Association Between Low Trough Levels of Vedolizumab During Induction Therapy for Inflammatory Bowel Diseases and Need for Additional Doses Within 6 Months.

BACKGROUND & AIMS: We investigated whether serum trough levels of vedolizumab, a humanized monoclonal antibody against integrin α4ß7, during the induction phase of treatment can determine whether patients will need additional doses (optimization of therapy) within the first 6 months. METHODS: We conducted an observational study of 47 consecutive patients with Crohn's disease (CD; n = 31) or ulcerative colitis (UC; n = 16) who had not responded to 2 previous treatment regimens with antagonists of tumor necrosis factor and were starting therapy with vedolizumab at 2 hospitals in France, from June 2014 through April 2016. All patients were given a 300-mg infusion of vedolizumab at the start of the study, Week 2, Week 6, and then every 8 weeks; patients were also given corticosteroids during the first 4-6 weeks. Patients not in remission at Week 6 were given additional doses of vedolizumab at Week 10 and then every 4 weeks (extended therapy or optimization). Remission at Week 6 of treatment was defined as CD activity score below 150 points for patients with CD and a partial Mayo Clinic score of <3 points, without concomitant corticosteroids, for patients with UC. Blood samples were collected each week and serum levels of vedolizumab and antibodies against vedolizumab were measured using an enzyme-linked immunosorbent assay. Median trough levels of vedolizumab and interquartile ranges were compared using the nonparametric Mann-Whitney test. The primary objective was to determine whether trough levels of vedolizumab measured during the first 6 weeks of induction therapy associated with the need for extended treatment within the first 6 months. RESULTS: Based on response to therapy at Week 6, extended treatment was required for 30 of the 47 patients (23 patients with CD and 7 patients with UC). At Week 2, trough levels of vedolizumab for patients selected for extended treatment were 23.0 µg/mL (interquartile range, 14.0-37.0 µg/mL), compared with 42.5 µg/mL in patients who did not receive extended treatment (interquartile range, 33.5-50.7; P = .15). At Week 6, trough levels of vedolizumab <18.5 µg/mL were associated with need for extended therapy (100% positive predictive value, 46.2%; negative predictive value; area under the receiver operating characteristic curve, 0.72) within the first 6 months. Among patients who required extended treatment at Week 10, all of those with trough levels of vedolizumab <19.0 µg/mL at Week 6 had achieved clinical remission 4 weeks later (secondary responders). CONCLUSIONS: In a prospective study of patients with CD or UC receiving induction therapy with vedolizumab, low trough levels of vedolizumab at Week 6 (<19.0 µg/mL) are associated with need for additional doses (given at Week 10 and then every 4 weeks). All patients receiving these additional doses achieved a clinical response 4 weeks later.

Development and Internal Validation of a Model Using Fecal Calprotectin in Combination with Infliximab Trough Levels to Predict Clinical Relapse in Crohn's Disease.

BACKGROUND: The best noninvasive method predicting clinical relapse remains undetermined in infliximab (IFX)-treated patients with Crohn's disease. METHODS: All patients with CD on IFX maintenance treatment and in clinical remission for at least 16 weeks, between 2011 and 2014, were enrolled in a prospective single-center study. The Crohn's Disease Activity Index (CDAI), fecal calprotectin, C-reactive protein levels, antibodies (ATI), and trough level (TLI) of IFX were measured at every IFX infusion. The best thresholds of TLI (2 versus 3 µg/mL) and calprotectin (50 versus 250 µg/g stools) were identified across four logistic regression models. RESULTS: One hundred nineteen patients (mean age: 34 ± 12 yrs, mean disease duration: 7.8 yrs) were included. Mean follow-up was 20.4 months, and 17% of the patients were on IFX and azathioprine at inclusion. During follow-up, 37 patients (31.1%) relapsed, 78% within the first 6 months. The clinical characteristics of the relapsed and nonrelapsed patients were similar. After logistic regression, fecal calprotectin >250 µg/g stools (OR: 4.09; 95% CI, 1.01-16.21; P = 0.049) and TLI <2 µg/mL (OR: 14.85; 95% CI, 3.67-60; P < 0.0001) were associated with loss of response. A training cohort of 55 patients was isolated randomly to implement prediction rules for loss of response. The best predictive rules were the combination of a TLI <2 µg/mL and a fecal calprotectin level >250 µg/g stools (78.3%). These rules were validated on a test cohort of 64 patients with an accuracy of 87%, (sensitivity = 0.94, specificity = 0.84, positive predictive value = 0.73, and negative predictive value = 0.97). CONCLUSIONS: In IFX-treated patients with CD in clinical remission, a combination of TLI (<2 µg/mL) and fecal calprotectin (>250 µg/g of stools) is a good model for predicting loss of response. In contrast with previous data, low TLIs ranging from 2 to 3 µg/mL should neither systematically lead to the optimization of IFX use nor a switch in the treatment.

The level of epidermal growth factor receptors expression is correlated with the advancement of colorectal adenoma: validation of a surface biomarker.

INTRODUCTION: Data about the expression of Epidermal Growth Factor Receptors (EGFRs) in colorectal adenomas remain scarce. RESULTS: 101 patients were enrolled including 53 controls. All adenomas (n = 38) and CRC (n = 5) were EGFR positive. Hyperplastic polyps (HP) (n = 8) and control colons (n = 53) were EGFR negative in half of cases (p < 0.0001). A well significant gradient of increased EGFR expression was observed between adjacent mucosa, hyperplastic lesions, low grade dysplasia (LGD) (n = 30), high grade dysplasia (HGD) adenomas (n = 9) and cancers (p < 0.0001). EGFR overexpression was reported in 100% of cancers, 77.8% of HGD, and 10% of LGD adenomas. By multivariate analysis in adenomas, associated factors with EGFR overexpression were HGD and tubulo-villous feature. MATERIALS AND METHODS: All patients undergoing colonoscopy in the university center of Saint-Etienne were eligible to the study from December 2015 to March 2016. In patients with colorectal neoplasia (lesions group), biopsies were performed on the lesion before its resection, and on the adjacent and distal colon mucosa. In control group, biopsies were performed in the right and left side colon. The EGFR expression was assessed by immunohistochemical scores (Goldstein grade, intensity of staining, composite score), using a primary mouse monoclonal antibody (EGFR, clone 113, Novocastra). Outcomes were compared using Kruskal-Wallis and/or Mann-Whitney-U tests, appropriately. The associated clinical, endoscopic and histological factors with EGFR overexpression (composite score ≥ 6) were assessed for adenomas by logistic regression. CONCLUSIONS: EGFR are early involved in colorectal carcinogenesis, and their expression is strongly correlated to the neoplasia stage, leading to validate EGFR as an interesting surface biomarker of adenomas.

Infliximab Does Not Worsen Outcomes During Flare-ups Associated with Cytomegalovirus Infection in Patients with Ulcerative Colitis.

BACKGROUND: Immunosuppressive therapies used for treating ulcerative colitis are known to favor chronic and latent viral diseases. This study aimed at evaluating prospectively the association between colonic cytomegalovirus (CMV) reactivation and anti-tumor necrosis factor (TNF) monoclonal antibodies (mabs) by comparison to azathioprine (AZA) in a series of flare-ups occurring in consecutive ulcerative colitis patients. METHODS: A total of 109 flare-ups were recorded in 73 patients receiving a maintenance therapy by anti-TNF mabs (n = 69) or AZA (n = 40). The CMV DNA load in colonic tissue was determined by reverse transcription polymerase chain reaction on a pair of biopsies. RESULTS: The number of CMV reactivation was of 35% and 38% in patients receiving anti-TNF mabs and AZA, respectively. The median of CMV DNA load was 378 [10-29,800] and 8300 [10-3,25,000] copies/mg of tissue in patients treated by anti-TNF mabs and AZA, respectively (P = 0.11 by Mann-Whitney U test). In a subgroup of 45 patients under anti-TNF mabs requiring an optimized treatment by infliximab, clinical remission (partial Mayo score <3) was not significantly impacted by the presence of CMV reactivation at the time of flare-up (P = 0.52). Twenty of these patients underwent a second colonic biopsy 8 weeks after the initiation of flare-up therapy; except for 3 patients, the colonic CMV DNA load was stable or decreased. CONCLUSIONS: Patients under anti-TNF maintenance therapy are not at higher risk of CMV reactivation in case of flare-up. No reciprocal adverse influence was observed between anti-TNF mabs and CMV infection, suggesting that these drugs must be considered for treating flare-ups associated to CMV reactivation.

Management of cytomegalovirus infection in inflammatory bowel diseases.

Cytomegalovirus is a deoxyribonucleic acid virus that infects a large part of the human population; after primary infection, it develops a latent state and can be reactivated, notably after a decrease in host immune defences. In patients with inflammatory bowel diseases, cytomegalovirus is frequently involved, either as an agent of colitis or through local asymptomatic reactivation. Due to the immune context of inflammatory bowel diseases and to the immunosuppressive therapies that are used to treat them, cytomegalovirus entertains complex relationships with these diseases. Whereas Crohn's disease seems little impacted by cytomegalovirus, this agent interferes strongly with the natural progression of ulcerative colitis. While immune treatments have a clear influence on the occurrence of cytomegalovirus colitis in ulcerative colitis (favourable for steroids and cyclosporine and rather inhibitory for infliximab), the role of cytomegalovirus infection on ulcerative colitis is more debated with roles ranging from innocent bystander to key pathogen suggested. There is however growing evidence for a participation of intestinal cytomegalovirus infection in the resistance of ulcerative colitis to steroids and the investigation of cytomegalovirus infection in intestinal biopsies by immunohistochemistry or quantitative polymerase chain reaction assay is strongly recommended. In several studies, treatment of cytomegalovirus infection by ganciclovir was shown to restore the response to immunomodulatory therapies and even to prevent the need for colectomy. All of these recently acquired data need to be validated by randomised clinical trials conducted on a large panel of ulcerative colitis patients.