Following ileal resection for Crohn's disease (CD), recurrence is very frequent. Although several clinical risk factors of recurrence have been identified, predicting relapse remains challenging. Performing an ileocolonoscopy within the first year after surgery is currently recommended to assess endoscopic recurrence and to adjust the treatment. We took advantage of a large prospective multicentric cohort to investigate the role of the ileal mucosa-associated microbiota in postoperative endoscopic recurrence. Ileal mucosa-associated microbiota was analysed by 16S sequencing at the time of surgery and/or of endoscopic evaluation in 201 patients (288 samples in total) prospectively recruited in France. Ileal mucosa-associated microbiota exhibits profound changes following surgery in CD. Compared with non-recurrence setting, endoscopic recurrence is associated with strong changes in ileal mucosa-associated microbiota that are highly reminiscent of those observed generally in ileal CD compared with healthy subjects with a reduction in alpha diversity, an increase in several members of the Proteobacteria phylum and a decrease in several members of the Lachnospiraceae and the Ruminococcaceae families within the Firmicutes phylum. At the time of surgery, we identified several bacterial taxa associated with endoscopic recurrence and that can better predict relapse than usual clinical risk factors. Surgery has an important impact on ileal mucosa-associated microbiota. Postoperative endoscopic recurrence is associated with changes in microbiota composition and alpha diversity. The gut microbiota has the potential to predict postoperative evolution and recurrence.
T cell clonal expansions are present in the inflamed mucosa of patients with Crohn’s disease (CD) and may be implicated in postoperative recurrence after ileocolonic resection. Methods T cell receptor (TCR) analysis was performed in 57 patients included in a prospective multicentre cohort. Endoscopic recurrence was defined by a Rutgeerts score >i0. DNA and mRNA were extracted from biopsies collected from the surgical specimen and endoscopy, and analysed by high throughput sequencing and microarray, respectively. Results TCR repertoire in the mucosa of patients with CD displayed diverse clonal expansions. Active smokers at time of surgery had a significantly increased proportion of clonal expansions as compared with non-smokers (25.9%vs17.9%, p=0.02). The percentage of high frequency clones in the surgical specimen was significantly higher in patients with recurrence and correlated with postoperative endoscopic recurrence (area under the curve (AUC) 0.69, 95% CI 0.54 to 0.83). All patients with clonality above 26.8% (18/57) had an endoscopic recurrence. These patients with a high clonality were more frequently smokers than patients with a low clonality (61% vs 23%, p=0.005). The persistence of a similar TCR repertoire at postoperative endoscopy was associated with smoking and disease recurrence. Patients with high clonality showed increased expression of genes associated with CD8 T cells and reduced expression of inflammation-related genes. Expanded clones were found predominantly in the CD8 T cell compartment. Conclusion Clonal T cell expansions are implicated in postoperative endoscopic recurrence. CD patients with increased proportion of clonal T cell expansions in the ileal mucosa represent a subgroup associated with smoking and where pathogenesis appears as T cell driven. Trial registration number NCT03458195.
Background: Crohn's disease displays heterogeneity in terms of disease location, progression and response to treatment. Most patients require an intestinal resection due to complicated disease, and a majority of them will experience disease recurrence. We aimed to characterize biological pathways driving postoperative recurrence and to identify predictors which could guide therapeutic management. Methods: In this multicentre prospective study, we conducted transcriptome analysis on ileal mucosa of CD patients undergoing ileocolonic resection. Samples were collected from the most inflamed part of the ileum (n=200), from the ileal resection margin (n=149) and in the neo-terminal ileum 6 months after surgery (n=122). The primary endpoint was postoperative endoscopic recurrence at month 6. We applied a regression model to identify gene signatures predicting for endoscopic recurrence. Findings: Molecular patterns of early endoscopic recurrence significantly differed from those observed in chronic inflammation. Gene expression analysis of the inflamed area of the surgical specimens identified clusters of CD patients. However, pathway gene signatures at the ileal margin were superior to those of the inflamed area to predict postoperative outcome. Several pathways, including JAK/STAT signalling, cell adhesion molecules and extracellular matrix protein were associated with a higher risk of endoscopic recurrence. JAK/STAT pathway activation at the ileal margin predicted early postoperative endoscopic recurrence (AUC of 0*74) and was associated with a higher of clinical relapse on the long term. A significant increase of p-STAT3 levels at the ileal margin was associated with severe endoscopic recurrence (i3, i4) compared to no recurrence (i0) (p=0*02) and moderate recurrence (i1, i2) (p=0*04). Interpretation: Gene expression analysis at the ileal margin of the surgical specimen may strongly predict postoperative outcome. The inflammatory processes associated with postoperative recurrence differ from those engaged in chronic inflammation. Activation of JAK/STAT signalling at the ileal margin of the surgical specimen is predictive of postoperative recurrence and should be specifically targeted.Trial Registration: ClinicalTrials.gov (NCT03458195).Funding Statement: This work was supported by Helmsley Charitable Trust and the Institut national de santé et de la recherche biomedical (INSERM). Declaration of Interests: SN received honoraria from MSD, Abbvie, Takeda, Janssen, HAC Pharma, Tillots, Ferring, and Novartis. BP received honoraria from AbbVie, MSD, Takeda, Janssen, Bioagaran, and Ferring. AB received honoraria from MSD, Abbvie, Ferring, Takeda, Vifor Pharma, Sanofi-Aventis, Hospira, and Janssen. XT received honoraria from Abbvie, MSD, Takeda, Ferring, Norgine, and Janssen. MF received honoraria from AbbVie, MSD, Takeda, Janssen, Pfizer, Ferring, and Boehringer. PS received honoraria from Takeda, MSD, Biocodex, Ferring and Abbvie and financial support from Takeda. MA received honoraria from Janssen, Takeda, Pfizer, MSD, Abbvie, Ferring, Amgen, Biogen, Celgene, and Genentech/Roche. All other authors have no conflict of interest regarding this study.Ethics Approval Statement: All patients provided an informed written consent. The study was approved by AFFSAPS (IDRCB: 2009-A00205-52) and the French Ethic Committee (CPP 2009/17).
Summary Background After ileocaecal resection for Crohn's disease ( CD ), inflammatory lesions frequently recur on the anastomosis and/or on the neo‐terminal ileum. Aim To identify predictors of early post‐operative endoscopic recurrence. Methods From September 2010 to September 2017, the REMIND group conducted a prospective nationwide study in nine French academic centres. Data were collected at the time of surgery and endoscopy, performed 6‐12 months after surgery. Endoscopic recurrence was defined as a Rutgeerts score ≥i2. Baseline factors associated with endoscopic recurrence were searched by univariate and multivariate regression analysis. Results Two hundred and eighty‐nine CD patients were included. Endoscopy within 1 year following surgery was performed in 225 (78%) patients (104M/121F). Mean age and disease duration were 35 (12.2) and 8.8 (8.9) years respectively. Seventy (32%) patients were active smokers at surgery. One hundred and forty‐two (63%) patients received at least one anti‐ TNF therapy before surgery. After surgery, 40 (18%) patients received thiopurines and 66 (29%) received an anti‐ TNF agent. Endoscopic recurrence occurred in 107 (47%) patients. In multivariate analysis, male gender ( OR = 2.48 [ IC 95% 1.40‐4.46]), active smoking at surgery ( OR = 2.65 [ IC 95% 1.44‐4.97]) and previous resection ( OR = 3.03 [ IC 95% 1.36‐7.12]) were associated with a higher risk of endoscopic recurrence. Inversely, post‐operative anti‐ TNF treatment decreased the risk of endoscopic recurrence ( OR = 0.50 [ IC 95% 0.25‐0.96]). Conclusions Male gender, active smoking at surgery and previous intestinal resection are associated with a higher risk of endoscopic post‐operative recurrence, while post‐operative anti‐ TNF treatment is associated with a lower risk.
INTRODUCTION: Early ileocolonoscopy within the first year after surgery is the gold standard to evaluate recurrence after ileocolonic resection for Crohn's disease (CD). The aim of the study was to evaluate the association between the presence and severity of anastomotic and ileal lesions at early postoperative ileocolonoscopy and long-term outcomes. METHODS: The REMIND group conducted a prospective multicenter study. Patients operated for ileal or ileocolonic CD were included. An ileocolonoscopy was performed 6 months after surgery. An endoscopic score describing separately the anastomotic and ileal lesions was built. Clinical relapse was defined by the CD-related symptoms, confirmed by imaging, endoscopy or therapeutic intensification; CD-related complications; or subsequent surgery. RESULTS: Among 225 included patients, long-term follow-up was available in 193 (median follow-up: 3.82 years [interquartile range: 2.56–5.41]). Median clinical recurrence-free survival was 47.6 months. Clinical recurrence-free survival was significantly shorter in patients with ileal lesions at early postoperative endoscopy whatever their severity was (I(1) or I(2,3,4)) as compared to patients without ileal lesions (I(0)) (I(0) vs I(2,3,4): P = 0.0003; I(0) vs I(1): P = 0.0008 and I(1) vs I(2,3,4): P = 0.43). Patients with exclusively ileal lesions (A(0)I(1,2,3,4)) had poorer clinical long-term outcomes than patients with exclusively anastomotic lesions (A(1,2,3)I(0)) ( P = 0.009). DISCUSSION: A score describing separately the anastomotic and ileal lesions might be more appropriate to define postoperative endoscopic recurrence. Our data suggest that patients with ileal lesions, including mild ones (I(1)), could beneficiate from treatment step-up to improve long-term outcomes.
Background: Autologous hematopoietic stem cell transplantation (HSCT) is a therapeutic option for Crohn's disease (CD) patients with severe disease, refractory to immunosuppressants and biologics, after consideration of all therapeutic options including surgery. Several mechanism of action may be involved, including a resetting of the adaptive immune system. The role of T cells in CD physiopathology is well established although no specific antigen nor T cell TCR have been associated with CD. The aim our study was to analyze the impact of HSCT on the T cell repertoire in the inflamed intestinal mucosa. Methods: Intestinal mucosal samples (ileal or colonic biopsies) were collected at baseline (pre-mobilization) and after HSCT (6 months and/or 1 year post transplant), in 16 CD patients recruited in the ASTIC trial or in the Barcelona Center. Endoscopic severity was evaluated by segment using SES-CD. T cell repertoire analysis was performed on DNA extracted from biopsies by next generation sequencing of the TCRβ locus (Adaptive Biotechnology Inc., Seattle, Washington, USA). TCR diversity of each sample was studied by quantification of the size taken in the repertoire by significantly expanded clones, and correlated with clinical outcome and endoscopic response (global and by segment) at one year. T cell clones were tracked and the repertoire similarities were quantified between different time points by the Morisita-Horn index (M-H; range 0–1). Results: Monoclonal expansions in the T cell compartment were present at baseline in the mucosa of CD patients prior to HSCT procedure, expanded clones represented from 5 to 30 per cent of the total repertoire. The T cell repertoire appeared more polyclonal than previously anticipated (from 1000 to 20 000 unique TCR sequences, diversity index 0.02 to 0.1). Importantly, no shared public TCR sequences were found in the mucosa of different patients. After HSCT, TCR clonality was significantly increased in the mucosa of patients. Although around 20 per cent of specific TCR sequences persisted between baseline and after HSCT, the similarity index comparing the TCR repertoire was low (mean M-H=0.17), indicating a profound resetting of the TCR repertoire. In contrast, a high degree of similarity (mean M-H=0.7) was observed between mucosal samples collected at different time points after the procedure in the same patient. Conclusions: Clonal expansions are present in the mucosa of refractory CD patients. HSCT induces dramatic changes and a significant resetting in the mucosal T cell repertoire.
Linked Content This article is linked to Auzolle et al and Allez and Auzolle papers. To view these articles visit https://doi.org/10.1111/apt.14944 and https://doi.org/10.1111/apt.14978 .
Background: Infliximab (IFX) is effective in maintenance therapy for Crohn's disease (CD) and ulcerative colitis (UC). IFX efficacy may be limited by immunogenicity. It was previously shown that intravenous hydrocortisone premedication reduces IFX antibodies (ATI) formation [1]. This premedication is still now commonly used although its benefit is unclear. The aim of our study was to determine short-term impact of hydrocortisone withdrawal on ATI formation and IFX pharmacokinetic in a cohort of patients treated with IFX. Methods: Patients were included between February and April 2016. Inclusion criteria were: – diagnosis of CD or UC; – IFX treatment with a stable dose for at least 6 months. Exclusion criteria were: – modification in IFX and/or immunosuppressant dosage; – pregnancy. Hydrocortisone premedication was withdrawn in all patients except during induction phase or if patients had a previous IFX-related infusion reaction. Trough levels and ATIs were measured at each infusion on a one year period (during the 3 infusions preceding and the 3 infusions following hydrocortisone withdrawal). Results: Hydrocortisone premedication was stopped in 246 patients. One hundred and nine patients were included in the study (median age 36 years-old; 62% men; CD: n=82, UC: n=17). Mean duration of the disease was 13.7 years (1–42). Mean duration of IFX treatment was 5 years. IFX was used in combotherapy in 49 patients (thiopurines: n=39, methotrexate: n=10; mean duration of combotherapy 2 years). IFX treatment was modified after hydrocortisone withdrawal in 14 patients (dose diminution: n=8, optimization: n=5, stop for failure: n=1). Pharmacokinetic analysis was performed in 95 patients who had a stable dose. None of the patients developed permanent ATI, 4 patients had transient ATI and high trough level (>3mcg/ml). Mean IFX trough level before hydrocortisone withdrawal was 5.5 mcg/ml (respectively 4.9, 6.9, 5.1, 5.3 at T-3, T-2, T-1 and T0) and 5.9 mcg/ml after (5.6, 6.0, 6.2 at T+1, T+2, T+3), (NS). There was no significant variation of IFX trough levels, even in patients under monotherapy. Seven patients had symptoms after hydrocortisone withdrawal, without trough level variation and didn't change their treatment. There was no significant variation of CRP (2.55 mg/L versus 2.14 mg/L). None of the patients had IFX related infusion reaction. Conclusions: In our study, performed in patients on stable IFX maintenance, hydrocortisone discontinuation had no impact on IFX trough levels and was not associated with ATI formation or infusion reactions. References: [1] Farrell, (2003), Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial.
