Do Vedolizumab trough Levels Predict the Outcome of Subsequent Therapy in Inflammatory Bowel Disease?

Background: Vedolizumab trough serum levels have been associated with clinical and endoscopic response in patients with inflammatory bowel disease (IBD). A recent study demonstrated that higher trough levels before dose escalation are associated with favorable outcomes. Objectives: We aimed to identify whether vedolizumab trough levels predict outcome of subsequent therapy. Methods: This retrospective study included IBD patients consecutively receiving vedolizumab therapy between November 2014 and June 2021. Only patients with a loss of response (LOR) to vedolizumab and available trough drug levels prior to therapy cessation were included. Clinical and endoscopic scores were recorded at 6 and 12 months post switching therapy. Results: Overall, 86 IBD patients (51 Crohn's disease, 35 ulcerative colitis) who discontinued vedolizumab were included; of those, 72 (83.7%) were due to LOR. Upon vedolizumab discontinuation, 66.3% of patients were switched to another biologic therapy. Trough vedolizumab levels at discontinuation due to LOR did not differ between patients with clinical response and LOR regarding subsequent therapy at 6 months [median 33.8 µg/mL (IQR 13.2-51.6) versus 31.7 µg/mL (IQR 9.1-64.8), p = 0.9] and at 12 months [median 29.6 µg/mL (IQR 14.3-51.6) versus 34.1 µg/mL (IQR 12.2-64.7), p = 0.6]. Patients progressing to subsequent surgery had numerically lower vedolizumab trough levels at LOR compared with patients who were treated with an additional medical therapy (median 14.3, IQR 4-28.2 µg/mL versus 33.5, IQR 13-51.6 µg/mL, p = 0.08). Conclusions: Vedolizumab trough levels upon LOR do not predict response to subsequent medical therapy; however, lower drug levels may suggest a more aggressive disease pattern and future need for surgery.

Distal Fecal Wash Host Transcriptomics Identifies Inflammation Throughout the Colon and Terminal Ileum.

BACKGROUND & AIMS: Noninvasive modalities for assessing active endoscopic and histologic inflammation in Crohn's disease and ulcerative colitis patients are critically needed. Fecal wash host shed-cell transcriptomics has been shown to be a robust classifier of endoscopic and histologic inflammation in inflammatory bowel disease patients with distal colitis. Whether such fecal washes can inform on inflammatory processes occurring in more proximal intestinal segments is currently unknown. METHODS: Fifty-nine inflammatory bowel disease patients and 50 controls were prospectively enrolled. Biopsy specimens and fecal washes from the distal colon, proximal colon, and terminal ileum were compared. Host transcriptomics were performed on the biopsy specimens and fecal washes obtained during colonoscopy at predefined locations throughout the colon and terminal ileum and results were associated with concurrent clinical, endoscopic, and histologic parameters. RESULTS: We found that host transcriptomics of distal fecal washes robustly classify histologic inflammation in ileal and proximal colonic Crohn's disease, even without distal colonic involvement (area under the receiver operating characteristic curve, 0.94 ± 0.09). We further found that fecal washes consist of modules of co-expressed genes of immune, stromal, and epithelial origin that are indicative of endoscopic disease severity. Fecal wash host transcriptomics also captures expression of gene modules previously associated with a lack of response to biological therapies. CONCLUSIONS: Our study establishes the accuracy of distal colonic fecal washes for identifying and scoring inflammatory processes throughout the entire ileal-colonic axis.

Ustekinumab and vedolizumab for extraintestinal manifestations in inflammatory bowel disease - a retrospective study.

INTRODUCTION: Extraintestinal manifestations (EIM) are associated with diminished quality of life. The efficacy of Ustekinumab and vedolizumab for EIM treatment is not well established. The aim was to compare the effectiveness of ustekinumab and vedolizumab for treatment of EIM in IBD. METHODS: We included IBD patients treated with vedolizumab or ustekinumab in the Gastroenterology department, Sheba Medical Center, for up to 52 weeks between 2015 and 2021. Patients with active EIM before treatment initiation were included. RESULTS: 111 patients were included. 53 patients (48%) were treated with ustekinumab; 88% (n-99) had CD. The most common EIM was arthralgia (95/111, 84%). Patients treated with ustekinumab were more likely to be anti-TNF experienced (n-51/53 [96%] compared with vedolizumab n = 36/58 [62%], p < 0.001). Clinical response of EIM at week 52 was achieved in 36% of patients treated with ustekinumab (n-18/50) and 34% of patients (n-19/54) treated with vedolizumab, with no statistically significant difference (p = 0.9). No statistical significance was achieved for patients presented with arthralgia. Clinical response of arthralgia at week 52 was seen in 34% (n-19/55) and 36% (n-18/46) of the patients treated with vedolizumab and ustekinumab, respectively, (p = 0.3). CONCLUSION: In this study, no difference was found between vedolizumab and ustekinumab regarding their effect on EIM in IBD patients for up to 52 weeks.

Dose optimisation for Loss of Response to Vedolizumab- Pharmacokinetics and Immune Mechanisms.

BACKGROUND: Real life data regarding pharmacokinetics of vedolizumab in patients needing dose optimisation are scarce. We set to examine whether pre-optimisation vedolizumab levels associate with therapy outcomes and which mechanisms explain the associations. METHODS: A multicentre observational study assessed the outcome of dose increase in association with pre-escalation levels in vedolizumab-treated patients. SubsequentIy, α4ß7 occupancy on peripheral blood [PB] and intestinal lamina propria [LP] tissues was investigated on various cellular subsets in patients undergoing lower endoscopy on infusion day. Cellular localisation of vedolizumab-bound α4ß7 and effects on M1 and M2 macrophages were also explored. RESULTS: A total of 161 inflammatory bowel disease [IBD] patients were included. Among 129/161 patients intensified during maintenance [Week 14 onward], pre-intensification trough levels were comparable or higher among those subsequently attaining post-optimisation clinical, biomarker, and endoscopic remission, compared with non-remitting patients [p = 0.09, 0.25, 0.04, respectively]. Similar results were demonstrated for those dose-optimised during induction [Week 6, n = 32]. In the immune sub-study [n = 43], free α4ß7 receptors at trough were similarly low among patients with/without mucosal healing, on PB T cells [p = 0.15], LP T cells [p = 0.88], and on PB eosinophils [p = 0.08]. Integrin receptors on M1 and M2 macrophages were also saturated by low levels of vedolizumab and anti-inflammatory cytokine secretion was not increased. Co-localisation and dissociation experiments demonstrated membranal α4ß7 receptors of two origins: non-internalised and newly generated α4ß7, but re-binding was still complete at very low concentrations. CONCLUSIONS: These results do not support pharmacokinetics as the mechanism responsible for loss of response to vedolizumab, nor do they support a need for higher drug concentration to enhance vedolizumab's immune effects. Higher pre-escalation levels may indicate less clearance [less severe disease] and higher likelihood of subsequent re-gained response, regardless of therapy escalation.