ABSTRACT
BACKGROUND: Risk stratification for endoscopic post-operative recurrence (ePOR) in Crohn's disease (CD) is required to identify patients who would benefit most from initiation of prophylactic medication and intensive monitoring of recurrence. AIMS: To assess the current evidence on patient-related, microbial, surgical and histopathological risk factors for ePOR in patients with CD after ileocolic (re-)resection. METHODS: Multiple online databases (Embase, MEDLINE, Web of Science and Cochrane Library) were searched up to March 2024. Studies with reported associations of patient-related, microbial, surgical and/or histopathological factors for ePOR (i.e., Rutgeerts' score ≥i2 or modified Rutgeerts' score ≥i2a) were included. The risk of bias was assessed with the Newcastle-Ottawa Scale for observational cohort studies and case-control studies. RESULTS: In total, 47 studies were included (four RCTs, 29 cohort studies, 12 case-control studies, one cross-sectional study and one individual participant data meta-analysis) including 6006 patients (median sample size 87 patients [interquartile range 46-170]). Risk of bias assessment revealed a poor quality in 41% of the studies. An association was reported in multiple studies of ePOR with active smoking at and post-surgery, male sex and prior bowel resection. A heterogeneous association with ePOR was reported for other risk factors included in the current guidelines (penetrating disease, perianal disease, younger age, extensive small bowel disease and presence of granulomas in the resection specimen or myenteric plexitis in the resection margin), and other patient-related, microbial, surgical and histopathological factors. CONCLUSION: Risk factors for ePOR in international guidelines are not consistently reported as risk factors in current literature except for active smoking and prior bowel resection. To develop evidence-based, personalised strategies, large prospective studies are warranted to identify risk factors for ePOR. Validation studies of promising (bio)markers are also required.
Subject(s)
Crohn Disease , Recurrence , Humans , Crohn Disease/surgery , Crohn Disease/pathology , Risk FactorsABSTRACT
BACKGROUND AND AIMS: The modified Rutgeerts score (mRS) is widely used for the assessment of endoscopic postoperative recurrence (ePOR) in Crohn's disease (CD) after ileocolic resection to guide therapeutic decisions. To improve the validity and prognostic value of this endoscopic assessment, 2 new scores have been proposed. This study assessed the interobserver agreement of the current score (mRS) and the new endoscopic score for ePOR in CD. METHODS: Sixteen Dutch academic and nonacademic inflammatory bowel disease specialists assessed endoscopic videos (n = 71) of postoperative CD patients (n = 66) retrieved from 9 Dutch centers. Each video was assessed for degree of inflammation by 4 gastroenterologists using the mRS and the new proposed endoscopic score: the REMIND score (separate score of anastomosis and neoterminal ileum) and the updated Rutgeerts score (assessment of lesions at the anastomotic line, ileal inlet, ileal body, and neoterminal ileum). In addition, lesions at the ileal body, ileal inlet, neoterminal ileum, and colonic and/or ileal blind loop were separately assessed. Interobserver agreement was assessed by using Fleiss' weighted kappa. RESULTS: Fleiss' weighted kappa for the mRS was .67 (95% confidence interval [CI], .59-.74). The weighted kappa for the REMIND score was .73 (95% CI, .65-.80) for lesions in the neoterminal ileum and .46 (95% CI, .35-.58) for anastomotic lesions. The weighted kappa for the updated Rutgeerts score was .69 (95% CI, .62-.77). The weighted kappa for lesions in the ileal body, ileal inlet, neoterminal ileum, and colonic and ileal blind loop was .61 (95% CI, .49-.73), .63 (95% CI, .54-.72), .61 (95% CI, .49-.74), .83 (95% CI, .62-1.00) and .68 (95% CI, .46-.89), respectively. CONCLUSIONS: The interobserver agreement of the mRS is substantial. Similarly, the interobserver agreement is substantial for the updated Rutgeerts score. According to the REMIND score, the interobserver agreement was substantial for lesions in the neoterminal ileum, although only moderate for anastomotic lesions. Because therapeutic decisions in clinical practice are based on these assessments, and these scores are used as outcome measure in clinical studies, further improvement of the interobserver agreement is essential.
ABSTRACT
BACKGROUND: Hypersensitivity reactions (HSR) to the administration of infliximab (IFX) in Inflammatory Bowel Diseases (IBD) patients are not rare and usually lead to drug discontinuation. We report data on safety and effectiveness of desensitization to IFX in patients with previous HSR. METHODS: We conducted a retrospective monocentric observational study. Patients for whom a desensitization protocol to IFX was realized after a previous HSR were included. Anti-drug antibodies (ADA) and IFX trough levels at both inclusion and six months after desensitization were collected. Clinical outcomes, including recurrence of HSR were evaluated. RESULTS: From 2005 to 2020, 27 patients (Crohn's Disease: 26 (96%) were included). Desensitization after HSR was performed after a median time of 10.4 months (2.9-33.1). Nineteen (70%) patients received immunosuppressants at time of desensitization. Eight (30%) patients presented HSR at first (n = 2), second (n = 4) or third (n = 2) IFX perfusion after desensitization. None led to intensive care unit transfer or death. Thirteen (48%) had clinical response at 6 months and 8 (29%) were still under IFX treatment two years after desensitization. IFX trough levels and ADA were available for 14 patients at time of desensitization. Most patients (12 out of 14) had ADA at a high level. At 6 months, among the 7 patients with long term response to IFX, 4 presented a decrease of ADA titers and 2 had a significant trough level of IFX. CONCLUSION: IFX desensitization in patients with IBD is a safe therapeutic alternative and represents a potential option for patients refractory to multiple biologics.What is already known? Hypersensitivity reactions to the administration of infliximab is frequent. Occurrence of hypersensitivity reaction, either immediate or delayed, usually leads to permanent drug discontinuation.What is new here? Infliximab desensitization is well tolerated with no hypersensitivity reaction recurrence in 70% of patients. Clinical success at 6 months was of 48% and around a third of patients remained under infliximab therapy two years after desensitization. Antidrug antibodies decreased and infliximab trough levels increased in these patients showing the impact of desensitization on immunogenicity.How can this study help patient care? Infliximab desensitization represents a potential option for patients refractory to multiple biologics who presented hypersensitivity reaction to the drug.
Subject(s)
Desensitization, Immunologic , Drug Hypersensitivity , Gastrointestinal Agents , Inflammatory Bowel Diseases , Infliximab , Humans , Infliximab/therapeutic use , Infliximab/administration & dosage , Infliximab/immunology , Infliximab/adverse effects , Female , Male , Retrospective Studies , Adult , Desensitization, Immunologic/methods , Drug Hypersensitivity/immunology , Drug Hypersensitivity/etiology , Middle Aged , Gastrointestinal Agents/therapeutic use , Gastrointestinal Agents/adverse effects , Gastrointestinal Agents/immunology , Gastrointestinal Agents/administration & dosage , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/immunology , Crohn Disease/drug therapy , Crohn Disease/immunology , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Outcomes after ileocolonic resection in Crohn's disease [CD] are heterogeneous, and a clear definition of postoperative recurrence remains to be determined. Our Endpoints Working Group of the International Organization for the study of Inflammatory Bowel Disease [IOIBD] aimed to standardise postoperative outcomes, to discuss which endpoints should be used for postoperative clinical trials, and to define those which could be used in trials or registries. METHODS: Based on a systematic review of the literature, recommendations and statements were drafted and sent to all IOIBD members for a first round of voting. Recommendations and statements were revised based on the voters' comments during a consensus hybrid conference open to all IOIBD members. If no agreement was reached after two rounds of voting, the statement was excluded. RESULTS: In the systematic review, 3071 manuscripts were screened of which 434 were included. Sixteen recommendations were identified, of which 11 were endorsed. Recommendations and statements include that endoscopy remains the gold standard and should be used as a short-term primary endpoint in both observational cohorts and randomised controlled trials. Clinical symptoms classically used in clinical trials for luminal CD are not reliable in this specific situation. For that reason, longer-term endpoints should be based on the evidence of macroscopic inflammation assessed by imaging techniques, endoscopy, or as reflected by the presence of complications. CONCLUSIONS: Agencies recommend the use of clinical evaluations, as in the case of luminal CD, and do not recognise primary endpoints based solely on endoscopy. This consensus has led to agreement on the need to define postoperative endoscopy-based and/or imaging-based endpoints.
Subject(s)
Crohn Disease , Recurrence , Crohn Disease/surgery , Humans , Ileum/surgery , Ileum/pathologyABSTRACT
BACKGROUND: Chronic tropical cutaneous ulcers remain a neglected medical condition in West Africa, particularly Buruli ulcer, which is caused by mycolactone cytotoxin-secreting Mycobacterium ulcerans (M. ulcerans). Medical management of this highly debilitating and necrotising skin infection may be modified by colonisation and co-infection of the ulcer by opportunistic and pathogenic microorganisms, which considerably delays and increases the cost of treatment. METHODOLOGY/PRINCIPAL FINDING: We diagnosed chronic tropical cutaneous ulcers in nine patients in Côte d'Ivoire using M. ulcerans-specific PCRs and culturomics. This revealed M. ulcerans in 7/9 ulcer swabs and 5/9 control swabs as well as an additional 122 bacterial species, 32 of which were specific to ulcers, 61 specifics to the controls, and 29 which were shared, adding 40 bacterial species to those previously reported. Whole genome sequencing of four Bordetella trematum (B. trematum) isolates in four Buruli ulcer swabs and no controls indicated cytolethal distending toxins, as confirmed by cytotoxic assay. CONCLUSIONS/SIGNIFICANCE: In four cases of Buruli ulcer in Côte d'Ivoire, B. trematum was a co-pathogen which was resistant to rifampicin and clarithromycin, unmatching M. ulcerans antibiotic susceptibility profile and counteracting the current treatment of Buruli ulcer in West Africa and Australia. Thus, we report here chronic mixed M. ulcerans-B. trematum chronic tropical ulcer as a specific form of Buruli ulcer in West Africa.
Subject(s)
Buruli Ulcer , Communicable Diseases , Mycobacterium ulcerans , Skin Ulcer , Humans , Mycobacterium ulcerans/genetics , Buruli Ulcer/drug therapy , Buruli Ulcer/microbiology , Ulcer , Cote d'Ivoire , Skin Ulcer/drug therapy , Skin Ulcer/microbiologyABSTRACT
Postoperative recurrence [POR] after an ileocolonic resection with ileocolonic anastomosis is frequently encountered in patients with Crohn's disease. The 8th Scientific Workshop of ECCO reviewed the available evidence on the pathophysiology and risk factors for POR. In this paper, we discuss published data on the role of the microbiome, the mesentery, the immune system and the genetic background. In addition to investigating the causative mechanisms of POR, identification of risk factors is essential to tailor preventive strategies. Potential clinical, surgical and histological risk factors are presented along with their limitations. Emphasis is placed on unanswered research questions, guiding prevention of POR based on individual patient profiles.
Subject(s)
Crohn Disease , Humans , Crohn Disease/surgery , Crohn Disease/pathology , Colon/surgery , Colon/pathology , Anastomosis, Surgical/adverse effects , Anastomosis, Surgical/methods , Ileum/surgery , Ileum/pathology , Retrospective Studies , Risk Factors , RecurrenceABSTRACT
Despite the introduction of potent biologic therapies, many patients with Crohn's disease [CD] still require an ileocolonic resection [ICR] during the course of their disease. Furthermore, the need of redo ICR has not decreased over the past few decades, highlighting the need for better strategies to prevent and treat postoperative recurrence [POR]. The first step to develop such a strategy would be to define and standardise the description of POR with adequate diagnostic instruments. In this article, we will describe the different methodologies used to report POR [endoscopic, histological, radiological, biochemical, clinical, and surgical], and review their potential benefits and limitations, as well as the optimal timing of evaluation.
ABSTRACT
BACKGROUND: Crohn's disease (CD) is associated with changes in the microbiota, and murine models of CD-like ileo-colonic inflammation depend on the presence of microbial triggers. Increased abundance of unknown Clostridiales and the microscopic detection of filamentous structures close to the epithelium of Tnf ΔARE mice, a mouse model of CD-like ileitis pointed towards segmented filamentous bacteria (SFB), a commensal mucosal adherent bacterium involved in ileal inflammation. RESULTS: We show that the abundance of SFB strongly correlates with the severity of CD-like ileal inflammation in two mouse models of ileal inflammation, including Tnf ΔARE and SAMP/Yit mice. SFB mono-colonization of germ-free Tnf ΔARE mice confirmed the causal link and resulted in severe ileo-colonic inflammation, characterized by elevated tissue levels of Tnf and Il-17A, neutrophil infiltration and loss of Paneth and goblet cell function. Co-colonization of SFB in human-microbiota associated Tnf ΔARE mice confirmed that SFB presence is indispensable for disease development. Screening of 468 ileal and colonic mucosal biopsies from adult and pediatric IBD patients, using previously published and newly designed human SFB-specific primer sets, showed no presence of SFB in human tissue samples, suggesting a species-specific functionality of the pathobiont. Simulating the human relevant therapeutic effect of exclusive enteral nutrition (EEN), EEN-like purified diet antagonized SFB colonization and prevented disease development in Tnf ΔARE mice, providing functional evidence for the protective mechanism of diet in modulating microbiota-dependent inflammation in IBD. CONCLUSIONS: We identified a novel pathogenic role of SFB in driving severe CD-like ileo-colonic inflammation characterized by loss of Paneth and goblet cell functions in Tnf ΔARE mice. A purified diet antagonized SFB colonization and prevented disease development in Tnf ΔARE mice in contrast to a fiber-containing chow diet, clearly demonstrating the important role of diet in modulating a novel IBD-relevant pathobiont and supporting a direct link between diet and microbial communities in mediating protective functions. Video Abstract.
Subject(s)
Crohn Disease , Ileitis , Adult , Humans , Mice , Animals , Child , Crohn Disease/microbiology , Inflammation , Ileitis/microbiology , Ileitis/pathology , Diet , Bacteria/genetics , Disease Models, AnimalABSTRACT
OBJECTIVE: T cells are major effectors of the antitumoural immune response. Their activation by tumour-associated antigens can unleash their proliferation and cytotoxic functions, leading to tumour cell elimination. However, tumour-related immunosuppressive mechanisms including the overexpression of immune checkpoints like programmed cell death protein-1 (PD-1), are also engaged, promoting immune escape. Current immunotherapies targeting these pathways have demonstrated weak efficacy in colorectal cancer (CRC). It is thus crucial to find new targets for immunotherapy in this cancer type. DESIGN: In a prospective cohort of patients with CRC, we investigated the phenotype of tumour-related and non-tumour related intestinal T cells (n=44), particularly the adenosinergic pathway, correlating with clinical phenotype. An autologous coculture model was developed between patient-derived primary tumour spheroids and their autologous tumour-associated lymphocytes. We used this relevant model to assess the effects of CD39 blockade on the antitumour T cell response. RESULTS: We show the increased expression of CD39, and its co-expression with PD-1, on tumour infiltrating T cells compared with mucosal lymphocytes. CD39 expression was higher in the right colon and early-stage tumours, thus defining a subset of patients potentially responsive to CD39 blockade. Finally, we demonstrate in autologous conditions that CD39 blockade triggers T cell infiltration and tumour spheroid destruction in cocultures. CONCLUSION: In CRC, CD39 is strongly expressed on tumour infiltrating lymphocytes and its inhibition represents a promising therapeutic strategy for treating patients.
Subject(s)
Colorectal Neoplasms , T-Lymphocytes , Humans , Programmed Cell Death 1 Receptor/metabolism , Prospective Studies , Intestines/pathology , Colorectal Neoplasms/pathologyABSTRACT
OBJECTIVE: We used the postoperative recurrence model to better understand the role of adherent and invasive Escherichia coli (AIEC) bacteria in Crohn's disease (CD), taking advantage of a well-characterised postoperative cohort. DESIGN: From a prospective, multicentre cohort of operated patients with CD, AIEC identification was performed within the surgical specimen (M0) (N=181 patients) and the neoterminal ileum (n=119 patients/181) during colonoscopy performed 6 months after surgery (M6). Endoscopic postoperative recurrence was graded using Rutgeerts' index. The mucosa-associated microbiota was analysed by 16S sequencing at M0 and M6. Relative risks or ORs were adjusted on potential confounders. RESULTS: AIEC prevalence was twofold higher within the neoterminal ileum at M6 (30.3%) than within the surgical specimen (14.9%) (p<0.001). AIEC within the neoterminal ileum at M6 was associated with higher rate of early ileal lesions (i1) (41.6% vs 17.1%; aRR 3.49 (95% CI 1.01 to 12.04), p=0.048) or ileal lesions (i2b+i3) (38.2% vs 17.1%; aRR 3.45 (95% CI 1.06 to 11.30), p=0.040) compared with no lesion (i0). AIEC within the surgical specimen was predictive of higher risk of i2b-endoscopic postoperative recurrence (POR) (aOR 2.54 (95% CI 1.01 to 6.44), p=0.049) and severe endoscopic POR (aOR 3.36 (95% CI 1.25 to 9.06), p=0.017). While only 5.0% (6/119) of the patients were AIEC-positive at both M0 and M6, 43.7% (52/119), patients with history of positive test for AIEC (M0 or M6) had higher risk of ileal endoscopic POR (aOR 2.32 (95% CI 1.01 to 5.39), p=0.048)), i2b-endoscopic postoperative recurrence (aOR 2.41 (95% CI 1.01 to 5.74); p=0.048) and severe endoscopic postoperative (aOR=3.84 (95% CI 1.32 to 11.18), p=0.013). AIEC colonisation was associated with a specific microbiota signature including increased abundance of Ruminococcus gnavus. CONCLUSION: Based on the postoperative recurrence model, our data support the idea that AIEC are involved in the early steps of ileal CD. TRIAL REGISTRATION NUMBER: NCT03458195.
Subject(s)
Crohn Disease , Escherichia coli Infections , Humans , Bacterial Adhesion , Colonoscopy , Crohn Disease/pathology , Escherichia coli , Escherichia coli Infections/epidemiology , Ileum/microbiology , Prospective Studies , RecurrenceABSTRACT
BACKGROUND: The modified Rutgeerts' score [RS] differentiates i2a-lesions confined to the anastomosis-and i2b-more than five aphthous ulcers in the neoterminal ileum with normal intervening mucosa, with or without anastomotic lesions-categories. Its relevance for the therapeutic management of Crohn's disease [CD] patients after ileocolic resection is still debated. Our objective was to compare the postoperative recurrence risk in patients with an i2a or i2b score, using an individual patient data meta-analysis. METHODS: We conducted a systematic literature search until July 2020, to identify all relevant studies reporting the i2a/i2b status in the year following ileocolic resection and clinical and/or surgical postoperative CD recurrence in their follow-up. Individual patient-level data were obtained from the corresponding authors. The association between the modified RS and time-to-event was evaluated using a mixed Cox model with the centre as the random effect. RESULTS: Seven studies published between 2008 and 2019 were included, corresponding to 400 patients: 189 [47%] i2a and 211 [53%] i2b. Median [interquartile range, IQR] time from ileocolic resection to ileocolonoscopy was 6.2 [5.5, 7.9] months and median [IQR] follow-up time after ileocolonoscopy was 4.5 [2.9, 7.3] years. The risk of clinical postoperative recurrence at 1 and 3 years was 11% [6-15%], and 25% [18-32%] in the i2a group versus 9% [5-13%] and 33% [26-41%] in the i2b group [pâ =â 0.63 and pâ =â 0.12, respectively]. No significant difference was observed in terms of time to clinical postoperative recurrence [pâ =â 0.16] or surgical postoperative recurrence [pâ =â 0.87]. Results did not change after excluding patients having initiated an immunosuppressant or a biologic in the 3 months after endoscopy [remaining cohort, nâ =â 361]. CONCLUSIONS: In this individual patient data meta-analysis, no difference was observed between i2a and i2b subcategories with regards to clinical or surgical postoperative recurrence. As we wait for prospective trials, the same treatment strategy could be applied to all patients classified as i2 on the Rutgeerts score.
Subject(s)
Crohn Disease , Humans , Crohn Disease/surgery , Crohn Disease/pathology , Colon/surgery , Colon/pathology , Prospective Studies , Colectomy/methods , Endoscopy, Gastrointestinal , Ileum/surgery , Ileum/pathology , Recurrence , Retrospective Studies , ColonoscopyABSTRACT
Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn's Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls. These findings were positively correlated with T cell infiltration of the organoids. This potential was inhibited by limiting lympho-epithelial interactions through CD103 and NKG2D blocking antibodies. These data directly demonstrate for the first time the direct deleterious effect of mucosal T cells on the epithelium of CD patients. Such ex-vivo models are promising techniques to unravel the pathophysiology of these diseases and the potential mode of action of current and future therapies.
Subject(s)
Crohn Disease , Inflammatory Bowel Diseases , Humans , Organoids/metabolism , Crohn Disease/metabolism , Coculture Techniques , Epithelial Cells/metabolismABSTRACT
BACKGROUND: Predictors of the efficacy of endoscopic dilation for caustic esophageal stricture have been poorly studied. METHODS: All patients undergoing an endoscopic dilation for an esophageal caustic stricture between 1990 and 2015 in a French national reference center were included. Success of dilation was defined by self-food autonomy without the need for reconstructive esophageal surgery. RESULTS: During the study period, 894 patients were admitted after caustic ingestion. Among them, 101 patients developed esophageal stricture and 92 patients were eligible for analysis (missing data in 8 cases, 1 patient died before endoscopic dilation). In this cohort (median age 42 years, women 53%, strong alkali 74%, suicide attempt 77%, hydrostatic balloon use 93%), the overall success rate of dilation was 57% with a median number of 3 dilation sessions (274 sessions, range 1-17). Factors predicting the success of the procedure were: non-inflammatory stricture or non-inflammatory intercalated mucosa between stricture (88% vs 47%, p = 0.001), a single stricture versus 2 or more strictures (69% vs 47% vs 33%, respectively, p = 0.04), a stricture of less than 5 cm (70% vs 27%, p < 0.001) and the existence of mild/ moderately tight or very tight stricture (70% vs 21% of success, p < 0.001). Perforation rate was 6.5% (18/274) requiring emergency surgery in 2 cases. CONCLUSION: Several characteristics of caustic esophageal strictures are significantly associated with the success rate of endoscopic dilation. Our data may be useful for customizing treatment strategies in patients with a caustic stricture.
Subject(s)
Caustics , Esophageal Stenosis , Adult , Caustics/toxicity , Constriction, Pathologic , Dilatation/methods , Esophageal Stenosis/chemically induced , Esophageal Stenosis/surgery , Female , Humans , Retrospective Studies , Treatment OutcomeABSTRACT
Whether Mycobacterium ulcerans, the etiological agent of Buruli ulcer in numerous tropical countries, would exist in a dormant state as reported for closely related Mycobacterium species, has not been established. Six M. ulcerans strains were exposed to a progressive depletion in oxygen for 2 months, using the Wayne model of dormancy previously described for M. tuberculosis, and further examined by microscopy after staining of dynamic, dormant, and dead mycobacteria (DDD staining), microcalorimetry and subculture in the presence of dead and replicative M. ulcerans as controls. Mycobacterium ulcerans CU001 strain died during the progressive oxygen depletion and four of five remaining strains exhibited Nile red-stained intracellular lipid droplets and a 14- to 20-day regrowth when exposed to ambient air, consistent with dormancy. A fifth M. ulcerans 19423 strain stained negative in DDD staining and slowly regrew in 27 days. Three tested M. ulcerans strains yielded microcalorimetric pattern similar to that of the negative (dead) homologous controls, differing from that of the homologous positive (replicative) controls. The relevance of these experimental observations, suggesting a previously unreported dormancy state of M. ulcerans, warrants further investigations in the natural ecological niches where M. ulcerans thrive as well as in Buruli ulcer lesions.
ABSTRACT
BACKGROUND AND AIMS: Ileocolonic resection is frequently needed in the course of Crohn's disease [CD] treatment and post-operative recurrence is extremely common. Our main objective was to analyse gene expression in the mucosa of CD patients at the time of surgery and at post-operative endoscopy, in order to identify predictors and mechanisms of early endoscopic recurrence. METHODS: We conducted transcriptome analyses on ileal mucosa samples collected from inflamed sections of the surgical specimens [n = 200], from ileal resection margins [n = 149] and in the neo-terminal ileum 6 months after surgery [n = 122]; these were compared with non-inflammatory bowel disease controls [n = 25]. The primary endpoint was post-operative endoscopic recurrence at 6 months. We applied regression models to identify gene signatures predicting endoscopic recurrence. RESULTS: Chronic inflammation was associated with strong expression of inflammatory genes [IL-6, IL-8, IL-1B] and decreased expression of genes involved in metabolic processes, but with a high inter-individual heterogeneity. Gene signatures associated with early endoscopic recurrence were mainly characterized by upregulation of TNFα, IFNγ, IL23A and IL17A. Pathway analyses showed that upregulation of mitochondrial dysfunction within the inflamed sections and JAK/STAT at the ileal margin were predictive of post-operative recurrence. A combined model integrating these top pathway signatures improved the prediction of endoscopic recurrence [area under the curve of 0.79]. STAT3 phosphorylation at the surgical ileal margin was associated with severe recurrence at 6 months. CONCLUSION: We identified several biological pathways in surgical ileal mucosa specimens associated with an increased risk of disease recurrence. Integration of the JAK/STAT and mitochondrial dysfunction pathways in the clinical model improved the prediction of post-operative recurrence.
Subject(s)
Crohn Disease , Anastomosis, Surgical , Crohn Disease/drug therapy , Crohn Disease/genetics , Crohn Disease/surgery , Endoscopy, Gastrointestinal , Humans , Ileum/surgery , Recurrence , TranscriptomeABSTRACT
BACKGROUND: Inflammatory bowel diseases (IBDs) are characterized by chronic inflammation and tissue damages in limited segments of the digestive tract. Pathogenesis in the tissue and mucosal inflammation probably differs according to disease location. Our aim was to further analyze transcriptomic profiles in different locations of IBD, differentiating ulcerative colitis (UC), colonic Crohn's disease (CD), ileal CD, and pouchitis, with respect to normal colonic and ileal mucosa. We thus performed a meta-analysis focusing on specific transcriptomic signatures of ileal and colonic diseases. METHODS: We identified 5 cohorts with available transcriptomic data in ileal or colonic samples from active IBD and non-IBD control samples. The meta-analysis was performed on 1047 samples. In each cohort separately, we compared gene expression in CD ileitis and normal ileum; in CD colitis, UC, and normal colon; and finally in pouchitis and normal ileum. RESULTS: We identified specific markers of ileal (FOLH1, CA2) and colonic (REG3A) inflammation and showed that, with disease, some cells from the ileum start to express colonic markers. We confirmed by immunohistochemistry that these markers were specifically present in ileal or colonic diseases. We highlighted that, overall, colonic CD resembles UC and is distinct from ileal CD, which is in turn closer to pouchitis. CONCLUSIONS: We demonstrated that ileal and colonic diseases exhibit specific signatures, independent of their initial clinical classification. This supports molecular, rather than clinical, disease stratification, and may be used to design drugs specifically targeting ileal or colonic diseases.
We perform a meta-analysis of publicly available inflammatory bowel disease transcriptomes and identify FOLH1, REG3A, and CA2 as specific markers of ileal and colonic diseases. We demonstrate that Crohn's colitis resembles ulcerative colitis, while Crohn's ileitis resembles pouchitis.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Pouchitis , Biomarkers/metabolism , Colitis, Ulcerative/pathology , Crohn Disease/pathology , Humans , Ileum/pathology , Inflammation/pathology , Inflammatory Bowel Diseases/pathology , Pouchitis/pathology , TranscriptomeABSTRACT
Environmental Mycobacterium ulcerans causes a disabling skin disease called Buruli ulcer. Recent studies completed the knowledge of the evolving geographic extension and epidemiology of Buruli ulcer in West Africa, where Côte d'Ivoire is reporting the highest number of cases. We report seven polymerase chain reaction-documented patients in Burkina Faso, a neighboring country of Côte d'Ivoire, where previously Buruli ulcer cases were confirmed primarily using clinical arguments.
Subject(s)
Buruli Ulcer/diagnosis , Mycobacterium ulcerans/genetics , Adolescent , Adult , Burkina Faso/epidemiology , Buruli Ulcer/epidemiology , Buruli Ulcer/transmission , Cote d'Ivoire , Disease Transmission, Infectious , Endemic Diseases , Female , Humans , Male , Middle Aged , Pathology, Molecular , Real-Time Polymerase Chain Reaction , Rural Population , Young AdultABSTRACT
Mycobacterium ulcerans, the opportunistic pathogen causing Buruli ulcer, is reported to affect rural populations in 36 tropical countries. We report one case of Buruli ulcer in a peri-urban area in Côte d'Ivoire, confirmed by whole genome sequencing which indicated a M. ulcerans genotype previously unreported in Côte d'Ivoire.