Signs and Symptoms of Acute Bowel Inflammation and the Risk of Progression to Inflammatory Bowel Disease: A Retrospective Analysis.

Episodes of acute ileitis or colitis have been associated with future development of inflammatory bowel diseases (IBD). Nevertheless, the rate of future IBD among patients diagnosed with signs or symptoms of acute bowel inflammation is unknown. We aimed to assess the risk of IBD development among patients presenting with signs or symptoms of ileitis or colitis. We searched for all patients that visited the emergency department (ED) and underwent abdominal computed tomography (CT) who were eventually diagnosed with IBD during gastroenterology follow-ups within 9 years from the index admission. Multivariable models identified possible predictors of patients to develop IBD. Overall, 488 patients visited the ED and underwent abdominal imaging with abnormal findings, and 23 patients (4.7%) were eventually diagnosed with IBD (19 Crohn's, 4 ulcerative colitis). Patients with a future IBD diagnosis were significantly younger (28 vs. 56 years, p < 0.001) with higher rates of diarrhea as a presenting symptom (17.4% vs. 4.1%, p = 0.015) compared to non-IBD patients. On multivariable analysis, age (p < 0.001), colitis (p = 0.004) or enteritis (p < 0.001) on imaging and a diagnosis of diarrhea in the ED (p = 0.02) were associated with development of IBD. Although alarming to patients and families, ED admission with intestinal inflammatory symptoms leads to eventual diagnosis of IBD in <5% of patients during long-term follow-up.

Delaying an infliximab infusion by more than 3 days is associated with a significant reduction in trough levels but not with clinical worsening.

Background: Higher infliximab trough levels (TLs) correlate with better clinical, inflammatory, and endoscopic outcomes among inflammatory bowel disease (IBD) patients. Although standard scheduled infliximab therapy regimen consists of infusions at pre-defined time-points (weeks 0, 2, 6, and every 8 weeks), short-period deviations from therapeutic schedule are common in 'real life', but the pharmacokinetic impact of these deviations has not been explored. In this study, we aim to determine whether short-period deviations from infusion schedule affect infliximab-TL. Methods: A retrospective analysis of all IBD patients receiving infliximab maintenance therapy every 8 weeks was conducted in a tertiary medical center. Patients with anti-drug antibodies, deliberate interval shortening and <3 sequential maintenance sera available were excluded. Associations between time since last infusion and TL were studied. Statistical analysis was performed using generalized estimating equations. Results: Out of over 10,000 sera, 2088 sera of 302 maintenance period stable infliximab-therapy-patients met inclusion criteria (median TL 4.1 µg/mL, interquartile range (IQR) 2.3-6.5 µg/mL). A delay beyond 3 days in infusion schedule (n > 59 days since last infusion) was found to significantly affect TL (mean difference in TL 0.9 µg/mL, 95% confidence interval (CI): 0.03-1.9 µg/mL, p < 0.04). Furthermore, among patients with delayed infusions, 80% had TL below 5 µg/mL, in comparison to 55% of patients who were not late (odds ratio (OR): 2.81, CI: 2.02-3.92, p < 0.0001). Conclusion: Real-life delays of ⩽3 days from infusion protocol can probably be allowed. Delays >3 days culminate in measurable decrease of TL, although effect on clinical outcome is unclear. This needs to be taken into account when interpreting drug-level test results. Summary: A total of 2088 sera of 302 maintenance period inflammatory bowel disease (IBD) patients treated with infliximab were analyzed, to assess effect of small deviations from infusion schedule on TLs. A significant decline in patients' trough level (TL) was noted as early as 3 days after scheduled infusion.

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.

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.

Infliximab therapy intensification upon loss of response: Is there an optimal trough level?

INTRODUCTION: Loss of response (LOR) to infliximab occurs in ∼30% of IBD patients. At time of LOR, lower infliximab-trough-levels (TL), in the absence of anti-drug-antibodies (ATI), have been associated with the need for therapy escalation. Nevertheless, few studies have examined the outcome of infliximab-therapy intensification, based on different TL. AIM: To evaluate the impact of infliximab-TL on efficacy of therapy intensification (dose-elevation/interval-shortening). METHODS: This was a retrospective observational study performed at two tertiary-centers between 2013-2017. Study population included IBD patients who underwent infliximab therapy escalation (dose elevation/interval shortening) due to clinical LOR. Patients with TL < 3 µg/ml or positive ATI were excluded. TL and clinical scores before intensification and after 6, 12 months were obtained prospectively. RESULTS: Forty-eight IBD patients were included; 23(49%), and 29(60%) reached clinical remission by 6, 12 months before intensification. TL among patients in clinical remission were significantly lower than among those clinically active, both at 6 (p = 0.001, median TL 4.7,8.7 µg/ml, IQR 3.6-8.1, 5.9-16 µg/ml) and 12 months (p = 0.005, median TL 4.6,8.7 µg/ml, IQR 3.6-8, 5.3-16 µg/ml), respectively. CONCLUSIONS: In IBD patients experiencing clinical LOR to infliximab in the absence of ATI, success of doubling the dose was inversely associated with baseline TL. Patients with baseline TL above 9 mcg/ml were very unlikely to reach clinical remission.