Tuberculosis and Immune Reconstitution Inflammatory Syndrome in Patients With Inflammatory Bowel Disease and Anti-TNFα Treatment: Insights From a French Multicenter Study and Systematic Literature Review With Emphasis on Paradoxical Anti-TNFα Resumption.

Background: The advent of anti-tumor necrosis factor α (anti-TNFα) has revolutionized the treatment of inflammatory bowel disease (IBD). However, susceptibility to active tuberculosis (TB) is associated with this therapy and requires its discontinuation. The risk of immune reconstitution inflammatory syndrome (IRIS) in this population is poorly understood, as is the safety of resuming anti-TNFα. Methods: This French retrospective study (2010-2022) included all TB cases in patients with IBD who were treated with anti-TNFα in 6 participating centers. A systematic literature review was performed on TB-IRIS and anti-TNFα exposure. Results: Thirty-six patients were included (median age, 35 years; IQR, 27-48). TB was disseminated in 86% and miliary in 53%. IRIS occurred in 47% after a median 45 days (IQR, 18-80). Most patients with TB-IRIS (93%) had disseminated TB. Miliary TB was associated with IRIS risk in univariate analysis (odds ratio, 7.33; 95% CI, 1.60-42.82; P = .015). Anti-TB treatment was longer in this population (median [IQR], 9 [9-12] vs 6 [6-9] months; P = .049). Anti-TNFα was resumed in 66% after a median 4 months (IQR, 3-10) for IBD activity (76%) or IRIS treatment (24%), with only 1 case of TB relapse. Fifty-two cases of TB-IRIS in patients treated with anti-TNFα were reported in the literature, complicating disseminating TB (85%) after a median 42 days (IQR, 21-90), with 70% requiring anti-inflammatory treatment. Forty cases of TB-IRIS or paradoxical reaction treated with anti-TNFα were also reported. IRIS was neurologic in 64%. Outcome was mostly favorable (93% recovery). Conclusions: TB with anti-TNFα treatment is often complicated by IRIS of varying severity. Restarting anti-TNFα is a safe and effective strategy.

Real-world comparison of the effectiveness between ustekinumab and vedolizumab in patients with ulcerative colitis exposed to at least one anti-TNF agent.

BACKGROUND: Both vedolizumab and ustekinumab can be considered for the treatment of ulcerative colitis (UC) but head-to-head trials are lacking. AIM: We aimed to compare the effectiveness of vedolizumab and ustekinumab after anti-TNF failure in UC patients. PATIENTS AND METHODS: In this multicenter study, we included consecutive adult patients with UC, with partial Mayo score >2 and prior anti-TNF exposure, treated with vedolizumab or ustekinumab between January 2019 and August 2022. Comparisons were performed using propensity score analyses (inverse probability of treatment weighting). RESULTS: Among a total of 293 patients included, 151 and 142 received vedolizumab and ustekinumab, respectively. After propensity-score analysis, steroid-free clinical remission (SFCR) (Mayo score partial ≤ 2) was achieved at week 16 in 38.0% and 40.3%, of patients treated with vedolizumab and ustekinumab, respectively (aOR = 1.11 [0.39-3.13], p = 0.85). Rate of SFCR in patients exposed to one line, 2 lines and 3 lines of biologics/small molecules among patients treated with vedolizumab and ustekinumab were respectively 53.3% vs 62.1% (p=0.52), 44.4% vs 33.8% (p=0.52) and 2.6% vs 19.1% (p=0.027). Endoscopic remission (SFCR and endoscopic Mayo score ≤1) and histological remission (SFCR, endoscopic remission and Nancy histological index ≤1) at W16 were achieved in respectively, 5.3% vs 17.5% (aOR = 3.77 [1.25-11.36], p=0.018) and 2.1% vs 11.1% (aOR = 5.85 [1.47-23.30], p=0.012) in vedolizumab and ustekinumab groups. No difference regarding the risk of drug discontinuation between the two groups (aHR = 1.03 [0.51-2.08], p = 0.92) were observed. While no factor was identified for vedolizumab, primary failure to at least one biologic/small molecule (OR=0.31, 95%CI [0.11-0.82], p=0.018) was significantly associated with decreased rate of SFCR among patients treated with ustekinumab. CONCLUSION: While no difference in terms of short-term clinical remission was observed, ustekinumab appears to be more effective than vedolizumab to induce endoscopic and histological remission at week 16 after failure of anti-TNFs in UC.

Systemically delivered adipose stromal vascular fraction mitigates radiation-induced gastrointestinal syndrome by immunomodulating the inflammatory response through a CD11b+ cell-dependent mechanism.

BACKGROUND: Stromal vascular fraction (SVF) treatment promoted the regeneration of the intestinal epithelium, limiting lethality in a mouse model of radiation-induced gastrointestinal syndrome (GIS). The SVF has a heterogeneous cell composition; the effects between SVF and the host intestinal immunity are still unknown. The specific role of the different cells contained in the SVF needs to be clarified. Monocytes-macrophages have a crucial role in repair and monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2. METHODS: Mice exposed to abdominal radiation (18 Gy) received a single intravenous injection of SVF (2.5 × 106 cells), obtained by enzymatic digestion of inguinal fat tissue, on the day of irradiation. Intestinal immunity and regeneration were evaluated by flow cytometry, RT-PCR and histological analyses. RESULTS: Using flow cytometry, we showed that SVF treatment modulated intestinal monocyte differentiation at 7 days post-irradiation by very early increasing the CD11b+Ly6C+CCR2+ population in the intestine ileal mucosa and accelerating the phenotype modification to acquire CX3CR1 in order to finally restore the F4/80+CX3CR1+ macrophage population. In CX3CR1-depleted mice, SVF treatment fails to mature the Ly6C-MCHII+CX3CR1+ population, leading to a macrophage population deficit associated with proinflammatory environment maintenance and defective intestinal repair; this impaired SVF efficiency on survival. Consistent with a CD11b+ being involved in SVF-induced intestinal repair, we showed that SVF-depleted CD11b+ treatment impaired F4/80+CX3CR1+macrophage pool restoration and caused loss of anti-inflammatory properties, abrogating stem cell compartment repair and survival. CONCLUSIONS: These data showed that SVF treatment mitigates the GIS-involving immunomodulatory effect. Cooperation between the monocyte in SVF and the host monocyte defining the therapeutic properties of the SVF is necessary to guarantee the effective action of the SVF on the GIS.

[Biotherapies for the treatment of ulcerative colitis]. / Biothérapies dans le traitement de la rectocolite hémorragique.

BIOTHÉRAPIES DANS LE TRAITEMENT DE LA RECTOCOLITE HÉMORRAGIQUE. Le traitement de la rectocolite hémorragique a considérablement évolué puisqu'il doit, pour la plupart des patients,permettre une cicatrisation des lésions inflammatoires coliques et non plus une simple rémission des symptômes cliniques. Ceci est désormais possible grâce aux biothérapies dont trois classes principales sont autorisées dans la rectocolite hémorragique. Les anti-TNF, classe la plus ancienne, ont fait la preuve de leur efficacité et peuvent être utilisés en première ligne de traitement après échec des traitements conventionnels. Parmi eux, seul l'infliximab est recommandé dans les colites aiguës graves. Le védolizumab, anti-intégrine, peut également être utilisé en première ligne, avec un excellent profil de tolérance mais pas d'effet sur les manifestations extradigestives. Les anti-interleukines 12 et 23 (ustékinumab), bientôt rejointes par d'autres anticorps spécifiques de l'interleukine 23, sont également très efficaces et leur tolérance excellente, mais se positionnent en échec d'une première ligne de biothérapie. S'ajoutent à cet arsenal les inhibiteurs de JAK, petites molécules orales, d'action très puissante mais dont le profil médiocre de tolérance les réserve aux sujets jeunes, sans comorbidité et généralement après échec de deux lignes de biothérapie. Tous ces traitements sont actuellement disponibles à domicile, par voie sous-cutanée, ou orale pour les inhibiteurs de JAK. Ceci implique pour les patients une bonne connaissance, acquise par l'éducation thérapeutique, et la mise en place d'un suivi coordonné avec tous les acteurs de soins : gastroentérologues, médecins généralistes et infirmières de coordination.

BIOTHERAPIES FOR THE TREATMENT OF ULCERATIVE COLITIS. The treatment of ulcerative colitis has evolved considerably since it must, for most patients, allow healing of inflammatory colonic lesions and no longer a simple remission of clinical symptoms. This is now possible thanks to biotherapies, of which three main classes are authorized in ulcerative colitis. Anti-TNFs, the oldest class, have proven their effectiveness and can be used as first-line treatment after failure of conventional treatments. Among them, only infliximab is recommended in severe acute colitis. Vedolizumab, anti-integrin, can also be used in first line with an excellent safety profile but no effect on extradigestive manifestations. The anti-interleukin 12/23 ustekinumab, soon joined by other antibodies specific for interleukin 23, is also very effective and its tolerance excellent, but is positioned after a failure of a first biologic. Janus kinase (JAK) inhibitors, small oral molecules, with a very powerful action, but whose poor tolerance profile reserves them for young subjects, without comorbidity and generally after failure of two lines of biologics. All these treatments are currently available at home, by subcutaneous route, or orally for JAK inhibitors. This implies their good knowledge and the implementation of patient follow-up coordinated with all healthcare providers: gastroenterologists, general practitioners and IBD coordinating nurses.

Real-world comparison of effectiveness between tofacitinib and vedolizumab in patients with ulcerative colitis exposed to at least one anti-TNF agent.

BACKGROUND: Data comparing tofacitinib and vedolizumab in ulcerative colitis (UC) are lacking. AIMS: To compare the effectiveness of tofacitinib and vedolizumab in patients with UC who had prior exposure to anti-TNF therapy METHODS: In this multicentre study, we included consecutive patients with UC ≥18 years old with partial Mayo score >2 and prior anti-TNF exposure, who started tofacitinib or vedolizumab between January 2019 and June 2021. Comparisons were performed using propensity score analyses (inverse probability of treatment weighting). RESULTS: Overall, 126 and 178 patients received tofacitinib and vedolizumab, respectively. Intensified induction (vedolizumab infusion at week 10 or tofacitinib 10 mg b.d until week 16) was performed in 28.5% and 41.5% of patients, respectively. After propensity-score analysis, corticosteroid-free clinical remission (partial Mayo score ≤2) was achieved at week 16 in 45.1% and 40.2% of patients receiving tofacitinib and vedolizumab, respectively (aOR = 0.82 [0.35-1.91], p = 0.64). Endoscopic improvement (corticosteroid-free clinical remission and endoscopic Mayo score ≤1) (aOR = 0.23[0.08-0.65], p = 0.0032) and histological healing (endoscopic improvement + Nancy histological index ≤1) (13.4% vs 3.2%, aOR = 0.21[0.05-0.91], p = 0.023) were higher at week 16 in patients treated with tofacitinib. No factor was predictive of tofacitinib effectiveness. At least one primary failure to a biologic (OR = 0.46[0.22-0.99], p = 0.049), partial Mayo score >6 (OR = 0.39[0.17-0.90], p = 0.029) and CRP level > 30 mg/L at baseline (OR = 0.08[0.01-0.85], p = 0.036) were associated with vedolizumab failure. CONCLUSION: Tofacitinib and vedolizumab are effective in UC after failure of anti-TNF agents. However, tofacitinib seems more effective, especially in severe disease and primary failure to biologics.

Crohn-like Disease Affecting Small Bowel Due to Monogenic SLCO2A1 Mutations: First Cases of Chronic Enteropathy Associated with SLCO2A1 Gene [CEAS] in France.

INTRODUCTION: Multiple chronic ulcers of small intestine are mainly ascribed to Crohn's disease. Among possible differential diagnoses are chronic ulcers of small bowel caused by abnormal activation of the prostaglandin pathway either in the archetypal but uncommon non-steroidal anti-inflammatory drug [NSAID]-induced enteropathy, or in rare monogenic disorders due to PLA2G4A and SLCO2A1 mutations. SLCO2A1 variants are responsible for CEAS [chronic enteropathy associated with SLCO2A1], a syndrome which was exclusively reported in patients of Asian origin. Herein, we report the case of two French female siblings, P1 and P2, with CEAS. CASE REPORT: P1 underwent iterative bowel resections [removing 1 m of small bowel in total] for recurrent strictures and perforations. Her sister P2 had a tight duodenal stricture which required partial duodenectomy. Next-generation sequencing was performed on P1's DNA and identified two compound heterozygous variants in exon 12 in SLCO2A1, which were also present in P2. CONCLUSION: CEAS can be detected within the European population and raises the question of its incidence and recognition outside Asia. Presence of intractable recurrent ulcerations of the small intestine, mimicking Crohn's disease with concentric strictures, should motivate a genetic search for SLCO2A1 mutations, particularly in the context of family history or consanguinity.

Role of adherent and invasive Escherichia coli in Crohn's disease: lessons from the postoperative recurrence model.

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.

Screening for spondyloarthritis in patients with inflammatory bowel diseases.

Inflammatory bowel diseases (IBDs) can be associated with various musculoskeletal (IBD-MSK) manifestations that could be difficult to classify for gastroenterologists. We aimed to evaluate the characteristics of patients with IBD-MSK and the prevalence of spondyloarthritis (SpA). In this observational cross-sectional study, we included patients with IBD-MSK complaints (peripheral or back pain). All patients underwent a standardized rheumatology evaluation including clinical, biological and imaging evaluations (MRI of spine and sacroiliac joints and ultrasonography of enthesis). We included 183 IBD patients (60.7% women; median [interquartile range] age 45 [36-56] years); 159 (87%) had joint pain. In 43 (23.5%) and 25/175 (14.3%) patients, enthesis abnormalities were found on ultrasonography and sacroiliitis on MRI, respectively. SpA was diagnosed in 54 (29.5%) patients. IBD-related arthralgia and degenerative spine disease were diagnosed in 105 (57.4%) and 72 (39.3%) patients. Sixteen (29.6%) SpA patients initiated a new conventional synthetic disease modifying anti-rheumatic drug (DMARD). A biologic DMARD was initiated in 10 patients or changed in 3. More than half of IBD-MSK patients had IBD-related arthralgia, and about one-third had definite SpA. Ultrasonography of enthesis and systematic MRI of sacroiliac joints seem useful for SpA classification and differential diagnosis in these patients who often have musculoskeletal pain complaints. Therapeutics were changed in most patients, which highlights the need for a multidisciplinary approach for managing IBD with extra-intestinal symptoms.

The Appendix Orchestrates T-Cell Mediated Immunosurveillance in Colitis-Associated Cancer.

BACKGROUND & AIMS: Although appendectomy may reduce colorectal inflammation in patients with ulcerative colitis (UC), this surgical procedure has been suggested to be associated with an increased risk of colitis-associated cancer (CAC). Our aim was to explore the mechanism underlying the appendectomy-associated increased risk of CAC. METHODS: Five-week-old male BALB/c mice underwent appendectomy, appendicitis induction, or sham laparotomy. They were then exposed to azoxymethane/dextran sodium sulfate (AOM/DSS) to induce CAC. Mice were killed 12 weeks later, and colons were taken for pathological analysis and immunohistochemistry (CD3 and CD8 staining). Human colonic tumors from 21 patients with UC who underwent surgical resection for CAC were immunophenotyped and stratified according to appendectomy status. RESULTS: Whereas appendectomy significantly reduced colitis severity and increased CAC number, appendicitis induction without appendectomy led to opposite results. Intratumor CD3+ and CD8+ T-cell densities were lower after appendectomy and higher after appendicitis induction compared with the sham laparotomy group. Blocking lymphocyte trafficking to the colon with the anti-α4ß7 integrin antibody or a sphingosine-1-phosphate receptor agonist suppressed the inducing effect of the appendectomy on tumors' number and on CD3+/CD8+ intratumoral density. CD8+ or CD3+ T cells isolated from inflammatory neo-appendix and intravenously injected into AOM/DSS-treated recipient mice increased CD3+/CD8+ T-cell tumor infiltration and decreased tumor number. In UC patients with a history of appendectomy, intratumor CD3+ and CD8+ T-cell densities were decreased compared with UC patients without history of appendectomy. CONCLUSIONS: In UC, appendectomy could suppress a major site of T-cell priming, resulting in a less efficient CAC immunosurveillance.

Intra-abdominal abscesses in CD - When to treat with biologics?

Management of intra-abdominal abscesses complicating Crohn's disease (CD) is challenging. After initial drainage and antibiotherapy treatment, surgery with delayed intestinal resection is often recommended but new data suggests efficacy of biotherapies in this context. This review aims to summarize new data regarding efficacy and safety of anti-TNF in the management of intra-abdominal abscesses complicating CD. We performed a review of the literature on medical management of intra-abdominal abscesses complicating CD. After effective drainage of abscess, treatment with anti-TNF can allow resolving of abscess. In some patients and at a specific timing, the use of biotherapies could avoid delayed surgery and long-term abscess recurrence.

The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis.

Defects in RNA splicing have been linked to human disorders, but remain poorly explored in inflammatory bowel disease (IBD). Here, we report that expression of the chromatin and alternative splicing regulator HP1γ is reduced in ulcerative colitis (UC). Accordingly, HP1γ gene inactivation in the mouse gut epithelium triggers IBD-like traits, including inflammation and dysbiosis. In parallel, we find that its loss of function broadly increases splicing noise, favoring the usage of cryptic splice sites at numerous genes with functions in gut biology. This results in the production of progerin, a toxic splice variant of prelamin A mRNA, responsible for the Hutchinson-Gilford Progeria Syndrome of premature aging. Splicing noise is also extensively detected in UC patients in association with inflammation, with progerin transcripts accumulating in the colon mucosa. We propose that monitoring HP1γ activity and RNA splicing precision can help in the management of IBD and, more generally, of accelerated aging.

Impact of Crohn's disease on obstetrical management.

OBJECTIVE: Patients with Crohn's disease (CD) may have perineal lesions or a history of anorectal surgery that raise concerns about complications during delivery resulting in a discussion of cesarean section. Our objective was to study the impact of CD on the mode of delivery. METHOD: We conducted a retrospective study between 2005 and 2019 of the pregnancy outcomes of patients with CD. The primary endpoint was the performance of a cesarean section for a reason related to CD. RESULTS: Among 76 consecutive pregnancies, 19 patients underwent CD-related cesarean section (25%). The main element associated with scheduling a cesarean section was the existence of perineal involvement in 94.7% of cases, compared to 12.3% in the rest of the CD population (p<0.05). The perineal lesions most often involved were fistulas (47.4% versus 1.7%; p = 0.042). There was a history of perineal surgery in 78.9% of cases in the cesarean group vs 10,5% (p < 0.05) and a history of obstetric anal sphincter injury (OASI) in 10.5% of cases vs. 0 (p = 0.047). In women who gave birth vaginally, there were 17.9% episiotomy and one case of OASI (2.6%). CONCLUSION: The factors that influenced the choice of delivery route were perineal damage, history of perineal surgery and history of OASI.

Anterior gradient proteins in gastrointestinal cancers: from cell biology to pathophysiology.

Most of the organs of the digestive tract comprise secretory epithelia that require specialized molecular machines to achieve their functions. As such anterior gradient (AGR) proteins, which comprise AGR1, AGR2, and AGR3, belong to the protein disulfide isomerase family, and are involved in secretory and transmembrane protein biogenesis in the endoplasmic reticulum. They are generally expressed in epithelial cells with high levels in most of the digestive tract epithelia. To date, the vast majority of the reports concern AGR2, which has been shown to exhibit various subcellular localizations and exert pro-oncogenic functions. AGR2 overexpression has recently been associated with a poor prognosis in digestive cancers. AGR2 is also involved in epithelial homeostasis. Its deletion in mice results in severe diffuse gut inflammation, whereas in inflammatory bowel diseases, the secretion of AGR2 in the extracellular milieu participates in the reshaping of the cellular microenvironment. AGR2 thus plays a key role in inflammation and oncogenesis and may represent a therapeutic target of interest. In this review, we summarize the already known roles and mechanisms of action of the AGR family proteins in digestive diseases, their expression in the healthy digestive tract, and in digestive oncology. At last, we discuss the potential diagnostic and therapeutic implications underlying the biology of AGR proteins.

A Preclinical Validation of Iron Oxide Nanoparticles for Treatment of Perianal Fistulizing Crohn's Disease.

Fistulizing anoperineal lesions are severe complications of Crohn's disease (CD) that affect quality of life with a long-term risk of anal sphincter destruction, incontinence, permanent stoma, and anal cancer. Despite several surgical procedures, they relapse in about two-thirds of patients, mandating innovative treatments. Ultrasmall particles of iron oxide (USPIO) have been described to achieve in vivo rapid healing of deep wounds in the skin and liver of rats thanks to their nanobridging capability that could be adapted to fistula treatment. Our main purpose was to highlight preclinical data with USPIO for the treatment of perianal fistulizing CD. Twenty male Sprague Dawley rats with severe 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced proctitis were operated to generate two perianal fistulas per rat. At day 35, two inflammatory fistulas were obtained per rat and perineal magnetic resonance imaging (MRI) was performed. After a baseline MRI, a fistula tract was randomly drawn and topically treated either with saline or with USPIO for 1 min (n = 17 for each). The rats underwent a perineal MRI on postoperative days (POD) 1, 4, and 7 and were sacrificed for pathological examination. The primary outcome was the filling or closure of the fistula tract, including the external or internal openings. USPIO treatment allowed the closure and/or filling of all the treated fistulas from its application until POD 7 in comparison with the control fistulas (23%). The treatment with USPIO was safe, permanently closed the fistula along its entire length, including internal and external orifices, and paved new avenues for the treatment of perianal fistulizing Crohn's disease.

Fecal microbiota and bile acids in IBD patients undergoing screening for colorectal cancer.

Due to the potential role of the gut microbiota and bile acids in the pathogenesis of both inflammatory bowel disease (IBD) and sporadic colorectal cancer, we aimed to determine whether these factors were associated with colorectal cancer in IBD patients. 215 IBD patients and 51 non-IBD control subjects were enrolled from 10 French IBD centers between September 2011 and July 2018. Fecal samples were processed for bacterial 16S rRNA gene sequencing and bile acid profiling. Demographic, clinical, endoscopic, and histological outcomes were recorded. Characteristics of IBD patients included: median age: 41.6 (IQR 22); disease duration 13.2 (13.1); 47% female; 21.9% primary sclerosing cholangitis; 109 patients with Crohn's disease (CD); 106 patients with ulcerative colitis (UC). The prevalence of cancer was 2.8% (6/215: 1 CD; 5 UC), high-grade dysplasia 3.7% (8/215) and low-grade dysplasia 7.9% (17/215). Lachnospira was decreased in IBD patients with cancer, while Agathobacter was decreased and Escherichia-Shigella increased in UC patients with any neoplasia. Bile acids were not associated with cancer or neoplasia. Unsupervised clustering identified three gut microbiota clusters in IBD patients associated with bile acid composition and clinical features, including a higher risk of neoplasia in UC in two clusters when compared to the third (relative risk (RR) 4.07 (95% CI 1.6-10.3, P < .01) and 3.56 (95% CI 1.4-9.2, P < .01)). In this multicentre observational study, a limited number of taxa were associated with neoplasia and exploratory microbiota clusters co-associated with clinical features, including neoplasia risk in UC. Given the very small number of cancers, the robustness of these findings will require assessment and validation in future studies.

Impact of the Ileal Microbiota on Surgical Site Infections in Crohn's Disease: A Nationwide Prospective Cohort.

BACKGROUND AND AIMS: Surgery is performed in 50-70% of Crohn's disease [CD] patients, and its main risk is surgical site infection [SSI]. The microbiota has been extensively assessed in CD but not as a potential risk factor for septic morbidity. The objective of this study was to assess the impact of the gut microbiota on SSI in CD. METHODS: We used the multicentric REMIND prospective cohort to identify all patients who experienced SSI after ileocolonic resection for CD, defined as any postoperative local septic complication within 90 days after surgery: wound abscess, intra-abdominal collection, anastomotic leakage or enterocutaneous fistula. The mucosa-associated microbiota of the ileal resection specimen was analysed by 16S gene sequencing in 149 patients. The variable selection and prediction were performed with random forests [R package VSURF] on clinical and microbiotal data. The criterion of performance that we considered was the area under the Receiver Operating Characteristic [ROC] curve [AUC]. RESULTS: SSI occurred in 24 patients [16.1%], including 15 patients [10.1%] with major morbidity. There were no significant differences between patients with or without SSI regarding alpha and beta diversity. The top selected variables for the prediction of SSI were all microbiota-related. The maximum AUC [0.796] was obtained with a model including 14 genera, but an AUC of 0.78 had already been obtained with a model including only six genera [Hungatella, Epulopiscium, Fusobacterium, Ruminococcaceae_ucg_009, Actinomyces and Ralstonia]. CONCLUSION: The gut microbiota has the potential to predict SSI after ileocolonic resection for CD. It might play a role in this frequent postoperative complication.

Identification of Gene Expression Profiles Associated with an Increased Risk of Post-Operative Recurrence in Crohn's Disease.

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.

Vedolizumab Clinical Decision Support Tool Predicts Efficacy of Vedolizumab But Not Ustekinumab in Refractory Crohn's Disease.

INTRODUCTION: Vedolizumab clinical decision support tool (VDZ-CDST) predicts response to vedolizumab, but whether this tool also predicts efficacy of other drugs in Crohn's disease (CD) is unknown. This study aimed to assess the value of VDZ-CDST to predict vedolizumab and ustekinumab efficacy in patients with CD. PATIENTS AND METHODS: We included consecutive CD patients refractory or intolerant to anti-TNF who started either vedolizumab or ustekinumab in 5 university hospitals between May 2014 and August 2018. The main end points were the rates of clinical remission and steroid-free clinical remission (SFCR) in each group of VDZ-CDST at week 48. RESULTS: One hundred eighty patients were included; 94 received vedolizumab (VDZ-CDST ≤13: 32; VDZ-CDST >13 and ≤19: 52; VDZ-CDST >19: 10), and 86 received ustekinumab (VDZ-CDST ≤13: 16; VDZ-CDST >13 and ≤19: 60; VDZ-CDST >19: 10). At week 48 in the vedolizumab group, clinical remission and SFCR were reached in 9.4% with a VDZ-CDST ≤13, in 38.5% and 28.8% with a VDZ-CDST >13 and ≤19, respectively, and in 80.0% with a VDZ-CDST >19 (P < 0.0001 and P < 0.0001, respectively). In the ustekinumab cohort, clinical remission and SFCR were reached in 43.8% and 37.5% with a VDZ-CDST ≤13, in 55.0% and 50.0% with a VDZ-CDST >13 and ≤19, and 50.0% with a VDZ-CDST >19, respectively (P = 0.65 and P = 0.46, respectively). VDZ-CDST identified SFCR with an area under the curve of 0.69 (95% CI, 0.57-0.82) for vedolizumab and 0.52 (95% CI, 0.40-0.65) for ustekinumab. CONCLUSION: The VDZ-CDST predicts clinical remission and SFCR at week 48 for vedolizumab but not for ustekinumab in CD patients refractory or intolerant to anti-TNF.

[Autologous hematopoietic cells for severe autoimmune diseases: Guidelines of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) for immune monitoring and biobanking]. / Suivi immunologique et collection biologique en vue de l'analyse de la réponse clinique après autogreffe de moelle pour maladies auto-immunes : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Autologous hematopoietic cell transplantation (AHCT) is a new treatment option for patients with severe autoimmune diseases (AD), based on the use of intensive or myeloablative chemotherapy to eradicate the pathogenic autoreactive immune cells and to allow the installation of a new and tolerant immune system during immune reconstitution process. Immune reconstitution analysis after AHCT is required for patients clinical follow-up and to further identify biological and immunological markers of the clinical response to develop individualized AHCT protocols. These MATHEC-SFGM-TC good clinical practice guidelines were developed by a multidisciplinary group of experts including members of the french reference center for stem Cell Therapy in Auto-immune Diseases (MATHEC), hematologists from the French speaking Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) and experts in immune monitoring and biobanking. The objectives are to provide practical recommandations for immune monitoring and biobanking of samples in patients with AD undergoing AHCT, for routine care purposes and investigational studies.