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.

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.

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.