Prospective Observational Evaluation of the Time-Dependency of Adalimumab Immunogenicity and Drug Concentration in Ulcerative Colitis Patients: the POETIC II Study.

BACKGROUND AND AIMS: Home self-injection of the human anti-tumour necrosis alpha [anti-TNFα] monoclonal adalimumab complicates prospective serial-sampling studies. Although a recent study examined adalimumab levels and immunogenicity in Crohn's disease [CD] patients, prospective real-world data from ulcerative colitis [UC] patients are lacking. METHODS: A three-monthly home-visit programme from induction was established prospectively for UC patients. Clinical scores were determined at each visit, and sera were obtained for assessment of drug and anti-adalimumab antibody levels. Calprotectin was measured using a smartphone-based app. This cohort was compared to a parallel prospective cohort of adalimumab-treated CD patients [POETIC1]. RESULTS: Fifty UC patients starting adalimumab [median follow-up 28 weeks] were compared to 98 adalimumab-treated CD patients [median follow-up 44 weeks]. Only 11/50 UC patients [22%] continued treatment to the end of the follow-up compared with 50/98 [51%] CD patients (odds ratio [OR] = 0.27, p = 0.001). Loss of response was significantly more common in UC patients [OR = 3.2, p = 0.001]. Seventeen patients [34%] in the UC cohort developed anti-adalimumab antibodies, 9/17 [52.9%] as early as week 2. There was no difference between patient cohorts in the overall development of anti-adalimumab antibodies [34% vs 30.6%, respectively, OR = 1.67, p = 0.67], nor was there a difference in early immunogenicity [OR = 1.39, p = 0.35]. There was no difference in low drug levels [<3 µg/mL] between the two cohorts [OR = 0.87, p = 0.83]. CONCLUSIONS: Loss of response to adalimumab therapy was significantly more common in the UC compared to the CD cohort and was driven by a higher rate of non-immunogenic, pharmacodynamic parameters.

Comparison of Short- and Long-Term Effectiveness between Anti-TNF and Ustekinumab after Vedolizumab Failure as First-Line Therapy in Crohn's Disease: A Multi-Center Retrospective Cohort Study.

BACKGROUND: The effectiveness of anti-TNF or ustekinumab (UST) as a second-line biologic after vedolizumab (VDZ) failure has not yet been described. AIMS AND METHODS: In this retrospective multicenter cohort study, We aim to investigate the effectiveness of anti-TNF and UST as second-line therapy in patients with Crohn's disease (CD) who failed VDZ as a first-line treatment. The primary outcome was clinical response at week 16-22. Secondary outcomes included the rates of clinical remission, steroid-free clinical remission, CRP normalization, and adverse events. RESULTS: Fifty-nine patients who failed on VDZ as a first-line treatment for CD were included; 52.8% patients received anti-TNF and 47.2% UST as a second-line therapy. In initial period (Week 16-22), the clinical response and remission rate was similar between both groups: 61.2% vs. 68%, p = 0.8 and 48.3% vs. 56%, p = 0.8 on anti-TNF and UST therapy, respectively. Furthermore, in the maintenance period the rate was similar: 75% vs. 82.3%, p = 0.8 and 62.5% vs. 70.5%, p = 0.8, respectively. Of the patients, 12 out of the 59 stopped the therapy, without a significant difference between the two groups (p = 0.6). CONCLUSION: Second-line biological therapy after VDZ failure therapy was effective in >60% of the patients with CD. No differences in effectiveness were detected between the use of anti-TNF and UST as a second line.

Risk of colorectal advanced neoplasia in patients with acute diverticulitis with and without previous colonoscopy.

BACKGROUND AND AIM: Guidelines recommend a colonoscopy after an episode of complicated diverticulitis and after a first episode of uncomplicated diverticulitis. The influence of a previous colonoscopy on postdiverticulitis colonoscopic findings has not been studied. The aim of this work was to examine the incidence of adenoma detection rate (ADR), advanced adenoma (AA) and colorectal cancer (CRC) in patients with diverticulitis with and without previous colonoscopy. METHOD: This was a retrospective case-control study of subjects with acute diverticulitis. Subsequent and previous colonoscopies were abstracted for ADR, AA and CRC diagnoses. The incidence of neoplasia was compared between patients with and without previous colonoscopy and also with that of a screening population. RESULTS: Compared with a healthy control group (n = 975), diverticulitis patients without prior colonoscopy (n = 325) had a significantly higher ADR (26.8% vs. 20.5%, p = 0.019) and invasive CRC rate (0.9% vs. 0%, p = 0.016). Risk factors for advanced neoplasia included age ≥ 70 years and complicated diverticulitis. Among subjects with diverticulitis and previous colonoscopy (n = 124), only one patient developed AA and there were no cancer cases. CONCLUSIONS: A previous normal colonoscopy within 5 years before diverticulitis probably overshadows other risk factors for findings of advanced neoplasia and should be considered in the decision to repeat a colonoscopy.

Characterization of blood-derived exosomal hTERT mRNA as a biomarker for colon cancer and Lynch syndrome.

Background: Human telomerase reverse transcriptase (hTERT)- mRNA was shown to be elevated in exosomes derived from the sera of a variety of hematological and solid cancer patients. We aimed to evaluate its role as a diagnostic marker in patients with newly diagnosed colon cancer and in hereditary syndromes with predisposition to colon cancer. Methods: hTERT -mRNA levels were determined in serum-derived exosomes from 88 patients with colon cancer, 71 Lynch-syndrome carriers with unknown active malignancies and 50 healthy controls. Data, including demographics, background diseases, clinical data regarding tumor characteristics and genetic data, were retrieved data from medical files. Results: Patients with colon cancer had both higher exosomal hTERT mRNA levels and a higher proportion of patients with positive exosomal hTERT mRNA than controls (29.5% vs. 4%, respectively, P values < 0.001). Within the cancer group, patients with a metastatic disease had higher levels of telomerase mRNA than non-metastatic disease patients, and these levels correlated with CEA levels. Likewise, Lynch syndrome carriers had a higher proportion of positive exosomal hTERT mRNA than controls (21.1% vs. 4%, respectively, P value 0.008) but only a trend towards higher exosomal hTERT mRNA levels. Higher telomerase mRNA levels were not correlated with the mutated gene. Conclusions: Exosomal serum hTERT -mRNA levels are associated with metastatic colon cancer and were also demonstrated in a subset of Lynch syndrome carriers. Its significance as a biomarker for developing malignancy should be elucidated.

Deep Learning Multi-Domain Model Provides Accurate Detection and Grading of Mucosal Ulcers in Different Capsule Endoscopy Types.

BACKGROUND AND AIMS: The aim of our study was to create an accurate patient-level combined algorithm for the identification of ulcers on CE images from two different capsules. METHODS: We retrospectively collected CE images from PillCam-SB3's capsule and PillCam-Crohn's capsule. ML algorithms were trained to classify small bowel CE images into either normal or ulcerated mucosa: a separate model for each capsule type, a cross-domain model (training the model on one capsule type and testing on the other), and a combined model. RESULTS: The dataset included 33,100 CE images: 20,621 PillCam-SB3 images and 12,479 PillCam-Crohn's images, of which 3582 were colonic images. There were 15,684 normal mucosa images and 17,416 ulcerated mucosa images. While the separate model for each capsule type achieved excellent accuracy (average AUC 0.95 and 0.98, respectively), the cross-domain model achieved a wide range of accuracies (0.569-0.88) with an AUC of 0.93. The combined model achieved the best results with an average AUC of 0.99 and average mean patient accuracy of 0.974. CONCLUSIONS: A combined model for two different capsules provided high and consistent diagnostic accuracy. Creating a holistic AI model for automated capsule reading is an essential part of the refinement required in ML models on the way to adapting them to clinical practice.

Orofacial Granulomatosis Associated with Crohn's Disease: a Multicentre Case Series.

BACKGROUND: Orofacial granulomatosis [OFG] is a rare syndrome that may be associated with Crohn's disease [CD]. We aimed to characterise this relationship and the management options in the biologic era. METHODS: This multicentre case series was supported by the European Crohn's and Colitis Organisation [ECCO], and performed as part of the Collaborative Network of Exceptionally Rare case reports [CONFER] project. Clinical data were recorded in a standardised collection form. RESULTS: This report includes 28 patients with OFG associated with CD: 14 males (mean age of 32 years, ±12.4 standard deviation [SD]) and 14 females [40.3 years, ±21.0 SD]. Non-oral upper gastrointestinal tract involvement was seen in six cases and perianal disease in 11. The diagnosis of OFG was made before CD diagnosis in two patients, concurrently in eight, and after CD diagnosis in 18. The distribution of OFG involved the lips in 16 cases and buccal mucosa in 18. Pain was present in 25 cases, with impaired swallowing or speaking in six. Remission was achieved in 23 patients, notably with the use of anti-tumour necrosis factors [TNFs] in nine patients, vedolizumab in one, ustekinumab in one, and thalidomide in two. A further five cases were resistant to therapies including anti-TNFs. CONCLUSIONS: OFG associated with CD may occur before, concurrently with, or after the diagnosis of CD. Perianal and upper gastrointestinal [UGI] disease are common associations and there is a significant symptom burden in many. Remission can be obtained with a variety of immunosuppressive treatments, including several biologics approved for CD.

Primary Hypogammaglobulinaemia with Inflammatory Bowel Disease-Like Features: An ECCO CONFER Multicentre Case Series.

BACKGROUND: Hypogammaglobulinaemia is a disorder characterized by low serum immunoglobulin levels and a high prevalence of gastrointestinal manifestations. In some cases, clinical and endoscopic features are indistinguishable from those of inflammatory bowel disease [IBD]. METHODS: This was a multicentre case series performed as a part of the European Crohn's and Colitis Organisation [ECCO] Collaborative Network of Exceptionally Rare case reports [CONFER] project. RESULTS: This report includes 27 patients with primary hypogammaglobulinaemia and IBD-like features: 20 males and seven females, median age 45.6 years (interquartile range [IQR] 35.2-59). Crohn's disease-like features were noted in 23 patients, and four patients had ulcerative colitis-like features. The diagnosis of hypogammaglobulinaemia preceded a diagnosis of IBD-like features in 20 patients [median of 7 years prior, IQR 2.6-20.6 years], and followed the appearance of IBD-like features in seven cases [median of 1 year after, IQR 0.45-5.6 years]. Hypogammaglobulinaemia aetiologies were common variable immunodeficiency [66.6%], agammaglobulinaemia [7.4%], selective IgA-deficiency [11.1%], Good's syndrome [7.4%], IgG subclass deficiency with IgA deficiency [3.7%] and hyper-IgM [3.7%]. In addition to antibiotics and intravenous immunoglobulin [IVIG] for hypogammaglobulinaemia, 12 patients received IBD-related treatment including 5-aminosalicylate agents [two patients], corticosteroids [one patient], thiopurines [three patients], anti-tumour necrosis factor [four patients] and vedolizumab [two patients]. By the end of the follow-up (44.5 months [IQR 18-81]), 21/27 [77%] patients were in clinical remission. CONCLUSION: This case series describes IBD-like features in patients with hypogammaglobulinaemia. The diagnosis of IBD-like features mainly occurred after that of hypogammaglobulinaemia, with successful recovery in the majority of cases after appropriate treatment.

Effectiveness of Third-Class Biologic Treatment in Crohn's Disease: A Multi-Center Retrospective Cohort Study.

BACKGROUND: Multiple studies have described the effectiveness of ustekinumab (UST) and vedolizumab (VDZ) in patients with Crohn's disease (CD) failing anti- Tumor necrosis factors (TNFs); however, the effectiveness of VDZ or UST as a third-class biologic has not yet been described. AIMS AND METHODS: In this retrospective multicenter cohort study, we aimed to investigate the effectiveness of VDZ and UST as a third-class biologic in patients with CD. RESULTS: Two-hundred and four patients were included; 156/204 (76%) patients received VDZ as a second- and UST as a third-class therapy (group A); the remaining 48/204 (24%) patients received UST as a second- and VDZ as a third-class therapy (group B). At week 16-22, 87/156 (55.5%) patients and 27/48 (56.2%) in groups A and B, respectively, responded to treatment (p = 0.9); 41/156 (26.2%) and 15/48 (31.2%) were in clinical remission (p = 0.5). At week 52; 89/103 (86%) patients and 25/29 (86.2%) of the patients with available data had responded to third-class treatment in groups A and B, respectively (p = 0.9); 31/103 (30%) and 47/29 (24.1%) were in clinical remission (p = 0.5). CONCLUSION: Third-class biological therapy was effective in more than half of the patients with CD. No differences in effectiveness were detected between the use of VDZ and UST as a third-class agent.

Prediction of Recurrent Emergency Department Visits among Patients with Crohn's Disease: A Retrospective Study.

Patients with Crohn's disease (CD) are frequently subject to symptoms causing them to seek medical care in emergency departments (ED). Recurrent ED visits are frequent after initial discharge. We aimed to identify the characteristics of patients with Crohn's who tend to have recurrent visits to the ED. We created an electronic data repository of all patients with inflammatory bowel diseases who visited the ED in our tertiary medical center during the period 2012-2018. For this study, we retrieved consecutive Crohn's patients who presented with CD-related symptoms to the ED and were eventually discharged. Patients who returned to the ED in 7 and 30 days were compared with those who did not. Overall, 2299 patients visited our ED with complaints related to Crohn's disease exacerbation or complication. A total of 1259 (60% of the adult patients) were admitted for hospitalization. Of the 632 (33%) who were discharged from the ED, 53 (8.4%) and 110 (17.4%) re-visited the ED, in 7 and 30 days from discharge, respectively. In multivariable analysis, tachycardia (odds ratio (OR) = 2.19, 95% confidence interval (CI): 1.11-4.33, p value = 0.02), elevated alkaline phosphatase (OR = 2.09, 95% CI: 1.07-4.07, p value = 0.02), and hyponatremia (OR = 2.52, 95% CI: 1.24-5.10, p value = 0.01) were associated with revisiting the ED within 7 days. Tachycardia (OR 2.88 (95% CI 1.33-6.2)), anemia (OR 2.44 (95% CI 1.24-4.8)), and elevated alkaline phosphatase (OR 2.68 (95% CI 1.25-5.78)) were independently associated with ED returns in 30 days. Knowing these risk factors may assist in minimizing the burden of recurrent ED visits among patients with CD.

Terminal Ileum Thickness During Maintenance Therapy Is a Predictive Marker of the Outcome of Infliximab Therapy in Crohn Disease.

BACKGROUND: Mucosal healing has been associated with long-term response to therapy for Crohn disease (CD). However, little is known about the significance of terminal ileum (TI) transmural thickness in predicting clinical outcomes. METHODS: In this retrospective observational cohort study, we examined the association of an index ultrasonographic assessment of TI thickness during the maintenance phase and the subsequent clinical outcome of CD in a cohort of patients treated with infliximab (IFX). Treatment failure was defined as treatment discontinuation because of lack of efficacy, a need for dose escalation, or surgery. Clinical response was defined as treatment continuation in the absence of any of the aforementioned failure criteria. RESULTS: Sixty patients with CD receiving IFX therapy were included in the study. The patients were followed for a median of 16 months (5-24 months) after an index intestinal ultrasound. Thirty-eight patients (63.3%) maintained response to the therapy and 22 patients (36.6%) failed the treatment, with a mean follow up of 10.5 months (6.5-17 months) vs 9.25 months (1-10.25 months), respectively. On univariate analysis, the only variables differing between treatment response and failure were a TI thickness of 2.8 vs 5 mm (P < 0.0001) and an IFX trough level of 6.6 vs 3.9 µg/mL (P = 0.008).On multivariable analysis, only a small bowel thickness of ≥4 mm was associated with the risk of treatment failure (odds ratio, 2.9; 95% CI, 1.49-5.55; P = 0.002). CONCLUSIONS: Our findings suggest that transmural thickness of ≥4 mm can predict subsequent treatment failure in patients with CD treated using IFX, indicating transmural thickness <4 mm as a potential novel valuable therapeutic target.

Lower adalimumab trough levels are associated with higher bowel wall thickness in Crohn's disease.

BACKGROUND: In Crohn's disease, higher adalimumab trough levels and negative anti-adalimumab-antibodies associate with better clinical and endoscopic outcomes. Intestinal ultrasound has become a relevant non-invasive method to monitor treatment. However, data on the association between adalimumab levels and bowel wall thickness measured with ultrasound is limited. OBJECTIVE: The purpose of this study was to examine the possible association between the sonographic transmural-thickness and adalimumab trough levels. METHODS: This prospective observational cohort study was conducted at Sheba Medical Center in 2014-2018. Crohn's disease patients on adalimumab maintenance therapy with intestinal ultrasound performed within <30 days of trough level measurement were included. Associations between terminal ileum and colonic thickness, adalimumab levels and therapy retention were assessed. RESULTS: Fifty events of ultrasound with concomitant adalimumab trough level measurements in 44 Crohn's disease patients were included. Patients with trough level <3 µg/ml had significantly higher bowel wall thickness, both for terminal ileum (p = 0.04) and colon (p = 0.02). Thirty-two patients continued adalimumab therapy over one year. The adalimumab retention rate was higher among those with terminal ileum thickness <4 mm (p = 0.03). CONCLUSION: Lower adalimumab trough levels were associated with higher bowel wall thickness indicating poorer therapy outcome. Transmural thickness measurement with ultrasound may be a useful target for guiding biologic therapy in Crohn's disease.

Deep learning algorithms for automated detection of Crohn's disease ulcers by video capsule endoscopy.

BACKGROUND AND AIMS: The aim of our study was to develop and evaluate a deep learning algorithm for the automated detection of small-bowel ulcers in Crohn's disease (CD) on capsule endoscopy (CE) images of individual patients. METHODS: We retrospectively collected CE images of known CD patients and control subjects. Each image was labeled by an expert gastroenterologist as either normal mucosa or containing mucosal ulcers. A convolutional neural network was trained to classify images into either normal mucosa or mucosal ulcers. First, we trained the network on 5-fold randomly split images (each fold with 80% training images and 20% images testing). We then conducted 10 experiments in which images from n - 1 patients were used to train a network and images from a different individual patient were used to test the network. Results of the networks were compared for randomly split images and for individual patients. Area under the curves (AUCs) and accuracies were computed for each individual network. RESULTS: Overall, our dataset included 17,640 CE images from 49 patients: 7391 images with mucosal ulcers and 10,249 images of normal mucosa. For randomly split images results were excellent, with AUCs of .99 and accuracies ranging from 95.4% to 96.7%. For individual patient-level experiments, the AUCs were also excellent (.94-.99). CONCLUSIONS: Deep learning technology provides accurate and fast automated detection of mucosal ulcers on CE images. Individual patient-level analysis provided high and consistent diagnostic accuracy with shortened reading time; in the future, deep learning algorithms may augment and facilitate CE reading.

CT-P13: a review on a biosimilar to infliximab in the treatment of inflammatory bowel disease.

Introduction: CT-P13 was developed as an infliximab biosimilar in 2013. The primary structure of CT-P13 is identical to that of original infliximab and it has highly similar higher order structure, physiochemical characteristics, and biological properties. To date, data from real-life cohorts and randomized controlled trials show comparable clinical efficacy, safety and immunogenicity of biosimilar CT-P13, and the original reference medicinal Product (RMP). Areas covered: This article reviews the comparability of CT-P13 and the RMP and focuses on the emerging clinical trial and observational cohorts data on efficacy and safety of CT-P13 in inflammatory bowel disease (IBD) patients. The development of a subcutaneous formulation of Infliximab CT-P13 is also addressed. Expert opinion: There is a plethora of evidence to show CT-P13 is non-inferior to infliximab RMP in IBD and that a switch from RMP to this biosimilar is feasible and safe. However, interchangeability and multiple switches can still not be endorsed for introduction into clinical practice.