Abstract
Background
Subcutaneous (SC) formulations of CT-P13 and vedolizumab (VED) are currently available as new treatment option for patients with inflammatory bowel disease (IBD). The decision to ...switch requires a shared decision making based on adequate education of the patient, to avoid negative outcomes due to a nocebo effect. The aims of this study were (1) to evaluate the percentage of patients with IBD in favour of switching to SC formulations and (2) to compare two educational strategies.
Methods
This was a multicentre study in patients with IBD on maintenance intravenous (IV) CT-P13 or VED. Patients attending the infusion unit were invited to complete a survey exploring the willingness to switch to SC formulations. In centre A, all patients were informed on the new SC formulations and the accompanying care pathway by an information leaflet and a face-to-face interaction with the IBD nurse, prior to completing the survey. In centre B, patients on a minimal interval of q8w were digital invited to the same survey via the e-health application of the hospital. Demographics, patient reported outcomes, willingness to switch and reasons for IV vs. SC preferences were captured.
Results
In total, 447 (n=183 Centre A; n=264 Centre B; participation ratio 83.6%) patients completed the survey (m/f: 212/235; CD/UC/IBD-U: 275/161/11; median age 45 IQR 33–57; remission CD/UC: 75%/82%) see table. Most patients were open to SC treatment (47% yes, 33% doubt, 20% no). The main driver to switch was an anticipated decrease in hospital visits (86%) and overall time gain (78%). The main reason to continue IV was fear of change (60%) and uncertainty in case of relapse after switch to a SC formulation (46%). In univariate analysis, the self-estimated compliance rate was associated with the willingness to switch (p<0.0001). To evaluate the impact of the approach in patient education between the two centres, we compared the subgroup of patients on ≥q8w interval with a dosing of 5-10mg/kg CT-P13 or 300 mg VED (n=335). The willingness to switch was higher after a face-to-face approach (centre A) compared to a merely digital approach (centre B; 53.9 % vs. 40.9 % p=0.038), although patients in centre B had a higher educational level (p=0.003), more prior experience with other IBD SC medication (p=<0.001), lived further from the hospital (p<0.001) and had a younger age at diagnosis (p=0.019).
Conclusion
In this multicentre comparative study exploring the willingness to switch from IV to SC maintenance therapy with CT-P13 and VED, the majority is open to switch to a SC formulation. The direct approach and education of the patient by the IBD nurse impacts significantly the willingness to switch. In a follow-up we will investigate the actual switch rates.
Abstract
Background
Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon.1 Ustekinumab (UST), a monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 has ...shown in the UNIFI trials to be effective and safe in patients with moderate-to-severe UC.2 Real-life data are still limited.3
The aim of this study was to assess the real-world effectiveness and safety of UST in patients with UC across Belgian hospitals.
Methods
In this multicentric, retrospective observational study, patients with UC who received UST from September 2020 onwards were included. Clinical and biochemical response was assessed at baseline, week 8, 16 and 52. The primary endpoint was steroid-free remission defined as partial Mayo score of ≤ 2 with no subscore > 1 at week 16. Secondary endpoints included clinical and biochemical response (defined respectively as a decrease in partial Mayo score ≥ 3 points and ≥ 3 plus a decrease in rectal bleeding score ≥ 1 or an absolute rectal bleeding score ≤ 1 and a decline of 50% or more in CRP and/or fecal calprotectin).
Results
107 patients with moderate-severe UC (86% patients with ≥ S2 severity) were included across 16 participating centers. Median disease duration was 10 years (1-73y) and 69 (64%) of patients had previously failed 2 or more biologicals. At week 16, 35 patients reached the primary endpoint of steroid-free clinical remission (33%), while 67 had a clinical response (62.6%) (Fig 1). There was a statistically significant decline in partial mayo score (median at baseline 6.0 range (1-9); W16 2.0 (0-9, p<.001), CRP (3.85 mg/L (0.4-181) vs 3.15 (0.88-10.3); p<.001) and calprotectin (1040 (13-6000) vs 300 (3.8-2980); p<.001) (Fig 2 and 3). Biochemical response was seen in 41 patients (38%). No predictors for steroid-free remission could be identified.
At the end of follow-up at week 52, 75 patients were still treated with UST (70%). Reasons for discontinuation were primary non-response (N=18 (17%), loss of response (N=8 (7.5%) and adverse events (N=2 (1.9%)). No predictor for UST failure could be identified. Eight patients needed to be referred for colectomy (7.5%). In 7 patients dose optimization via IV reinduction occurred. No difference in occurrence of extra-intestinal manifestations was noted during treatment, severe infections occurred in 1 patient (0.9%). No other new safety signals were observed.
Conclusion
In this multi-centric, real-life cohort with highly refractory UC patients, UST was associated with a clinical response rate of 63% at 16 weeks while steroid-free remission was achieved in 33% of patients. No important new safety signals were observed.
Abstract
Background
Rigorous donor preselection on microbiota level, strict anaerobic processing, and repeated FMT administration were hypothesized to improve FMT outcomes for induction of remission ...in UC in the RESTORE-UC trial, for which we here report on the clinical results and observed microbial changes.
Methods
The RESTORE-UC trial was a multi-centric double-blind, sham-controlled randomized trial. Patients with moderate to severe UC (total Mayo 4-10, endoscopic subscore ≥2) were randomly allocated to receive 4 weekly anaerobic-prepared allogenic or autologous donor FMT. Allogenic healthy donors were selected after a rigorous screening by microbial cell count, enterotype, and the abundance of specific genera. The primary endpoint was steroid-free clinical remission (total Mayo ≤2, no subscore >1) at week 8. A pre-planned futility analysis was performed after 66% (n=72) of intended inclusions (n=108). Quantitative microbiota profiling (n=44) was performed at weeks 0 and 8.
Results
In total, 72 patients were included of which 66 received at least one FMT (allogenic-FMT n=30 and autologous-FMT n=36, Fig. A). At week 8, resp. 3 and 5 patients reached the primary endpoint (p=0.72), indicating no treatment difference of at least 5% in favour of allogenic-FMT. Hence, the study was stopped due to futility. The procedure was well tolerated, and only 2 SAE were observed.
Microbial analysis showed no significant differences in baseline microbiome composition between treatment groups. However, numerically more enterotype transitions upon allogenic-FMT compared to autologous-FMT (Fig. B), and more transitions were observed when patients were treated with a different enterotype than their own at baseline (p=0.01). Primary response was associated with lower total Mayo scores, lower bacterial cell counts (Fig. C,D) and a tendency to more Bact 2 prevalence at baseline, independently from FMT origin. At the allogenic donor side, a positive association was suggested between stool moisture and treatment success (Wilcoxon test, p=0.057; Fig. F). However, no indications pointed towards a highly effective ‘superdonor’ profile.
Conclusion
The RESTORE-UC trial comparing preselected allogenic to autologous FMT did not meet its primary endpoint of steroid-free clinical remission at week 8. Notably, participants exhibited more severe disease, aligning with recent guidelines recommending FMT for mild to moderate cases (Lopetuso & Deleu et al., 2023). In addition, our findings support adding microbial load and dysbiosis to the patient inclusion criteria based on a pre-treatment microbiome screening. Next to patient-selection, further research should additionally consider sterilized sham-control, increased frequency, density, and viability of FMT prior to administration.
Abstract
Background
Therapeutic drug monitoring (TDM) of infliximab (IFX) improves patient outcomes and is cost-effective. The short turnaround time of point-of-care testing (POCT) allows ad hoc dose ...adjustment. We aimed to determine the feasibility and pilot effectiveness of an ultra-proactive TDM algorithm including POCT of IFX in patients with inflammatory bowel disease (IBD).
Methods
All IBD patients with maintenance IFX treatment at our referral IBD clinic were prospectively included between June and August 2018. An ultra-proactive IFX TDM algorithm was applied as follows. All patients had an ELISA trough level (TL) measurement at baseline, of which the result determined the follow-up pathway: (A) TL between 3–7 μg/ml: continuation at same dose and interval; (B) TL >7 μg/ml: interval prolongation allowed; (C) TL <3 μg/ml: interval shortening with minimum 2 weeks, with the next IFX TL measured using a POCT. (i) If the POCT showed an IFX TL <3 μg/ml, dose was optimised ad hoc using a linear dosing formula (Dosen = (TLtarget * Dosen−1) / TLmeasured), followed by a new POCT test at next visit with the same interval. (ii) If the POCT showed an IFX TL ≥3 μg/ml, no additional dose was given and routine TL testing with ELISA was retaken at next visit. Physician’s global assessment, C-reactive protein (CRP), haemoglobin and albumin levels were sequentially evaluated according to standard of care.
Results
In total, 115 patients were included (Crohn’s disease/ulcerative colitis/IBDU n = 80/34/1; median CRP 1.2 mg/l (IQR 0.6–3.8); median TL 4.6 μg/ml (IQR 2.6–7.4)). A median of 3 infusions (IQR 3–4) during follow-up led to a total number of 371 TL measurements. There was a significant drop of low TL (<3 μg/ml) over time (38/115 at baseline vs. 22/256 during follow-up; p = 0.0001). The need for POCT reduced from an initial 28% to 8.7% (p = 0.0001). Additional dosing based on POCT measurement was needed in 7/43 (16.3%) cases. Patients needing ad hoc dose adjustment after interval shortening had significant lower TL at the previous measurement than those who did not (median (IQR) TL 0.9 μg/ml (0.7–1.8) vs. 2.3 μg/ml (1.5–2.6); p = 0.036). An IFX TL cut-off of 1 µg/ml predicted an ad hoc extra dose after interval shortening with an NPV of 96% (90% sens, 75% spec). In patients with elevated CRP at baseline (n = 26), ultra-proactive TDM resulted in a significant reduction of CRP over time, with a median (IQR) of 7.8 (6.5–18.3) mg/l at baseline compared with 6.3 (4–9.9) mg/l during follow-up (p = 0.025).
Conclusions
Ultra-proactive TDM based on a strict algorithm including POCT and ad hoc dose adjustment is feasible and significantly lowers CRP levels in IBD patients treated with maintenance IFX. Less than 10% of patients need POCT over time.
Abstract
Background
Four randomized controlled trials studying faecal microbiota transplantation (FMT) in active UC patients showed variable success rates. The efficacy of FMT appears to be ...influenced by various factors including donor- and procedure-specific characteristics. We hypothesized that the outcome of FMT in patients with active UC could be improved by donor preselection on microbiota level, by using a strict anaerobic approach, and by repeated FMT administration.
Methods
The RESTORE-UC trial (NCT03110289) was a national, multi-centric double-blind, sham-controlled randomized trial. Active UC patients (Total Mayo score 4–10 with endoscopic sub-score ≥2) were randomly allocated (1:1) to receive 4 anaerobic-prepared superdonor (S) FMT or autologous (A) FMT (Figure 1) by permutated blocks (2 and 4) and stratified for weight, concomitant steroid use, and therapy refractoriness.
S-FMTs were selected after a rigorous screening excluding samples with Bacteroides2 enterotype, high abundances of Fusobacterium, Escherichia coli and Veillonella and the lowest microbial loads (Q1).
A futility analysis after 66% (n=72) of inclusions was planned per protocol including a modified intention-to-treat (mITT) analysis using non-responder imputation (NRI) for patients receiving at least one FMT. The primary endpoint was steroid-free clinical remission (Total Mayo ≤ 2, with no sub-score >1) at week 8.
Results
Between March 2017–2021, 72 patients signed the ICF and 66 were randomly allocated to S-FMT (n=30) or A-FMT (n=36) and received at least one FMT. In the S-FMT and the A-FMT resp. 4 and 5 patients terminated the trial early due to worsening of colitis (4 in both arms) or FMT enema intolerance (1 A-FMT). They were included in the mITT analysis using NRI (Fig. 2). Both study arms were matched for baseline characteristics (Table 1), yet a trend (p= 0.066) towards higher concomitant biological use in the S-FMT arm was observed.
After 66% of intended inclusions, the primary endpoint was reached in 3/30 (10%) S-FMT and 5/31 (13.9%) patients randomized to A-FMT (p=0.72).
As the predefined minimum difference between both treatment arms was not attained, the study was stopped due to futility. The full set of endpoints are summarized in Table 2.Of note, no patients on concomitant biologicals reached the primary endpoint.
There were 2 serious adverse events in the A-FMT arm: dysuria requiring hospitalization and worsening of UC requiring colectomy.
Conclusion
In this double-blind sham-controlled trial comparing repeated administrations of anaerobic-prepared S-FMT with A-FMT in patients with active UC, no significant difference in steroid-free remission rates at week 8 were observed. The FMT procedure was generally well tolerated, and no new safety signals were observed.
Abstract
Background
The efficacy of faecal microbiota transplantation (FMT) in UC has been reported to be donor-, patient- and procedure-dependent (Rees et al., 2022). The RESTORE-UC trial ...NCT03110289 aimed to improve the outcome of FMT in patients with active UC by donor preselection on microbiota level, a strict anaerobic preparation and repeated FMT administration. The trial was prematurely stopped for futility (Caenepeel et al., 2022). We investigated changes in resp. biopsy and faecal samples obtained host transcriptomics and microbiota profiles from baseline to primary endpoint (PE) at week 8 to understand reasons for the observed lack of efficacy.
Methods
Active UC patients (total Mayo score 4-10 with endoscopic sub-score ³2, n=72) were randomly allocated to receive 4 anaerobic-prepared superdonor (S) FMT or autologous (A) FMT. Primary endpoint was defined as steroid-free clinical remission (Total Mayo ≤ 2, with no sub-score >1). Host RNA extractions were performed from mucosal biopsies collected at week 0 (n=63) and 8 (n=54) using the Qiagen AllPrep DNA/RNA Mini kit, and sequenced using Illumina HiSeq4000. Sequencing data was further processed (read-count filtering, normalization) and further analyzed using DESeq2 package. Corresponding faecal samples (resp. n=62 and n=50) were submitted to DNA extractions using MagAttract PowerMicrobiome DNA/RNA kit on an automated extraction platform, followed by library prep and 16S rDNA-sequencing using Illumina MiSeq. The obtained sequences were subjected to the DADA2 pipeline in R and the Quantitative Microbial Composition (QMP) was quantified by flow cytometry.
Results
Eight responders were observed: 3 after S-FMT and 5 after A-FMT, as well as 58 non-responders considering the intention-to-treat population. Responders to FMT tended to cluster at baseline (adonis p=0.34) and PCA analysis on the top 500 mucosal genes with the highest variance (Fig.1), showed a significant host effect at week 8 between responders and non-responders (adonis p<0.05). Likewise, PCA analysis of the currently available QMP (Fig.2) showed a trend towards clustering by response at week 0 and 8 resp. adonis p=0.18 and p=0.11). An overall decrease in Bacteroides-2 enterotype prevalence was observed (Fig.3) over both treatment groups and independently from reaching the PE (All McNemar's p=0.077).
Conclusion
A trend towards clustering of responders on host mRNA level and QMP was observed at baseline as well as at the primary endpoint, showing a potential role for pre-FMT patient selection by phenotype. Moreover, the dysbiotic enterotype Bacteroides-2 seems to be decreased after FMT. However, further analyses are mandatory to identify specific predictors of response and the origin of the microbiota shift.
Abstract
Background
Despite the increased availability of biological therapies, postoperative recurrence (POR) after an ileocolonic resection with ileocolonic anastomosis frequently occurs in ...patients with Crohn’s disease.
Methods
Over the last two years, a mixed panel of 24 gastroenterologists and colorectal surgeons collaborated within the 8th Scientific Workshop of ECCO. The available evidence on diagnosis, pathophysiology and risk factors, prevention and treatment of POR was reviewed and unanswered research questions were listed.
Results
In recent years, surgeons have been utilising innovative surgical techniques to reduce POR. Whilst the side-to-side anastomosis has become more common, the benefits of newer procedures such as Kono-S anastomosis or over-the-valve strictureplasty remain unproven. Consistency in describing and reporting POR is crucial both in routine practice and in clinical research. Ileocolonoscopy six to twelve months after ileocolonic anastomosis remains the gold standard to diagnose POR. However, an effort to adapt the Rutgeerts score to surgical techniques different from end-to-end anastomosis is required. Significance of isolated ulcers of the anastomotic line, specifically in case of stapled anastomoses, is still debated. In the coming years, intestinal ultrasound combined to faecal calprotectin may ultimately decrease the reliance on ileocolonoscopy.
Research on the microbiome and genetic background of patients with POR is promising although not applicable in daily clinical practice yet. Smoking is the only risk factor clearly identified in POR, whereas previous ileocolonic resection or penetrating disease have not been validated in prospective studies. Stronger emphasis on smoking cessation for all patients should include specific active measures to make it successful.
The prevailing gap in accurate predictors of POR disempowers clinicians from stratifying between systematic prophylaxis and endoscopy-driven approach. Immediate prophylaxis therapy may lead to overtreatment.Ongoing randomized controlled trials comparing (i) systematic prophylaxis and endoscopy-guided introduction of biological therapy (NCT05169593), and (ii) therapy escalation to status quo in patients with moderate endoscopic POR (NCT05072782) should be informative.
Conclusion
Despite important progress in the field of POR in the last 30 years, POR management remains a challenge. The IBD community should strive to optimise diagnostic procedures of POR including ileocolonoscopy and non-invasive techniques, define patients at high risk of POR using microbiome and/or genetic profiling and clarify the optimal medical treatment strategy after surgery.
Abstract
Background
There is evidence for an exposure-efficacy relationship for vedolizumab induction therapy in patients with inflammatory bowel disease (IBD). In contrast to anti-tumour necrosis ...factor agents, the correlation between the response to dose optimisation and changes in the pharmacokinetic profile of vedolizumab-treated patients remains unknown.
Methods
This was a retrospective analysis of all vedolizumab-treated patients that increased dosing frequency because of primary non-response or secondary loss of response in a tertiary referral IBD centre between April 1, 2016 and May 31, 2017. Treatment response, defined as an improvement in clinical symptoms and objective signs of inflammation at the end of follow-up, was correlated with early changes from baseline of vedolizumab trough concentrations after dose optimisation.
Results
A total number of 23 IBD patients, eight with ulcerative colitis (UC) and 15 with Crohn’s disease (CD), underwent dose optimisation of vedolizumab. The median time since the start of vedolizumab was 6 months (IQR 3–9.5 months). There were seven patients (1 UC, 6 CD) with primary non-response to vedolizumab and 16 patients (7 UC, 9 CD) with secondary loss of response to vedolizumab. After complete follow-up with a median time of 9 months (IQR 5–13 months), treatment response could be restored in 12 of 23 (52.2%) vedolizumab-treated patients (4 of 8 UC, 8 of 15 CD). Median vedolizumab trough concentration at baseline was 9.5 μg/ml (IQR 5.5–14.4 μg/ml) in patients with response to dose optimisation and 7.0 μg/ml (IQR 2.0–16.0 μg/ml) in patients without response to dose optimisation (p-value = 0.26). Mean change from baseline of vedolizumab trough concentrations at Month 3 after dose optimisation was numerically higher in the group of responders vs. the group of non-responders (22.9 μg/ml vs. 11 μg/ml; p-value = 0.07).
Time point
Responders (n = 12)
Non-responders (n = 11)
Baseline
Vedolizumab TC, μg/ml, mean (SD)
11.4 (9.0)
10.5 (11.1)
Month 3
Vedolizumab TC, μg/ml, mean (SD)
34.3 (21.8)
21.5 (14.9)
Vedolizumab TC compared with baseline, ∆, μg/ml, mean (SD)
22.9 (19.3)
11 (7.3)
Mean vedolizumab trough concentrations and change from baseline after dose optimisation in the group of responders vs. the group of non-responders (SD: standard deviation, TC: trough concentration)
Conclusions
Dose optimisation resulted in a treatment response in more than half of IBD patients with primary non-response or secondary loss of response to vedolizumab. Early changes in the pharmacokinetic profile of vedolizumab tended to predict response after dose optimisation at the end of follow-up.
Abstract
Background
The regularly administration of intravenous (IV) therapy negatively impacts on the work productivity and social functioning of patients with inflammatory bowel disease (IBD). The ...advent of new IV therapies leads to an increased workload at the IBD infusion unit and pharmacy, demanding a more efficient organisation. E-health tools may optimise patient time consumption and workflow at the IBD infusion unit and pharmacy. Our aim was to assess the feasibility, adoption and impact on time consumption of an automatic online pre-admission assessment and order system for patients with IBD.
Methods
We developed an online platform, directly linked to the electronic agenda of the IBD infusion unit, enabling a pre-admission order of IV therapy. This system sends an automated email to the patient the day before the admission. Using the secured link in this email, the patient is required to answer several red flag and open questions about their health status since the previous infusion. These answers are reviewed by the healthcare provider and, if approved, the IV therapy is ordered and prepared for subsequent administration at arrival on the infusion unit. All patients treated with IV therapy at the IBD clinic of our hospital were invited to participate in this program, which was GDPR (General Data Protection Regulation) approved. Time consumption was prospectively evaluated in patients with maintenance infliximab treatment (1 h infusion) before and after implementation in June 2018.
Results
In total 172 IBD patients (n = 77 male, n = 119/51 Crohn/ulcerative colitis, n = 112/60 infliximab/vedolizumab) were invited to the program, 150 (87%) of which accepted to participate and 22 (13%) declined. The most important reason to decline participation was the lack of email access, which can be attributed to the median age of this subgroup (median age 73 years (IQR 65–75) vs. 46 years (IQR 36–56); p ≤ 0.0001). Inclusion rates were not influenced by gender, disease type or treatment duration. The effective adoption of the e-health system (number of IV therapies ordered online) increased from 42% in the first month to 59% in the fifth month. The use of the e-health system reduced the median admission time at the infusion unit significantly from 169 min (IQR 153–192) to 108 min (IQR 101–122) (p < 0.0001) in infliximab-treated patients (Figure 1).
Conclusions
The use of an e-health pre-admission assessment and order system for IV therapy in IBD is feasible, well adopted and leads to a significant reduction in admission time.
Figure 1 Admission time at the day clinic before and after implementation of e-health tool.
Abstract
Background
Loss of response (LOR) to infliximab (IFX) remains a challenge in routine management of IBD patients. We evaluated IFX high-resolution pharmacokinetics (PK) during induction with ...intermediate and peak PK levels.
Methods
This is a prospective, multicentre (n = 9), interventional study approved by EC (P2017/484). Fourteen blood samples were collected per patient from baseline to week 30. All patients were IFX naïve with active disease according to clinical, biological and endoscopy criteria. The primary outcome evaluated the inter-individual variability of IFX PK during induction and correlation with remission at week 30. In addition to trough levels (TLs), intermediate (ILs) and peak levels (PLs) were also measured and defined as drug level between two infusions and drug level early on after infusion (+2h), respectively. Remission was defined as having a Harvey Bradshaw Index (HBI) ≤ 4 and C-Reactive Protein (CRP) ≤5 for Crohn’s disease (CD), and as a clinical Mayo score ≤2 and faecal calprotectin <250 µg/g for ulcerative colitis (UC). IFX samples were measured by ELISA (Apdia) while a drug-tolerant affinity capture elution anti-infliximab assay was used to measure anti-infliximab antibodies (ATI) at weeks 6, 22 and 30.
Results
Demographic and baseline data of the study population are presented in Table 1.
Among the 62 patients enrolled, 33.9% of patients (n = 21/62) were in remission at week 30. Eight patients dropped out due to disease worsening. Median TLs at week 6 were higher among patients in clinical remission at week 30 (p = 0.02) confirming previous observations. However, ILs at day 3 as well as PLs after the third infusion were also significantly higher in patients in clinical remission at week 30 (Figure 1a–c).
ATI were detected as soon as week 6. At week 2, infliximab levels were significantly lower among patients in which ATI developed at a later time point (p = 0.006) and this observation was confirmed when measuring ILs at day 17 (p = 0.002), TLs at week 6 (p = 0.002) and ILs at week 10 (p = 0.001).
Conclusion
This multicentre prospective study demonstrates that intermediate levels as early as day 3 predict remission at week 30 in IBD patients. Low IFX levels during induction were correlated to future ATI development. PK modelling may allow to better select patients early on for sustained remission with infliximab.
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