ENDURE. Methods Clinical responders to upadacitinib 45 mg in U-EXCEL and U-EXCEED induction trials were re-randomised 1:1:1 to upadacitinib 30 mg, 15 mg, or placebo for 52 weeks of maintenance in U-ENDURE. Clinically meaningful improvements in Inflammatory Bowel Disease Questionnaire [IBDQ] response, IBDQ remission, Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-Fatigue], and Work Productivity and Activity Impairment were evaluated. Percentages of patients achieving clinically meaningful improvements were assessed at induction Weeks 4 and 12 and maintenance Week 52. Clinical Registration number U-EXCEED induction trial [NCT03345836], U-EXCEL induction trial [NCT03345849], U-ENDURE maintenance trial [NCT03345823]. Results Analysis included 1021 and 502 patients assessed at induction and maintenance, respectively. In U-EXCEL, greater improvements [all p  ≤ 0.001] in IBDQ response [71.0% vs 50.2%], IBDQ remission [44.2% vs 23.7%], and FACIT-Fatigue [42.0% vs 27.0%] were observed in upadacitinib-treated patients versus placebo at Week 4. Improvements in IBDQ response, IBDQ remission, and FACIT-Fatigue were similar or greater at Week 12. Clinically meaningful improvement in overall work impairment [52.1% vs 38.1%, p  ≤ 0.05] was demonstrated at Week 12. Similar results were observed in U-EXCEED. Improvements were sustained through 52 weeks of upadacitinib maintenance treatment. Conclusions In patients with active Crohn's disease, upadacitinib treatment relative to placebo significantly improved fatigue, quality of life, and work productivity as early as Week 4. These effects were sustained through 52 weeks of maintenance. [ABSTRACT FROM AUTHOR]

Background and Aim Contemporary techniques to assess disease activity or bowel damage in patients with inflammatory bowel disease [IBD], such as endoscopy and imaging, are either invasive or lack accuracy. Non-invasive biomarkers for this purpose remain an unmet medical need. Herein, we provide a comprehensive systematic review of studies evaluating blood extracellular matrix [ECM] biomarkers and their relevance in IBD. Methods We conducted a systematic review of PubMed, EMBASE, Web of Science, and Scopus to identify citations pertaining to ECM biomarkers of IBD up to March 1, 2024. Studies were categorized based on marker subtype and clinical use. Results Thirty-one ECM markers were identified, 28 of which demonstrated the ability to differentiate IBD disease activity. Collagen III emerged as the most extensively investigated [1212 IBD patients], with the degradation marker C3M and deposition marker PRO-C3 being associated with IBD and subtypes. Collagen V markers C5M and PRO-C5 emerged as the most accurate single markers for diagnosis of IBD, with an area under the curve of 0.91 and 0.93, respectively. Overall, studies were characterized by variable endpoints. None of the studies included histological grading of intestinal damage, repair, or fibrosis formation as the primary outcome in relation to the ECM blood markers. Conclusions Multiple ECM markers are linked with IBD and its phenotypes. However, more rigorous study designs and clearly defined endpoints are needed to ensure reproducibility and develop reliable and accurate biomarkers. ECM markers hold promise as they provide a 'window' into transmural tissue remodelling and fibrosis burden, warranting further investigation. [ABSTRACT FROM AUTHOR]

Summary: Background: The performance of bowel preparation (BP) in patients with Crohn's disease (CD) is unknown. Aims: To evaluate the operating properties of instruments used to assess BP quality in patients with CD. Methods: We used the Boston Bowel Preparation Scale, modified Boston Bowel Preparation Scale, Harefield Cleansing Scale, Food and Drug Administration Bowel Cleansing Assessment Scale (BCAS), and a 100‐mm visual analogue scale of bowel cleanliness to assess BP quality in 50 videos from 40 patients with CD. We assessed endoscopic activity with the Simple Endoscopic Score for CD (SES‐CD). Assessments were on endoscope insertion and withdrawal. Reliability was quantified using the intraclass correlation coefficient (ICC). We assessed validity by within‐patient correlation between instruments and the visual analogue scale using mixed‐effect models. The correlation between BP quality and SES‐SD scores was assessed using Spearman's rho. Results: Inter‐ and intra‐rater reliability for all BP quality instruments was substantial (ICC ≥0.61) except for the Food and Drug Administration BCAS on insertion (inter‐rater reliability ICC ≥0.41). The visual analogue scale had substantial inter‐ and almost perfect (ICC ≥0.81) intra‐rater reliability. Correlation coefficients for the validity of the instruments exceeded 0.58. BP quality and endoscopic disease activity scores in the colon were negatively correlated. Conclusion: Most existing instruments reliably assess BP quality in patients with CD. These results support the use of these instruments in clinical practice, provide a framework for scoring BP quality in CD clinical trials, and support evaluation of novel BP agents in patients with CD. [ABSTRACT FROM AUTHOR]