Publications by authors named "Franck Carbonnel"

150 Publications

Bariatric Surgery in Patients With Inflammatory Bowel Disease: A Case-Control Study from the GETAID.

Inflamm Bowel Dis 2021 Oct 12. Epub 2021 Oct 12.

AP-HP, Hôpital Louis Mourier, DMU ESPRIT, Service de Gastroentérologie, Université de Paris, Colombes, France.

Background: The prevalence of obesity and the number of bariatric surgeries in both the general population and in patients with inflammatory bowel disease (IBD) have increased significantly in recent years. Due to small sample sizes and the lack of adequate controls, no definite conclusions can be drawn from the available studies on the safety and efficacy of bariatric surgery (BS) in patients with IBD. Our aim was to assess safety, weight loss, and deficiencies in patients with IBD and obesity who underwent BS and compare findings to a control group.

Methods: Patients with IBD and a history of BS were retrospectively recruited to centers belonging to the Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID). Patients were matched 1:2 for age, sex, body mass index (BMI), hospital of surgery, and type of BS with non-IBD patients who underwent BS. Complications, rehospitalizations, weight, and deficiencies after BS were collected in cases and controls.

Results: We included 88 procedures in 85 patients (64 Crohn's disease, 20 ulcerative colitis, 1 unclassified IBD) with a mean BMI of 41.6 ± 5.9 kg/m2. Bariatric surgery included Roux-en-Y gastric bypass (n = 3), sleeve gastrectomy (n = 73), and gastric banding (n = 12). Eight (9%) complications were reported, including 4 (5%) requiring surgery. At a mean follow-up of 34 months, mean weight was 88.6 ± 22.4 kg. No difference was observed between cases and controls for postoperative complications (P = .31), proportion of weight loss (P = .27), or postoperative deficiencies (P = .99).

Conclusions: Bariatric surgery is a safe and effective procedure in patients with IBD and obesity; outcomes in this patient group were similar to those observed in a control population.
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http://dx.doi.org/10.1093/ibd/izab249DOI Listing
October 2021

Serious Infections in Children Born to Mothers With Inflammatory Bowel Disease With In Utero Exposure to Thiopurines and Anti-Tumor Necrosis Factor.

Clin Gastroenterol Hepatol 2021 Jul 21. Epub 2021 Jul 21.

EPIPHARE, Épidémiologie des Produits de Santé, ANSM-CNAM, Saint Denis, France.

Background & Aims: We aimed to compare the risk of serious infections in children with in utero exposure to thiopurines and/or anti-tumor necrosis factor (TNF) born to mothers with inflammatory bowel disease (IBD).

Methods: Using the French national health database, which covers 99% of the French population (around 66,000,000 people), we identified live births among women with IBD in France between 2010 and 2018. The risks of serious infections in children during the first 5 years of life were compared according to treatment exposures during pregnancy using propensity score-weighted marginal Cox models.

Results: A total of 26,561 children were included: 3392 were exposed to thiopurine monotherapy, 3399 to anti-TNF monotherapy, 816 to combination therapy, and 18,954 were not exposed to any of these drugs. The risks of serious infections during the first year of life among children exposed to thiopurine monotherapy (adjusted hazard ratio [aHR], 0.94; 95% confidence interval [CI], 0.83-1.07) and anti-TNF monotherapy (aHR, 1.10; 95% CI, 0.95-1.27) were similar to those of unexposed children; a higher risk was observed in children exposed to combination therapy (aHR, 1.36; 95% CI, 1.04-1.79). The highest increased risks were observed for nervous system infections and viral infections. The risk of serious infections during the second to fifth years of life was not associated with IBD treatments.

Conclusions: In children born to mothers with IBD, in utero exposure to thiopurine and anti-TNF monotherapies do not increase the risk of serious infections during the first 5 years of life. Combination therapy is associated with an increased risk of serious infections during the first year of life.
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http://dx.doi.org/10.1016/j.cgh.2021.07.028DOI Listing
July 2021

Obesity is Associated With Increased Risk of Crohn's disease, but not Ulcerative Colitis: A Pooled Analysis of Five Prospective Cohort Studies.

Clin Gastroenterol Hepatol 2021 Jul 7. Epub 2021 Jul 7.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Background And Aims: It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC).

Methods: We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs).

Results: Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I = 0%) compared with normal BMI (18.5 to <25 kg/m). Each 5 kg/m increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I = 0%). Similarly, with each 5 kg/m increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I = 0%). No associations were observed between measures of obesity and risk of UC.

Conclusions: In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC.
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http://dx.doi.org/10.1016/j.cgh.2021.06.049DOI Listing
July 2021

Comparative study of pregnancy outcomes in women with inflammatory bowel disease treated with thiopurines and/or anti-TNF: a French nationwide study 2010-2018.

Aliment Pharmacol Ther 2021 08 23;54(3):302-311. Epub 2021 Jun 23.

EPIPHARE, Épidémiologie des produits de santé, ANSM-CNAM, Denis, France.

Background: Data about thiopurines or anti-TNF use during pregnancy in women with inflammatory bowel diseases (IBD) are reassuring. However, many studies are based upon small sample sizes.

Aims: To assess IBD medication safety during pregnancy.

Methods: Using the French national health database, which covers more than 99% of the French population, around 65 000 000 people, we identified pregnancies ending with a birth in IBD patients in France between 2010 and 2018. Pregnancy outcomes (vital status at birth, birth term, and weight for gestational age) were compared according to treatment exposure during pregnancy using propensity score-weighted marginal logistic regression models.

Results: 27 729 pregnancies were included: 3554 were exposed to thiopurines monotherapy, 3525 to anti-TNF monotherapy, 839 to combination therapy, and 19 811 unexposed. Pregnancies exposed to thiopurines monotherapy compared to unexposed pregnancies more frequently resulted in stillbirths (1.0% vs 0.5%, aOR 2.04; 95%CI: 1.18-3.55), preterm birth (12.3% vs 7.1%, aOR 1.76; 95%CI: 1.55-2.00), large for gestational age (10.6% vs 8.4%, aOR 1.32; 95%CI: 1.13-1.53) and less frequently in small for gestational age (9.6% vs 11.1%, aOR 0.79; 95%CI: 0.67-0.92). By contrast, pregnancies exposed to anti-TNF monotherapy were not different from unexposed pregnancies as regards to these outcomes. Compared to unexposed pregnancies, those exposed to combination therapy more frequently resulted in preterm births (aOR 1.55; 95%CI: 1.15-2.11) and larger for gestational age (aOR 1.61; 95%CI: 1.13-2.29) but did not differ as regards to stillbirths.

Conclusions: Pregnancies exposed to thiopurines more frequently resulted in stillbirths, preterm births and large for gestational age compared to pregnancies exposed to anti-TNF or unexposed pregnancies. By contrast, pregnancies exposed to anti-TNF monotherapy were not associated with these outcomes.
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http://dx.doi.org/10.1111/apt.16448DOI Listing
August 2021

Tofacitinib as salvage therapy for 55 patients hospitalised with refractory severe ulcerative colitis: A GETAID cohort.

Aliment Pharmacol Ther 2021 08 20;54(3):312-319. Epub 2021 Jun 20.

Clichy, France.

Background: Up to 25% of patients with ulcerative colitis (UC) will require hospitalization for severe flare. In patients hospitalised for severe flare, who previously experienced multiple drug failures, including steroids and anti-TNF agents, new quick-acting medical options are needed. Tofacitinib is effective in refractory UC and has a rapid onset of action.

Aim: To evaluate effectiveness and safety of tofacitinib as rescue therapy in patients hospitalised for UC flare.

Methods: We conducted an observational and multicentre study with both retrospective and prospective collections in 14 GETAID centres. The primary objective was to assess the survival without colectomy following tofacitinib initiation in patients hospitalised for a UC flare. We determined rates of clinical response, clinical remission, and steroid-free clinical remission at week 6 and week 14 and safety.

Results: Fifty-five patients were included (49 with prior infliximab failure and 19 previously exposed to ciclosporin). With a median follow-up of 6.5 months (interquartile range [IQR] [3-12.3]), rate of colectomy-free survival was estimated at 78.9% (95 CI [68.5-90.9]) and 73.6% (95 CI [61.9-87.3]) at 3 and 6 months, respectively. Rates of clinical response, clinical remission and steroid-free clinical remission were 60%, 45.5% and 37.5% at week 6 and 41.8%, 34.5% and 32.7% at week 14. Regarding safety, no death was observed, three patients withdrew tofacitinib due to adverse events. Two herpes zoster infections occurred in patients aged over 60 years old. No venous thrombotic or major adverse cardiovascular events occurred.

Conclusion: Tofacitinib appears as a promising option in patients hospitalised with a UC flare but needs further validation in controlled trials.
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http://dx.doi.org/10.1111/apt.16463DOI Listing
August 2021

Monitoring established Crohn's disease with pan-intestinal video capsule endoscopy in Europe: clinician consultation using the nominal group technique.

Curr Med Res Opin 2021 09 30;37(9):1547-1554. Epub 2021 Jun 30.

Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza - University of Rome, Rome, Italy.

Objective: Monitoring established Crohn's disease (CD) through a "treat-to-target" strategy aims to reduce and prevent long-term bowel damage and disability. Despite the availability of different monitoring techniques, there is a current lack of integrated evidence to guide optimal monitoring in terms of appropriate tools and timing. Pan-intestinal video capsule endoscopy (PCE) enables non-invasive and direct visualization of the entire intestinal tract with proven safety and efficacy. This study aims to generate insights on the value of PCE for monitoring established CD from the physician's perspective.

Methods: The Nominal Group Technique (NGT) was used to create discussion around pre-defined research questions aimed at identifying target patient populations for PCE, benefits of PCE in terms of improving disease management, comparative benefits of PCE over standard of care, research priorities to ratify the use of PCE, and hurdles to PCE utilization. A NGT panel was held in Brussels, Belgium in October 2018 with 9 gastroenterology experts. Data were collected from multiple rankings of statements to the research questions and analyzed descriptively.

Results: Consensus indicated that PCE is differentiated from other diagnostic tools, allowing for non-invasive and direct visualization of the luminal intestinal tract in one single procedure. Participants agreed that PCE is beneficial for mapping and grading established CD in all patients, enabling individual and tailored treatment decision-making. Time required to read PCE results was identified as the main utilization hurdle by participants. Well-designed studies are needed to confirm improved outcomes amongst patients with CD managed through a PCE-guided approach.

Conclusions: This study, using the NGT, generated expert opinion on the value of PCE for monitoring established CD in terms of target patient populations and benefits compared to other diagnostic modalities. Participants perceived PCE to facilitate a "treat-to-target" strategy for CD management. Further research is needed to support this value perception.
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http://dx.doi.org/10.1080/03007995.2021.1940910DOI Listing
September 2021

Notch inhibitors induce diarrhea, hypercrinia and secretory cell metaplasia in the human colon.

EXCLI J 2021 26;20:819-827. Epub 2021 Apr 26.

Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hopitaux de Paris, Le Kremlin Bicêtre, France.

In humans, inhibition of Notch oncogenic signaling leads to tumor regression. Preclinical studies indicate that Notch signaling contributes to the maintenance of intestinal homeostasis. Here, we sought to describe the intestinal effects of a first-in-human Notch inhibitor in an indication of refractory cancer. Between 2014 and 2017, adult patients treated for refractory cancer with the novel Notch inhibitor LY3039478 and who had grade ≥ 2 diarrhea were referred to the gastroenterology department of a tertiary hospital in the Paris region of France. Eleven patients (median (range) age: 72 (29-83)) were included in the study. All patients had advanced cancer: adenoid cystic carcinoma (n=3, 27 %), sarcoma (n=3, 27 %), and other types (n=5, 46 %). In all cases, digestive tract endoscopy revealed abundant mucus in the intestinal lumen, and digestive tract biopsies showed an abnormally low proportion of enterocytes and marked elevation of the proportion of pseudostratified goblet cells. Microscopic inflammation was seen in colon biopsies from 2 of the 11 patients (18 %). The clinical, endoscopic and histological abnormalities were dependent on the dose of Notch inhibitor. All patients resolved their digestive signs or symptoms after discontinuing the dose and the median (range) time interval between discontinuation of the Notch inhibitor and resolution of all the gastrointestinal signs and symptoms was 7 days (4-24). Likewise, the median time interval between discontinuation and resolution of the histological abnormalities was 7 days (1-10). Blocking Notch signaling induces secretory cell metaplasia of the intestinal epithelium, which in turn leads to transient diarrhea. Our results confirm the role of Notch signaling in intestinal homeostasis in humans.
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http://dx.doi.org/10.17179/excli2021-3572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192874PMC
April 2021

Risk of severe COVID-19 in patients treated with IBD medications: a French nationwide study.

Aliment Pharmacol Ther 2021 07 10;54(2):160-166. Epub 2021 Jun 10.

EPIPHARE, Épidémiologie des produits de santé, ANSM-CNAM, Saint Denis, France.

Background: Recently, the SECURE-IBD study, based on a physician-reported registry, suggested that thiopurines, either alone or combined with anti-TNF, may increase risk of severe COVID-19.

Aims: To compare the risk of severe COVID-19 according to IBD medications in a large and unselected population.

Methods: Using the French national health data system, the risks of hospitalisation and of death or mechanical ventilation for COVID-19 from 15 February 2020 to 31 August 2020 in IBD patients were compared according to IBD treatment (immunomodulators and biologics), using multivariable Cox models adjusted for socio-demographic characteristics, budesonide/corticosteroids and aminosalicylates use, and comorbidities.

Results: Among 268 185 IBD patients, 600 were hospitalised for COVID-19 and 111 of them died or were mechanically ventilated (including 78 deaths). In multivariable analysis, the risk of hospitalisation for COVID-19 did not differ according to IBD treatment category, with adjusted Hazard Ratios (aHR, unexposed patients used as reference) of 0.94 (95%CI: 0.66-1.35) for immunomodulator monotherapy, 1.05 (0.80-1.38) for anti-TNF monotherapy, 0.80 (0.38-1.69) for anti-TNF combination therapy, 1.06 (0.55-2.05) for vedolizumab and 1.25 (0.64-2.43) for ustekinumab. Similarly, the risk of death or mechanical ventilation for COVID-19 did not differ according to IBD treatment.

Conclusions: Immunomodulators and biologics prescribed in patients with IBD do not appear to increase the severity of COVID-19 infection.
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http://dx.doi.org/10.1111/apt.16410DOI Listing
July 2021

[Hypophosphatemia following the administration of intravenous iron formulations: A case report and literature review].

Therapie 2021 Apr 21. Epub 2021 Apr 21.

Assistance publique-Hôpitaux de Paris (AP-HP), hôpital Bicêtre, Centre de Recherche Clinique AP-HP, université Paris-Saclay, 78, rue du Général-Leclerc, 94270 Le Kremlin-Bicêtre, France.

Iron deficiency and iron-deficiency anemia are common medical conditions. Management of the etiology and iron supplementation are both necessary to treat this condition. Use of intravenous iron preparations is increasing due to its advantages over oral iron. Indeed, the total dose required can be provided in a single infusion, and it is more effective and increases hemoglobin levels more quickly than oral iron. Hypophosphatemia, sometimes severe, following intravenous iron administration, has been described in literature these past years, in particular with ferric carboxymaltose. We report here a case of severe hypophosphatemia with ferric carboxymaltose and carry out a literature review to determine the incidence of hypophosphatemia and to precise its clinical presentation, its pathophysiological mechanisms and its treatment. We found that hypophosphatemia is frequent with ferric carboxymaltose. Most of the time, there are no clinical manifestations, but cases of symptomatic osteomalacia have been described. Duration of hypophosphatemia is variable, from a few weeks to several months in case of prolonged administration. Hypophosphatemia owing to renal phosphate wasting is caused by an increase in intact fibroblast growth factor 23 (FGF-23) levels. However, the mechanism of ferric carboxymaltose- induced increase in intact FGF-23 is still unknown.
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http://dx.doi.org/10.1016/j.therap.2021.04.008DOI Listing
April 2021

Chronic pouchitis and Crohn's disease of the pouch after ileal pouch-anal anastomosis: Incidence and risk factors.

Dig Liver Dis 2021 Sep 27;53(9):1128-1135. Epub 2021 Apr 27.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, CHU Bicêtre, 78, rue du Général Leclerc, Le Kremlin Bicêtre 94270, France.

Background: Restorative proctocolectomy with ileal-pouch anal-anastomosis (IPAA) is the operation of choice for patients with ulcerative colitis (UC) or with inflammatory bowel diseases unclassified (IBDU).

Aims: to assess the incidence and risk factors of chronic pouchitis (CP) and Crohn's disease of the pouch (CDP) in patients with UC or IBDU.

Methods: We conducted a retrospective study. We included consecutive patients who underwent IPAA between 2011 and 2019. The main outcome was the occurrence of CP or CDP. We looked for risk factors with multivariable and a least absolute shrinkage and selection operator (LASSO) Cox models.

Results: 247 patients were included. The 5-year cumulative incidence of CP or CDP was 35.3% (95%CI: 26.2-43.2). In multivariable analysis, diagnosis of IBDU, age less than 35 years at surgery and extra-intestinal manifestations other than articular and primary sclerosing cholangitis were associated with higher incidence. The LASSO analysis identified these three prognostic factors and articular manifestations. In patients with two or more prognostic factors, 5-year cumulative incidence, was 65.2% (95%CI: 41.8-79.2).

Conclusions: Five years after IPAA, approximately one-third of patients had either CP or CDP. Risk factors were IBDU, an age less than 35 years at surgery, articular manifestations and other extra-intestinal manifestations.
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http://dx.doi.org/10.1016/j.dld.2021.03.027DOI Listing
September 2021

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

Inflamm Bowel Dis 2021 Apr 13. Epub 2021 Apr 13.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, Le Kremlin Bicêtre, France.

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.
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http://dx.doi.org/10.1093/ibd/izab060DOI Listing
April 2021

Local treatment of pancreatic cancer metastases: A multicenter French study of the AGEO group.

Clin Res Hepatol Gastroenterol 2021 Mar 1;45(6):101607. Epub 2021 Mar 1.

Department of Oncology, Institute Mutualiste Montsouris, 42 Boulevard Jourdan, 75014 Paris, France.

Objective: This study reports the efficacy and safety of local treatment of metastases of pancreatic ductal adenocarcinoma (PDAC), with a curative intent.

Methods: We retrospectively included patients with histologically proven PDAC, who underwent a local treatment for metastases between January 1, 2000 and December 31, 2017, from 11 French hospitals. Complications of local treatment were reported. Univariate Cox models were performed to identify prognosis factors associated with overall survival (OS) and disease-free survival (DFS).

Results: We included 52 patients treated for 68 metastases; 33 (64%) of whom had metachronous metastases. Metastatic sites treated were: 39 (57%) hepatic, 18 (27%) pulmonary and 11 (16%) others. Metastases treatments were: 45 (66%) surgery, 9 (13%) radiofrequency and 14 (21%) other procedures. The rates of severe complications and mortality were respectively 10% and 4%. The median OS and DFS after local treatment were 36.5 months and 12.7 months, respectively. Prognosis factors associated with a shorter OS were: liver metastases when compared with lung metastases (HR 4.04; 95%CI: 1.18-13.81), N2 status of primary pancreatic tumor when compared to N0-N1 (HR 9.43; 95%CI: 2.44-36.36) and synchronous metastases when compared to metachronous metastases (HR 2.34; 95%CI: 1.05-5.23). N2 status of primary pancreatic tumor was associated with a shorter DFS when compared to N0-N1 (HR 2.82; 95%CI: 1.05-7.58).

Conclusion: In this series of highly selected patients, local treatment of metastases from PDAC is associated with prolonged survival. The rate of severe complications was low. Factors associated with shorter OS were liver metastases, N2 status and synchronous metastases.
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http://dx.doi.org/10.1016/j.clinre.2020.101607DOI Listing
March 2021

A pragmatic non-invasive assessment of liver fibrosis in patients with psoriasis, rheumatoid arthritis or Crohn's disease receiving methotrexate therapy.

Clin Res Hepatol Gastroenterol 2020 Jan-Jun;44S:100003. Epub 2020 Feb 8.

Service d'hépatologie et de soins intensifs digestifs, CHRU Jean-Minjoz, 25030 Besançon cedex, France.

Background And Aims: The reported hepatotoxicity of methotrexate underlines the need for a repeated non-invasive and reliable evaluation of liver fibrosis. We estimated, using a non-invasive strategy, the prevalence of significant liver fibrosis in patients treated by methotrexate and the predictors of significant fibrosis (fibrosis≥F2).

Methods: Fibrosis was prospectively evaluated using 9 non-invasive tests in consecutive patients with psoriasis, rheumatoid arthritis, or Crohn's disease. Significant fibrosis was assessed without liver biopsy by defining a "specific method" (result given by the majority of the tests) and a "sensitive method" (at least one test indicating a stage≥F2).

Results: One hundred and thirty-one patients (66 Psoriasis, 40 rheumatoid arthritis, and 25 Crohn's disease) were enrolled, including 83 receiving methotrexate. Seven tests were performed on average per patient, with a complete concordance in 75% of cases. Fibroscan® was interpretable in only 61% of patients. The best performances (AUROC>0.9) for predicting significant fibrosis were obtained by tests dedicated to steatohepatitis (FibroMeter NAFLD, NFS and FPI). The prevalence of fibrosis≥F2 according to the "specific" or the "sensitive" assessment of fibrosis was 10% and 28%, respectively. Methotrexate exposure did not influence the fibrosis stage. Factors independently associated with significant fibrosis according our "sensitive method" were age, male gender, and metabolic syndrome.

Conclusion: We provided a non-invasive approach for identifying liver fibrosis≥F2 by using 8 biochemical tests and Fibroscan®. In this population, the risk of significant fibrosis was related to age, male gender, and presence of metabolic syndrome, but was not influenced by methotrexate.
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http://dx.doi.org/10.1016/j.clirex.2020.100003DOI Listing
February 2020

Drug use for gastrointestinal symptoms during pregnancy: A French nationwide study 2010-2018.

PLoS One 2021 22;16(1):e0245854. Epub 2021 Jan 22.

GIS-EPIPHARE, Épidémiologie des produits de santé, ANSM-CNAM, 42 bd de la Libération, Saint Denis, France.

Purpose: To describe drug prescription for gastrointestinal symptoms during pregnancy.

Methods: Using the French national health database, we identified pregnancies ending with a birth between April 2010 and December 2018, in France. We studied prescription of antacids, antispasmodics, antinauseants, laxatives and antidiarrheals during pregnancy, between two trimesters before and two trimesters after delivery. We also assessed hospitalization for gastrointestinal symptoms during pregnancy.

Results: Among 6,365,471 pregnancies, 4,452,779 (74.0%) received at least one gastrointestinal drug during pregnancy; 2,228,275 (37.0%) received an antacid, 3,096,858 (51.5%) an antispasmodic, 1,861,731 (31.0%) an antinauseant, 919,116 (15.3%) a laxative and 617,808 (10.3%) an antidiarrheal. Prescription of proton pump inhibitors doubled from 12.2% in 2010 to 26.0% in 2018, while domperidone use decreased from 18.3% in 2010 to 2.2% in 2018. In addition, prescription of antacids increased from 7.0% during the trimester before pregnancy to 11.8% during the 1st trimester, 17.0% during the 2nd trimester and 23.4% during the 3rd trimester. Antispasmodic use was 10.6% during the trimester before pregnancy, 23.1% during the 1st trimester, 25.2% during the 2nd trimester and 24.0% during the 3rd trimester. Prescription of antinauseant drugs increased from 5.0% during the trimester before pregnancy to 25.7% during the 1st trimester, then decreased to 6.4% during the 2nd trimester and 3.2% during the 3rd trimester. Nausea/vomiting was the most common cause of hospitalization for gastrointestinal symptoms or diseases during pregnancy, although it accounted for only 1.0% of pregnancies.

Conclusions: Approximately three-quarters of women use drugs for gastrointestinal symptoms during pregnancy in France. Prescription of gastrointestinal drugs during pregnancy should be the subject of more detailed risk-benefit assessment and recommendations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245854PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822332PMC
June 2021

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

PLoS Med 2020 10 30;17(10):e1003348. Epub 2020 Oct 30.

Department of Neurology, Medical University of Graz, Austria.

Background: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.

Methods And Findings: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.

Conclusion: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.
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http://dx.doi.org/10.1371/journal.pmed.1003348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598520PMC
October 2020

Pregnancy in women with inflammatory bowel disease: a French nationwide study 2010-2018.

Aliment Pharmacol Ther 2020 11 10;52(9):1480-1490. Epub 2020 Sep 10.

GIS-EPIPHARE, Épidémiologie des produits de santé, ANSM-CNAM, Saint Denis, France.

Background: Inflammatory bowel disease (IBD) most commonly occurs in young adults, including women of child-bearing age.

Aim: To describe pregnancy in women with IBD in the age of widespread use of biologics METHODS: Using French national health data system (SNDS) data, we identified all pregnancies ending between 1 April 2010 and 31 December 2018 in patients with and without IBD in France. Pregnancy and IBD characteristics were described. Pregnancy outcomes were compared between IBD and non-IBD pregnancies using multivariable logistic regression models.

Results: We included 36 654 IBD and 8 595 562 non-IBD pregnancies. Among IBD pregnancies, 75.6% ended in live births and 0.4% in stillbirths. Pregnancies in women with IBD vs those without IBD more frequently resulted in preterm birth (8.0% vs 5.5%, aOR 1.51; 95% CI: 1.45-1.58), small for gestational age birth (11.1% vs 9.8%, aOR 1.15; 95% CI: 1.10-1.20) and caesarean section (26.1% vs 20.0%, aOR 1.39; 95% CI: 1.35-1.42). Active IBD before and during pregnancy was associated with particularly marked increases in the rates of prematurity and small for gestational age as compared to non-IBD pregnancies. Active IBD during pregnancy was associated with more stillbirths than non-IBD pregnancies (aOR 1.43 95% CI: 1.09-1.86). Crohn's disease activity decreased during pregnancy, while ulcerative colitis activity did not change.

Conclusions: Pregnancies in women with IBD are associated with increased risks of prematurity, small for gestational age and caesarean section, especially among women with active IBD. Disease activity decreased during pregnancy in women with Crohn's disease, but was unchanged in women with ulcerative colitis.
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http://dx.doi.org/10.1111/apt.16074DOI Listing
November 2020

Long-term outcome of Crohn's disease patients with upper gastrointestinal stricture: A GETAID study.

Dig Liver Dis 2020 11 20;52(11):1323-1330. Epub 2020 Sep 20.

Department of Gastroenterology, Claude Huriez hospital, University of Lille, Lille, France; Inserm Unit 995, University of Lille 2, Lille, France. Electronic address:

Background: There are few data concerning patients with Crohn's disease (CD) complicated by a stricture of the upper gastrointestinal tract (UGT).

Aims: We evaluated the outcome and management of CD patients complicated by a stricture of the UGT.

Methods: We performed a retrospective multicenter study including all CD patients with a non-passable symptomatic UGT stricture on endoscopy. Primary outcome measure was surgery-free survival from diagnosis of stricture. Efficacy of medical, endoscopic, and surgical treatments, and identification of predictors of surgery were also evaluated.

Results: 60 CD patients with an UGT stricture were included. 60% of the strictures were located in the duodenum. With a median follow-up of 5.5 (IQR: 3.0-12.0) years since stricture diagnosis, surgical-free survival was 75% and 64% at 1 and 5 years, respectively. At the end of the follow up, 27 (45%) patients underwent surgery. 77 endoscopic procedures were performed in 30 patients with an immediate success of 81% and a clinical benefit in 84% of the procedures. In multivariate analysis, anti-TNF treatment initiation was associated with a reduced risk of surgery.

Conclusion: CD UGT strictures are mainly located in the duodenum. Medical and endoscopic treatments allow to avoid surgery in half of the patients.
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http://dx.doi.org/10.1016/j.dld.2020.08.034DOI Listing
November 2020

Duration of combination therapy and risk of treatment failure in patients with inflammatory bowel disease.

Clin Res Hepatol Gastroenterol 2021 Mar 4;45(2):101503. Epub 2020 Sep 4.

Hôpital du Kremlin-Bicêtre, Service de Gastroentérologie, APHP, Université Paris Sud, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France.

Background: Patients who receive infliximab (IFX) combined with a thiopurine, for inflammatory bowel disease, have a better clinical response and less frequent immunization towards IFX than those treated with IFX alone. The benefits of combination therapy must be weighed against the risks of infection and cancer. We studied the association between the duration of combination therapy and the risk of treatment failure by two year from initiation.

Methods: Participants had Crohn's disease or ulcerative colitis and were in clinical and biological remission, 6 months after initiation of combination therapy. The risk of subsequent treatment failure (i.e., undetectable trough IFX levels and/or clinical relapse followed by surgical treatment or switch of maintenance treatment) was estimated using Kaplan-Meier method and adjusted Hazard Ratios (aHRs), in patients whohadreceived 6 to 11 months vs. 12 months or more of combination therapy. We performed a similar analysis in which the follow-up was started at discontinuation of the immunosuppressant.

Results: Among 139 patients (48% women; median age 31.1), with a median follow-up of 18.9 months, we observed 26 treatment failures (including 15 patients with undetectable trough IFX levels). After adjustment for gender and type of immunomodulator, a shorter duration of combination therapy was not associated with a higher risk of treatment failure (aHR=0.42; 95% confidence interval (95%CI): 0.13-1.40; p=0.16). When the follow-up was started at discontinuation of the immunosuppressant, a combination therapy of 6-11 months was associated with a numerically lower risk of treatment failure as compared with a longer combination therapy (HR=0.12; 95%CI: 0.01-1.05; p=0.055).

Conclusion: Our results do not show any benefit for continuation of combination therapy for more than 12 months after achieving clinical remission in IBD patients.
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http://dx.doi.org/10.1016/j.clinre.2020.07.008DOI Listing
March 2021

Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses.

BMC Med 2020 09 3;18(1):229. Epub 2020 Sep 3.

Public Health Directorate, Asturias, Spain.

Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.

Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.

Results: The associations between circulating UCB levels and CRC risk differed by sex (P = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P ≥ 0.2).

Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.
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http://dx.doi.org/10.1186/s12916-020-01703-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469292PMC
September 2020

Systematic review with meta-analysis: comparative risk of lymphoma with anti-tumour necrosis factor agents and/or thiopurines in patients with inflammatory bowel disease.

Aliment Pharmacol Ther 2020 10 25;52(8):1289-1297. Epub 2020 Aug 25.

Department of Gastroenterology, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris and Université Paris Saclay, Le Kremlin-Bicêtre, France.

Background: The risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with anti-TNF agents remains unclear.

Aim: To assess the comparative risk of lymphoma with anti-TNF agents and/or thiopurines in IBD METHODS: We searched PubMed, EMBASE and Cochrane Library to identify studies that evaluated lymphoproliferative disorders associated with anti-TNF agents with or without thiopurines. The risk of lymphoma was assessed through four comparator groups: combination therapy (anti-TNF plus thiopurine), anti-TNF monotherapy, thiopurine monotherapy and control group. Pooled incidence rate ratios (IRR) were estimated through Poisson-normal models.

Results: Four observational studies comprising 261 689 patients were included. As compared with patients unexposed to anti-TNF and thiopurines, those exposed to anti-TNF monotherapy, thiopurine monotherapy or combination therapy had pooled IRR (per 1000 patient-years) of lymphoma of 1.52 (95% CI: 1.06-2.19; P = 0.023), 2.23 (95% CI: 1.79-2.79; P < 0.001) and 3.71 (95% CI: 2.30-6.00; P ≤ 0.01), respectively. The risk of lymphoma associated with combination therapy was higher than with thiopurines or anti-TNF alone with pooled IRR of 1.70 (95% CI: 1.03-2.81; P = 0.039) and 2.49 (95% CI: 1.39-4.47; P = 0.002), respectively. The risk did not differ between anti-TNF monotherapy and thiopurine monotherapy with pooled IRR of 0.72 (95% CI: 0.48-1.07; P = 0.107). All observational studies were of high quality according to the Newcastle-Ottawa scale.

Conclusions: There is an increased risk of lymphoma in IBD patients treated with anti-TNF agents, either alone or when combined with thiopurines.
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http://dx.doi.org/10.1111/apt.16050DOI Listing
October 2020

The outcome of Crohn's disease patients refractory to anti-TNF and either vedolizumab or ustekinumab.

Dig Liver Dis 2020 10 20;52(10):1148-1155. Epub 2020 Aug 20.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, Le Kremlin Bicêtre, France.

Aims: The aims of this study were to describe outcomes in patients with Crohn's disease who fail anti-tumor necrosis factor (TNF) and either vedolizumab or ustekinumab.

Methods: Multicenter, retrospective study of 100 patients with Crohn's disease who failed anti-TNF and either vedolizumab or ustekinumab from 2015 to 2019. Using multivariable Cox regression, we sought to identify factors associated with need for surgery.

Results: 75 patients received a third line treatment, resulting in 23 (30.7%) clinical remission at week 48. Among the 71 patients included after vedolizumab failure, 46 received ustekinumab, resulting in 46 (28.3%) clinical remission; 13 patients were retreated with an anti-TNF, resulting in 13 (46.2%) clinical remission. Among the 29 patients included after ustekinumab failure, 12 were retreated with an anti-TNF, resulting in 2 (16.7%) clinical remission. The rate of surgery-free survival at 48 weeks was 76.5% (95% confidence interval 68.4% - 85.4%). In multivariable analysis, ileal disease localization (hazard ratio 9.0, 95% confidence interval 1.0-81.9) was associated with a higher risk of surgery.

Conclusion: In patients with Crohn's disease who have failed anti-TNF and either vedolizumab or ustekinumab, at week 48, the surgery rate is 23.5% and the remission rate after a third line biologic therapy is 30.7%.
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http://dx.doi.org/10.1016/j.dld.2020.07.031DOI Listing
October 2020

Worldwide Management of Inflammatory Bowel Disease During the COVID-19 Pandemic: An International Survey.

Inflamm Bowel Dis 2021 05;27(6):836-847

Department of Medicine, University of Otago, Christchurch, New Zealand.

Background And Aims: Persons with inflammatory bowel disease (IBD) may be particularly vulnerable to COVID-19 either because of their underlying disease or its management. Guidance has been presented on the management of persons with IBD in the time of this pandemic by different groups. We aimed to determine how gastroenterologists around the world were approaching the management of IBD.

Methods: Members of the World Gastroenterology Organization (WGO) IBD Task Force contacted colleagues in countries largely beyond North America and Europe, inviting them to review the WGO website for IBD and COVID-19 introduction, with links to guideline documents, and then to respond to 9 ancillary open-ended management questions.

Results: Fifty-two gastroenterologists from 33 countries across 6 continents completed the survey (April 14 to May 16, 2020). They were all adhering for the most part to published guidelines on IBD management in the COVID-19 era. Some differences and reductions in services related to access, and some related to approach within their communities in terms of limiting virus spread. In particular, most gastroenterologists reduced in-person clinics (43 of 52), limited steroid use (47 of 51), limited elective endoscopy (45 of 52), and limited elective surgeries (48 of 51). If a patient was diagnosed with COVID-19, immunomodulatory therapy was mostly held.

Conclusions: In most countries, the COVID-19 pandemic significantly altered the approach to persons with IBD. The few exceptions were mostly based on low burden of COVID-19 in individual communities. Regardless of resources or health care systems, gastroenterologists around the world took a similar approach to the management of IBD.
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http://dx.doi.org/10.1093/ibd/izaa202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454666PMC
May 2021

Evolution of Endoscopic Lesions in Steroid-Refractory Acute Severe Ulcerative Colitis Responding to Infliximab or Cyclosporine.

Clin Gastroenterol Hepatol 2021 06 7;19(6):1180-1188.e4. Epub 2020 Aug 7.

INSERM UMR-S-1153, Equipe ECSTRA, Hôpital Saint-Louis, Paris Diderot University, Paris, France.

Background/aims: Few data on the evolution of endoscopic findings are available in patients with acute severe ulcerative colitis (ASUC). The aim of this study was to describe this evolution in a prospective cohort.

Methods: Patients admitted for a steroid-refractory ASUC and included in a randomized trial comparing infliximab and cyclosporine were eligible if they achieved steroid-free clinical remission at day 98. Flexible sigmoidoscopies were performed at baseline, days 7, 42 and 98. Ulcerative colitis endoscopic index of severity (UCEIS) and its sub-scores - vascular pattern, bleeding and ulceration/erosion - were post-hoc calculated. Global endoscopic remission was defined by a UCEIS of 0, and partial endoscopic remission by any UCEIS sub-score of 0.

Results: Among the 55 patients analyzed (29 infliximab and 26 cyclosporine), 49 (83%) had UCEIS ≥6 at baseline at baseline. Partial endoscopic remission rates were higher for bleeding than for vascular pattern and for ulcerations/erosions at day 7 (20% vs. 4% and 5% (n = 55); p = .004 and p=.04), for bleeding and ulceration/erosion than for vascular pattern at day 42 [63% and 65% vs. 33% (n=54); p<.001 for both] and at day 98 [78% and 92% vs. 56% (n = 50); p = .007 and p < .001]. Global endoscopic remission rates at day 98 were higher in patients treated with infliximab than with cyclosporine [73% vs. 25% (n = 26 and 24); p < .001].

Conclusion: In steroid-refractory ASUC patients responding to a second-line medical therapy, endoscopic remission process started with bleeding remission and was not achieved in half the patients at day 98 for vascular pattern. Infliximab provided a higher endoscopic remission rate than cyclosporine at day 98.
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http://dx.doi.org/10.1016/j.cgh.2020.08.001DOI Listing
June 2021

Letter: choosing between ustekinumab and vedolizumab in anti-TNF refractory Crohn's disease-the devil is in the detail. Authors' reply.

Aliment Pharmacol Ther 2020 08;52(3):563-564

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, Le Kremlin Bicêtre, France.

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http://dx.doi.org/10.1111/apt.15888DOI Listing
August 2020

Letter: how can we reduce mortality in elderly patients with acute severe ulcerative colitis? Authors' reply.

Aliment Pharmacol Ther 2020 06;51(12):1445-1446

Department of Gastroenterology, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris Saclay, Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1111/apt.15776DOI Listing
June 2020

Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer.

Nat Commun 2020 05 1;11(1):2168. Epub 2020 May 1.

Université Paris-Saclay, Institut Gustave Roussy, Inserm, CNRS, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Laboratoire d'Immunomonitoring en Oncologie, F-94805, Villejuif, France.

Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
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http://dx.doi.org/10.1038/s41467-020-16079-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195489PMC
May 2020

Long-term outcome of patients with acute severe ulcerative colitis responding to intravenous steroids.

Aliment Pharmacol Ther 2020 06 28;51(11):1096-1104. Epub 2020 Apr 28.

Department of Gastroenterology, Henri Mondor Hospital, APHP, EC2M3-Equipe, Universitaire, Paris Est-Créteil (UPEC) Val de Marne University, Creteil, France.

Background: The long-term outcome of patients with acute severe ulcerative colitis (ASUC) responding to intravenous steroids (IVS) has been poorly reported.

Aims: To assess relapse-free survival in patients with ASUC responding to IVS.

Methods: Between January 2006 and December 2017, 142 consecutive patients with ASUC (according to modified Truelove-and-Witts criteria) responding to IVS were included in this multicentre retrospective study. Relapse was defined by a partial Mayo Clinic score >4 and/or the need for another maintenance therapy.

Results: Among the 142 included patients (100 naïve of immunomodulator and/or biological agent) hospitalised for ASUC, 59 (41.5%) were treated at discharge with 5-aminosalicylic acid, 60 (42%) with immunomodulators, 18 (13%) with anti-tumour necrosis factor (TNF) agents and 5 (3.5%) with vedolizumab. After a median follow-up of 4.8 (2.6-7.3) years, 90 (63.4%) had relapsed and 12 (8.5%) had required colectomy. The probabilities of relapse-free survival were 58%, 48% and 40% at 1, 2 and 5 years respectively. The multivariate analysis demonstrated that patients with <6 liquid stools per day at day 3 (hazard ratio 0.56, 95%CI [0.34-0.91]), a partial Mayo Clinic score <2 at day 5 (0.41 [0.21-0.80]) and anti-TNF maintenance therapy (0.37 [0.16-0.87]) were less likely to relapse. The probabilities of colectomy-free survival were 96%, 95% and 91% at 1, 2 and 5 years respectively.

Conclusion: Despite a high relapse rate, patients with ASUC responding to IVS had a low rate of colectomy after 5 years of follow-up. Early response to IVS and maintenance therapy with biological agents were associated with a lower rate of relapse.
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http://dx.doi.org/10.1111/apt.15751DOI Listing
June 2020

Antibody Responses to and Risk of Developing Colorectal Cancer in a European Cohort.

Cancer Epidemiol Biomarkers Prev 2020 07 24;29(7):1475-1481. Epub 2020 Apr 24.

CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Background: While () is the major cause of gastric cancer, it has also been suggested to be involved in colorectal cancer development. However, prospective studies addressing and colorectal cancer are sparse and inconclusive. We assessed the association of antibody responses to proteins with colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Methods: We applied multiplex serology to measure antibody responses to 13 proteins in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls nested within the EPIC study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable conditional logistic regression to estimate the association of overall and protein-specific seropositivity with odds of developing colorectal cancer.

Results: Fifty-one percent of colorectal cancer cases were seropositive compared with 44% of controls, resulting in an OR of 1.36 (95% CI, 1.00-1.85). Among the 13 individual proteins, the association was driven mostly by seropositivity to cysteine-rich protein C (HcpC; OR: 1.66; 95% CI, 1.19-2.30) and Vacuolating cytotoxin A (VacA) (OR: 1.34; 95% CI, 0.99-1.82), the latter being nonstatistically significant only in the fully adjusted model.

Conclusions: In this prospective multicenter European study, antibody responses to proteins, specifically HcpC and VacA, were associated with an increased risk of developing colorectal cancer.

Impact: Biological mechanisms for a potential causal role of in colorectal carcinogenesis need to be elucidated, and subsequently whether eradication may decrease colorectal cancer incidence.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1545DOI Listing
July 2020

Articular manifestations in patients with inflammatory bowel disease treated with vedolizumab.

Rheumatology (Oxford) 2020 Nov;59(11):3275-3283

Department of Rheumatology, INSERM UMR1184, Université Paris-Saclay, Le Kremlin Bicêtre, France.

Objective: Vedolizumab (VDZ) has been incriminated in the occurrence of articular manifestations in patients with inflammatory bowel diseases (IBDs). The aim of this study was to describe musculoskeletal manifestations occurring in IBD patients treated by VDZ and to identify risk factors.

Methods: In this retrospective monocentric study, we included all consecutive patients treated by VDZ for IBD in our hospital. Incident musculoskeletal manifestations occurring during VDZ treatment were analysed and characteristics of patients with and without articular inflammatory manifestations were compared.

Results: Between 2013 and 2017, 112 patients were treated with VDZ for IBD: ulcerative colitis (n = 59), Crohn's disease (n = 49) and undetermined colitis (n = 4). Four patients (3.6%) had a history of SpA, whereas 13 (11.6%) had a history of peripheral arthralgia. Some 102 (91.1%) patients had previously received anti-TNF. After a mean (S.d.) follow-up of 11.4 (8.6) months, 32 (28.6%) patients presented 35 musculoskeletal manifestations, of which 18 were mechanical and 17 inflammatory. Among the latter, 11 had axial or peripheral SpA, 5 had early reversible arthralgia and 1 had chondrocalcinosis (n = 1). Among the 11 SpA patients, only 3 (2.6%) had inactive IBD and may be considered as paradoxical SpA. The only factor associated with occurrence of inflammatory manifestations was history of inflammatory articular manifestation [7/16 (43.8%) vs 10/80 (12.5%), P = 0.007].

Conclusion: Musculoskeletal manifestations occurred in almost 30% of IBD patients treated with VDZ, but only half of them were inflammatory. Since most of the patients previously received anti-TNF, occurrence of inflammatory articular manifestations might rather be linked to anti-TNF discontinuation than to VDZ itself.
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http://dx.doi.org/10.1093/rheumatology/keaa107DOI Listing
November 2020

The effectiveness of either ustekinumab or vedolizumab in 239 patients with Crohn's disease refractory to anti-tumour necrosis factor.

Aliment Pharmacol Ther 2020 05 6;51(10):948-957. Epub 2020 Apr 6.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, Le Kremlin Bicêtre, France.

Background: There is no head-to-head trial comparing ustekinumab and vedolizumab in patients with Crohn's disease (CD) refractory to anti-tumour necrosis factor (anti-TNF).

Aim: To compare the effectiveness and safety of ustekinumab and vedolizumab in patients with CD refractory to anti-TNF in a multicentre retrospective observational cohort.

Methods: All consecutive patients with CD refractory or intolerant to anti-TNF who initiated either vedolizumab or ustekinumab were included between May 2014 and August 2018. Clinical remission, steroid-free clinical remission (SFCR) and treatment persistence were assessed at week 48 with intention-to-treat analysis and propensity scores weighted comparison.

Results: A total of 239 patients were included, 107 received ustekinumab and 132 received vedolizumab. At week 48, ustekinumab was associated with a higher clinical remission rate (54.4% vs 38.3%; odds ratios, OR = 1.92, 95% CI [1.09-3.39]) and treatment persistence (71.5% vs 49.7%; OR = 2.54, 95% CI [1.40-4.62]) than vedolizumab. The rate of SFCR did not differ significantly between ustekinumab and vedolizumab (44.7% vs 34.0%; OR = 1.57, 95% CI [0.88-2.79]). Subgroup analyses showed that ustekinumab was associated with a higher clinical remission rates at week 48 in patients with ileal location (OR = 3.49, 95% CI [1.33-9.17) and penetrating behaviour (OR = 6.58, 95% CI [1.91-22.68]). Regardless of the treatment group, combination therapy at initiation was associated with a higher clinical remission rate at week 48 (OR = 1.93, 95% CI [1.09-3.43]).

Conclusion: This study suggests that ustekinumab is associated with a higher rate of clinical remission and treatment persistence than vedolizumab after 48 weeks of follow-up, in patients with CD refractory or intolerant to anti-TNF. The rate of SFCR was not significantly different.
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http://dx.doi.org/10.1111/apt.15706DOI Listing
May 2020
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