scholarly journals OP12 Blood proteins related to immunoregulation or cellular junctions reveal distinct biological profiles associated with the risk of short-term versus mid/long-term relapse in Crohn’s Disease patients stopping infliximab

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S011-S013
Author(s):  
N Pierre ◽  
V A Huynh-Thu ◽  
M Allez ◽  
Y Bouhnik ◽  
D Laharie ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Cox Model ◽  
Combined Therapy ◽  
Blood Proteins ◽  
Short Term ◽  
Faecal Calprotectin ◽  
Cellular Junctions ◽  
Risk Of Relapse

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.

Discovery of biomarker candidates associated with the risk of short-term and mid/long-term relapse after infliximab withdrawal in Crohn’s patients: a proteomics-based study

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322100
Author(s):  
Nicolas Pierre ◽  
Dominique Baiwir ◽  
Vân Anh Huynh-Thu ◽  
Gabriel Mazzucchelli ◽  
Nicolas Smargiasso ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Cox Model ◽  
Combined Therapy ◽  
Selected Reaction Monitoring ◽  
Rank Statistic ◽  
Short Term ◽  
Baseline Serum ◽  
Risk Of Relapse

ObjectiveA subset of Crohn’s disease (CD) patients experiences mid/long-term remission after infliximab withdrawal. Biomarkers are needed to identify those patients.DesignNew biomarkers of relapse were searched in the baseline serum of CD patients stopping infliximab when they were under combined therapy (antimetabolite and infliximab) and stable clinical remission (diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors cohort, n=102). From shotgun proteomics experiment (discovery step), biomarker candidates were identified and further targeted by selected reaction monitoring (verification step). The dataset was stratified to search for markers of short-term (<6 months) or mid/long-term relapse (>6 months). The risk of relapse and the predicting capacity associated with biomarker candidates were evaluated using univariate Cox model and log-rank statistic, respectively. To test their complementary predicting capacity, biomarker candidates were systematically combined in pairs.ResultsDistinct biomarker candidates were associated with the risk (HR) of short-term (15 proteins, 2.9<HR<16.1, p<0.05) and mid/long-term (17 proteins, 2.1<HR<4.7, p<0.05) relapse, they reflect different pathophysiological processes. In stratified and non-stratified datasets, novel marker combinations exhibited a high predicting capacity as shown by their higher Z-scores (false discovery rate <0.001) than C reactive protein and faecal calprotectin (current references in predicting relapse).ConclusionWe identified for the first time circulating biomarker candidates associated with the risk of mid/long-term relapse in CD patients stopping infliximab. We also highlight a sequence of pathophysiological processes leading to relapse, this could help to better understand the disease progression. Our findings may pave the way for a better non-invasive evaluation of the risk of relapse when contemplating antitumour necrosis factor α withdrawal in CD patients.

scholarly journals Mycophenolate mofetil for Crohn's disease: short-term efficacy and long-term outcome

2004 ◽  
Vol 19 (4) ◽  
pp. 427-434 ◽  
Author(s):  
H. H. Wenzl ◽  
T. A. Hinterleitner ◽  
B. W. Aichbichler ◽  
P. Fickert ◽  
W. Petritsch
Keyword(s):  
Crohn’S Disease ◽  
Mycophenolate Mofetil ◽  
Crohn's Disease ◽  
Short Term ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Term Efficacy

scholarly journals Experiences with the Kono-S anastomosis in Crohn’s disease of the terminal ileum—a cohort study

2020 ◽  
Author(s):  
K. Horisberger ◽  
D. L. Birrer ◽  
A. Rickenbacher ◽  
M. Turina
Keyword(s):  
Cohort Study ◽  
Crohn’S Disease ◽  
Postoperative Complications ◽  
Crohn's Disease ◽  
Terminal Ileum ◽  
Ileocecal Resection ◽  
Anastomotic Recurrence ◽  
Short Term ◽  
Recurrence Rates

Abstract Purpose The most frequent long-term complication after ileocecal resection in Crohn’s disease is anastomotic recurrence and subsequent stenosis. Recurrence typically begins at the site of the anastomosis, raising the question of whether the surgical technique of the anastomosis could affect recurrence rates. Kono-S anastomosis is a hand-sewn antimesenteric functional end-to-end anastomosis that offers a wide lumen that is well accessible for endoscopic dilatation. The purpose of our study is to review the rate of postoperative complications almost 2 years after the introduction of this technique. Materials and methods This is a prospective single-center cohort study of all consecutive patients with Crohn’s disease undergoing ileocecal resection. Patients’ characteristics as well as specific data for the surgical procedure and short-term outcome were evaluated. Results Thirty patients were operated for Crohn’s disease of the terminal ileum (n = 24) or anastomotic recurrence (n = 6). Postoperative complications with a Clavien-Dindo Score ≥ IIIb were observed in three patients. One patient showed a hemorrhage and underwent surgical hemostasis. Two patients developed anastomotic leakage; in both cases, ileostomy was created after resection of the anastomosis. The median hospital stay was 9 days (IQR 7–12). A comparison with a historic group of conventionally operated patients of our hospital revealed no differences in short-term results except for the duration of surgery. Conclusion The Kono-S anastomosis is associated with acceptable short-term results, complications, and recurrence rates comparable with the established anastomotic techniques. Longer operation times are observed, but the few published studies concerning long-term recurrence are promising.

scholarly journals P665 Which second-line biologic after anti-TNF failure during Crohn’s disease: Ustekinumab or vedolizumab, a multicentre retrospective study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S547-S547 ◽  
Author(s):  
C Rayer ◽  
X Roblin ◽  
D Laharie ◽  
B Caron ◽  
M Flamant ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Side Effects ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Risk Model ◽  
Second Line ◽  
Faecal Calprotectin ◽  
Drug Survival ◽  
Cumulative Probabilities

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 &gt; 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.

scholarly journals P451 Short-and long-term effectiveness of ustekinumab in patients with Crohn’s disease: real-world data from a German IBD cohort

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S405-S405
Author(s):  
A Kubesch ◽  
L Rueter ◽  
K Farrag ◽  
T Krause ◽  
K Stienecker ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Real World ◽  
Treatment Options ◽  
Real World Data ◽  
Free Response ◽  
Faecal Calprotectin ◽  
Short And Long Term

Abstract Background The IL-12/23 inhibitor ustekinumab (UST) opened up new treatment options for patients with Crohn’s disease (CD). Due to the recent approval, Real-World German data on long-term efficacy and safety are lacking. This study aimed to assess the clinical course of CD patients under UST therapy and to identify potential predictive markers. Methods Patients with CD receiving UST treatment in three hospitals and two outpatient centres were included and retrospectively analysed. Rates for short- and long-term remission and response were analysed with the help of clinical (Harvey–Bradshaw Index [HBI]) and biochemical (C-reactive protein [CRP], faecal calprotectin [fCal]) parameters for disease activity. Results Data from 180 patients were evaluated. One hundred six patients had a follow-up of at least 8 weeks and were included. 96.2% of the patients were pre-exposed to anti- TNFα agents and 34.4% to both anti-TNFα and anti-integrin. The median follow-up was 49.1 weeks (95% CI 42.03–56.25). At week 8, 51 patients (54.8%) showed response to UST, and 24 (24.7%) were in remission. At week 48, 39 (41.9%) responded to UST, and 20 patients (21.5%) were in remission. Steroid-free response and remission at week eight were achieved by 30.1%, and 19.3% of patients. At week 48, 26.9% showed steroid-free response to UST, and 15.1% of the initial patient population was in steroid-free remission. Clinical response at week 16 was independently associated with remission at week 48. Conclusion Our study confirms short- and long-term UST effectiveness and tolerability in a cohort of multi-treatment exposed patients.

Week 6 Calprotectin Best Predicts Likelihood of Long-term Endoscopic Healing in Crohn’s Disease: A Post-hoc Analysis of the UNITI/IM-UNITI Trials

2020 ◽  
Author(s):  
Neeraj Narula ◽  
Emily C L Wong ◽  
Parambir S Dulai ◽  
John K Marshall ◽  
Jean-Frederic Colombel ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Predictive Performance ◽  
Drug Level ◽  
Symptom Improvement ◽  
Faecal Calprotectin ◽  
Post Hoc Analysis ◽  
Post Hoc ◽  
The Relationship

Abstract Objectives There is need for biomarkers as predictors of outcome of medical treatment in Crohn’s disease. The purpose of this study was to evaluate the predictive performance of faecal calprotectin for short- and long-term clinical and endoscopic outcomes. Methods This post-hoc analysis of the UNITI/IM-UNITI studies [NCT01369329, NCT01369342, and NCT01369355; YODA #2019–4026] included 677 patients to evaluate the relationship of Week 6 calprotectin cut-offs and changes from baseline assessments in calprotectin for prediction of outcomes at Weeks 8, 32, and 52, using receiver operating characteristic curves with comparisons of areas under the curve [AUC]. The relationship between clinical and biomarker assessments at Week 6 and endoscopic remission [ER] at Week 52 was evaluated using multivariate logistic regression models adjusted for confounders. Results A Week 6 calprotectin &lt;250 mg/kg demonstrated a significant ability to predict Week 52 ER (AUC 0.709, 95% confidence interval [CI] 0.566–0.852, p = 0.014) with fair accuracy, and performed better than other calprotectin cut-offs and deltas from baseline for prediction of Week 52 ER. When adjusted for covariates, patients with a Week 6 faecal calprotectin &lt;250 mg/kg had 3.48 times [95% CI 1.31–9.28, p = 0.013] increased odds of Week 52 ER. No other Week 6 clinical assessment [clinical remission or clinical response] or biomarker [CRP &lt;5 or drug level] had an association with Week 52 ER. Conclusions In summary, the results of this post-hoc analysis suggest that Week 6 calprotectin levels &lt; 250 mg/kg can be predictive of future endoscopic healing and may be more informative than clinical symptom improvement. Podcast This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast

scholarly journals P587 Adalimumab in pediatric Crohn’s disease: A long-term multi-centre real-world experience

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S491-S492
Author(s):  
S Lawrence ◽  
H Huynh ◽  
W El-Matary ◽  
J DeBruyn ◽  
M Carroll ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Combination Therapy ◽  
Clinical Remission ◽  
Long Term Outcomes ◽  
Faecal Calprotectin ◽  
Significant Difference ◽  
Necrosis Factor

Abstract Background There is a paucity of data regarding long-term outcomes for adalimumab (ADA) in pediatric Crohn’s disease (CD). We describe the long-term effectiveness of ADA, in achieving clinical and biochemical remission in a Canadian multi-centre pediatric CD cohort. Moreover, we report the effects of prior anti-TNF exposure and use of a concomitant immunomodulator (IM) on durability of clinical and biochemical response. The primary outcome was 24-month corticosteroid (CS) free remission. Secondary objectives included biochemical and faecal calprotectin response over the study period. Methods Retrospective review of electronic records of all children aged 3–18 years with CD requiring ADA at 4 centres across Canada (Vancouver, Edmonton, Winnipeg and Calgary) between January 2005 and December 2017. Results One hundred and nine children (68% male; median age 13.07 [IQR 10.6–15.1]) with CD (L1 21.7%, L2 28.3%, L3 50%) were included with a median follow-up of 15.9 months [IQR 7.6–24]. Seventy-four patients (67.9%) were anti-tumour necrosis factor (TNF) naïve. Concomitant IM therapy was used in 51 (46.8%). CS free clinical remission at 24 months was observed in 45/66 (68%). Over time, the median PCDAI, CRP, ESR and faecal calprotectin significantly improved (Table 1). During follow-up, 36 (33%) patients discontinued ADA; 6 (5.5%) had primary non-response, 28 (25.7%) had secondary LOR and 2 (1.8%) had intolerance. At 24 months, clinical remission was achieved more frequently in patients who were Anti-TNF naïve (81% vs. 43.5% p 0.002). There was no significant difference in biochemical or faecal calprotectin outcomes between those who were bio-naive or experienced. There was no significant difference in the time to loss of response between those on monotherapy and combination therapy with an IM and ADA (HR 0.64 [95% CI 0.33–1.26] p0.2). Conclusion This study demonstrates that ADA is effective and durable in pediatric CD. Over 24 months, clinical, biochemical and faecal calprotectin improvement was seen. In our cohort, clinical response to ADA was greater in anti-TNF naïve compared with anti-TNF experienced patients; however,, biochemical and faecal calprotectin outcomes did not differ. ADA response appears durable with no significant difference in patients on monotherapy or combination therapy.

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