Dana J. Lukin

The Real-World Effectiveness and Safety of Vedolizumab for Moderate-Severe Crohn's Disease: Results From the US VICTORY Consortium.

Objectives:We assessed the real-world effectiveness and safety of vedolizumab (VDZ) in moderate–severe Crohn’s disease (CD).Methods:Retrospective cohort study of seven medical centers, from May 2014 to December 2015. Adults with moderate-severe CD treated with VDZ, with follow-up after initiation of therapy, were included. Using the multivariable Cox proportional hazard analyses, we identified independent predictors of clinical remission or mucosal healing with VDZ. Rates of serious infection (requiring antibiotics, resulting in discontinuation of VDZ, hospitalization or death) and serious adverse events (discontinuation of VDZ, hospitalization or death) were described quantitatively.Results:We included 212 patients with moderate–severe CD (median age 34 years; 40% male; 90% tumor necrosis factor (TNF)-antagonist exposed) with a median follow-up (IQR) of 39 weeks (25–53). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission+mucosal healing) were 35%, 63%, and 26%, respectively. Individuals with prior TNF-antagonist exposure (hazard ratio (HR) 0.40; 95% confidence interval (CI): 0.20–0.81), smoking history (HR 0.47; 95% CI: 0.25–0.89), active perianal disease (HR 0.49; 95% CI: 0.27–0.88), and severe disease activity (HR 0.54; 95% CI: 0.31–0.95) were less likely to achieve clinical remission. Those with prior TNF-antagonist exposure (HR 0.29; 95% CI: 0.12–0.73), and severe disease activity (HR 0.54; 95% CI: 0.31–0.95) were less likely to achieve mucosal healing. During 160 patient years of follow-up (PYF) and 1,433 VDZ infusions, 5 patients developed infusion reactions (3.5 per 1,000 infusions), 21 developed serious infections (13 per 100 PYF), and 17 developed serious adverse events (10 per 100 PYF). A minority of adverse events required discontinuation of therapy (6 per 100 PYF).Conclusions:VDZ is a safe and effective treatment option for moderate–severe CD in routine practice. Clinical remission and deep remission (clinical remission and mucosal healing) can be achieved in 1/3 of individuals, and a minority of individuals require discontinuation of therapy due to adverse events.

Vedolizumab for Ulcerative Colitis: Treatment Outcomes from the VICTORY Consortium

OBJECTIVES: We aimed to quantify the safety and effectiveness of vedolizumab (VDZ) when used for UC, and to identify predictors of response to treatment. METHODS: Retrospective review (May 2014‐December 2016) of VICTORY Consortium data. Adults with follow‐up after starting VDZ for clinically active UC were included. Primary effectiveness outcomes were cumulative rates of clinical remission (resolution of all UC‐related symptoms) and endoscopic remission (Mayo endoscopic sub‐score 0). Key secondary effectiveness outcomes included cumulative rates of corticosteroid‐free remission and deep remission (clinical remission and endoscopic remission). Cox proportional hazard analyses were used to identify independent predictors of treatment effectiveness. Non‐response imputation (NRI) sensitivity analyses were performed for effectiveness outcomes. Key safety outcomes were rates of serious infection, serious adverse events, and colectomy. RESULTS: We included 321 UC patients (71% prior TNF&agr; antagonist exposure, median follow‐up 10 months). The 12‐month cumulative rates of clinical remission and endoscopic remission were 51% and 41%, respectively. Corresponding rates for corticosteroid‐free remission and deep remission were 37% and 30%, respectively. Using NRI, 12‐month rates were 20% (n = 64/321) for clinical remission, 17% (n=35/203) for endoscopic remission, 15% (n=30/195) for corticosteroid‐free remission, and 14% (n = 28/203) for deep remission. A majority of the patients without adequate follow‐up at 12 months who were deemed non‐responders using NRI had already achieved clinical remission (n = 70) or a significant clinical response (n=36) prior to 12 months. VDZ discontinuation prior to 12 months was observed in 91 patients, for lack of response (n =56), need for surgery (n=29), or adverse event (n=6). On multivariable analyses, prior exposure to a TNF&agr; antagonist was associated with a reduced probability of achieving clinical remission (HR 0.53, 95% CI 0.38–0.75) and endoscopic remission (HR 0.51, 95% CI 0.29–0.88). Serious adverse events and serious infections were reported in 6% and 4% of patients, respectively. Overall cumulative rates of colectomy over 12 months were 13%, with lower rates observed in patients naive to TNF&agr; antagonist therapy (2%) than those who had been exposed to TNF&agr; antagonists (19%). CONCLUSION: In this large real‐world cohort we observed that VDZ was well tolerated and effective in achieving key clinical outcomes.

Predictors and Management of Loss of Response to Vedolizumab in Inflammatory Bowel Disease

Background We quantified loss of response (LOR) to vedolizumab (VDZ) in clinical practice and assessed the effectiveness of VDZ dose intensification for managing LOR. Methods Retrospective review (May 2014-December 2016) of a prospectively maintained inflammatory bowel disease (IBD) registry. Kaplan-Meier estimates were used to determine rates of LOR to VDZ . Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. Success of recapturing response (>50% reduction in symptoms from baseline) and remission (complete resolution of symptoms) after dose intensification was quantified. Results Cumulative rates for VDZ LOR were 20% at 6 months and 35% at 12 months, with slightly lower rates in Crohns disease than in ulcerative colitis (6 months 15% vs 18% and 12 months 30% vs 39%, P = 0.03). On multivariable analysis, LOR to a tumor necrosis factor (TNF) antagonist before VDZ use was associated with an increased risk for LOR to VDZ [hazard ratio (HR) 1.93; 95% confidence interval (CI) 1.25-2.97] in all patients. For Crohns disease patients specifically, higher baseline C-reactive protein concentration was associated with increased risk for LOR to VDZ (HR 1.01 per mg/dL increase, 95% CI 1.01-1.02). Shortening of VDZ infusion interval from 8 to every 4 or 6 weeks recaptured response in 49% and remission in 18% of patients. Conclusions LOR to a TNF antagonist before VDZ use and higher baseline C-reactive protein are important predictors of VDZ LOR. Treatment response can be recaptured in almost half of these patients with VDZ infusion interval shortening.

Sa1138 Patients With Inflammatory Bowel Disease and a History of Cancer: The Risk of Cancer Following Exposure to Immunosuppression

Back ground: The calcineurin inhibitor (CNI) tacrolimus (TAC) has been reported to be effective for induction and maintenance of remission in patients with refractory ulcerative colitis (UC). However, CNI has nephrotoxic potential leading to acute and chronic renal damage in some cases. To date, little is known about the influence of long term administration of oral TAC on renal function in patients with UC. Aim: The aim of our study was to evaluate the incidence and the severity of renal function impairment in UC patient who received TAC treatment. Methods: In this retrospective study, the medical charts of 71 adult patients with steroid-refractory UC treated with TAC between 2012 and 2014 in a single Japanese center were analyzed. In principle, TAC was orally administrated as a 2 week-induction (target trough levels 10-15ng/ml) followed by a maintenance therapy (target trough levels 5-10ng/ml). Estimated glomerular filtration rate (eGFR) was evaluated during the treatment. Acute kidney injury (AKI) was defined by the RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of function, Loss of function and End-stage kidney disease) consensus criteria using the maximal change in serum creatinine (Scr) and eGFR during the TAC treatment compared with baseline value before treatment. Results: The mean duration of TAC administration was 210 days. At 12weeks, TAC produced a clinical response in 54 patients (76.1%) and remission was achieved in 29 of those 54 (40.8%). The AKI rate during TAC treatment was 46.5% (33 of 71 patients). RIFLE class R (Scr increase > 1.5 times or eGFR decrease > 25%) accounted for 27 patients (38.0%), and RIFLE class I (Scr increase > 2 times or eGFR decrease > 50%) for six (8.5%). The AKI rate was 76.8% (10/13) in patients who had been administrated TAC for more than 1 year and 37.5% (18/48) in patients with TAC treatment within 6 months (p=0.006). After withdrawal of TAC, renal function impairment (eGFR decrease > 25%) was still observed in 10 patients (14.1%). Conclusions: Oral TAC therapy appears to be effective for patients with refractory UC. However, renal function impairment was frequently observed during this treatment. Thus, careful monitoring of renal function must be required to avoid irreversible chronic renal damage during long-term administration of TAC.

281 Mutant K-RAS in the Epithelial Stem Cell Compartment Promotes Symmetric Stem Cell Division and Crypt Fission but Not Tumorigenesis in the Mouse Intestine and Colon

cell sorting and 3) significantly expand organoids as either enriched for stem cells or as differentiated cells that retain a site-specific program of differentiation and are free from mesenchymal contamination. Here we present an improved isolation and culture method that addresses these needs. METHOD: Human gastrointestinal epithelial cells were cultured using an adaptation of our published mouse epithelium culturing system. This system utilizes conditioned media collected from an L cell line (L-WRN) engineered to secrete the factors required for epithelial stem cell growth (Wnt3a, R-spondin3 and Noggin). Importantly, cultures were established from biopsy tissue (2-3 biopsies with area of 6-24 mm2) collected during routine endoscopy. Cell sorting enrichment was not required. Epithelial cells were maintained as 3-dimensional organoids in basement membrane matrix (Matrigel) with 50% conditioned media (1:1 dilution with fresh crypt culture media). Analysis of cellular markers of proliferative and differentiated cells was performed using qRT-PCR, immunofluorescence and flow assisted cell sorting. RESULTS: Human epithelial cultures were established from multiple regions of the gastrointestinal tract, including small intestine (n=9), colon (n=23), stomach (n=2) and Barretts esophagus (n=2). Biopsy donors included healthy and IBD patients. Mesenchymal cells carried over from the isolation process were eliminated during initial passages. Subsequent studies focused on intestinal organoids, which were maintained for.40 passages (.120 days) and were able to be stored as frozen stocks. In 50% conditioned media, the majority of cells were proliferative and expressed high levels of the stem cell markers, LGR5 and OLFM4. Accordingly, organoids expanded at a rapid rate and were split 1:3 every 3 days. An intestine-specific program of differentiation was achieved using lower percentage conditioned media plus additional factors, including the Notch inhibitor DAPT. CONCLUSIONS:We have generated a culture system that will allow for large-scale, functional experiments of human intestinal epithelial cells. This system will enable us to create a biobank of human epithelial cell lines. Moreover, because cultures can be established from endoscopic biopsies, tissue donors could potentially be pre-selected based on genotype to facilitate studies of the interactions between genotype and environmental factors.