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Background While surgery was considered as the reference for stricturing Crohn's disease (CD), anti-TNF agents are now the first-line treatment thanks to the CREOLE study. However, there is no efficacy data after anti-TNF failure. We aimed to compare the effectiveness of ustekinumab and a second anti-TNF agent after failure of a first anti-TNF in symptomatic stricturing Crohn’s disease (CD). Methods In this multicenter study, we retrospectively included all adult patients with CD treated with ustekinumab or anti-TNF for symptomatic stricture (confirmed on imaging or endoscopy) after prior exposure ≥ one anti-TNF for the current stricture, without surgery between the failure of the last anti-TNF and the study. The primary endpoint was clinical remission (composite endpoint) at 6 months was defined as no pain, no vomiting, no food restriction, no sub-occlusive episode, no steroid, no surgery or discontinuation of treatment. The long-term endpoints were discontinuation of treatment for failure, bowel damage progression and surgery. The comparisons were performed after using propensity score analysis adjusted on potential confounders. Results Overall, 70 patients were analyzed, including 34 in the ustekinumab group and 36 in the anti-TNF group (29 on infliximab and 7 on adalimumab). The two groups were similar for age (38.5 vs 37.6 years), CD duration (12.2 vs 13.5 years), female gender (41.2% vs 51.8%), CD location (p=0.43) and CD phenotype (p=0.38). Concomitant immunosuppressant was observed in 63.9% with an anti-TNF versus 8.8% with ustekinumab. The number (p=0.56) and the length (p=0.10) of stricture were also similar. The proportion of patients ≥ 2 prior biologics was higher in the ustekinumab group (41.2% vs 8.3%; p=0.001). The rate of primary failure to anti-TNF agent was comparable (16.7% vs 20.6%). After adjustment based on propensity scores, the rate of clinical remission at 6 months was 73.9% and 42.7% (p = 0.24), under ustekinumab and anti-TNF, respectively. The predictive factors of remission in patients receiving ustekinumab were prior bowel resection (p=0.001) and length of stricture < 12 cm (p=0.042), while no predictor was found in those treated with anti-TNF agent. The risk of treatment discontinuation for failure (HR =2.86 [1.33-6.15]; p=0.008) or bowel damage progression (HR=3.90 [1.64-9.24]; p=0.003) were significantly greater in patients receiving another anti-TNF agent compared to those on ustekinumab. We did not observe any significant difference concerning the risk of surgery (HR=2.60 [0.70-9.61]; p=0.15). Conclusion Ustekinumab seems to be more effective than a 2nd anti-TNF to treat symptomatic stricturing CD after failure of a first anti-TNF. However, these data need to be confirmed by independent prospective data.

Background We aimed to compare the effectiveness of tofacitinib and ustekinumab in patients with ulcerative colitis (UC) previously exposed to at least one anti-TNF agent. Methods In this multicenter study, we retrospectively included consecutive UC adult patients previously exposed to at least one anti-TNF agent, with partial Mayo score (pMS) > 2, having who started tofacitinib or ustekinumab between January 2019 and June 2022. The primary endpoint was steroid-free clinical remission (pMS ≤ 2) (CFREM) at week 16 (W16). Secondary endpoints were endoscopic remission (CFREM + Mayo endoscopic score (MES) ≤ 1), and histological remission (CFREM + MES ≤ 1 + Nancy index ≤ 1). Comparisons were performed using propensity score analyses adjusted on potential confounders. Results Overall, 289 patients were included (tofacitinib = 124 patients, ustekinumab = 165 patients). The groups were comparable (tofacitinib vs vedolizumab) for male gender (50.8% vs 43.3%), mean age (40.7 vs 42.9 years), median UC duration (8.6 vs 9.3 years), concomitant use of 5-ASA (13.7% vs 9.7%), steroids (25.0% vs 29.7%), immunosuppressants (7.3% vs 5.5%), and ≥ 2 prior biologics (85.5% vs 82.4%). Tofacitinib group had more pancolitis (55.6% vs 42.4%, p = 0.026) and UC with pMS > 6 (64.5% vs 50.3%, p = 0.016). In our study, 42.1 % of the patients treated with tofacitinib continued using a dose of 10 mgx2/day until W16 while 47.3% of the patients on ustekinumab required dose escalation to 90 mg/4 weeks before W16. After propensity score analysis, the rate of CFREM at W16 was 37.8% and 35.6% in the tofacitinib and ustekinumab arms, respectively arm (p=0.75). CFREM at W16 was achieved in 43.3% vs 57.1% (p = 0.48) after failure of one biologic, 20.7% vs 37.9% (p=0.16) two biologics and 46.7% vs 23.2% (p=0.047) or ≥ 3 biologics, in tofacitinib and vedolizumab arms, respectively. After primary failure to at least one biologic, the rate of CFREM at W16 was 46.3% on tofacitinib vs 25.9% on ustekinumab (p = 0.13). CFREM at W16 was similar with tofacitinib and ustekinumab in case of more severe UC such as pMS ≥ 6 (40.6% vs 41.5%) and CRP > 30 (27.2% vs 33.0%). No predictor of tofacitinib effectiveness has been identified. Factors associated with no CFREM at W16 on ustekinumab were male gender (p=0.035), ≥ 3 prior biologics (p=0.013), prior use of tofacitinib (p=0.03), primary failure to at least one biologic (p=0.013). Endoscopic remission was achieved in 17.0% vs 11.7% (p =0.47) and histological remission in 4.4% vs 7.8% (p=0.32) of the patients treated with tofacitinib and ustekinumab, respectively. Conclusion Tofacitinib and ustekinumab have similar effectiveness in UC after anti-TNF failure. However, the efficacy of ustekinumab could be more impacted by prior therapeutic failures.

Background Crohn's disease (CD) is associated with disability by affecting physical and emotional well-being, and by altering social interactions. In the era of treat to target, endoscopic remission has become the therapeutic target to prevent parietal destruction and disability. A deeper remission such as transmural healing would reduce long-term complications related to CD. The impact of transmural healing on disability is currently unknown. Methods We conducted a monocentric cross-sectional study between September 2019 and January 2022. Patients followed for CD in endoscopic remission (CDEIS Results A total of 85 patients were included. Forty-four (51.7%) were female, the median age and disease duration were respectively 38 years (interquartile range [IQR], 33-44) and 12.0 years (IQR, 5-20). There was no difference between the four groups in terms of age, sex, BMI, smoking status, disease location or phenotype or number of biologics failure. The median global IBD-Disk score was 25 (IQR, 9-41) and 24 patients (28.2%) had moderate to severe disability. Transmural healing (group A) was observed in 40 patients (47.1%). Moderate to severe disability was identified in 17.5% (7/40) of patients with transmural healing, 25% (4/16) with endoscopic healing, 44.4% (8/18) with ultrasound healing and 45.4 % (5/11) without healing. In univariate analysis, transmural healing reduced the risk of severe disability (group C vs A OR = 3.77, 95% CI [1.10, 13.45], p = 0.035), group D vs A OR = 3 .75, 95% CI [0.91, 17.12], p=0.063). There was no difference in terms of severe disability between patients with transmural healing and complete endoscopic healing (group B versus A OR = 1.57 95% CI [0.36, 6.23], p = 0.525). Conclusion Transmural healing did not provide any benefit in terms of disability compared to complete endoscopic healing. Mucosal healing therefore remains the objective to be achieved in order to reduce the risk of short-term disability.

Background Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor approved for the treatment of ulcerative colitis (UC) in Europe and Japan. Previous analyses of the SELECTION programme showed that, in patients with moderately to severely active UC, C-reactive protein, rectal bleeding and stool frequency at day 7 predicted response to FIL at week 10,1 and that patients who did not respond to FIL induction benefited from an additional 12 weeks of FIL 200 mg.2 This post hoc analysis was conducted to identify factors associated with late response to FIL. Methods The SELECTION programme comprises a phase 2b/3, randomized, double-blind, placebo (PBO)-controlled study (SELECTION; NCT02914522) and its open-label, long-term extension (SELECTIONLTE; NCT02914535). Adult patients aged 18–75 years were randomized to FIL 100 mg, FIL 200 mg or PBO once daily for 11 weeks in the induction study. This post hoc analysis only included patients receiving FIL 200 mg who did not have clinical remission or a Mayo Clinic Score (MCS) response at week 10 of induction and who subsequently entered SELECTIONLTE on FIL 200 mg. Patient characteristics at induction baseline and changes in surrogate markers of response from baseline to week 4 of induction were compared between patients who had observed partial MCS (pMCS) response (pMCS late responders) or observed non-response (pMCS non-responders) at week 12 of SELECTIONLTE using univariate and multivariate logistic regression models. Results In total, 160 patients were included (102 [63.8%] pMCS late responders and 58 [36.3%] pMCS non-responders) (Table 1). In univariate analysis, prior use of biologics was not significantly associated with late response to FIL. Changes in surrogate markers of response showed that none were significantly associated with late response (Figure 1). In multivariate analysis of baseline characteristics, older age was positively associated with late response to FIL (odds ratio [OR]: 1.042, 95% confidence interval [CI]: 1.011–1.073, p = 0.007), while body mass index (BMI) < 18.5 kg/m2 (OR: 0.041, 95% CI: 0.003–0.519, p = 0.014) was negatively associated with late response. Conclusion In SELECTION programme participants, older age was positively associated with late response to FIL 200 mg and BMI < 18.5 kg/m2 was negatively associated with late response. These factors should be taken into account when monitoring patients on FIL with insufficient response at week 10. No other strong predictors were identified. The results of this analysis should be interpreted in the context of previous findings.1 1. Feagan B et al. United European Gastroenterol J 2022;10(S8):462–3 2. Vermeire S et al. United European Gastroenterol J 2021;9(S8):215–6

Background CD is classically seen as a progressive disease leading to bowel damage and disability. Disability has been proposed by the Spirit-IOIBD consensus1 as an endpoint in disease modification trials. However, there is a paucity of data regarding disability in CD patients at diagnosis. Methods The “Crohn′s Disease Cohort Study” (CROCO) is an ongoing prospective cohort aiming to study the longitudinal evolution of bowel damage and disability following diagnosis of CD. All patients are included within 12 months following CD diagnosis and will be followed over 5 years with serial assessments of bowel damage and disability. At recruitment patients completed an IBD disability score questionnaire (DS),2 comprising several domains: mobility, self-care, major daily life activities, gastrointestinal-related problems, mental health and interaction with the environment. We here describe the baseline DS and its association with disease features, disease activity score (Harvey-Bradshaw Index), and biomarkers of disease activity, on the first patients recruited into CROCO. Results Ninety-four patients were recruited, of which 66 filled at least 80% of the questions in the DS questionnaire; of those 55% were male and median age at diagnosis was 30.6 [IQR 24.2;38.8]. The baseline visit occurred at a median time of 6 months [IQR 2.6;9.2] after CD diagnosis. Ileal involvement (L1/L3) was reported in 82% of patients; 68% had B1 phenotype, and 26% presented extra-intestinal manifestations. Overall, 32% of patients had been hospitalised, and 6% had a history of CD-related surgery. Regarding medication [from diagnosis to baseline], 55% received steroids, 56% immunosuppressants, and 65% Anti-TNF therapy. The median DS was 79 [IQR 67;108.2] (range: 49;198); only 2 patients (3%) patients presented DS>162 (the central value of the DS), indicating no or mild disability. No correlations were found between clinical or analytical biomarkers of disease activity at the time of recruitment (Table 1). Associations between disease features and DS are displayed in Table 2. A history of CD-related hospitalisation was associated with a significantly higher DS (103 [IQR 79;157] versus 76.5 [65.5;97], p=0.013). No other associations were observed. Conclusion In a cohort of newly diagnosed CD patients, disability was mostly mild and independent of disease activity, disease location or behaviour; around 1/3 required hospitalisation within the first year of diagnosis, which was associated with increased disability. These data add to the growing concept that newly diagnosed disease represents a window of opportunity for intervention.

Background Endoscopy is still the gold-standard to assess disease activity in Crohn's disease (CD). Its invasiveness, acceptability and cost limit its use in the era of tight control and treat-to-target. Fecal calprotectin and intestinal ultrasound (IUS) are non-invasive alternatives to colonoscopy to assess disease activity. The objective of this study was to evaluate the performance of IUS and fecal calprotectin to assess mucosal healing in CD. Methods All consecutive CD patients who underwent colonoscopy for mucosal healing assessment and IUS and/or calprotectin within 4 weeks between September 2019 and April 2022 were included in a prospective cohort. Bowel wall thickness (BWT) and color doppler signal (CDS) were assessed on each segment. Endoscopic mucosal healing was defined by a CDEIS score < 3. Results A total of 153 patients were included, of whom 122 had endoscopic mucosal healing. Eighty-two (53.6%) were female, the median age and disease duration were respectively 36 years (IQR, 28-46) and 10 years (IQR, 4-19). Respectively 56 (56/120, 46.7%) and 93 (93/120, 77.5%) patients presented a BWT < 3 mm and an absence of CDS. The sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of BWT < 3 mm to predict endoscopic mucosal healing were 56%, 88%, 95% and 36% (patients misclassified as endoscopic mucosal healing 2.5%). The association of an absent of CDS with a normal BWT did not modify the performances. For a calprotectin < 250 µg/g , The Se, Sp, PPV and NPV were respectively 91%, 63%, 90% and 67% for (patients misclassified 8%). The association of a calprotectin < 250 µg/g, with a BWT < 3 mm and the absence of CDS increased the specificity and the PPV (Se 58%, Sp 95%, PPV 97%, VPN 43%, patients misclassified 1%). Conclusion Ultrasound is an efficient non-invasive tool to identify patients with Crohn's disease who have achieved endoscopic mucosal healing.

Background We report the results of TOFAST, a French ongoing prospective observational multicenter study, evaluating the clinical benefit of tofacitinib for the treatment of moderate to severe UC. Methods In this descriptive interim analysis, effectiveness and safety were assessed at the end of induction therapy (up to 4 months after tofacitinib initiation). Clinical response was defined as a decrease in partial Mayo score (PMS) (≥ 3 points and ≥ 30%) from inclusion with a concomitant decrease in rectal bleeding (RB) subscore ≥ 1 point (absolute subscore of 0 or 1). Clinical remission was defined as PMS ≤2 with no subscore >1. Change in daily PRO2 scores [RB and stool frequency (SF)] during the first 14 days and the median time to patient relief were also analyzed. Results Among the 102 patients included, 86 had available data at the first follow-up visit, corresponding to the end of induction period. At inclusion, 53.9% of patients were male with a mean (± SD) age of 37.1 ±13.6 years, a median disease duration of 6.1 years [Q1; Q3: 2.8; 10.8]. 48% of patients had pancolitis and 24.5% an extraintestinal manifestation; mean PMS was 6 ±1.8 with median SF and RB scores of 3.0 [Q1; Q3: 2.0; 3.0] and 2.0 [1.0; 2.0], respectively. Regarding prior drug exposure, 92.2% of patients had received at least one anti-TNF agent, 62.7% vedolizumab and 34.3% ustekinumab. Tofacitinib was initiated at 10 mg b.i.d, in combination with 5-ASA and corticosteroids for 19.6% and 33.3% of patients, respectively. At the first follow-up visit (median 1.9 months after treatment initiation), tofacitinib was ongoing in 87.2%, mostly (73.3%) at 10 mg b.i.d. Corticosteroids were ongoing in 29.1% of patients. At the end of induction period, rates of clinical response and remission were 52.3% and 43%, respectively. Median changes in RB and SF scores were identical at days 7 and 14, -1 point [Q1; Q3: -1.0; 0.0] and -1 point [Q1; Q3: -2.0 - 0.0], respectively. For patients who reported improvement (68.6%), the median time to relief was 7 days [Q1-Q3: 4.0-15.0]. PRO2 scores normalisation during the first 14 days is shown in the figure. RRegarding safety, 73.5% of patients reported at least one adverse event (AE) and 12.6% reported at least one serious AE. Ten (9.8%) infections (none considered as serious) and 2 (1.9%) Herpes Zoster were reported. No major cardiovascular or venous thromboembolic event, nor malignancy or death were observed (Table). Conclusion The interim results of TOFAST study show that at the end of induction therapy with tofacitinib, 52.3% of patients achieved clinical response and >40% achieved remission. Rapid improvement in SF and RB scores was observed within 2 weeks. AEs were consistent with the known tofacitinib safety profile.

Background In the "treat-to-target" era, the development of non-invasive markers to assess endoscopic healing in ulcerative colitis (UC) is essential. Fecal calprotectin (FC) and intestinal ultrasound (IUS) are alternatives to colonoscopy to assess UC activity. The objective of this study was to evaluate the performance of IUS and FC to assess endoscopic mucosal healing in UC patient. Methods All consecutive patients between January 2021 and August 2022 with UC who underwent (1) a complete colonoscopy (2) an intestinal ultrasound and/or (3) a fecal calprotectin (4) within 4 weeks were included in a prospective cohort. Bowel wall thickness (BWT) and color doppler signal (CDS) were assessed on each segment. Endoscopic mucosal healing was defined by a MAYO score of 0-1. Results A total of 57 patients were included, 57.9% had endoscopic healing (22/57 MAYO 0 and 11/57 MAYO 1). Thirty-two (56.1%) were female, the median age and disease duration were respectively 43 years (IQR, 30-58) and 29 years (IQR, 18-39). Respectively 16 (16/57, 28.1%) and 41 (41/57, 71.9%) patients had BWT < 3 mm and an absence of Doppler signal. The sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of BWT < 3 mm to predict endoscopic mucosal healing were 37%, 77%, 72% and 44%. The association of the absence of CDS with normal BWT did not modify these performances. The same values for fecal calprotectin < 150 µg/g were respectively 81%, 78%, 84% and 74%. The association of a fecal calprotectin < 150 µg/g, with a BWT < 3mm and the absence of Doppler signal increased the specificity and the PPV (Se 33%, Sp 94%, PPV 89%, VPN 48%). The same values were found for patients classified as MAYO 0 or MAYO 0-1 (Table 1). Conclusion The combination of intestinal ultrasound and fecal calprotectin is effective to identify endoscopic mucosal healing in UC.

Background and Aims Optimal management of patients with inflammatory bowel disease [IBD] after anti-tumour necrosis factor [TNF] discontinuation due to severe induced skin lesions is unclear. Our study aimed to describe dermatological and IBD evolution after anti-TNF discontinuation for this side effect. Methods We conducted a multicentre retrospective study including consecutive IBD patients who discontinued anti-TNF due to severe induced skin lesions. Our objectives were to determine factors associated with dermatological remission [complete disappearance of skin lesions] and with IBD relapse in patients with inactive disease at inclusion, notably the impact of an early switch to another biological agent within 3 months of anti-TNF discontinuation. Results Among the 181 patients [134 women, 160 Crohn’s disease] included in the 13 participating centres, dermatological remission occurred in 110 [62%] patients with a median [interquartile range, IQR] interval of 8.0 [6.8–11.0] months. Scalp location was independently associated with less remission of skin lesions (hazard ratio [HR] = 0.64 [95% CI 0.43–0.94], p = 0.02) while early switch was independently associated with a higher probability of remission of skin lesions (HR = 1.64 [95% CI 1.1–2.5], p = 0.02). Among the 148 patients with inactive IBD at inclusion, disease relapse occurred in 75 [51%] patients with a median [IQR] interval of 26.0 [23.0–39.1] months. Survival rates without IBD relapse at 1 year were 85.8% [95% CI 77.5–94.9] in the early switch group and 59.3% [95% CI 48.9–71.9] in the other group [p Conclusions Early switch to a new biological is associated with a higher probability of healing of anti-TNF-induced skin lesions and significantly reduces the risk of IBD relapse.

Introduction Knowledge about the cancer risk when initiating a biologic in inflammatory bowel disease [IBD] patients with prior malignancy remains scarce, especially for vedolizumab. Our aim was to evaluate the rate of incident cancer in a cohort of IBD patients with prior non-digestive malignancy, according to the subsequent treatment given. Methods A multicentre retrospective study included consecutive IBD patients with prior non-digestive malignancy. Inclusion date corresponded to the diagnosis of index malignancy. Patients were categorized into different cohorts according to the first treatment [none, conventional immunosuppressant, anti-TNF, or vedolizumab] to which they were exposed after inclusion and before incident cancer [recurrent or new cancer]. Results Among the 538 patients {58% female; mean (standard deviation [SD]) age inclusion: 52 [15] years} analyzed, the most frequent malignancy was breast cancer [25%]. The first immunomodulator given after inclusion was a conventional immunosuppressant in 27% of patients, anti-TNF in 21%, or vedolizumab in 9%. With a median (interquartile range [IQR]) follow-up duration of 55 [23-100] months, 100 incident cancers were observed. Crude cancer incidence rates per 1000 person-years were 47.0 for patients receiving no immunomodulator, 36.6 in the anti-TNF cohort, and 33.6 in the vedolizumab cohort [p = 0.23]. Incident-cancer free survival rates were not different between patients receiving anti-TNF and those receiving vedolizumab [p = 0.56]. After adjustment, incidence rates were not different between patients receiving no immunomodulator, anti-TNF, or vedolizumab. Conclusions In this large multicentre cohort study, there was no difference of cancer incidence in those IBD patients with prior non-digestive malignancy, treated with vedolizumab or anti-TNF.

Background Breast cancer is the most common malignancy observed in patients with inflammatory bowel diseases (IBD) unrelated to the disease or its treatment (Poullenot F et al. JCC 2022). The main aim of our study was to assess the risk of incident cancer according to the IBD treatment given in patients with prior breast cancer. Methods Consecutive IBD patients with prior breast cancer diagnosis were included in a multicenter retrospective cohort from 25 tertiary centres. Inclusion date corresponded to the diagnosis of index cancer. Follow up was calculated from the first administration of immunomodulator after cancer diagnosis (or cancer diagnosis date in absence of treatment) to the occurrence of incident cancer, corresponding to recurrence of breast cancer or de novo cancer, or to the last follow-up visit. Patients were categorized according to the use or not of immunomodulator after cancer diagnosis: thiopurines, methotrexate, anti-TNF, vedolizumab, ustekinumab. Crude incidence rates were compared between patients receiving at least one immunomodulator and those without immunomodulator before and after matching on age, lymph node, and metastasis extension and tumor’s grade, using a propensity-score analysis with a 1:1 ratio. Results Among the 151 identified patients, 80 patients with full available data were analyzed: 76 (95%) women; mean age at index cancer diagnosis: 51.5 years [standard deviation (SD): 11.5 years]; 44 (55%) with Crohn’s disease, 35 (44 %) ulcerative colitis and 1 (1 %) indeterminate colitis; median IBD duration at inclusion was 13 years [interquartile range (IQR) 6-21]. After a median follow up of 84 months [IQR 49-154], 16 (20%) incident cancers were observed: 12 (15%) recurrences and 4 (5%) cancer de novo. Three (4%) patients died from cancer related cause during the follow up. 39 (49%) patients received no immunomodulator and, 11 (14%) were treated with thiopurines, 6 (7.5%) with methotrexate, 18 (22.5%) with anti-TNF, 5 (6%) with vedolizumab and one (1%) with ustekinumab. Those treatments were initiated with a median interval of 24 months [IQR 7-48] after cancer diagnosis. Crude incidence rate per 1000 person-years were 47.97 for patients not exposed to any immunomodulator and 12.61 for the others (p=0.0248). After matching, adjusted crude incidence rates per 1000 person-years were 50 and 27.27, respectively (p=0.3798). Rates of survival without incident cancer were not different between the two groups after matching on age, lymph node, metastasis extension, and tumor’s grade (p=0.17) (Figure 1). Conclusion In the present multicenter retrospective cohort, incident cancer risk among patient with IBD and prior breast cancer was not increased in patients subsequently exposed to immunomodulators.

Background Inflammatory bowel diseases (IBD) associated with primary immunodeficiency (PID) remain poorly known. We aimed to isolate characteristics of IBD associated with PID. Methods Using a GETAID register, we reviewed medical files of recorded patients with PID and IBD (Crohn’s disease, ulcerative colitis (UC) or microscopic colitis) followed in 9 adult university hospitals. Results of genetic investigations were available for 46 patients (62%). Results 74 patients (30 F, 44M) were included with a mean age of 26 years (median: 24 years) at diagnosis of IBD. Forty-four (59%) patients had Crohn’s disease with anoperineal lesions in 12, 26(35%) patients had microscopic (mainly lymphocytic) colitis and 4 patients had UC. PID was predominantly antibody deficiency in 40(54%) patients [34 common variable immunodeficiency, 4 X-linked agammaglobulinemia, 2 selective IgA deficiencies], disease of immune dysregulation in 18(24%) patients [CTLA4, LRBA, NFKB1, TNFAi3, XIAP deficiencies, STAT3 and STAT1 hyperactivation], phagocytosis deficiency in 15(20%) patients (12 chronic granulomatous diseases (CGD), 3 congenital neutropenia] and C1s deficiency (n=1). In order of frequency, Crohn’s disease was associated with antibody deficiencies (52%), phagocytosis deficiencies (29%) and immune dysregulation (18%), microscopic colitis with antibody deficiencies (65%), immune dysregulation (27%) and more rarely with phagocytosis deficiencies (8%) and UC with antibody deficiencies (75%) and immune dysregulation (25%). 46% of patients received immunoglobulin supplementation, 70% steroids, equally corticosteroids and budesonide, 49% biotherapy mainly anti-TNF-alpha antibody (38%) and ustekinumab (16%), 23% immunosuppressive drugs, mainly azathioprine and sirolimus and 18% aminosalicylates. Three patients (2 CGD, 1 XIAP) had been treated with allogeneic stem cell transplantation (SCT) and one patient (TNFRS13B deficiency) with autologous SCT. Eleven (15%) patients had intestinal surgery, mainly ileocecal resection. During follow-up [mean: 16 years], 51% of patients had transient or sustained clinical remission mainly with an anti-TNF-alpha antibody, ustekinumab, steroids (budesonide) and specific therapy (targeted therapy such as abatacept and ASCT), 41% of patients had severe infections, 22% developed neoplasia mainly gastrointestinal dysplasia and/or cancers (n=8), B cell lymphoma (n=3) and 4 patients died. Conclusion At adulthood in our series, IBD associated with PID are mainly Crohn’s disease and lymphocytic colitis. The first most frequent associated PID is antibody deficiency. Biotherapies (anti-TNF-alpha antibody, ustekinumab), steroids and specific therapies are commonly used to induce clinical remission.

Background Knowledge about the cancer risk when initiating a biologic in Inflammatory Bowel Disease (IBD) patients with prior malignancy remains scarce especially for vedolizumab. Our aim was to evaluate the rate of incident cancer in a cohort of IBD patients with prior non-digestive malignancy according to the subsequent treatment given. Methods Consecutive cases of patients with IBD and a malignancy were retrospectively collected in, 33 centers in two countries. Patients with a biliary- or digestive tract cancer were excluded. Inclusion date corresponded to diagnosis of malignancy. Patients were categorized into different cohorts according to the first treatment they were exposed to after the malignancy diagnosis and before incident cancer. Follow-up time was calculated from the first administration of therapy to last follow-up visit. For patients receiving no therapy, follow-up started at diagnosis of cancer. Incident cancer during follow-up was defined as recurrence of the known cancer or occurrence of a new cancer. Crude cancer incidence rates were compared between the cohorts using chi-square test. Patients from the anti-TNF, vedolizumab, and no treatment cohorts were matched on age, lymph node and metastasis extension and malignancy recurrence risk according to the Penn classification using a propensity-score analysis with a, 1:1 ratio. Results Among the, 538 patients (58% female; mean [standard deviation (SD)] age inclusion:, 52 [15] years) analyzed, the most frequent malignancy was breast cancer (25%). First immunomodulator given after inclusion was a conventional immunosuppressant in, 27% of patients, anti-TNF in, 21% or vedolizumab in, 9%. With a median (inter-quartile range (IQR)) follow-up duration of, 55 (23–100) months, 100 incident cancers were observed. Crude cancer incidence rates per, 1000 person-years were, 47.0 for patients receiving no immunomodulator, 36.6 in the anti-TNF cohort and, 33.6 in the vedolizumab cohort (p=0.23). Incident-cancer free survival rates were not different between patients receiving anti-TNF and those receiving vedolizumab (p=0.56). After adjustment, incidence rates were not different between patients receiving no immunomodulator, anti-TNF or vedolizumab. On multivariate analysis, age ≥, 52 years at inclusion, follow-up after index cancer Conclusion In this large multicenter cohort study, we found no difference in terms of incident cancer rates in patients with IBD and a prior non-digestive malignancy treated by vedolizumab compared to those treated by other immunomodulatory therapies including anti-TNF.

Background Owing to similar efficacy, switching from intravenous (IV) to subcutaneous (SC) infliximab (IFX) is an attractive option, but the feasibility of switching patients with intensified IFX therapy remains unknown. We assessed the clinical and pharmacological evolution after switching from IV to SC IFX in IBD patients to evaluate the feasibility and to determine the equivalence between IV and SC doses. Methods All IBD patients in clinical remission (CDAI Results Among, 246 screened patients, 65 (26.4%) were not eligible (no clinical remission or physician’s decision), and, 71.8% (130/181) accepted to switch to SC IFX (Crohn’s disease = 73,1%, concomitant immunosuppressant = 25.4%, median faecal calprotectin = 35 µg/g [16–104])., 43.1% of the, 130 patients received, 5mg/kg/8 wk. In, 130 patients, clinical relapse leading to therapeutic escalation was observed in, 11.1% including, 4.0%, 8.6%, 11.1% and, 40.0% in patients treated with, 5mg/kg/8wk, 10 mg/kg/8wk, 10mg/kg/6 wk and, 10mg/kg/4 wk, respectively. Dose increase (240 mg/2 wk) induced clinical remission in, 92.3% of relapsers. Infliximab trough levels (TL) were significantly higher after switching from IV to SC IFX:, 9.8 ±6.4 vs, 14.4 ±5.7 (p Infliximab TL remained stable (variation V1-V0 < ±, 1) in, 4.3%, 15.0 %, 33.3 % and, 50.0 % of the patients with the following IV doses:, 5 mg/kg/8 wk, 10 mg/kg/8 wk, 10 mg/kg/6 wk and, 10 mg/kg/4 wk, respectively (p=0.003). No patient developed anti-IFX antibodies. TL before the switch (8.4 ±5.6 for non-relapsers vs, 12.0 ±7.2 for relapsers; p=0.12) and TL after the switch (14.5 ±5.6 vs, 13.6 ±5.6; p=0.63) were not significantly associated with the risk of relapse. In contrast, the risk of relapse was higher in patients with stable or decreasing TL after the switch compared to those with increased TL (31.8% vs, 7.1%; p=0.024). The type of IBD and concomitant immunosuppressant were not associated with the risk of relapse. Patients’ acceptability was better with SC injections compared to IV infusions (10pts-acceptability numerical scale = 8.7 ±1.6 vs, 6.8 ±0.9; p Conclusion Switching from IV to SC IFX is feasible and well-accepted leading to a low risk of relapse in patients with IBD.

Background Anal ulcerations are frequently observed in Crohn’s disease (CD). Their natural history remains poorly known, especially in pediatric-onset CD. The aims of this study were: to determine in a population-based study the risk of anal ulcerations in pediatric onset CD; to identify risk factors for anal ulcerations; to evaluate the risk of progression towards suppurative lesions; to evaluate the risk factors of progression towards suppurative lesions. Methods All patients with a diagnosis of CD before the age of 17 years between 1988 and 2011 within the population-based registry EPIMAD were followed retrospectively until 2013. A specific collection of additional data was performed in patients with anal ulcerations at diagnosis or during follow-up. The variables collected included: proctological examination, diagnostic management (perineal MRI, endoscopic ultrasound, examination under general anaesthesia) and treatment (medical or surgical). Multivariate Cox models were used to identify factors associated with anal ulcerations and factors of progression towards suppurative lesions. An adjusted time-dependent Cox model was used to evaluate the risk of progression of anal ulcerations towards suppurative lesions. Results 1005 patients were included (females, 450 (44.8%); median age at diagnosis 14.4 years (IQR, 12.0–16.1)). 257 (25.6%) had anal ulceration at diagnosis. Cumulative incidence of anal ulceration at 5 and 10 years from diagnosis was 38.4% (CI95%, 35.2–41.4) and 44.0% (CI95%, 40.5–47.2). The presence of extra-intestinal manifestations (HR 1.46, CI95% 1.19–1.80, p=0.0003) and upper digestive location (HR 1.51, CI95% 1.23–1.86, p In patients with anal ulceration, the diagnostic period (before or since the “biologic era”), exposure to immunosuppressants and/or anti-TNF did not influence the risk of perianal suppuration. Conclusion Anal ulceration is frequent in pediatric-onset CD, with nearly half of patients presenting with at least one episode after 10 years of evolution. Perianal suppurations are twice as frequent in patients with present or past anal ulceration. These results plead for a proactive therapeutic approach in case of anal ulcerations.

Background The modified Rutgeerts’ score (mRS) differentiates i2a – lesions confined to the anastomosis – and i2b – neoterminal ileum lesions – categories. Its relevance for therapeutic management of Crohn’s disease (CD) patients after ileocolonic resection is still debated. Our objective was to compare the postoperative recurrence (POR) risk in patients with a mRS i2a or i2b score using an individual patient data meta-analysis. Methods We conducted a systematic literature search of Medline, Embase and abstracts from international conferences (until July 2020) to identify all relevant studies reporting the risk of clinical and/or surgical POR and the i2a/i2b status in the year following ileocolonic resection. Initial datasets were obtained from the corresponding authors. Time from endoscopy to clinical and surgical POR was estimated using Kaplan-Meier method. The association between time to event and mRS was evaluated using a mixed Cox with centre as the random effect. Results From the 17 studies identified, 7 published between 2008 and 2019 (cohort studies, n=4; clinical trials, n=2) corresponding to a total of 400 patients (median (InterQuartileRange) age at surgery 34 (26,47) years; 52% female) were included. In the year following ileocolonic resection, 189 (47%) patients displayed an i2a mRS and 211 (53%) an i2b. In the i2b group, we observed more male patients (56% versus 41%, p=0.01), more patients with previous ileocolonic resection (31% versus 21%, p=0.03) and temporary ileostomy (14% versus 6%, p=0.03) and an immunosuppressant or antiTNF therapy was more frequently initiated after endoscopy (42% versus 26%, p Conclusion In this individual patient data meta-analysis, no difference is observed between i2a and i2b mRS subcategories in terms of clinical, surgical or endoscopic POR. Limits of the mRS may explain this lack of predictive value.

Background We used the postoperative recurrence model to better understand the role of AIEC bacteria in Crohn’s disease (CD), taking advantage of a well-characterized postoperative cohort. Methods From the REMIND prospective, multicenter cohort of operated CD patients (ileocolonic resection), AIEC identification was performed within the surgical specimen (M0) (N=181 patients) and the neo-terminal ileum (n=119 patients/181) during colonoscopy performed 6 months after surgery (M6). Endoscopic postoperative recurrence was graded using Rutgeerts’ index, which was interpreted, either from a clinical point of view (postoperative endoscopic recurrence ≥ i2b or severe ≥ i3), or from a pathophysiological point of view (reappearance of the first ileal lesions = i1 and more advanced postoperative ileal recurrence = i2b + i3). The mucosa-associated microbiota was analyzed by 16S sequencing at M0 and M6. Relative risks (RR) or odds ratios (OR) were adjusted on potential confounders ((gender, smoking, CD duration, CD phenotype, prior bowel resection, indication for surgery, granuloma, preventive treatment, antibiotics). Results Among the 228 patients included at the time of the analyzes, the search for AIEC was carried out in 181 patients at M0, and 119 patients at M6. Among these 181 patients included in our study, 46.3% did not receive any preventive treatment for endoscopic postoperative endoscopic recurrence while 24.3% have been treated with anti-TNF to prevent postoperative recurrence. AIEC prevalence was two-fold higher within the neo-terminal ileum at M6 (30.3%) than within the surgical specimen (14.9%) (p Conclusion Based on the postoperative recurrence model, our data support the role of AIEC in the early steps of ileal CD.

Background Data to manage patients with Inflammatory Bowel Disease (IBD) after anti-TNF discontinuation due to severe induced skin lesions are scarce. Our study aimed to assess dermatological and IBD outcomes after discontinuation of an anti-TNF agent related to skin side effects. Methods We conducted a multicenter retrospective study including consecutive IBD patients who discontinued anti-TNF due to induced skin lesions. Objectives were to determine factors associated with remission of induced skin lesions and with IBD relapse in patients with inactive disease at inclusion, particularly the impact of early introduction of a new biological agent within three months of anti-TNF discontinuation. Results Among the 181 patients (134 women, 160 Crohn’s disease) included in the 13 participating centers, 99 (55%) started a new biological agent within the first three months that was mainly ustekinumab in 75% of them. Remission of induced skin lesions occurred in 110 (62%) patients with a median [interquartile range (IQR)] interval of 8.0 (6.8–11.0) months since anti-TNF discontinuation. Scalp location was independently associated with a reduced risk of remission of induced skin lesions [HR 0.64 (95%CI 0.43- 0.94), p=0.02] while early biological therapy was independently associated with a higher probability of remission of skin lesions [HR 1.64 (95%CI 1.1–2.5), p=0.02]. Among the 148 patients with inactive IBD at inclusion, disease relapse occurred in 75 (51%) patients with a median (IQR) interval of 26.0(23.0–39.1) months. Survival rates without IBD relapse at 1 year were 85.8% (95%CI 77.5–94.9) in the early introduction group and 59.3% (95%CI 48.9–71.9) in the other group (p Conclusion Early introduction of a new biological is associated with higher probability of healing of anti-TNF-induced skin lesions and significantly reduces risk of IBD relapse.

Background Ulcerative colitis is a chronic inflammatory bowel disease., 20% of patients will experienced acute severe colitis during their life. In acute severe colitis, when IV steroids failed, two strategies can be used with equivalent efficacy: Ciclosporin and Infliximab. Recently, Pellet et al reported the interest of association ciclosporin – vedolizumab. Regarding results from Varsity trial, more patients are treated before a CAG with vedolizumab. Recently, UNIFI trial showed the interest of ustekinumab in UC patients. So, it should be interesting to analyze the interest of the association Ciclosporin -Ustekinumab in case of acute severe ulcerative colitis. In this study, we retrospectively evaluated the clinical response and the rate of colectomy when we used anticalcineurin and Ustekinumab in acute severe colitis refractory to IV steroids. Methods All patients with acute severe colitis who failed to IV steroid and who were treated with calcineurin inhibitor and Ustekinumab, can be included. They were treated with a, 6mg/kg infusion and then a, 90mg subcutaneous injection every, 8 weeks. Eight referral French center and a Switzerland referral center were involved in this study. The primary endpoint was clinical response at, 6 months. We also evaluated the rate of colectomy and survival without Ustekinumab discontinuation. We reported also adverse events in this cohort. Results Eleven patients were included., 82% were women, with a median age of, 32.2 years (range, 25.5–36.5 y). The median disease duration was, 8.2 years (range, 3–9.5 y). Ten patients failed to Infliximab and, 9 to Vedolizumab. At inclusion, median Lichtiger score, Mayo score and CRP were respectively, 13,4 [IC95, 12.5–14.5], 10.6 [IC95, 10–11.5] et de, 24.5 mg/L [IC95, 4.5–35.7mg/l]. The mean Endoscopic Mayo score was, 2.6 +/-0.7. The median time between beginning of Calcineurin inhibitor and Ustekinumab was, 22 days (minimum, 6d, maximum, 128d). Median follow-up was, 11 months. None of the patients underwent colectomy at, 6 months. The mean full Mayo score was significantly lower during the follow-up (10.6 at baseline and, 1.0 at, 6 months; p = 0.005). The mean CRP level was significantly reduced (from, 24.5 mg / L [CI95, 4.5–35.7] to, 2.6 mg / L [2–3.1], p = 0.02). Only one patient stopped ustekinumab at the end of follow-up. Two patients required treatment optimization. Tolerance to treatment was well with only one case of alopecia described without withdrawal of treatment. Conclusion In this retrospective study including patients hospitalized for IV Steroid-resistant acute severe colitis, the sequence of treatment with induction anti-calcineurin with ustekinumab therapy appears to be effective and well tolerated. These results need to be confirmed on a larger number of patients.

Vedolizumab is a humanized monoclonal antibody that binds to the human a4β7 integrin and is approved for use in inflammatory bowel diseases. We describe a patient with severe, refractory erosive gingivostomatitis, which appeared a few days after the first dose of vedolizumab and resolved after discontinuation of the drug. We believe the gingivostomatitis to be a direct side effect of vedolizumab, rather than an extraintestinal manifestation of the underlying inflammatory bowel diseases. The clinicians need to be aware of this adverse event, which could be mistakenly considered as an extraintestinal manifestation of inflammatory bowel diseases.

Vedolizumab is a humanized monoclonal antibody that binds to the human a4β7 integrin and is approved for use in inflammatory bowel diseases. We describe a patient with severe, refractory erosive gingivostomatitis, which appeared a few days after the first dose of vedolizumab and resolved after discontinuation of the drug. We believe the gingivostomatitis to be a direct side effect of vedolizumab, rather than an extraintestinal manifestation of the underlying inflammatory bowel diseases. The clinicians need to be aware of this adverse event, which could be mistakenly considered as an extraintestinal manifestation of inflammatory bowel diseases.

Resume Les maladies inflammatoires chroniques de l’intestin (MICI) sont des pathologies touchant les patientes en âge de procreer. Le defaut d’information de ces patientes est responsable d’une infertilite volontaire mais aussi d’une mauvaise observance des traitements en cours de grossesse. L’objectif de ce travail est de faire une mise au point sur les liens entre les MICI et la grossesse de la conception a l’accouchement. L’activite de la maladie joue un role majeur. En cas de maladie non active, la fertilite n’est pas diminuee et la grossesse se deroulera sans sur-risque de complications. La plupart des traitements, a l’exception du thalidomide et du methotrexate, sont compatibles avec la grossesse et l’allaitement. Toute poussee doit etre prise en charge de facon optimale. Un accouchement par les voies naturelles n’est pas contre-indique sauf en cas de lesions anoperineales actives. Un accouchement par cesarienne est a discuter systematiquement en cas d’anastomose ileo-anale.

Few data are available to describe the changes in incidence of pediatric-onset inflammatory bowel disease (IBD). The aim of this study was to describe changes in incidence and phenotypic presentation of pediatric-onset IBD in northern France during a 24-year period.Pediatric-onset IBD (17 years) was issued from a population-based IBD study in France between 1988 and 2011. Age groups and digestive location were defined according to the Paris classification.1,350 incident cases were recorded (8.3% of all IBD) including 990 Crohn's disease (CD), 326 ulcerative colitis (UC) and 34 IBD unclassified (IBDU). Median age at diagnosis was similar in CD (14.4 years (Q1=11.8-Q3=16.0)) and UC (14.0 years (11.0-16.0)) and did not change over time. There were significantly more males with CD (females/males=0.82) than UC (females/males=1.25) (P=0.0042). Median time between onset of symptoms and IBD diagnosis was consistently 3 months (1-6). Mean incidence was 4.4/10In this population-based study, CD and UC incidences increased dramatically in adolescents across a 24-year span, suggesting that one or more strong environmental factors may predispose this population to IBD.

Background Anti-TNFs antibodies are the first biologic treatment option in inflammatory bowel disease (IBD). The long-term effectiveness of this strategy at the population level is poorly known, particularly in pediatric-onset IBD. Methods All patients diagnosed with Crohn’s disease (CD) or ulcerative colitis (UC) before the age of 17 between 1988 and 2011 in a population-based registry were followed retrospectively until 2013. Among patients treated with anti-TNFs, the cumulative probabilities of anti-TNF failure defined by primary failure, loss of response or intolerance were evaluated. Factors associated with anti-TNF failure were investigated by a Cox model. Results Among a total of 1007 patients with CD (median disease duration, 3.2 years IQR (1.2–7.6) and median follow-up 8.8 years (IQR, 4.6–14.2)) and 337 patients with UC (median disease duration, 2.5 years IQR [1.1–4.5] and median follow-up 7.2 years (IQR, 3.8–13.0)), respectively 481 (48%) and 81 (24%) were treated with anti-TNFs. Median age at anti-TNF initiation was 17.4 years (IQR, 15.1–20.9). Median duration of anti-TNF therapy was 20.4 months (IQR, 6.0–59.9). In CD, the probability of failure of 1st line anti-TNF therapy at 1, 3 and 5 years was respectively 29.3%, 47.0% and 54.6% for infliximab (n = 397) and 22.6%, 37.7% and 48.0% for adalimumab (n = 83). In UC, the probability of failure of 1st line anti-TNF therapy at 1, 3 and 5 years was respectively 37.3%, 49.0% and 61.0% for infliximab (n = 71) and 12.5% for these 3 timepoints for adalimumab (n = 10). In CD, probabilities of primary failure, loss of response and intolerance at 5 years were 10.4%, 36.7% and 6.8% (n = 480), respectively; in UC, these same probabilities were 7.5%, 39.2% and 11.3% (n = 81), respectively. Female sex (Hazard Ratio (HR) 1.43, 95% CI 1.09–1.87; p = 0.010) and intestinal resection prior anti-TNF initiation (HR 1.73, 95% CI 1.21–2.47, p = 0.003) were associated with anti-TNF failure in multivariate analysis. Conclusion In a population-based study of pediatric-onset IBD, approximately half of anti-TNFs users discontinue use within 5 years. Loss of response account for around two-thirds of failure, both for CD and UC.

Background Hereditary colorectal cancer syndromes (HCCS) are rare polyposis or nonpolyposis syndromes with a higher risk of developing colorectal cancer (CRC). Coexisting inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), with HCCS is exceedingly rare and presumably increases the risk of early-onset colorectal cancer. Methods This was a multicenter case series performed as a part of the European Crohn’s and Colitis Organisation (ECCO) Collaborative Network of Exceptionally Rare case reports (CONFER) project. Results This report includes 26 patients with IBD (10 UC, 15 CD, and one with IBD unclassified (IBD-U)) and concomitant HCCS. Among these 26 patients (median age 33 years, IQR 20–44), 15 (57.7%) were males, 24 (92.3%) Caucasians and 2 (7.7%) of Arab origin. Among patients with UC, 4 (40%) had proctitis, 3 (30%) left-sided colitis and 3 (30%) an extensive disease; while, among patients with CD, 8 (53.3%) had ileal, 5 (33.3%) ileocolonic, 2 (13.3%) colonic disease. One of these patients had ileocolonic disease associated with upper disease location and six (40%) had an associated perianal disease. Many of patients with CD had a non-stricturing non-penetrating phenotype (53.3%, n=8), while 20.0% (n=3) and 26.7% (n=4) had a stricturing or penetrating phenotype, respectively. HCCS was diagnosed before the IBD diagnosis in 11 patients (42.3%), after diagnosis of IBD in 11 patients (42.3%) and concurrently in 4 patients (15.4%). Sixteen patients had Lynch syndrome, 7 had FAP, 2 had AFAP and one had MAP. The most frequent genetic mutations were those of APC (n=7) and MLH1 (n= 7). Thirteen patients were treated with immunomodulatory (IMM) therapy. During IMM therapy, only 5 patients developed drug-induced side-effects which did not require drug interruption. One patient treated with vedolizumab developed CRC, despite yearly colonoscopy surveillance, after 4 years of treatment. Overall, CRC developed in 38.5% of patients (n=10): in 5 patients (50%) after IBD diagnosis, in 4 (40%) patients before IBD diagnosis, and in 1 patient the 2 conditions were diagnosed simultaneously. Eighteen (69.2%) patients underwent colectomy or abdominal surgery: 9 patients due to CRC diagnosis, 7 patients preventively due to the underlying HCCS and 2 patients because of active IBD disease. On follow-up, one patient died due to CRC. Conclusion This case series describes the largest series to date of patients with IBD patients and HCCS, with special emphasis on the use of IMM in this population. The most frequent diagnosis of HCCS associated with IBD was Lynch syndrome. These data demonstrate the high malignancy rate and surgical intervention rate in this IBD cohort. The optimal medical approach still needs to be addressed.

Background Several therapeutic options are now available in ulcerative colitis after anti-TNF failure, but no data compared hitherto tofacitinib and vedolizumab. We compared the effectiveness of tofacitinib and vedolizumab in UC patients with prior exposure ≥ 1 anti-TNF. Methods In this multicentre retrospective study, we consecutively included all adult UC patients with partial Mayo score > 2, with ≥ 1 prior anti-TNF agent and started either tofacitinib (10mg b.i.d ± decreased to 5 mg b.i.d from week 8 (W8)) or vedolizumab (300 mg IV at W0-W2-W6 -W14 [± additional W10]) between January 2019 and June 2021. The primary endpoint was corticosteroid-free clinical remission or CFREM (partial Mayo score ≤ 2) at W16. Secondary endpoints were endoscopic improvement (CFREM + endoscopic Mayo score ≤ 1) and mucosal healing (CFREM + endoscopic and histological remission defined as Nancy index ≤ 1). All the comparisons were performed using propensity score analyses (inverse probability of treatment weighting) adjusted on gender, smoking, UC duration and extent, number of prior biologics or prior primary failure to biologics, concomitant 5-ASA, steroids or immunosuppressive agents, and disease severity. Results Overall, 400 patients will be included. Among the 200 first patients, 87 and 112 received tofacitinib and vedolizumab, respectively (one missing patient). Except for more pancolitis (54.0% vs 38.4%, p=0.028), less immunosuppressive therapies (4.6% vs 27.7%, p < 0.001), and higher rate of prior exposure ≥ 2 biologics (87.4% vs 37.5%, p < 0.001) in tofacitinib arm, baseline characteristics were similar across the two groups including concomitant 5-ASA (10.3% vs 18.8%) and steroids (23.0% vs 31.2%). Vedolizumab infusion at W10 was performed in 34.3% while 42.5% received tofacitinib 10 mg b.i.d until W16. CFREM was achieved in 54.2% and 42.5% in tofacitinib and vedolizumab, respectively p=0.089). The rate of CFREM at W16 was 57.4% vs 51.1% (p=0.77) after one biologic, 55.4% vs 41.8% (p=0.61) after 2 biologics, 56.9% vs 6.3% (p=0.007) after at least 3 biologics, and 59.0% vs 33.3% (p=0.17) in the subgroup with partial Mayo score ≥ 6, in tofacitinib and vedolizumab groups, respectively. Tofacitinib was more effective than vedolizumab to achieve CFREM at W16 in patients with primary failure to at least biologic (71.6% vs 30.8%, p=0.049). Among 177 patients, endoscopic improvement was higher in patients treated with tofacitinib (33.6 % vs 7.1%, p=0.048). Mucosal healing was observed in 6.4% vs 3.8% in tofacitinib and vedolizumab arms, respectively (p=0.27). Conclusion Tofacitinib and vedolizumab are effective after failure to anti-TNF agents. Tofacitinib seems to be more effective in case of primary failure to biologics and multiple therapeutic failure.

Inflammatory Bowel Diseases (IBD) are chronic conditions affecting young people in their reproductive age. Patient misinformation can be responsible for a self-imposed infertility as well as a suboptimal observance during pregnancy. The aim of this work was to review the influence of IBD and pregnancy on one another at each gestational stage and according to current literature. IBD activity is a major influential factor. In case of a well-controlled IBD, fertility won't be affected and pregnancy will take place without increase risk of complications. With the exception of thalidomide and methotrexate, most of treatments used in IBD are compatible with pregnancy and breastfeeding. Each flare should be optimally managed. Vaginal delivery is a safe option except for patients with active anoperineal lesions. Cesarean section should be systematically discuss in patient with ileal pouch-anal anastomosis.

Background The multiplication of therapeutic options with close efficacy and safety, leads to consider acceptability of treatment regimen as a key point for therapeutic decision in inflammatory bowel disease (IBD). We aimed to compare acceptability of IBD treatment regimen and to identify its associated factors. Methods From a nationwide prospective study conducted in 24 public or private centres, IBD patients were consecutively included for 6 weeks. A dedicated questionnaire was developed, tested and validated for the study. It was administered to each included patient and his/her related physician. Acceptability was graded with an acceptability numerical scale (ANS) from 0 (absolutely not acceptable) to 10 (totally acceptable). Results Overall, 1850 patients were included (65.9% with Crohn’s disease (CD), mean age = 41.0 ± 14.7, 22.2% experiencing IBD flare at inclusion). The medications at inclusion were none in 9.0%, oral (PO) monotherapy in 17.3%, subcutaneous (SC) injections in 29.2% and intra-venous (IV) infusions in 44.5% of the patients. The ANS were 8.68 ± 2.52 for PO, 7.67 ± 2.94 for SC and 6.79 ± 3.31 for IV (p < 0.001 for each comparison). The patients reported PO, SC and IV as their first choice in 65.8%, 21.4% and 12.8%, respectively. The reasons for reduced acceptability were the need to come to the hospital (63.0%) for IV infusion, none for SC injections and the fear to forget to take pills (30.5%), the number of daily dose (28.4%) and daily medication as a reminder of disease every day (24.8%) for PO therapy. In multivariable analyses, the following factors were associated with a better acceptability of IV infusion (current IBD flare: p = 0.003 and current IV therapy for IBD: p < 0.001), SC injections (Private practice: p = 0.006 and current SC injections for IBD: p < 0.001) and PO medication (male gender: p = 0.018, higher studies level: p < 0,001 and current oral medication: p = 0.002). The mean ANS for all IBD treatment regimen were compared in the 1850 patients (Figure 1). No difference was observed between CD and UC. In biologics-naïve patients (n = 315), the treatment regimens were ranked in the following order: PO once daily (8.8 ± 2.2), SC/12 weeks (week) (7.9 ± 3.0), SC/8 week and PO twice daily (7.2 ± 3.2 et 6.9 ± 3.4; ns), SC/4 week (6.2 ± 3.4), SC/2 week et IV/8 week (5.1 ± 3.4 and 5.0 ± 3.5; ns)(p < 0.001 except if ns was mentioned). For the patients, the acceptable loss of efficacy to receive a more convenient medication was 5.2% (non-inferiority trial limit). Conclusion While PO administration was preferred by most of IBD patients, the acceptability of treatment regimen is highly impacted by the interval between two doses and the previous medications. Our data could be helpful to guide therapeutic decision in daily practice in IBD.

International audience; Background Guidelines recommend using risk stratification tools in acute myocardial infarction (AMI) to assist decision-making. The Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS-2P) has been recently developed to characterize long-term risk in patients with MI. Hypothesis We aimed to assess the TRS-2P in the French Registry of Acute ST Elevation or non-ST elevation MI registries. Methods We used data from three 1-month French registries, conducted 5 years apart, from 2005 to 2015, including 13 130 patients with AMI (52% ST-elevation myocardial infarction [STEMI]). Atherothrombotic risk stratification was performed using the TRS-2P score. Patients were divided in to three categories: G1 (low-risk, TRS-2P = 0/1); G2 (intermediate-risk, TRS-2P = 2); and G3 (high-risk, TRS-2P >= 3). Baseline characteristics and outcomes were analyzed according to TRS-2P categories. Results A total of 12 715 patients (in whom TRS-2P was available) were included. Prevalence of G1, G2, and G3 was 43%, 24%, and 33% respectively. Clinical characteristics and management significantly differed according to TRS-2P categories. TRS-2P successfully defined residual risk of death at 1 year (C-statistic 0.78): 1-year survival was 98% in G1, 94% in G2, and 78.5% in G3 (P < 0.001). Using Cox multivariate analysis, G3 was independently associated with higher risk of death at 1 year (hazard ratio [HR] 4.61; 95% confidence interval [CI]: 3.61-5.89), as G2 (HR 2.08; 95% CI: 1.62-2.65) compared with G1. The score appeared robust and correlated well with mortality in STEMI and NSTEMI populations, as well as in each cohort separately. Conclusions The TRS-2P appears to be a robust risk score, identifying patients at high risk after AMI irrespective of the type of MI and historical period.

SummaryBackground Anti-tumour necrosis factor (TNF) agents have improved the care of Crohn's disease (CD). After the first anti-TNF discontinuation, it is possible to switch to another anti-TNF. Three anti-TNF agents are available for ulcerative colitis (infliximab, adalimumab and golimumab), but only the first 2 have been approved for CD because golimumab has not been studied for this indication. Aim To report the efficacy and safety of golimumab in CD. Methods Crohn's disease patients who received golimumab were identified in 12 French tertiary centres and were retrospectively analysed. The primary endpoint was the duration of golimumab treatment before escalation or discontinuation. The clinical response was defined as a decrease of more than 3 points in the Harvey-Bradshaw index or by global physician assessment. Results One hundred and fifteen patients were included. The golimumab treatment duration was 9.8 months (0.55-44), and 48.7% of the patients were still under treatment at the end of follow-up. Clinical response was observed in 55.8% of the patients after a mean duration of 3.8 months. The probability of remaining under treatment without escalation at 6, 12 and 24 months was 54.6%, 34.9% and 19.3% respectively. In multivariate analysis, discontinuation of the first anti-TNF agent due to intolerance (odds ratio, OR = 2.16; 95% CI, confidence interval [1.25-3.86]; P = .005) and co-immunosuppression for more than 6 months (OR = 3.98; 95% CI [2.3-7.1]; P < .0001) were predictive factors of efficacy. Six per cent of the patients discontinued treatment due to intolerance. Conclusion After failure of infliximab or adalimumab for Crohn's disease, golimumab was safe and seemed beneficial in half of the patients.

Introduction Le vedolizumab (VDZ) est un anticorps monoclonal humanise qui se fixe sur l’integrine α4β7, utilise dans le traitement des maladies inflammatoires chroniques intestinales (MICI). Nous decrivons le cas d’un patient atteint d’une gingivostomatite stomatite severe, apparue quelques jours apres la premiere dose de VDZ et qui a regresse apres l’arret du traitement. Observations Un homme âge de 31 ans traite par VDZ en 6e ligne de traitement pour une rectocolite hemorragique (RCH) severe, presentait cinq jours apres la premiere injection de VDZ, des lesions de la muqueuse buccale. Elles se s’aggravaient ( Fig. 1a ) apres la poursuite du traitement par VDZ, avec extension aux gencives et a la langue. Les corticoides topiques, per os et mesalazine etaient inefficaces. Les symptomes gastro-intestinaux du patient s’amelioraient. Les prelevements locaux bacteriologiques et viraux etaient negatifs. La biopsie de la muqueuse buccale montrait un infiltrat inflammatoire avec de nombreux polynucleaires neutrophiles et eosinophiles dans la lamina propria, et quelques cellules inflammatoires dans l’epiderme. Aucun granulome n’etait present. L’immunofluorescence directe ne montrait pas de depots immuns dans l’epithelium ou la membrane basale. Les anticorps anti-peau etaient tous negatifs, excluant les maladies bulleuses auto-immunes. Le VDZ etait implique et arrete. Les lesions buccales commencaient a s’ameliorer et avaient completement disparu dans les deux mois suivant la derniere injection de VDZ ( Fig. 1b ). Discussion Des ulcerations de la muqueuse buccale sont decrites chez des patients traites par anti-TNF et VDZ. Dubinski et al., dans Inflamm Bowel Dis en 2018, ont rapporte une incidence de la stomatite aphteuse trois fois plus elevee chez les patients traites par VDZ que par traitement par anti-TNF alpha, et l’ont decrite comme une manifestation extra-intestinale (MEI), au meme titre que le syndrome de Sweet, l’erytheme noueux ou la cholangite sclerosante. Dans notre cas, les lesions sont apparues quelques jours apres la premiere injection de VDZ et se sont aggravees dans les semaines qui ont suivi, malgre l’amelioration des symptomes de la maladie sous-jacente. Nous avons exclu les infections et les maladies bulleuses auto-immunes. Il n’y avait aucun antecedent de lesions buccales similaires chez ce patient. Plusieurs traitements, y compris les corticoides systemiques a forte dose, n’ont pas ameliore la stomatite. En revanche, c’est apres l’arret du VDZ que l’affection buccale a completement gueri. Au vu de l’evolution, nous pensons que la gingivostomatite est un effet secondaire direct du VDZ, plutot qu’une manifestation extra-intestinale de la maladie sous-jacente. Conclusion La gingivostomatite est un effet secondaire rare direct du VDZ, plutot qu’une MEI des MICI sous-jacentes. Les cliniciens doivent etre conscients de cet evenement indesirable, qui pourrait etre considere a tort comme une MEI des MICI.

Paragangliomas are rare tumors arising from extraadrenal chromaffin cells. We report a 43-year-old man who presented with abdominal pain. An abdominal computed tomography scan revealed a large retroperitoneal mass. During an endoscopic biopsy of this tumor, the patient experienced marked hemodynamic fluctuations with tachycardia and high blood pressure, and an extraadrenal pheochromocytoma was suspected. Measurements of plasma and urinary catecholamines and urinary total metanephrines ruled in the diagnosis. Echocardiography disclosed acute myocardial dysfunction that returned to normal after surgical resection of the paraganglioma. This report also underlines the importance of the anesthetic preparation and monitoring around the surgical procedure and the need of a long-term follow-up to detect malignant paraganglioma in the absence of histological criteria of benign tumor.

Les maladies inflammatoires chroniques intestinales (MICI), maladie de Crohn et rectocolite hemorragique, ont une incidence croissante a travers le monde. Il existe une augmentation du risque thromboembolique veineux au cours des MICI. Cet etat pro-coagulant n’est pas lie a des anomalies genetiques de l’hemostase mais a des facteurs acquis secondaires a l’etat inflammatoire. Ce risque est au moins multiplie par deux en comparaison a la population generale, et est lie a l’activite de la maladie. Ces complications sont actuellement une des premieres causes de mortalite chez les patients atteints de MICI. La majorite des accidents thrombotiques veineux surviennent en ambulatoire ou le risque semble superieur. La prevention medicamenteuse est recommandee en cas d’hospitalisation, elle devrait aussi s’imposer en cas de maladie active en ambulatoire. Plusieurs travaux ont montre que ce risque etait peu connu des gastro-enterologues et que la prevention thromboembolique recommandee n’etait pas respectee en pratique clinique. Independamment des facteurs de risques cardiovasculaires classiques, l’inflammation systemique associee aux MICI actives est responsable d’une augmentation du risque de complications cardiovasculaires telles que l’infarctus du myocarde, l’accident vasculaire cerebral, ainsi qu’a la mortalite cardiovasculaire. A la difference des pathologies inflammatoires articulaires, l’impact des immunosuppresseurs et des traitements biologiques sur le risque cardiovasculaire des patients atteints de MICI reste a demontrer. Il n’existe pas de recommandation sur la prise en charge du risque cardiovasculaire chez ces patients. La prevention et le depistage de ces complications devraient cependant faire partie de leur prise en charge globale et les professionnels de sante devraient etre informes sur ces risques.

Introduction L’ipilimumab (IPI), le pembrolizumab (PZM) et le nivolumab (NVM) sont des anticorps monoclonaux indiques pour le traitement du melanome metastatique. Le premier inhibe le CTLA-4 et les suivants le PD-1. Les colites auto-immunes (CAI) sont des effets indesirables connus de ces medicaments, mais les colites infectieuses sont peu decrites. Patients et methodes Etude retrospective analysant tous les cas de CAI compliques d’infection a Clostridium difficile (CD) dans les CHU d’Amiens, Lille et Rouen entre 2010 et 2015. Observations Trois patients avaient developpe une CAI apres 1 a 2 cures d’IPI en premiere ligne pour un melanome metastatique. Une CAI etait apparue chez un quatrieme malade apres la cinquieme cure de PZM en deuxieme ligne apres IPI. Les CAI, de grade 2 a 3, avaient toutes ete traitees par corticotherapie orale ou IV a forte dose, dans un cas avec infliximab. Une colite a CD avait ete diagnostiquee dans un delai de 1 jour a 3 mois apres le debut de la CAI. Le traitement avait ete difficile, necessitant plusieurs lignes d’antibiotiques pour les cas 1, 2 et 4 (metronidazole, vancomycine et fidaxomicine). Aucune complication grave n’etait relevee. Discussion Les CAI sont observees chez respectivement 8 et 2 % des patients traites par IPI et PZM. Leur presentation clinique est variable, souvent sous forme de diarrhee glairo-sanglante, parfois grave. L’aspect endoscopique va de l’erytheme aux ulcerations creusantes. L’histologie est aspecifique. La corticotherapie, puis les anti-TNF alpha sont le traitement de reference. Les surinfections bacteriennes des CAI sont peu rapportees. Les CAI sont souvent comparees aux MICI, avec des similitudes phenotypiques, immunologiques et therapeutiques. Comme dans les MICI, il pourrait exister une augmentation du risque d’infection a CD lors des CAI, favorisee par les alterations du microbiote, les modifications de la reponse immunitaire locale et les immunosuppresseurs. La presentation clinique (de la diarrhee aqueuse benigne au syndrome dysenterique) et endoscopique (d’un aspect normal a la colite pseudomembraneuse) de l’infection a CD etant tres variable, la recherche de CD et de ses toxines dans les selles devrait etre systematique en cas de diarrhee sous anti-CTLA-4 ou anti-PD-1, avant l’introduction d’une corticotherapie ou d’infliximab. Le traitement par metronidazole ou vancomycine oral doit etre precoce avant le resultat des prelevements en cas de critere de gravite. Comme dans les MICI, les infections a CD des CAI sont marquees dans notre serie par l’absence d’antibiotherapie prealable, dans 3 cas sur 4 par une diarrhee glairo-sanglante, par l’absence de pseudomembrane et par une moindre sensibilite au metronidazole. En revanche, les formes graves ne sont pas frequentes. Conclusion Nous decrivons 4 cas d’infection a CD suivant une CAI sous anti-CTLA-4 ou anti-PD-1. Une recherche de CD et de ses toxines dans les selles doit etre systematique en cas de diarrhee sous ces traitements.

Paragangliomas are rare tumors arising from extraadrenal chromaffin cells. We report a 43-year-old man who presented with abdominal pain. An abdominal computed tomography scan revealed a large retroperitoneal mass. During an endoscopic biopsy of this tumor, the patient experienced marked hemodynamic fluctuations with tachycardia and high blood pressure, and an extraadrenal pheochromocytoma was suspected. Measurements of plasma and urinary catecholamines and urinary total metanephrines ruled in the diagnosis. Echocardiography disclosed acute myocardial dysfunction that returned to normal after surgical resection of the paraganglioma. This report also underlines the importance of the anesthetic preparation and monitoring around the surgical procedure and the need of a long-term follow-up to detect malignant paraganglioma in the absence of histological criteria of benign tumor.

Background Articular manifestations are the most common extra-intestinal manifestations associated to inflammatory bowel diseases (IBD). They are named “paradoxical” when they occur during treatment, notably anti-TNF drugs, that are expected to prevent or at least treat them. Objectives The aim of this study was to assess the frequency, the characteristics and the associated factors of paradoxical articular manifestations during anti-TNF treatment for IBD. Methods In this prospective single-center study, a rheumatological examination was systematically proposed to all IBD patients treated with infliximab (IFX) or adalimumab (ADA) to assess the prevalence of articular manifestations and distinguish those related to IBD treatment of those associated with IBD. Paradoxical manifestations were defined by the occurrence of articular manifestations (excluding induced-lupus and hypersensitivity reaction) during anti-TNF therapy in a patient in IBD intestinal remission. Dosage of biological inflammatory (WBC, ESR,CRP) immunological markers (immunoglobulins, anti-nuclear antibody (Ab), anti-DNA Ab, anti-CCP Ab, complement factor, rheumatoid factor, ASCA) and HLA-B27 allele and through serum IFX and anti-IFX Ab were systematically performed. Results Between May 2013 to April 2014, 79 patients with Crohn9s disease (CD) and 20 ulcerative colitis (UC) treated with IFX (n=80) or ADA (n=19) were included. Immunosuppressors (azathioprine/methotrexate) were associated in 12% of cases. Articular manifestations were observed in 50 (62%) patients treated by IFX and 12 (63%) patients treated by ADA. Twelve percent (n=12) were considered associated to IBD and 16% (n=16) associated to anti-TNF therapy. Among patients with articular manifestations associated to anti-TNF therapy, we identified 12% (n=12) of paradoxical effects, 2% (n=2) of induced lupus and 2% (n=2) of hypersensitivity reaction. Among the 12 patients with paradoxical effects during IFX (n=9) or ADA (n=3) therapy, 11 were treated for CD and presented peripheral arthritis; 3 patients presented a spondyloarthropathy. Paradoxical cutaneous manifestations (psoriasis) were associated in 25% of cases. The median duration of anti-TNF therapy was 47 months (Q1=30-Q3=77). No patient has discontinued anti-TNF because of the articular manifestations. Three patients were treated with methotrexate. No clinical or biological factors were associated with the occurrence of paradoxical manifestations. Conclusions Paradoxical articular manifestations in IBD patients treated by anti-TNF are common, affecting more than 10% of patients. These events are generally mild and not followed by the discontinuation of anti-TNF drugs Disclosure of Interest None declared

Introduction Les descriptions des eruptions psoriasiformes paradoxales sous anti-TNF au cours des maladies inflammatoires chroniques intestinales (MICI) sont issues d’etudes retrospectives, avec des facteurs de risque suspectes mais encore jamais demontres de maniere prospective. Le but de cette etude etait d’identifier de facon prospective les facteurs cliniques associes au risque de survenue d’un effet paradoxal des anti-TNF au cours du traitement des MICI. Patients et methodes Il s’agissait d’une etude prospective, portant sur la realisation d’un examen cutane systematique chez les patients adultes traites par anti-TNF pour MICI, incites par les gastro-enterologues du CHU a consulter dans le service de dermatologie sur une periode d’1 an. L’objectif primaire etait de deceler les eruptions psoriasiformes paradoxales et d’en determiner les facteurs de risque. Resultats Entre fevrier 2012 et mars 2013, sur 89 patients adresses par les gastro-enterologues, 68 patients se sont presentes a leur consultation et ont ete inclus. L’âge moyen des patients etait de 40,2 ans (19–78), dont 68,2 % de femmes, suivis pour un Crohn (83,3 %) ou une RCH (16,7 %), traites par infliximab (68,2 %) ou adalimumab (31,8 %.). Au total, 26 patients (38,2 %) presentaient une eruption psoriasiforme paradoxale avec une atteinte privilegiee des plis (34,6 %), des zones bastions (genoux, coudes, face d’extension des avants bras, sacrum) (30,7 %), du cuir chevelu (26,9 %) et palmoplantaire (19,2 %). Le delai median d’apparition etait de 31,1 mois (1–120), avec un delai median 2 fois plus long sous infliximab que sous adalimumab (32,7 mois vs 16,4 mois). En analyse univariee, la survenue d’une eruption psoriasiforme etait significativement associee au surpoids ( p = 0,03), a un antecedent personnel d’eczema ( p = 0,01), au tabagisme ( p = 0,02), a l’utilisation anterieure d’un immunosuppresseur ( p = 0,05). En multivariee, seul le surpoids etait significativement associe a une eruption paradoxale psoriasiforme (OR 10,91 ; IC 95 %, 1,40–84,8). La majorite des patients etaient traites par topiques seuls (20/26), avec un recourt peu frequent a la phototherapie (3/26), a l’acitretine (2/26) et methotrexate (1/26). Le suivi a constate 7 echecs therapeutiques avec necessite d’un switch (2 cas) ou d’un arret definitif des anti-TNF (2 cas). Conclusion Meme si la proportion d’effets paradoxaux est peut etre surestimee dans notre etude, notre etude revele que la decouverte de cet effet indesirable au degre de severite variable est frequent au cours d’un examen dermatologique systematique. Notre etude a permis de conforter le role des facteurs de risque suspectes dans la litterature (antecedent d’eczema, surpoids, tabagisme) et d’en suggerer d’autre (antecedent de prise d’immunosuppresseur). Dans la majorite des cas, les traitements dermatologiques ont permis la poursuite de l’anti-TNF.