Early Intestinal Ultrasound Predicts Clinical and Endoscopic Treatment Response and Demonstrates Drug-Specific Kinetics in Moderate-to-Severe Ulcerative Colitis.

BACKGROUND: Intestinal ultrasound (IUS) is an emerging modality in monitoring disease activity in ulcerative colitis (UC). Here, we aimed to identify early IUS predictors of treatment response as evaluated by endoscopy and assessed the kinetics of IUS changes. METHODS: This prospective, longitudinal study included UC patients with endoscopic disease activity (endoscopic Mayo score [EMS] ≥2) starting anti-inflammatory treatment. Clinical scores, biochemical parameters and IUS were assessed at baseline (W0), at week 2 (W2), at W6(W6), and at the time of second endoscopy (W8-W26). Per colonic segment, endoscopic remission (EMS = 0), improvement (EMS ≤1), response (decrease in EMS ≥1), and clinical remission (Lichtiger score ≤3) were assessed and correlated with common IUS parameters. Additionally, drug-specific responsiveness of bowel wall thickness (BWT) was assessed. RESULTS: A total of 51 patients were included and followed, and 33 patients underwent second endoscopy. BWT was lower from W6 onward for patients reaching endoscopic improvement (3.0 ±â€…1.2 mm vs 4.1 ±â€…1.3 mm; P = .026), remission (2.5 ±â€…1.2 mm vs 4.1 ±â€…1.1 mm; P = .002), and clinical remission (3.01 ±â€…1.34 mm vs 3.85 ±â€…1.20 mm; P = .035). Decrease in BWT was more pronounced in endoscopic responders (-40 ±â€…25% vs -4 ±â€…28%; P = .001) at W8 to W26. At W6, BWT ≤3.0 mm (odds ratio [OR], 25.13; 95% confidence interval, 2.01-3.14; P = .012) and color Doppler signal (OR, 0.35; 95% confidence interval, 0.14-0.88; P = .026) predicted endoscopic remission and improvement, respectively. Submucosal layer thickness at W6 predicted endoscopic remission (OR, 0.09; P = .018) and improvement (OR, 0.14; P = .02). Furthermore, BWT decreased significantly at W2 for infliximab and tofacitinib and at W6 for vedolizumab. CONCLUSIONS: BWT and color Doppler signal predicted endoscopic targets already after 6 weeks of treatment and response was drug specific. IUS allows close monitoring of treatment in UC and is a surrogate marker of endoscopy.

Intestinal ultrasound (IUS) is an emerging modality to monitor treatment response in ulcerative colitis. In this study, we investigated the responsiveness of IUS parameters such as bowel wall thickness (BWT) and color Doppler signal after start of treatment and evaluated these parameters early on in treatment follow-up (week 2 and W6). We found that BWT and color Doppler signal at W2 and W6 could predict endoscopic remission and improvement later on in treatment follow-up (between W8 and W26). Furthermore, we provide accurate cutoff values for BWT to predict and determine endoscopic endpoints. The timing of monitoring treatment response is drug specific, and IUS is a surrogate marker of endoscopy.

Intestinal Ultrasound Is Accurate to Determine Endoscopic Response and Remission in Patients With Moderate to Severe Ulcerative Colitis: A Longitudinal Prospective Cohort Study.

BACKGROUND & AIMS: Intestinal ultrasound (IUS) is noninvasive, cost-effective, and accurate to determine disease activity in ulcerative colitis (UC). In this study, we prospectively evaluated IUS for treatment response in a longitudinal cohort by using endoscopy and histology as gold standards. METHODS: Consecutive patients with moderate to severe UC (endoscopic Mayo score [EMS] ≥2) starting tofacitinib treatment were included. Patients were evaluated at baseline and after 8 weeks of tofacitinib induction by means of clinical, biochemical, endoscopic (EMS and UC endoscopic index for severity), histologic (Robarts Histopathologic Index) and IUS assessments. Readers of IUS, endoscopy, and histology were blinded for all other outcomes. The primary outcome was difference in bowel wall thickness (BWT) for endoscopic improvement vs no endoscopic improvement. Endoscopic remission was defined as EMS = 0, improvement as EMS ≤1, and response as a decrease of EMS ≥1. RESULTS: Thirty patients were included, with 27 patients completing follow-up. BWT correlated with EMS (ρ = 0.68, P < .0001), UC endoscopic index for severity (ρ = 0.73, P < .0001) and Robarts Histopathologic Index (ρ = 0.49, P = .002) at both time points. BWT in the sigmoid was lower in patients with endoscopic remission (1.4 mm vs 4.0 mm, P = .016), endoscopic improvement (1.8 mm vs 4.5 mm, P < .0001) and decrease in BWT was more pronounced in patients with endoscopic response (-58.1% vs -13.4%, P = .018). The most accurate cutoff values for BWT were 2.8 mm (area under the curve [AUC] 0.87) for endoscopic remission, 3.9 mm (AUC 0.92) for improvement, and decrease of 32% (AUC 0.87) for response. The submucosa was the most responsive wall layer. CONCLUSION: IUS, importantly BWT as the single most important parameter, is highly accurate to detect treatment response when evaluated against endoscopic outcomes.

Prediction of Relapse After Anti-Tumor Necrosis Factor Cessation in Crohn's Disease: Individual Participant Data Meta-analysis of 1317 Patients From 14 Studies.

BACKGROUND & AIMS: Tools for stratification of relapse risk of Crohn's disease (CD) after anti-tumor necrosis factor (TNF) therapy cessation are needed. We aimed to validate a previously developed prediction model from the diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressants (STORI) trial, and to develop an updated model. METHODS: Cohort studies were selected that reported on anti-TNF cessation in 30 or more CD patients in remission. Individual participant data were requested for luminal CD patients and anti-TNF treatment duration of 6 months or longer. The discriminative ability (concordance-statistic [C-statistic]) and calibration (agreement between observed and predicted risks) were explored for the STORI model. Next, an updated prognostic model was constructed, with performance assessment by cross-validation. RESULTS: This individual participant data meta-analysis included 1317 patients from 14 studies in 11 countries. Relapses after anti-TNF cessation occurred in 632 of 1317 patients after a median of 13 months. The pooled 1-year relapse rate was 38%. The STORI prediction model showed poor discriminative ability (C-statistic, 0.51). The updated model reached a moderate discriminative ability (C-statistic, 0.59), and included clinical symptoms at cessation (hazard ratio [HR], 2.2; 95% CI, 1.2-4), younger age at diagnosis (HR, 1.5 for A1 (age at diagnosis ≤16 years) vs A2 (age at diagnosis 17 - 40 years); 95% CI, 1.11-1.89), no concomitant immunosuppressants (HR, 1.4; 95% CI, 1.18-172), smoking (HR, 1.4; 95% CI, 1.15-1.67), second line anti-TNF (HR, 1.3; 95% CI, 1.01-1.69), upper gastrointestinal tract involvement (HR, 1.3 for L4 vs non-L4; 95% CI, 0.96-1.79), adalimumab (HR, 1.22 vs infliximab; 95% CI, 0.99-1.50), age at cessation (HR, 1.2 per 10 years younger; 95% CI, 1-1.33), C-reactive protein (HR, 1.04 per doubling; 95% CI, 1.00-1.08), and longer disease duration (HR, 1.07 per 5 years; 95% CI, 0.98-1.17). In subanalysis, the discriminative ability of the model improved by adding fecal calprotectin (C-statistic, 0.63). CONCLUSIONS: This updated prediction model showed a reasonable discriminative ability, exceeding the performance of a previously published model. It might be useful to guide clinical decisions on anti-TNF therapy cessation in CD patients after further validation.

Intestinal Ultrasound to Evaluate Treatment Response During Pregnancy in Patients With Inflammatory Bowel Disease.

INTRODUCTION: Active disease in inflammatory bowel disease patients during pregnancy is associated with poor maternal and fetal outcomes. Objective evaluation of disease activity is a core strategy in IBD, and during pregnancy noninvasive modalities are preferred. We aimed to evaluate feasibility and accuracy of intestinal ultrasound (IUS) to objectify disease activity throughout pregnancy. METHODS: Pregnant patients with known IBD were included and followed throughout pregnancy for clinical disease activity, with fecal calprotectin (FCP) and with IUS every trimester. Feasibility of IUS was assessed for all colonic segments and terminal ileum (TI). Intestinal ultrasound outcomes to detect active disease and treatment response were compared with clinical scores combined with FCP. RESULTS: In total, 38 patients (22 CD, 16 UC) were included, with 27 patients having serial IUS. Feasibility of IUS decreases significantly in third trimester for TI (first vs third trimester: 91.3% vs 21.7%, P < .0001) and sigmoid (first vs third trimester: 95.6% vs 69.5%, P = .023). Intestinal ultrasound activity showed moderate to strong correlation with clinical activity (r = 0.60, P < .0001) and FCP (r = 0.73, P < .0001). Throughout pregnancy, IUS distinguished active from quiescent disease with 84% sensitivity and 98% specificity according to FCP combined with clinical activity. IUS showed disease activity in >1 segment in 52% of patients and detected treatment response with 80% sensitivity and 92% specificity. CONCLUSIONS: IUS is feasible and accurate throughout pregnancy, although visualization of the sigmoid and TI decreases in the third trimester. IUS provides objective information on disease activity, extent, and treatment response, even during second and third trimester, and offers a noninvasive strategy to closely monitor patients during pregnancy.

Anti-Drug Antibody Formation Against Biologic Agents in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Immunogenicity 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. METHODS: MEDLINE, 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. RESULTS: Data 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). CONCLUSIONS: Differences 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.

Intestinal Ultrasound to Assess Disease Activity in Ulcerative Colitis: Development of a novel UC-Ultrasound Index.

INTRODUCTION: Intestinal ultrasound [IUS] is useful to assess inflammation in ulcerative colitis [UC] patients. We aimed to develop an ultrasonographic activity index using endoscopy as the reference standard. METHODS: Patients were included consecutively. IUS was performed within 3 weeks from endoscopy. IUS parameters and endoscopy were compared for each colonic segment [except the rectum]. The best parameters were used to construct a UC-IUS index, which was correlated with endoscopic disease activity using the Spearman's rank test. RESULTS: In 60 patients, 207 colonic segments were evaluated endoscopically. Bowel wall thickness [BWT] > 2.1 mm was optimal to discriminate between Mayo 0 and Mayo 1-3 (sensitivity 82.6%; specificity 93.0%; area under the curve [AUC] 0.910), a cut-off of 3.2 mm was optimal to discriminate between Mayo 0-1 and Mayo 2-3 [sensitivity 89.1%; specificity 92.3%; AUC 0.946] and BWT > 3.9 mm was optimal for detection of Mayo 3 [sensitivity 80.6%; specificity 84.1%; AUC 0.909]. The presence of colour Doppler signal [CDS] predicted active disease, stretches of CDS were associated with Mayo 2-3, lack of haustrations predicted active disease and fat wrapping was associated with severe disease. Inter- and intra-rater intraclass correlation for BWT was substantial. Inter-rater agreement for CDS was substantial and ranged from slight to substantial for haustrations. Intra-rater agreement for CDS was substantial and ranged from moderate to almost perfect for haustrations. The index showed strong correlation with endoscopic disease activity [Mayo: ρ 0.830; p < 0.001, UCEIS: ρ 0.759; p < 0.001]. CONCLUSION: We developed an UC-IUS index which showed strong correlation with endoscopic disease activity using internal validation. It is currently being validated in prospective studies.

Relapse rates and predictors for relapse in a real-life cohort of IBD patients after discontinuation of anti-TNF therapy.

Objective: We investigated relapse rates after anti-tumor necrosis factor (anti-TNF) withdrawal in inflammatory bowel disease (IBD) patients, response to restart of anti-TNF treatment and predictors for relapse. Methods: IBD patients in remission receiving infliximab or adalimumab treatment for ≥1 year who discontinued treatment were included. Relapse rates and predictors for relapse were studied using survival and Cox regression analysis. Results: In total, 101 patients were included (77 CD, 24 UC). A total of 56 patients (55%) experienced a relapse (CD 38, UC 18) with a median time to relapse of 32 and 18 months in CD and UC, respectively. Of patients that were retreated with the same anti-TNF agent, 84% responded. A trough serum concentration ≥2 µg/ml within 1 year prior to anti-TNF discontinuation was associated with a higher relapse rate in CD patients (HR 2.89; p = .018), which was more evident in patients requiring retreatment with biologicals, bowel-related surgery or experimental medication (HR: 4.18; p = .009). A young age (<17 years) at diagnosis was associated with a higher relapse rate (HR: 2.29; p = .040) and fecal calprotectin levels <25 µg/g with a lower relapse rate in CD patients (HR: 0.34; p = .041). Relapse rates, requiring treatment with biologicals or experimental medication, was lower in UC patients who continued immunosuppressive treatment (HR: 0.26; p = .042). Conclusions: Approximately 55% of patients relapsed after anti-TNF withdrawal with a median time to relapse of 32 and 18 months in CD and UC, respectively. Retreatment with the same anti-TNF was successful in 84% of patients.

Combination Immunosuppression in IBD.

Whether to use biologic treatment for inflammatory bowel disease as monotherapy or in combination with immunosuppressives has been a matter of debate in the last 2 decades. Combination therapy was not superior in any of the registration trials for Crohn's disease and ulcerative colitis for TNF antagonists, vedolizumab, or ustekinumab. It needs to be mentioned, though, that none of these trials were powered to detect such differences, and that many patients entered the trial after having failed conventional immunosuppressives.Postmarketing studies revealed that patients on background immunosuppression have a lower risk of immunogenicity (often resulting in infusion/injection reactions) than patients on monotherapy. In the SONIC and UC-SUCCESS trials, superiority of the combination azathioprine-infliximab was demonstrated in Crohn's disease and ulcerative colitis, respectively. This trial design has not been used with any other biologic for IBD, so far. Meanwhile, it has also become clear that combination treatment with TNF antagonists is associated with increased toxicity, mainly infections, but also malignancy such as lymphoproliferative disease. This toxicity could perhaps be reduced by using lower doses of immunosuppressives, a strategy that has been shown to be equally potent in reducing immunogenicity. Additionally, combination treatment could be used for a limited period of time (12 months or even shorter) since most immunogenicity develops in the beginning of the biologic treatment. Patients who develop anti-drug-antibodies later on can often be rescued by reintroduction of thiopurines or methotrexate.In summary, combination treatment is certainly beneficial with infliximab, at least in the first 12 months of treatment. With other TNF antagonists, vedolizumab, and ustekinumab, the available data do not offer clear guidance. In patients without increased risk of toxicity, and certainly in those with limited treatment options, it may be wise to offer combination treatment with all biologics for the time being and at least during the initiation phase.