Confocal laser endomicroscopy as predictive biomarker of clinical and endoscopic efficacy of vedolizumab in ulcerative colitis: The DETECT study.

AIMS: In patients with ulcerative colitis (UC), no biomarker is available to help the physician to choose the most suitable biotherapy. The primary objective of this pilot study was to assess the feasibility of identification of α4ß7- and TNF-expressing cells, to predict the response to vedolizumab using confocal laser endoscopy (CLE). METHODS: Patients with moderate-to-severe UC, naïve of biotherapy, received vedolizumab. Clinical evaluation was performed at each infusion. Endoscopic evaluation was performed before inclusion and at week 22. Fresh colonic biopsies were stained using FITC-labelled vedolizumab and Alexa fluor-labelled adalimumab and ex vivo dual-band CLE images were acquired. Blood samples were collected to measure trough concentrations of vedolizumab and to determine absolute counts of T and B cells subpopulations, NK cells and monocytes. RESULTS: Nineteen patients were enrolled in the study and received at least one dose of vedolizumab. Clinical remission and endoscopic improvement were observed in 58% of whom 5 patients (45%) had an endoscopic subscore of 0. In terms of clinical response and remission, endoscopic improvement and histologic response, FITC-conjugated vedolizumab staining tended to be higher in responder patients compared to non-responders at week 22. A threshold value of 6 positive FITC-vedolizumab staining areas detected by CLE seemed informative to discriminate the responders and non-responders. The results were similar in terms of clinical remission and endoscopic improvement with a sensitivity of 78% and a specificity of 85% (p = 0.05). Trough concentrations and blood immune cells were not associated with responses to vedolizumab. CONCLUSION: This pilot study demonstrate that dual-band CLE is feasible to detect α4ß7- and TNF-expressing cells. Positive α4ß7 staining seems to be associated with clinical and endoscopic remission in UC patients treated by anti-α4ß7-integrin, subject to validation by larger-scale studies. Clinical-trial.gov: NCT02878083.

Identification of the optimal medical and surgical management for patients with perianal fistulising Crohn's disease.

AIM: The aim of our study was to assess the best medical and surgical approaches for perianal Crohn's disease (PCD) in order to identify an optimal combined medical and surgical treatment. METHODS: Medical records of all patients with PCD treated with TNFα antagonists in two referral centres between 1998 and 2018 were reviewed. Predictors of long-term outcomes were identified using a Cox proportional hazard model. RESULTS: A total of 200 patients were included. Fifty-three patients (26.5%) were treated with adalimumab and 147 (73.5%) with infliximab. A combination of TNFα antagonist with an immunosuppressant and the presence of proctitis were independently associated with fistula closure. Seton was placed in 127 patients (63.5%) before starting biological therapy. Eighty patients (40%) underwent additional perineal surgery. Prior PCD surgery, seton positioning, additional perineal surgery, and additional surgery within 52 weeks of anti-TNFα treatment were associated with an increased rate of fistula closure. Finally, medical combination therapy (anti-TNFα plus immunosuppressant) along with seton placement and additional surgery within 1 year was the best management for PCD patients (p = 0.02). CONCLUSION: Combined medical and surgical management is required for the treatment of PCD patients. Medical combination therapy associated with seton placement and additional surgery within 1 year is the best management for PCD patients.

Efficacy of ustekinumab, vedolizumab, or a second anti-TNF agent after the failure of a first anti-TNF agent in patients with Crohn's disease: a multicentre retrospective study.

BACKGROUND: No study has performed a face-to-face comparison of biologics after the failure of the first anti-TNF agent in patients with Crohn's disease (CD). The aim of the study was to compare the efficacy of biologics in this setting. METHODS: Patients with CD who were refractory to a first anti-TNF agent, and treated with ustekinumab (UST), vedolizumab (VDZ), or a second anti-TNF drug as a second-line biological agent at 10 French tertiary centres from 2013 to 2019 were retrospectively included in this study. RESULTS: Among the 203 patients included, 90 (44%) received UST, 42 (21%) received VDZ and 71 (35%) received a second anti-TNF agent. The first anti-TNF agent was discontinued due to a primary nonresponse in 42 (21%) patients. At weeks 14-24, the rates of steroid-free remission were similar between the UST, VDZ and second anti-TNF groups (29%, 38% and 44%, respectively, p = 0.15). With a mean follow-up of 118 weeks, drug survival was shorter for patients who received ustekinumab treatment (p = 0.001). In the case of trough level less than 5 µg/ml, patients treated with a second anti-TNF agent had a higher postinduction remission rate (p = 0.002), and drug survival (p = 0.0005). No other relevant factors were associated with treatment efficacy, including trough levels greater than 5 µg/ml. CONCLUSIONS: VDZ, UST and a second anti-TNF agent exhibit similar efficacy in the short term, as second-biological line treatment in patients with CD who are refractory to a first anti-TNF agent, but shorter drug maintenance is observed for patients treated with UST.

Cumulative Exposure to Infliximab, But Not Trough Concentrations, Correlates With Rate of Infection.

BACKGROUND & AIMS: Infliximab increases the risk of infection in patients with inflammatory bowel diseases (IBD), but there is controversy over the relationship between drug concentration and infections. We aimed to assess factors associated with infection in infliximab-treated patients, including pharmacokinetic features. METHODS: We collected data from 209 patients with IBD (102 men; mean age, 39 y; 159 with Crohn's disease; 54 received combination therapy) who received an infliximab maintenance regimen from November 2016 through April 2017 in France. Data were collected from each infusion visit (total of 640 infusions). Infliximab exposure was estimated based on the area under the curve (AUC) of drug concentration in pharmacokinetic models; individual exposures over the 6-month period were estimated based on the sum of the AUC (ΣAUC). RESULTS: The mean infliximab trough level was 5.46 mg/L, and the mean ΣAUC was 3938 ± 1427 mg.d/L. A total of 215 infections were collected from the 640 infusion visits; 123 patients (59%) had at least 1 infection. Factors independently associated with infection after multivariate analysis were smoking (odds ratio [OR], 2.05; P = .046), IBD flare (OR, 2.71; P = .006), and a high ΣAUC of infliximab (above 3234 mg x d/L) (OR, 2.02; P = .02). The ΣAUC was higher in patients with an occurrence of infection (P = .04) and correlated with the number of infections (P = .04). Trough concentration of infliximab alone was not associated with infection. CONCLUSIONS: Almost two-thirds of patients treated with infliximab developed an infection; risk was individually correlated with cumulative increase in drug exposure, but not infliximab trough level.

VALIDation of the IBD-Disk Instrument for Assessing Disability in Inflammatory Bowel Diseases in a French Cohort: The VALIDate Study.

BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD] are disabling disorders. The IBD-Disability Index [IBD-DI] was developed for quantifying disability in IBD patients but is difficult to use. The IBD-Disk is a visual adaptation of the IBD-DI. It has not been validated yet. The main objectives were to validate the IBD-Disk and to assess the clinical factors associated with a change in the score and its variability over time. METHODS: From May 2018 to July 2019, IBD patients from three university-affiliated hospitals responded twice to both IBD-Disk and IBD-DI at 3-12 month intervals. Validation included concurrent validity, reproducibility, and internal consistency. Mean IBD-Disk scores were compared according to clinical factors. Variability was assessed by comparing scores between baseline and follow-up visits. RESULTS: A total of 447 patients [71% Crohn's disease, 28% ulcerative colitis] were included in the analysis at baseline and 265 at follow-up. There was a good correlation between IBD-Disk and IBD-DI [r = 0.75, p <0.001]. Reproducibility was excellent [intra-class correlation coefficient = 0.90], as well as internal consistency [Cronbach's α = 0.89]. The IBD-Disk was not influenced by IBD type but was associated with female gender and physician global assessment. Extra-intestinal manifestations, history of resection, elevated C-reactive protein and faecal calprotectin also tended to be associated with higher disability. The IBD-Disk score decreased in patients becoming inactive over time. CONCLUSIONS: This study validated the IBD-Disk in a large cohort of IBD patients, demonstrating that it is a valid and reliable tool for quantifying disability for both CD and UC.

Predictors of relapse following infliximab de-escalation in patients with inflammatory bowel disease: the value of a strategy based on therapeutic drug monitoring.

BACKGROUND: There are limited data concerning infliximab drug monitoring during de-escalation of the treatment of inflammatory bowel disease (IBD). AIM: To define the rate and the predictors of relapse following infliximab de-escalation in IBD patients in remission. METHODS: All IBD patients at a single referral centre in clinical and biological remission and in whom the dose of infliximab had been de-escalated were included. Patients in remission with a high trough level of infliximab (>7 mg/L) were considered to be trough level-based de-escalation patients. The data were retrieved from a prospective IBD database. Actuarial analysis was performed for statistical purposes. RESULTS: A total of 146 de-escalations were performed in 96 patients (Crohn's disease/ulcerative colitis: 68%/32%); 54 (37%) were based on clinical remission only, and 92 (63%) were based on clinical remission associated with a trough level above 7 mg/L. The cumulative probabilities of relapse following infliximab de-escalation were 16% and 47% at 1 and 2 years, respectively. Ulcerative colitis was associated with an increased risk of relapse (HR = 3.2, P = 0.005). Conversely, combination therapy at infliximab initiation (HR = 0.39, P = 0.0110) and trough level-based de-escalation were associated with decreased risk of relapse (HR = 0.45, P = 0.024). Trough levels before and after de-escalation were well correlated; a decrease by half was observed following a 2-week interval increase or a half-dose decrease. CONCLUSION: The use of trough levels to assess the feasibility of dose de-escalation seems to be a prerequisite for decreasing the risk of relapse.

Outcomes of Perianal Fistulising Crohn's Disease Following Anti-TNFα Treatment Discontinuation.

Background: Discontinuation of antitumour necrosis factor (TNF)α therapy with perianal fistulising Crohn's disease remains controversial due to the risk of severe relapse without any clear evidence. Aim: The aim of this study was to assess the rate and type of perianal and luminal relapses following anti-TNFα discontinuation. Methods: All patients treated with anti-TNFα for perianal fistulising Crohn's disease with subsequent discontinuation of therapy were retrospectively reviewed from a prospective database (1998-2016). Cumulative probabilities of relapse-free survival were estimated by actuarial analysis. Results: After a median follow-up of 62 months, 24 of the 45 patients experienced perianal relapse. A new surgical drainage was needed in 19 (79%) patients. The cumulative probabilities of perianal relapse at 1 and 5 years were 24% and 55%, respectively. Ileal localization (L1) at diagnosis, persistence of an external fistula opening, second line anti-TNFα use, or prior dose optimization was associated with perianal relapse, whereas continuation of immunosuppressive agents decreased this risk (HR = 0.3). Luminal relapse occurred in 42% of patients at 5 years. The cumulative probability of global relapse at 5 years was 67%. Retreatment with anti-TNFα allowed further remission in 23 of 24 (96%) patients. Conclusion: Half of patients with perianal fistulising Crohn's disease relapse within 5 years after anti-TNFα discontinuation. Immunosuppressant continuation may decrease this risk. The high risk of relapse (perianal and luminal) may suggest a benefit in pursuing biologics over a longer period in patients with perianal fistulas.

Anal Fistulas in Severe Perineal Crohn's Disease: Mri Assessment in the Determination of Long-Term Healing Rates.

Background & Aims: The European Crohn's and Colitis Organization recommends magnetic resonance imaging (MRI) of anal fistulas to decide on the drug/surgery strategy. No evidence is available on the long-term impact of MRI features on fistula healing. The aim of this study was to evaluate the benefit of combined drug/surgery strategies for the treatment of perianal Crohn's fistulas based on MRI factors at referral. Methods: The clinical event (anal abscess, new fistula tract, cellulitis), therapeutic intervention (introduction/optimization of immunosuppressant/biologics, anal surgery, intestinal resection, stoma), and MRI data were prospectively recorded for patients with Crohn's disease (CD) and anal fistulas. Healing was defined by fulfilment of all the following conditions: no discharge or pain, closure of the external opening of the fistula, no visible internal opening, no abscess, and no subsequent draining seton or drainage procedure performed during at least 1 year of follow-up. Results: Seventy CD patients with anal fistulas and MRI evaluations were followed for 70 months. The cumulative rates of fistula healing were 25%, 40%, 50%, and 70% at 12, 24, 36, and 72 months, respectively. Severe, complex, branched, and high fistulas were associated with a less favorable outcome. Surgical closure of the tract improved the healing rates better than treatment with biologics or thiopurines. Male sex, A1 luminal phenotype, and anal ulceration at referral were independently associated with a higher healing rate. Conclusions: Therapeutic strategies for perianal fistulizing CD require robust anatomical and healing evaluations. Combined strategies using biologics to improve both drainage and secondary closure of the fistula tracts merit further study.

Clinical, histological, and molecular risk factors for cancer recurrence in patients with stage II colon cancer.

INTRODUCTION: The assessment of risk factors of cancer recurrence in patients with stage II colon cancer (CC) is crucial. Our aim was to study the clinical, histological, and molecular features associated with 3-year disease-free survival in a series of consecutive patients with stage II CC treated in three regional digestive oncology centers. METHODS: Clinical and histological data of all patients after curative surgery for stage II CC, treated from 2001 until 2009, were collected retrospectively. Histological samples were obtained and tested prospectively for microsatellite instability using fluorescent PCR amplification. Cox proportional hazards regression models were used to calculate P values, hazard ratios (HRs), and 95% confidence intervals (CIs). RESULTS: Among 195 patients studied, 22 (11%) had disease recurrence during the 3-year period following diagnosis. On multivariate analysis, only low number of lymph nodes (HR=3.81, 95% CI: 1.19-12.19, P=0.02) and T4 status (HR=5.49, 95% CI: 1.06-28.43, P=0.04) were associated significantly with an increased risk of relapse. CONCLUSION: In this series of stage II CC patients, only T4 status and low number of lymph nodes were independent risk factors for poor 3-year disease-free survival, suggesting that patients with these features should be considered for adjuvant chemotherapy.

Reversibility of gastric mucosal lesions induced by sodium phosphate tablets and characterized by probe-based confocal laser endomicroscopy.

BACKGROUND AND STUDY AIMS: Adequate bowel preparation is key for the optimal quality of colonoscopy. The sodium phosphate laxatives used for preparation may induce gastric injuries. However, in vivo studies monitoring the effects of sodium phosphate on the gastric mucosa are currently lacking. We aimed to characterize the effects of sodium phosphate tablets (Colokit®; Mayoly Spindler, Chatou, France) on the gastric mucosa in a large-animal model. METHODS: Fourteen anesthetized pigs were used for this study. Fundic mucosal sites were analyzed at 1.5, 24, and 72 hours after the endoscopically guided application of sodium phosphate tablets (NaPT) and placebo tablets (PlaT) and were compared with unexposed sites. Different mucosal parameters were assessed with white light endoscopy, probe-based confocal laser endomicroscopy (pCLE), histology, and ex vivo permeability measurements. RESULTS: At 90 minutes after the application of NaPT, significant increases in epithelial irregularity and crypt pit intensity were observed with pCLE. These microscopic lesions persisted at 24 hours but were resolved at 72 hours. In addition, white light endoscopy revealed local exanthema in 57 % of the animals at 1.5 hours after NaPT application. Such lesions were observed in 22 % of the pigs at 24 hours and disappeared at 72 hours after application. After 1.5 hours, PlaT induced a slight but significant increase in epithelial irregularity, as well as architectural scores that were significantly lower than the ones induced by NaPT and that disappeared after 72 hours. CONCLUSIONS: The direct and prolonged gastric application of NaPT in pigs can induce acute superficial macroscopic and microscopic injuries that are reversible within 72 hours.