Abstract
Background
In Crohn’s disease (CD), biologics can induce mucosal healing and stable remission. After reaching this target, treatment de-escalation could be considered but the risk of relapse ...needs to be estimated. Current biomarkers used to predict relapse (C-reactive protein: CRP, faecal calprotectin) offer a limited prognostic capacity. Furthermore, they only monitor inflammation while we recently highlighted various and distinct pathological processes associated with the risk of short-term (<6 months) and mid/long-term (>6 months) relapse in CD patients stopping infliximab. Herein, the aim of our study was to further characterise this distinction.
Methods
Serum abundance of 92 proteins were measured by proximity extension assay (immune response panel, Olink) at baseline of the STORI cohort (infliximab diScon-Tinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors, n=102). Association of markers with the risk of relapse was determined by univariable Cox model in stratified (relapse <6 months or >6 months) and non-stratified datasets. Study of protein characteristics and enrichment analyses were performed to find biological patterns differentiating short-term from mid/long-term relapsers. To evaluate the predictive capacity of markers, we combined them systematically by pairs (‘AND’ or ‘OR’ logical operators) and used log-rank statistics with false discovery rate (FDR) correction (Benjamini-Hochberg).
Results
The risk of mid/long-term relapse was associated with a decreased circulating level of anti-inflammatory effectors while the risk of short-term relapse was associated with an increased circulating level of pro-inflammatory effectors (Fig. 1A, 1B).
The risk associated with the downstream signalling of cytokine and pattern recognition receptors showed an opposite pattern in the short-term versus mid/long-term relapsers (Fig. 1D, 1E).
The risk of short-term relapse was characterised by a perturbed circulating level of proteins inducing tolerance and immunity in antigen presenting cells (Fig. 2A, 2B).
The risk of mid/long-term relapse was characterised by an increased circulating level of proteins promoting lymphocyte tolerance (Fig. 2D, 2E) and a decreased circulating level of cellular junction proteins (Fig. 3).
We found 1223 (short-term relapse dataset), 233 (mid/long-term relapse dataset) and 101 (non-stratified dataset) novel marker combinations with FDR<0.05 and higher Z-scores than CRP and faecal calprotectin. The best combinations are showed in Fig. 4.
Conclusion
In CD patients stopping infliximab, blood proteins linked to immunoregulation or cellular junctions support the distinct profiles of short-term and mid/long-term relapsers. These proteins showed a capacity to predict the relapse.
Crohn's disease and ulcerative colitis are lifelong diseases seen predominantly in the developed countries of the world. Whereas ulcerative colitis is a chronic inflammatory condition causing diffuse ...and continuous mucosal inflammation of the colon, Crohn's disease is a heterogeneous entity comprised of several different phenotypes, but can affect the entire gastrointestinal tract. A change in diagnosis from Crohn's disease to ulcerative colitis during the first year of illness occurs in about 10 % - 15 % of cases. Inflammatory bowel disease (IBD) restricted to the colon that cannot be characterized as either ulcerative colitis or Crohn's disease is termed IBD-unclassified (IBDU). The advent of capsule and both single- and double-balloon-assisted enteroscopy is revolutionizing small-bowel imaging and has major implications for diagnosis, classification, therapeutic decision making and outcomes in the management of IBD. The role of these investigations in the diagnosis and management of IBD, however, is unclear. This document sets out the current Consensus reached by a group of international experts in the fields of endoscopy and IBD at a meeting held in Brussels, 12-13th December 2008, organised jointly by the European Crohn's and Colitis Organisation (ECCO) and the Organisation Mondiale d'Endoscopie Digestive (OMED). The Consensus is grouped into seven sections: definitions and diagnosis; suspected Crohn's disease; established Crohn's disease; IBDU; ulcerative colitis (including ileal pouch-anal anastomosis IPAA); paediatric practice; and complications and unresolved questions. Consensus guideline statements are followed by comments on the evidence and opinion. Statements are intended to be read in context with qualifying comments and not read in isolation.
Abstract
Background
Total coloproctectomy with ileoanal anastomosis (IAA) is the procedure of choice for patients with treatment-resistant ulcerative colitis (UC). It is most often curative, but can ...be complicated by pouchitis in 30% of cases, which becomes chronic in 10% of patients. Its treatment is not codified after failure of conventional treatments and a first line of anti-TNF. The objective of our study was to determine the efficacy and safety of vedolizumab (VDZ) in patients with anti-TNF refractory chronic pouchitis.
Methods
This was a retrospective, multicenter study conducted in 17 hospital centers. Patients were selected from July 2019 to January 2021. All patients had chronic pouchitis refractory to a first line of anti-TNF. We evaluated clinical, endoscopic and biological characteristics at initiation of VDZ therapy, at week (W) 10 as well as at W52. The primary objective of the study was to assess clinical response (improvement ≥ 50% in stool frequency and rectal bleeding) at W52. Secondary objectives were to assess clinical response and remission (absence of symptom) at W10, endoscopic response (improvement ≥ 50% of endoscopic lesions) and remission (mucosal healing) at W10 and 52. Adverse events were also collected.
Results
Forty-nine patients were included in the study (23 women, 26 men, mean age 48 years). Thirty-one patients (63%) had received only one line of biologic.
Forty-four (90%) patients had endoscopic evaluation before initiation of VDZ, and 25 (51%) patients at W10 and 52. CRP was assessed in all patients at baseline, 43 (88%) patients at W10, and 33 (67%) patients at W52.At W10, 17 (34%) patients were clinically responders without corticosteroids, of whom 3 (6%) were in remission; among the 25 patients evaluated, endoscopic response was obtanine in 5 (20%) patients and endoscopic remission in 11 (44%) patients. At W52, 22 (44%) patients were clinically responders, 12 (24%) of whom were in remission; endoscopic response was obtained in 15 (60%) patients and endoscopic remission in 5 (20%) patients.
Although there was a trend for CRP to decrease during follow-up (17.3 mg/L at inclusion vs. 7.9 mg/L at W52) in the responder group, there was no significant difference between this subgroup and the non-responder patients at W52. Eight patients (16%) had adverse events, leading to discontinuation of treatment in three of them.
Optimization of VDZ at W10 was the only factor predicting nonresponse at W52: 40% in the non-responder group vs 8% in the responder group (p=0.05).
At 1 year, 69% of patients were continuing treatment.
Conclusion
This retrospective multicenter study shows that VDZ is a therapeutic option that may be considered in the treatment of chronic pouchitis refractory to anti-TNF.
Abstract
Background
Prospective data after switch from intravenous infliximab (IV-IFX) to subcutaneous (SC-IFX) in Inflammatory Bowel Disease (IBD) is needed. The aim of this prospective multicenter ...cohort was to describe SC-IFX persistence, efficacy and tolerance after switch from IV-IFX.
Methods
IBD patients in steroid-free clinical remission (defined by a Harvey Bradshaw index (HBI) ≤ 4 for Crohn’s disease (CD), and partial Mayo Score (PMS) ≤ 2 with no subscore >1 for ulcerative colitis UC)) for at least 6 months on IV-IFX, were enrolled in this prospective cohort if they switched to SC-IFX.
Clinical (HBI, PMS), biological (CRP, fecal calprotectin (FC)) and pharmacokinetic evaluations were performed at 3, 6, 12 and 24 months from switch. In case of clinical or biological relapse, as per physicians’ judgement, SC-IFX dose could be increased, or drug changed.
Primary endpoint was SC-IFX persistence at week 48 (W48). Secondary endpoints comprised steroid-free clinical remission at W48, proportion of patients who switched back to IV-IFX, HBI and PMS changes and FC, CRP and infliximab serum level changes. Statistical comparisons were performed using Fisher’s exact test. Survival without treatment discontinuation was analysed using a Kaplan-Meyer curve.
Results
426 patients were included (72.4% CD, 45.1% female, median age 37 years), with a median time from diagnosis of 143 months in CD, 154 months in UC. At baseline, 74% were on IV-IFX standard dose (5mg/kg every 8-week) and 68 (16%) received combination therapy with an immunosuppressant.
Among patients with complete data until W48, SC-IFX persistence was 95.3% (CI, 93.2-97.5). 319/367 (89.9%) were on steroid-free clinical remission.
From baseline to W48, median HBI and PMS scores were 0, CRP did not change significantly, median FC rate decreased significantly from 52µg/g to 36 µg/g (p=0.015). Mean Infliximab trough level at inclusion was 7.97µg/mL, while it reached 17.96µg/mL at W48 (p<0.0001).
23 (5.4%) patients had an increase of SC-IFX dose and 22 (5.2%) stopped SC-IFX, of which 6 patients switched back to IV-IFX. SC-IFX persistence was significantly higher among patients treated with SC-IFX monotherapy (98.8%) as compared to those on combination therapy (90.0%) (HR=0.14 0.04-0.53).
Adverse events were reported in 181/426 patients (42.4%), 12 led to treatment discontinuation. Nine severe adverse events (2%) were reported. Three patients (0.7%) had IBD-related surgery and 8 (1.9%) IBD-related hospitalization.
Conclusion
In this large multicenter prospective cohort of IBD patients in remission, one-year persistence of SC-IFX after switch from IV-IFX was 95.3%, supporting excellent efficacy and tolerance of SC-IFX.
Abstract
Background
Wireless capsule endoscopy (WCE) is the most efficient exam to detect small bowel (SB) mucosal lesions of Crohn’s disease (CD). Unfortunately, videos reading is time consuming. ...The aim of this study was to develop a computer aided model able to detect CD lesions in SB using WCE.
Methods
Forty-five pathologic videos corresponding to 35 patients have been selected among the 250 WCE performed between 2013 and 2017 in patients with a known CD. Three-hundred-sixty-seven pathologic frames have been annotated as follow: aphtoïd ulceration (AU), ulceration 3–10 mm (U3), ulceration >10 mm (U10), oedema (E), stenosis (S) and fistula (F). Several transformations were applied to each pathologic frame (rotation (R), symmetry (S), elastic transformation (ET)) up to increase the number of images (24 times, N = 17664). The complete original dataset was composed of 736 images, 367 positive and 369 negative (randomly extracted from the same videos than positive frames). They were then used to train our model, a convolutional neural network. The whole 736 original images were randomly split into three groups: 80% for the training phase, 10% for the validation phase and 10% for the test phase. The training phase was performed 20-times with random split of data to get a robust 20 folds cross-validation.
Results
Sensitivity, specificity, positive predictive value and accuracy for the detection of all types of lesions together were 62.18%, 66.81%, 66.85%, 64.63% respectively. The sensitivity for the detection of all types of ulcerations was 56.84% (N = 277), 87.29% for stenosis (N = 50), 56.35% for oedema (N = 29) and 84.44% for pseudopolype (N = 11). None fistula was identified in our dataset. Performances of our model have been increased using several images transformations together (rotation, symmetry, and elastic deformation): without data augmentation sensitivity was 33.9% and specificity was 67.02%. The application of rotations alone increased the accuracy to 54.62%.
Conclusions
The study demonstrated the feasibility of a computer aided model for automatic detection of SB lesions in patients with CD using WCE. The improvement of the model depends mostly to the number of positive and negative frames of the original dataset.
Abstract
Background
IL-22 is an epithelium-targeting cytokine of major importance in the gut. Its secretion is dramatically increased during inflammatory bowel diseases (IBD) flares. Actions of IL-22 ...during gut inflammation have been largely addressed, placing IL-22 as a chief cytokine to orchestrate intestinal epithelial cell (IEC) barrier functions (AMPs and mucus expression induction) and regeneration and therefore to promote mucosal healing. However, excessive actions of IL-22 could also promote tumour cell proliferation, indicating that IL-22 actions need to be tightly controlled. IL-22 binding protein (IL-22BP) is a soluble, secreted and specific inhibitor preventing IL-22 binding to its membrane IL-22R expressed on epithelial cells. Using IL-22BP-deficient rats, we demonstrated an IL-22BP-dependent inhibition of IL-22-protective functions on IEC during DSS-colitis. In human, we previously showed that IL-22BP was up-regulated in IBD inflammatory lesions and identifed dendritic cells (DCs) and eosinophils as the sources of IL-22BP. A recent report suggests that CD4+ T cells represent another cellular source of IL-22BP during IBD both in human and mice. Given these controversies, we decided to extensively revisit the cellular sources of IL-22BP.
Methods
The expression of IL-22BP mRNA was assessed by Q-PCR in FACS-sorted cells isolated from human mesenteric lymph nodes (MLN) and intestinal mucosa from IBD patients.
Results
We observed that in the gut mucosa of IBD patients, only DCs and eosinophils expressed IL-22BP mRNA. DCs from MLN also strongly expressed IL-22BP mRNA. Lamina propria and MLN CD4+ and CD8+ T cells, either of the naïve or memory/effector phenotype, did not significantly express IL-22BP mRNA, even after in vitro stimulation. Confirming these data, we did not observe any IL-22BP protein expression in CD3+ cells in colon biopsies from IBD patients analysed by immunofluorescence. We therefore generated IL-22BPGFP reporter rats and confirmed our previous data that IL-22BP expression is restricted to mononuclear phagocytes in this species. Again, T cells did not express IL-22BP in gut mucosa or lymphoid organs. Finally, we demonstrated that T cells from Il22ra2−/− rats induced similar colitis and wasting disease upon transfer in Il2rg−/− rats when compared with T cells from Il22ra2+/+ rats.
Conclusions
Taken together, our data confirm that IL-22BP expression is restricted to myeloid cells (DCs and eosinophils) and do not support a role of T cells as a source of IL-22BP in IBD.
Abstract
Background
The STAR study was conducted to describe the management of ulcerative colitis (UC) in private practices in France and to compare real-life data with European guidelines.
Methods
...STAR is an observational, retrospective, multicentre French study, conducted with private practice gastroenterologists. Data were collected in the medical records of patients, aged ≥18 years (yr), diagnosed with UC in the last 36 months (M) and followed-up for at least 12 M.
Results
Ninety physicians included 249 patients, median age 36 yr, 48.7% women and 11.8% smokers. Median UC duration was 17.7 M. The Montreal classification of UC extent was E1 41.5%, E2 39.4% and E3 19.1%. Mean disease severity perceived by physicians (EVA 0–100 mm) was 35.07 at diagnosis and 19.00 at last visit. Mean Partial Mayo Score (PMS) was 4.20 at diagnosis and 2.02 at last visit. PMS at diagnosis was 58.2% mild, 25.8% moderate, and 11.1% severe. At last visit PMS was 51.1% remission, 37.1% mild, 7.4% moderate and 4.4% severe. The first endoscopy at diagnosis showed 38.3% light activity, 54.7% moderate and 5.5% severe activity. During the first yr of treatment (trt), 76.8% patients had no endoscopy, 9.1% had colonoscopy, 4.1% rectoscopy and 10% sigmoidoscopy. In the first yr of trt, endoscopies showed healing in 28.3% patients, mild activity 39.6%, moderate 26.4% and severe 5, 7%. Trt was 5-ASA in 97.9% patients, steroids 44.9%, immunosuppressants 20.3%, anti-TNF 18.2%. At last visit, 37.3% patients were no longer receiving 5-ASA. Oral 5-ASA was prescribed in 39.7% patients, rectal 27.5% and both 32.8% patients. 5-ASA was effective from first M in 79% patients. Mean dose oral 5-ASA induction trt was 3.60 g/day. Sixty-seven per cent patients had optimal mesalazine induction trt ( ≥4 g/day) and 13.1% had lower dose than European recommendations ( < 2.4 g/day). Mean oral 5-ASA maintenance dose was 2.14 g/day. Mean rectal induction dose mesalazine was 1.36 g/day. Median duration of oral induction trt was 83.5 vs. 48.5 d for rectal. 66.8% patients treated with 5-ASA first-line required no other drug class. 6.8% patients were hospitalised from diagnosis until the day of the visit. Since the diagnosis until the day of the last visit, 44.9% patients had steroids, 20.3% had immunosuppressants and 18.2% had at least one anti-TNF. Initiation of anti-TNF trt was not related to the severity of the disease at diagnosis (Mayo score 5).
Conclusions
5-ASA is the gold standard trt in UC induction and maintenance management and was effective from the first M of trt. 1/5 patients were treated with immunosuppressants and 1/5 with anti-TNF indicating that many patients went directly from 5-ASA to anti-TNF without exposition to immunosuppressants. The very high use of anti-TNF in mild-to-moderate UC could partly be explained by 5-ASA underdosing.
Abstract
Background
The main issue to validating new molecules in the field of IBD is insufficient patient enrollment into clinical trials, resulting in premature trials termination and cost ...increase. CT-SCOUT™ platform is a web-based solution to help clinicians to pre-screen potential candidates and facilitating the coordination of the research team. Our aim was to compare the number of patients enrolled in IBD clinical trials in sites equipped or not with CT-SCOUT™.
Methods
We conducted a prospective, multicenter, open-label, observational study in sites participating to phase 3 trials evaluating the efficacy and safety of etrolizumab in ulcerative colitis (UC, Hickory) and in Crohn’s disease (CD, Bergamot). Recruitment figures were provided by the sponsor, and we considered the 21 French sites equipped with CTscout and 134 sites in other countries not equipped with CT-SCOUT™. The primary endpoint was the mean number of patients randomised per site in both trials. Secondary endpoints included a mean number of patients randomised in each study. Patients screened and those finally randomised were compared in sites equipped and non-equipped using one-way ANOVA followed by post-hoc Tukey test and Mann–Whitney test.
Results
During the observational period of 40 months (September 2015–December 2018), 644 and 289 patients were screened and randomised in Hickory and/or Gardenia, respectively. There were 307 and 149 patients in 78 sites for Hickory, and 337 and 140 patients for Bergamot in 102 sites. The mean numbers of screened and randomised patients in CT-SCOUT™ equipped sites vs. non-equipped are given in the table.
French sites equipped with CT-SCOUTTM
Sites from other countries non-equipped with CT-SCOUTTM
P
Screened in both studies (UC + CD)
7.55
3.05
<0.001
Randomised in both studies (UC + CD)
3.79
1.28
<0.001
Screened in Hickory (UC)
9.17
3.14
<0.001
Randomised in Hickory (UC)
5.17
1.28
<0.001
Screened in Bergamot (CD)
5.94
2.95
0.003
Randomised in Bergamot (CD)
2.41
1.28
0.009
The mean number of patients randomised in Hickory in CT-SCOUT™ sites increased by 4.0 folds as compared with non-equipped sites (p < 0.001). The mean number of patients randomised in Bergamot in CT-SCOUT™ equipped sites has been increased by 1.9-folds as compared with non-equipped sites (p = 0.009).
Conclusion
This multicentric study demonstrated a significant increase in patient recruitment in IBD clinical trials. Randomisation rates were twice to four times higher in equipped sites compared with non-equipped ones. CT-SCOUT™ appears to be a promising digital solution to the global issue of patient enrollment in clinical trials.
Abstract
Background
Anti-TNF antibodies treatments are the only first-line reimbursed biologics for Crohn’s disease (CD) in several countries. Recently, Vedolizumab (VDZ) and Ustekinumab (UST) were ...added to the therapeutic armamentarium for CD refractory to a first anti-TNF antibody. However, studies comparing these two compounds remain unavailable. Our aim was to compare their efficacy in second-line treatment in CD after failure of one TNF antagonist.
Methods
All patients with CD refractory (primary or secondary non-responders) to first anti-TNF treatment and receiving UST or VDZ as a second biologic were included retrospectively in 10 French tertiary centres. The remission and clinical response were assessed at week 14. On the long-term, the cumulative probabilities of being in remission were estimated using the Kaplan–Meier method and the associated factors using a Cox proportional risk model. The drug survival to assess efficacy as well as side effects was assessed by actuarial analysis.
Results
88 patients were included, 50 (57%) females (mean age: 41 ± 15 years), 61 (69%) being treated with UST and 27 (31%) with VDZ. The first anti-TNF was discontinued for primary or secondary non-response in 66 (75%) patients and for side effects in 22 (25%) patients, without any difference between the anti-TNF antibody previously used. Among the 55 patients with endoscopic data at baseline, 55 (98%) had ulceration, a CRP above 5mg/l for 33/71 (46%) patients and a faecal calprotectin > 250 µg/g for the 12 patients tested. At week 14, no difference was observed for clinical response and clinical remission according to the type of treatment: the rate of clinical response and remission were 74% (UST)/58% (VDZ) (p = 0.20) and 33% (UST)/26% (VDZ) (p = 0.56), respectively. The only factor associated with short-term remission was the lack of optimisation prior to anti-TNF discontinuation (p = 0.038) regardless of the type of second-line therapy (UST, p = 0.02; VDZ, p = 0.03). After a mean follow-up of 67 weeks, the cumulative probabilities of being in remission at 6 and 12 months were 16% and 34% for UST and 25% and 44% for VDZ, respectively (p = 0.24 for UST vs. VDZ). The drug survival was higher in the UST group as compared with the VDZ group (HR (UST vs. VDZ) = 2.36 1.02–5.5, p = 0.04).
Conclusion
Our preliminary results suggest that VDZ and UST have similar efficacy in the short- and long-term response when used as a second-line biologic therapy in CD refractory to a first anti-TNF antibody. These results will be complemented for the congress by the inclusion of additional patients recruited into this registry.
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