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Aim: The aim of this study was to evaluate the real-life clinical and radiological efficacy of darvadstrocel injection into complex perianal fistulas in Crohn's disease. Secondary endpoints were to assess symptomatic efficacy, adverse effects and factors associated with complete combined clinical-radiological response (deep remission)., Methods: After marketing the product in France, all first patients treated consecutively were included. A complete clinical response was defined by a complete closure of all external openings with no discharge on pressure. A complete radiological response (MRI), evaluated at least after six months of follow-up, was defined by a completely fibrotic sequela without abscess. A deep remission was defined as the association of a complete clinical response with a complete radiological response., Results: A total of 43 patients were included (M/F: 22/21, median age 37 [26-45] years). The fistulas were already drained with seton(s) and were on biologic treatment. After a median follow-up of 383 (359-505) days, 28 (65%) patients showed a clinical response (22 complete and 6 partial) and 16 (37%) achieved a deep remission. The Perineal Disease Activity Index decreased significantly after treatment: 39 (91%) patients reported symptomatic improvement in terms of discharge, pain, and induration, and 28 (65%) no longer had any perineal symptoms. No severe adverse events were reported. A short history of Crohn's disease <3 years was significantly associated with deep remission (OD 4.5 [1.0-19.1], p = 0.04)., Conclusion: Darvadstrocel injection resulted in a clinical response for two thirds of patients and deep remission for one third. A shorter duration of Crohn's disease was associated with deep remission., (© 2023 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Introduction: Anal ulcerations are frequently observed in Crohn's disease (CD). However, their natural history remains poorly known, especially in pediatric-onset CD., 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. At diagnosis and during follow-up, the clinical and therapeutic features of perianal disease were recorded. An adjusted time-dependent Cox model was used to evaluate the risk of evolution of anal ulcerations toward suppurative lesions., Results: Among the 1,005 included patients (females, 450 [44.8%]; median age at diagnosis 14.4 years [interquartile range 12.0-16.1]), 257 (25.6%) had an anal ulceration at diagnosis. Cumulative incidence of anal ulceration at 5 and 10 years from diagnosis was 38.4% (95% confidence interval [CI] 35.2-41.4) and 44.0% (95% CI 40.5-47.2), respectively. In multivariable analysis, the presence of extraintestinal manifestations (hazard ratio [HR] 1.46, 95% CI 1.19-1.80, P = 0.0003) and upper digestive location (HR 1.51, 95% CI 1.23-1.86, P < 0.0001) at diagnosis were associated with the occurrence of anal ulceration. Conversely, ileal location (L1) was associated with a lower risk of anal ulceration (L2 vs L1 HR 1.51, 95% CI 1.11-2.06, P = 0.0087; L3 vs L1 HR 1.42, 95% CI 1.08-1.85, P = 0.0116). The risk of fistulizing perianal CD (pCD) was doubled in patients with a history of anal ulceration (HR 2.00, 95% CI 1.45-2.74, P < 0.0001). Among the 352 patients with at least 1 episode of anal ulceration without history of fistulizing pCD, 82 (23.3%) developed fistulizing pCD after a median follow-up of 5.7 years (interquartile range 2.8-10.6). In these patients with anal ulceration, the diagnostic period (pre vs biologic era), exposure to immunosuppressants, and/or anti-tumor necrosis factor did not influence the risk of secondary anoperineal suppuration., Discussion: Anal ulceration is frequent in pediatric-onset CD, with nearly half of patients presenting with at least 1 episode after 10 years of evolution. Fistulizing pCD is twice as frequent in patients with present or past anal ulceration., (Copyright © 2023 by The American College of Gastroenterology.)

Background: The most effective treatment for anal fistula is fistulotomy, but it involves a risk of anal incontinence. To reduce this morbidity, sphincter-sparing treatments have been developed, but their success in real life is often less than 50%. The aim is to determine the clinical healing rate 6 months after radiofrequency treatment., Methods: We planned to evaluate 50 patients from three French proctology centres. Treatment efficacy was evaluated at 6 and 12 months by means of clinical and magnetic resonance imaging examination. We evaluated morbidity and healing prognostic factors., Results: Fifty patients with a mean age of 51 years (22-82) were included. Eleven patients had a low trans-sphincteric fistula (LTS), 21 patients had a high trans-sphincteric fistula (HTS), eight had a complex fistula and nine had Crohn's disease fistula. After 6 months, 17 patients (34.7%) had a clinically healed fistula, including five (45.5%) with LTS fistula, seven (33.3%) with HTS fistula, one (12.5%) with complex fistula, four (44.4%) with Crohn's disease, with no significant difference between these fistula types (p: 0.142). At 12 months, the healing rate was identical. MRI in 15 out of 17 clinically healed patients showed a deep remission of 73.3% at 12 months. Energy power was associated with the success of the treatment. There was an 8.2% incidence of post-surgical complications with 4.1% being abscesses (one required surgical management). Postoperative pain was minor. No new cases or deterioration of continence have been shown., Conclusion: Radiofrequency is effective in 34.7% of the cases as an anal fistula treatment in this first prospective study, with low morbidity and no effect on continence. Clinical healing was deep (MRI) in three-quarters at 1 year. The increase in energy power during the procedure seems to be a key point to be analysed to optimise results., (© 2022 Association of Coloproctology of Great Britain and Ireland.)

Aim: The aim of our study was to assess the best medical and surgical approaches for perianal Crohn's disease (PCD) in order to identify an optimal combined medical and surgical treatment., Methods: Medical records of all patients with PCD treated with TNFα antagonists in two referral centres between 1998 and 2018 were reviewed. Predictors of long-term outcomes were identified using a Cox proportional hazard model., Results: A total of 200 patients were included. Fifty-three patients (26.5%) were treated with adalimumab and 147 (73.5%) with infliximab. A combination of TNFα antagonist with an immunosuppressant and the presence of proctitis were independently associated with fistula closure. Seton was placed in 127 patients (63.5%) before starting biological therapy. Eighty patients (40%) underwent additional perineal surgery. Prior PCD surgery, seton positioning, additional perineal surgery, and additional surgery within 52 weeks of anti-TNFα treatment were associated with an increased rate of fistula closure. Finally, medical combination therapy (anti-TNFα plus immunosuppressant) along with seton placement and additional surgery within 1 year was the best management for PCD patients (p = 0.02)., Conclusion: Combined medical and surgical management is required for the treatment of PCD patients. Medical combination therapy associated with seton placement and additional surgery within 1 year is the best management for PCD patients., (© 2022 Association of Coloproctology of Great Britain and Ireland.)

Background: No study has performed a face-to-face comparison of biologics after the failure of the first anti-TNF agent in patients with Crohn's disease (CD). The aim of the study was to compare the efficacy of biologics in this setting., Methods: Patients with CD who were refractory to a first anti-TNF agent, and treated with ustekinumab (UST), vedolizumab (VDZ), or a second anti-TNF drug as a second-line biological agent at 10 French tertiary centres from 2013 to 2019 were retrospectively included in this study., Results: Among the 203 patients included, 90 (44%) received UST, 42 (21%) received VDZ and 71 (35%) received a second anti-TNF agent. The first anti-TNF agent was discontinued due to a primary nonresponse in 42 (21%) patients. At weeks 14-24, the rates of steroid-free remission were similar between the UST, VDZ and second anti-TNF groups (29%, 38% and 44%, respectively, p = 0.15). With a mean follow-up of 118 weeks, drug survival was shorter for patients who received ustekinumab treatment (p = 0.001). In the case of trough level less than 5 µg/ml, patients treated with a second anti-TNF agent had a higher postinduction remission rate (p = 0.002), and drug survival (p = 0.0005). No other relevant factors were associated with treatment efficacy, including trough levels greater than 5 µg/ml., Conclusions: VDZ, UST and a second anti-TNF agent exhibit similar efficacy in the short term, as second-biological line treatment in patients with CD who are refractory to a first anti-TNF agent, but shorter drug maintenance is observed for patients treated with UST., (© 2022. The Author(s).)

Background: The identification of early prognostic factors during Crohn's disease (CD) remains needed for physician decision-making to minimize structural bowel damage, which this study aimed to assess in a population-based setting., Methods: All incident cases of CD were prospectively registered from 1994 to 1997 in Brittany, a limited area of France. All charts of patients were reviewed from the diagnosis to the last clinic visit in 2015. Disabling CD course was defined according to the Saint-Antoine criteria., Results: Among the 331 incident cases of CD, 272 (82%) were followed-up for a median time of 12.8 years. The cumulative probability of developing stricturing or fistulizing CD was 66% at 15 years, and 107 (39%) patients underwent surgery. The cumulative probabilities of immunosuppressant and TNF antagonist use at 15 years were 37% and 22%, respectively. The cumulative risks for disabling disease and bowel damage were 74% and 71% at 15 years, respectively. Systemic symptoms and perianal lesions at diagnosis were independently associated with a disabling disease course. Perianal disease and short disease extension were associated with the onset of bowel damage. Deep ulcers was not predictive of any outcome., Conclusions: A disabling disease course and bowel damage occurred early in the course of CD, which suggests the need for early diagnosis and early treatment, particularly for patients with systematic symptoms and perianal disease., Competing Interests: Declaration of Competing Interest ALM, AD, LBH, KC, CB, and CB received lecture fees from IPSEN. CR, BB, and LS received lecture fees from Abbvie, Amgen, Ferring, Janssen, MSD, and Takeda and consultant fees from Takeda. GB received lecture fees from Abbvie, Ferring, MSD, Takeda and Pfizer and consultant fees from Takeda, Janssen, Mylan, and Abbvie. VB and AN declared no conflict of interest., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Since our last publication of algorithms for the management of perianal fistulas in patients with Crohn's disease, researchers have proposed a treat to target strategy systematic combotherapy for anal lesions, and indications for stem cell injection. In the absence robust publications, the Société Nationale Française de Coloproctologie (French National Society of Coloproctology [SNFCP]) wished to establish a group consensus using the Delphi method., Methods: From October 2020 to January 2021, a scientific committee and panel of gastroenterologists and surgeons established answers which were submitted to the members of the SNFCP during a national conference in November 2020. Three questions were clarified and reformulated, and then submitted during a third and final round of consultation of members of the SNFCP., Results: The target was defined as being the response obtained in every domain (symptoms, physical and radiological evaluation) which could be considered satisfactory, without the need to intensify therapeutic management. By consensus, the time required for clinical evaluation of the efficacy of treatment was 6 months. A response on magnetic resonance imaging (MRI) should include the absence of a collection of 10 mm or more in size at 6 months, and a frank decrease or complete disappearance of hyperintensity in T1 and T2 sequences of the main tract at 12 months. Systematic association of an immunosuppressant with tumor necrosis factor inhibitors did not reach the consensus level for adalimumab (50%), but just did for infliximab (70%). The majority of the respondents considered failure of one, or even two lines of different biotherapies to be potential indications for injection of stem cells., Conclusions: These findings reinforce the importance of composite targets including MRI evaluation, and underscore the need for precise timing of evaluation. Combotherapy is only recommended with infliximab. Injection of stem cells is a second- or third-line option., (© 2022. Springer Nature Switzerland AG.)

Background: Crohn's disease (CD) is complicated by perianal fistulas in approximately 20% of patients. Achieving permanent fistula closure remains a challenge for physicians. An association between serum anti-tumor necrosis factor-α concentrations and clinical outcomes in patients with CD has been demonstrated; however, little information is available on serum adalimumab (ADA) concentrations and remission of perianal fistulas in such patients., Aim: To study the relationship between serum ADA concentrations and clinical remission of CD-associated perianal fistulas., Methods: This cross-sectional study of patients with CD-associated perianal fistulas treated with ADA was performed at four French hospitals between December 2013 and March 2018. At the time of each serum ADA concentration measurement, we collected information about the patients and their fistulas. The primary study endpoint was clinical remission of fistulas defined as the absence of drainage (in accordance with Present's criteria), with a PDAI ≤ 4, absence of a seton and assessment of the overall evaluation as favorable by the proctologist at the relevant center. We also assessed fistula healing [defined as being in clinical and radiological (magnetic resonance imaging, MRI) remission] and adverse events., Results: The study cohort comprised 34 patients who underwent 56 evaluations (patients had between one and four evaluations). Fifteen patients had clinical remissions (44%), four of whom had healed fistulas on MRI. Serum ADA concentrations were significantly higher at evaluations in which clinical remission was identified than at evaluations in which it was not [14 (10-16) vs 10 (2-15) μg/mL, P = 0.01]. Serum ADA concentrations were comparable at the times of evaluation of patients with and without healed fistulas [11 (7-14) vs 10 (4-16) μg/mL, P = 0.69]. The adverse event rate did not differ between different serum ADA concentrations., Conclusion: We found a significant association between high serum ADA concentrations and clinical remission of CD-associated perianal fistulas., Competing Interests: Conflict-of-interest statement: Sirmai L reports having received grant support from Abbvie and congress invitations from Roche and Sandoz and having received conference or consultancy fees from Gilead, MSD, Abbvie, Mayoly Spindler, Takeda, Ipsen, Allergan France and Ferring; Pelletier AL reports having received grant support from Abbvie and financial support from Ferring; Zallot C reports having received financial support from Takeda, Abbvie, Ferring, Janssen and Pfizer; Bouguen G reports having received lecture fees from Abbvie, Ferring, MSD, Takeda and Pfizer and consultant fees from Takeda, Janssen, Mylan and Abbvie; Bouchard D reports having received speaking fees from Abbvie, MSD and Janssen, consultancy fees from Takeda, and congress invitations from Abbvie, Pfizer and Takeda; Gault N, Roland Nicaise P, Peyneau M, Sironneau S, Bittencourt M, Petitcollin A, Fernandez P all declare they have no conflicts of interest; Roblin X reports having received financial support from Abbvie, Amgen, Pfizer, Takeda, Janssen, MSD and Theradiag; Siproudhis L reports having received conference or consultancy fees from Gilead, MSD, Abbvie, Mayoly Spindler, Takeda, Ipsen, Allergan France and Ferring; Abramowitz L reports having received grant support from Abbvie and financial support from Takeda., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: The natural history of perianal Crohn's disease (PCD) remains poorly described and is mainly based on retrospective studies from referral centers. The aim of this study was to assess the incidence, outcomes and predictors of the onset of PCD., Methods: All incident cases of patients diagnosed with possible CD were prospectively registered from 1994 to 1997 in Brittany, a limited area in France. At diagnosis, the clinical features of perianal disease were recorded. All patient charts were reviewed from the diagnosis to the last clinic visit in 2015., Results: Among the 272 out of 331 incident CD patients followed up, 51 (18.7%) patients had PCD at diagnosis. After a mean follow-up of 12.8 years, 93 (34%) patients developed PCD. The cumulative probabilities of perianal CD occurrence were 22%, 29%, and 32% after 1 year, 5 years, and 10 years, respectively. The cumulative probabilities of anal ulceration were 14%, and 19% after 1 year and 10 years, respectively. Extraintestinal manifestations were associated with the occurrence of anal ulceration. The cumulative probabilities of fistulizing PCD were 11%, 16%, and 19% after 1 year, 5 years, and 10 years, respectively. Extraintestinal manifestations, rectal involvement and anal ulceration were predictors of fistulizing PCD. The cumulative probability of developing anal stricture was 4% after 10 years., Conclusions: PCD is frequently observed during CD, in approximately one-third of patients. These data underline the need for targeted therapeutic research on primary perianal lesions (proctitis, anal ulceration) to avoid the onset of fistulizing perianal disease., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim: In patients with fistulizing perianal Crohn's disease (CD), the need for a secondary surgical step is not defined. The aim was to assess the efficacy of surgical closure compared to a single seton removal in patients with drained fistulizing perianal CD treated with adalimumab., Methods: This was a multicentre, randomized controlled trial, comparing seton removal + surgical closure (closure group) to seton removal alone (control group) with a stratification according to the American Gastroenterological Association classification. The primary end-point was fistula closure at month 12 defined by the association of the following criteria: no seton, absence of a visible external opening, absence of discharge from the tract after finger compression, absence of an internal opening, absence of perianal pain/abscess and absence of fistula-related abnormalities., Results: Among the 64 included patients (262 expected) (48 complex fistula, 75%), 33 were randomized to the closure group and 31 to the control group. In the closure group, 26 patients (78.8%) had glue. At month 12, overall fistula closure was achieved in 35 of the evaluable 58 patients (60%): 18/32 (56%) in the surgery group and 17/26 (65%) in the control group (P = 0.479). In the closure group, fistula closure was observed in 13/25 (52%) and 5/7 (71%) patients with complex and simple fistula respectively (P = 0.426), compared with 12/18 (67%) and 5/8 (63%), respectively in the control group (P = 1.000)., Conclusions: Seton removal alone seems to be no more effective than a secondary surgical step (in particular glue injection) in patients having fistulizing perianal CD controlled by an initial drainage combined with adalimumab. The results should be interpreted with caution., (© 2021 Association of Coloproctology of Great Britain and Ireland.)

Background & Aims: Infliximab increases the risk of infection in patients with inflammatory bowel diseases (IBD), but there is controversy over the relationship between drug concentration and infections. We aimed to assess factors associated with infection in infliximab-treated patients, including pharmacokinetic features., Methods: We collected data from 209 patients with IBD (102 men; mean age, 39 y; 159 with Crohn's disease; 54 received combination therapy) who received an infliximab maintenance regimen from November 2016 through April 2017 in France. Data were collected from each infusion visit (total of 640 infusions). Infliximab exposure was estimated based on the area under the curve (AUC) of drug concentration in pharmacokinetic models; individual exposures over the 6-month period were estimated based on the sum of the AUC (ΣAUC)., Results: The mean infliximab trough level was 5.46 mg/L, and the mean ΣAUC was 3938 ± 1427 mg.d/L. A total of 215 infections were collected from the 640 infusion visits; 123 patients (59%) had at least 1 infection. Factors independently associated with infection after multivariate analysis were smoking (odds ratio [OR], 2.05; P = .046), IBD flare (OR, 2.71; P = .006), and a high ΣAUC of infliximab (above 3234 mg x d/L) (OR, 2.02; P = .02). The ΣAUC was higher in patients with an occurrence of infection (P = .04) and correlated with the number of infections (P = .04). Trough concentration of infliximab alone was not associated with infection., Conclusions: Almost two-thirds of patients treated with infliximab developed an infection; risk was individually correlated with cumulative increase in drug exposure, but not infliximab trough level., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim: The medico-surgical strategy for the treatment of perianal fistulizing Crohn's disease (CD) following surgical drainage remains challenging and debated. Our aims were to describe the failure rate of therapeutic interventions after drainage of the fistula tract and determine the factors associated with failure to optimize medico-surgical strategies., Method: All consecutive patients with perianal fistulizing CD who underwent surgical drainage with at least a 12-week follow-up were included. Failure was defined as the occurrence of at least one of the following items: abscess recurrence, purulent discharge from the tract, visible external opening and further drainage procedure(s)., Results: One hundred and sixty-nine patients were included. The median follow-up was 4.0 years. The cumulative failure rates were 20%, 30% and 36% at 1, 3 and 5 years, respectively. The cumulative failure rates in patients who had sphincter-sparing surgeries or seton removal were significantly higher than in those who had a fistulotomy. Anterior fistula [hazard ratio (HR) = 2.52 (1.13-5.61), P = 0.024], supralevator extension [HR = 20.78 (3.38-127.80), P = 0.001] and the absence or discontinuation of immunosuppressants after anal drainage [HR = 3.74 (1.11-12.5), P = 0.032] were significantly associated with failure in the multivariate analysis model., Conclusion: Combined strategies for perianal fistulizing CD lead to a failure rate of 36% at 5 years. Where advisable, fistulotomy may be preferred because it has a lower rate of recurrence. The benefits of immunosuppressants require a dedicated prospective randomized trial., (© 2020 Association of Coloproctology of Great Britain and Ireland.)

Background and Aims: Inflammatory bowel diseases [IBD] are disabling disorders. The IBD-Disability Index [IBD-DI] was developed for quantifying disability in IBD patients but is difficult to use. The IBD-Disk is a visual adaptation of the IBD-DI. It has not been validated yet. The main objectives were to validate the IBD-Disk and to assess the clinical factors associated with a change in the score and its variability over time., Methods: From May 2018 to July 2019, IBD patients from three university-affiliated hospitals responded twice to both IBD-Disk and IBD-DI at 3-12 month intervals. Validation included concurrent validity, reproducibility, and internal consistency. Mean IBD-Disk scores were compared according to clinical factors. Variability was assessed by comparing scores between baseline and follow-up visits., Results: A total of 447 patients [71% Crohn's disease, 28% ulcerative colitis] were included in the analysis at baseline and 265 at follow-up. There was a good correlation between IBD-Disk and IBD-DI [r = 0.75, p <0.001]. Reproducibility was excellent [intra-class correlation coefficient = 0.90], as well as internal consistency [Cronbach's α = 0.89]. The IBD-Disk was not influenced by IBD type but was associated with female gender and physician global assessment. Extra-intestinal manifestations, history of resection, elevated C-reactive protein and faecal calprotectin also tended to be associated with higher disability. The IBD-Disk score decreased in patients becoming inactive over time., Conclusions: This study validated the IBD-Disk in a large cohort of IBD patients, demonstrating that it is a valid and reliable tool for quantifying disability for both CD and UC., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: New therapeutic options for patients with Crohn's disease (CD) with perianal lesions failing anti-tumor necrosis factor (TNF) agents are needed. We aimed to assess the effectiveness of ustekinumab in perianal CD (pCD) and predictors of clinical success in a real-life multicenter cohort., Methods: We conducted a national multicenter retrospective cohort study in patients with either active or inactive pCD who received ustekinumab. In patients with active pCD at treatment initiation, the success of ustekinumab was defined by clinical success at 6 months assessed by the physician's judgment without additional medical or surgical treatment for pCD. Univariate and multivariable logistic regression analyses were performed to identify predictors of success. In patients with inactive pCD at ustekinumab initiation, the pCD recurrence-free survival was calculated using the Kaplan-Meier method., Results: Two hundred seven patients were included, the mean age was 37.7 years, the mean duration of CD was 14.3 years, and the mean number of prior perianal surgeries was 2.8. Two hundred five (99%) patients had previously been exposed to at least 1 anti-TNF and 58 (28%) to vedolizumab. The median follow-up time was 48 weeks; 56/207 (27%) patients discontinued therapy after a median time of 43 weeks. In patients with active pCD, success was reached in 57/148 (38.5%) patients. Among patients with setons at initiation, 29/88 (33%) had a successful removal. The absence of optimization was associated with treatment success (P = 0.044, odds ratio 2.74; 95% confidence interval: 0.96-7.82). In multivariable analysis, the number of prior anti-TNF agents (≥3) was borderline significant (P = 0.056, odds ratio 0.4; 95% confidence interval: 0.15-1.08). In patients with inactive pCD at initiation, the probability of recurrence-free survival was 86.2% and 75.1% at weeks 26 and 52, respectively., Discussion: Ustekinumab appears as a potential effective therapeutic option in perianal refractory CD. Further prospective studies are warranted.

Introduction: Most studies of elderly-onset Crohn's disease [CD; diagnosed in patients aged 60 or over] have described a mild course. However, data on the natural history of perianal fistulising CD [pfCD] in this population are scarce. In a population-based cohort study, we described the prevalence, natural history, and treatment of pfCD in patients with elderly-onset CD vs patients with paediatric-onset CD., Method: All patients diagnosed with CD at or after the age of 60 between 1988 and 2006, were included [n = 372]. Logistic regression, Cox models, and a nested case-control method were used to identify factors associated with pfCD., Results: A total of 34 elderly patients [9% of the 372] had pfCD at diagnosis. After a median follow-up of 6 years (interquartile range [IQR]: 3; 10), 59 patients [16%] had pfCD; the same prevalence [16%] was observed in paediatric-onset patients. At last follow-up, anal incontinence was more frequent in elderly patients with pfCD than in elderly patients without pfCD [22% vs 4%, respectively; p < 10-4]. Rectal CD at diagnosis was associated with pfCD: hazard ratio (95% confidence interval [CI] = 2.8 [1.6-5.0]). Although 37% of the patients received immunosuppressants and 17% received anti-tumour necrosis factor agents, 24% [14 out of 59] had a definitive stoma at last follow-up., Conclusion: During the first 6 years of disease, the prevalence of pfCD was similar in elderly and paediatric patients. Rectal involvement was associated with the appearance of pfCD in elderly-onset patients. Around a quarter of patients with elderly-onset CD will have a stoma. Our results suggest that treatment with biologics should be evaluated in these patients., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: Few data are available on the effects of tumor necrosis factor (TNF) antagonist therapy for patients with internal fistulizing Crohn's disease (CD) and there is debate regarding the risk of abscess. We aimed to assess the long-term efficacy and safety of anti-TNF therapy for patients with internal fistulas., Methods: We performed a retrospective study of data collected from the Groupe d'Etude Thérapeutique des Affections Inflammatoires Digestives trial, from January 1, 2000, through December 31, 2017. Our final analysis included 156 patients who began treatment with an anti-TNF agent for CD with internal fistula (83 men; median disease duration, 4.9 y). The primary end point was the onset of a major abdominal surgery. Secondary analysis included disappearance of the fistula tract during follow-up evaluation and safety. The Kaplan-Meier method was used for statistical analysis., Results: After a median follow-up period of 3.5 years, 68 patients (43.6%) underwent a major abdominal surgery. The cumulative probabilities for being surgery-free were 83%, 64%, and 51% at 1, 3, and 5 years, respectively. A concentration of C-reactive protein >18 mg/L, an albumin concentration <36 g/L, the presence of an abscess at the fistula diagnosis, and the presence of a stricture were associated independently with the need for surgery. The cumulative probabilities of fistula healing, based on imaging analyses, were 15.4%, 32.3%, and 43.9% at 1, 3, and 5 years, respectively. Thirty-two patients (20.5%) developed an intestinal abscess and 4 patients died from malignancies (3 intestinal adenocarcinomas). One patient died from septic shock 3 months after initiation of anti-TNF therapy., Conclusions: In a retrospective analysis of data from a large clinical trial, we found that anti-TNF therapy delays or prevents surgery for almost half of patients with CD and luminal fistulas. However, anti-TNF therapy might increase the risk for sepsis-related death or gastrointestinal malignancies., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Any gastroenterologist must be trained to properly diagnose anoperineal lesions in patients with Crohn's disease (APLOC). The aim of this study was to establish whether adding pictures would improve teaching effectiveness of the diagnosis of APLOC to French gastroenterology trainees., Method: Trainees were asked to answer a first web-based survey consisting of evaluating 12 pictures of APLOC with a closed answer questionnaire. They were then randomized in 2 groups. Group A received an online teaching with typical pictures and APLOC definitions and group B definitions only. Trainees were asked again seven days later to answer a second survey with 12 other pictures of APLOC and 14 experts also answered this survey. Diagnostic scores were expressed in %. The primary endpoint was the comparison of the score of survey 2 between the two groups of trainees. Secondary endpoints were to compare results of survey 2 between trainees of both groups and experts, and assess diagnosis of each lesion., Results: Two hundred fourty eight trainees among 465 answered survey 1, and 195 survey 2. The diagnostic score was 71.9% for groups A and B and 74.6% for experts (differences NS). After training diagnosis of ulceration was 72% for group A and 72.9% for group B, fistulae 85.2% versus 85.8%, erythema 44.1% vs. 55.6%, anoperineal scars 67.5% vs. 65.6%, and abscess 100% (differences NS)., Conclusion: There was no difference between the two teaching methods. Further research should be performed aiming at improving teaching material and quotation baremes., (Copyright © 2018. Published by Elsevier Masson SAS.)

The French National Society of Coloproctology established national recommendations for the treatment of anoperineal lesions associated with Crohn's disease. Treatment strategies for anal ulcerations and anorectal stenosis are suggested. Recommendations have been graded following international recommendations, and when absent professional agreement was established. For each situation, practical algorithms have been drawn.

Aim: Rectal flap advancement is still a part of therapeutic management of anal fistulas. Data on the outcome of rectal flap advancement in patients with Crohn's disease (CD) is scarce. Our objective was to ascertain rates of failure of rectal flap advancement and to determine predictive factors for failure, with a special focus on CD METHOD: The patients' details, the characteristics of the fistula and the main clinical and therapeutic events were prospectively assessed among patients who underwent rectal flap advancement. All patients had a partial-thickness rectal flap advancement. Failure of primary rectal flap advancement was defined as the occurrence of at least one of the following: abscess, discharge, visible external opening, further drainage procedure. The rates of failure of rectal flap and the predictive factors of failure were assessed., Results: Eighty-seven patients (34 patients with CD) were included. The median (interquartile range) follow-up was 13.3 (3.8-38.1) months. The cumulative failure rates were 15.9% (10.3-23.6), 23.0% (16.0-31.8), 31.6% (22.9-41.8) and 41.3% (30.5-53.0) at 3, 6, 12 and 24 months respectively. These data were comparable in Crohn's patients. Those with a supralevator fistula [hazard ratio 2.53 (1.01-7.71), P = 0.0476] and patients who had fewer than two fistula drainages before rectal flap [hazard ratio 3.19 (1.40-8.23), P = 0.005] were associated with higher rectal flap failure rates. In CD patients, the absence of biological therapy at referral was predictive of failure., Conclusion: Rectal flap advancement is a satisfactory option for the therapeutic management of anal fistula, including CD populations. Fistula drainage is needed before performing this surgical technique., (Colorectal Disease © 2018 The Association of Coloproctology of Great Britain and Ireland.)

The French National Society of Coloproctology established national recommendations for the treatment of anoperineal lesions associated with Crohn's disease. Treatment strategies for acute abscesses, active fistulas (active denovo and still active under treatment), fistulas in remission, and rectovaginal fistulas are suggested. Recommendations have been graded following the international recommendations, and when absent, professional agreement has been established. For each situation, practical algorithms have been drawn.

Background & Aims: The European Crohn's and Colitis Organization recommends magnetic resonance imaging (MRI) of anal fistulas to decide on the drug/surgery strategy. No evidence is available on the long-term impact of MRI features on fistula healing. The aim of this study was to evaluate the benefit of combined drug/surgery strategies for the treatment of perianal Crohn's fistulas based on MRI factors at referral., Methods: The clinical event (anal abscess, new fistula tract, cellulitis), therapeutic intervention (introduction/optimization of immunosuppressant/biologics, anal surgery, intestinal resection, stoma), and MRI data were prospectively recorded for patients with Crohn's disease (CD) and anal fistulas. Healing was defined by fulfilment of all the following conditions: no discharge or pain, closure of the external opening of the fistula, no visible internal opening, no abscess, and no subsequent draining seton or drainage procedure performed during at least 1 year of follow-up., Results: Seventy CD patients with anal fistulas and MRI evaluations were followed for 70 months. The cumulative rates of fistula healing were 25%, 40%, 50%, and 70% at 12, 24, 36, and 72 months, respectively. Severe, complex, branched, and high fistulas were associated with a less favorable outcome. Surgical closure of the tract improved the healing rates better than treatment with biologics or thiopurines. Male sex, A1 luminal phenotype, and anal ulceration at referral were independently associated with a higher healing rate., Conclusions: Therapeutic strategies for perianal fistulizing CD require robust anatomical and healing evaluations. Combined strategies using biologics to improve both drainage and secondary closure of the fistula tracts merit further study.

Background: Discontinuation of antitumour necrosis factor (TNF)α therapy with perianal fistulising Crohn's disease remains controversial due to the risk of severe relapse without any clear evidence., Aim: The aim of this study was to assess the rate and type of perianal and luminal relapses following anti-TNFα discontinuation., Methods: All patients treated with anti-TNFα for perianal fistulising Crohn's disease with subsequent discontinuation of therapy were retrospectively reviewed from a prospective database (1998-2016). Cumulative probabilities of relapse-free survival were estimated by actuarial analysis., Results: After a median follow-up of 62 months, 24 of the 45 patients experienced perianal relapse. A new surgical drainage was needed in 19 (79%) patients. The cumulative probabilities of perianal relapse at 1 and 5 years were 24% and 55%, respectively. Ileal localization (L1) at diagnosis, persistence of an external fistula opening, second line anti-TNFα use, or prior dose optimization was associated with perianal relapse, whereas continuation of immunosuppressive agents decreased this risk (HR = 0.3). Luminal relapse occurred in 42% of patients at 5 years. The cumulative probability of global relapse at 5 years was 67%. Retreatment with anti-TNFα allowed further remission in 23 of 24 (96%) patients., Conclusion: Half of patients with perianal fistulising Crohn's disease relapse within 5 years after anti-TNFα discontinuation. Immunosuppressant continuation may decrease this risk. The high risk of relapse (perianal and luminal) may suggest a benefit in pursuing biologics over a longer period in patients with perianal fistulas.

Background: The natural history of anal ulcerations in Crohn's disease remains unknown., Aims: To assess the long-term outcomes of anorectal ulcerations., Methods: Data from consecutive patients with perineal Crohn's disease were prospectively recorded. The data of patients with anal ulceration were extracted., Results: Anal ulcerations were observed in 154 of 282 patients (54.6%), and 77 cases involved cavitating ulcerations. The cumulative healing rates were 47%, 70% and 82% at 1, 2 and 3 years, respectively. Patients with a primary fistula phenotype had a shorter median time to healing of their anal ulceration (28 [13-83] weeks) than those with a stricture (81 [28-135] weeks) or those with isolated ulceration (74 [31-181] weeks) (p=0.004). Among patients with ulcerations but no fistula at referral (n=67), only 4 (6%) developed de novo abscesses and/or fistula during follow-up. There was no benefit associated with introducing or optimising biologics, nor with combining immunosuppressants and biologics., Conclusion: Anal ulceration in Crohn's disease usually requires a long time to achieve sustained healing. Determining the impact of biologics on healing rates will require dedicated randomised trials although it does not show a significant healing benefit in the present study., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Anoperineal lesion (APL) occurrence is a significant event in the evolution of Crohn's disease (CD). Management should involve a multidisciplinary approach combining the knowledge of the gastroenterologist, the colorectal surgeon and the radiologist who have appropriate experience in this area. Given the low level of evidence of available medical and surgical strategies, the aim of this work was to establish a French expert consensus on management of anal Crohn's disease. These recommendations were led under the aegis of the Société Nationale Française de Colo-Proctologie (SNFCP). They report a consensus on the management of perianal Crohn's disease lesions, including fistulas, ulceration and anorectal stenosis and propose an appropriate treatment strategy, as well as sphincter-preserving and multidisciplinary management., Methodology: A panel of French gastroenterologists and colorectal surgeons with expertise in inflammatory bowel diseases reviewed the literature in order to provide practical management pathways for perianal CD. Analysis of the literature was made according to the recommendations of the Haute Autorité de Santé (HAS) to establish a level of proof for each publication and then to propose a rank of recommendation. When lack of factual data precluded ranking according to the HAS, proposals based on expert opinion were written. Therefore, once all the authors agreed on a consensual statement, it was then submitted to all the members of the SNFCP. As initial literature review stopped in December 2014, more recent European or international guidelines have been published since and were included in the analysis., Results: MRI is recommended for complex secondary lesions, particularly after failure of previous medical and/or surgical treatments. For severe anal ulceration in Crohn's disease, maximal medical treatment with anti-TNF agent is recommended. After prolonged drainage of simple anal fistula by a flexible elastic loop or loosely tied seton, and after obtaining luminal and perineal remission by immunosuppressive therapy and/or anti-TNF agents, the surgical treatment options to be discussed are simple seton removal or injection of the fistula tract with biological glue. After prolonged loose-seton drainage of the complex anal fistula in Crohn's disease, and after obtaining luminal and perineal remission with anti-TNF ± immunosuppressive therapy, surgical treatment options are simple removal of seton and rectal advancement flap. Colostomy is indicated as a last option for severe APL, possibly associated with a proctectomy if there is refractory rectal involvement after failure of other medical and surgical treatments. The evaluation of anorectal stenosis of Crohn's disease (ARSCD) requires a physical examination, sometimes under anesthesia, plus endoscopy with biopsies and MRI to describe the stenosis itself, to identify associated inflammatory, infectious or dysplastic lesions, and to search for injury or fibrosis of the sphincter. Therapeutic strategy for ARSCD requires medical-surgical cooperation.

Aim: To establish consensual definitions of anoperineal lesions of Crohn's (APLOC) disease and assess interobserver agreement on their diagnosis between experts., Methods: A database of digitally recorded pictures of APLOC was examined by a coordinating group who selected two series of 20 pictures illustrating the various aspects of APLOC. A reading group comprised: eight experts from the Société Nationale Française de Colo Proctologie group of study and research in proctology and one academic dermatologist. All members of the coordinating and reading groups participated in dedicated meetings. The coordinating group initially conducted a literature review to analyse verbatim descriptions used to evaluate APLOC. The study included two phases: establishment of consensual definitions using a formal consensus method and later assessment of interobserver agreement on the diagnosis of APLOC using photos of APLOC, a standardised questionnaire and Fleiss's kappa test or descriptive statistics., Results: Terms used in literature to evaluate visible APLOC did not include precise definitions or reference to definitions. Most of the expert reports on the first set of photos agreed with the main diagnosis but their verbatim reporting contained substantial variation. The definitions of ulceration (entity, depth, extension), anal skin tags (entity, inflammatory activity, ulcerated aspect), fistula (complexity, quality of drainage, inflammatory activity of external openings), perianal skin lesions (abscess, papules, edema, erythema) and anoperineal scars were validated. For fistulae, they decided to follow the American Gastroenterology Association's guidelines definitions. The diagnosis of ulceration (κ = 0.70), fistulae (κ = 0.75), inflammatory activity of external fistula openings (86.6% agreement), abscesses (84.6% agreement) and erythema (100% agreement) achieved a substantial degree of interobserver reproducibility., Conclusion: This study constructed consensual definitions of APLOC and their characteristics and showed that experts have a fair level of interobserver agreement when using most of the definitions., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.

Background: Fecal incontinence is common in women with Crohn's disease, but little is known about the impact of childbirth, perianal Crohn's disease, and past surgical history on fecal incontinence., Methods: Self-administered questionnaires were mailed to consecutive women referred to a tertiary gastroenterology centre with a focus on fecal incontinence and childbirth. These data were cross-referenced with a prospective database of the same patients' own Crohn's disease histories. Fecal incontinence was defined as a Cleveland Clinic Incontinence Score ≥5. Factors associated with fecal incontinence were analyzed., Results: A total of 173 patients were assessed, including 113 parous women. The prevalence of fecal incontinence was 37.5% (95% CI, 30.7-45.0). The disease duration, a history of anal surgery for fistula, the number of childbirths per woman and Crohn's activity were all independently associated with fecal incontinence in a multivariate analysis model. Specifically, among the group of parous women, fecal incontinence was associated with prior abdominal surgery, prior anal surgery, and Crohn's activity. The mode of delivery was not statistically associated with fecal incontinence., Conclusions: Fecal incontinence is a significant complaint in at least one-third of women of childbearing age with Crohn's disease. Patients'disease and treatment histories seem to have a comparable effect to their childbirth history concerning the presence of fecal incontinence. Both physicians and surgeons who are involved in the management of Crohn's disease need to keep this in mind.

Purpose: Perianal Crohn's disease (CD) encompasses a variety of lesion similar to luminal disease, which are usually not distinctly assessed. Links between luminal and perianal CD phenotype remains therefore underreported, and we aimed to describe both luminal and perianal phenotype and their relationships., Methods: From January 2007, clinical data of all consecutive patients with CD seen in a referral center were prospectively recorded. Data recorded until October 2011 were extracted and reviewed for study proposal., Results: A total of 282 patients (M/F, 108/174; aged 37.8 ± 16.2 years) were assessed that included 154 cases (54.6%) with anal ulceration, 118 cases (41.8%) with fistula, 49 cases (17.4%) with stricture, and 94 cases without anal lesion (33.3%). Anal ulcerations were associated with fistulas (N = 87/154) in more than half of patients (56.5%) and were isolated in 55 patients (35.7%). Most of strictures (94%) were associated with other lesions (N = 46/49). Harvey-Bradshaw score was significantly higher in patients with ulcerations (p < 0.001) as compared to those with perianal fistulas (p = 0.15) or with anal strictures (p = 0.16). Proportions of complicated behavior (fistulizing or stricturing) of luminal CD were similar according to anal lesions: anal fistulas were not significantly associated to penetrating Montreal phenotype (N = 4/31 p = 0.13) as well as anal stricture and stricturing Montreal phenotype (N = 3/49, p = 0.53)., Conclusions: The phenotype of luminal disease does not link with the occurrence and the phenotype of perianal Crohn's disease. Anal ulcerations denote a more severe disease on both luminal and perianal locations and should consequently be taking into account in physician decision-making.

Background and Aims: Anal fistula plug [AFP] is a bioabsorbable bioprosthesis used in ano-perineal fistula treatment. We aimed to assess efficacy and safety of AFP in fistulising ano-perineal Crohn's disease [FAP-CD]., Methods: In a multicentre, open-label, randomised controlled trial we compared seton removal alone [control group] with AFP insertion [AFP group] in 106 Crohn's disease patients with non- or mildly active disease having at least one ano-perineal fistula tract drained for more than 1 month. Patients with abscess [collection ≥ 3mm on magnetic resonance imaging or recto-vaginal fistulas were excluded. Randomisation was stratified in simple or complex fistulas according to AGA classification. Primary end point was fistula closure at Week 12., Results: In all, 54 patients were randomised to AFP group [control group 52]. Median fistula duration was 23 [10-53] months. Median Crohn's Disease Activity Index at baseline was 81 [45-135]. Fistula closure at Week 12 was achieved in 31.5% patients in the AFP group and in 23.1 % in the control group (relative risk [RR] stratified on AGA classification: 1.31; 95% confidence interval: 0.59-4.02; p = 0.19). No interaction in treatment effect with complexity stratum was found; 33.3% of patients with complex fistula and 30.8% of patients with simple fistula closed the tracts after AFP, as compared with 15.4% and 25.6% in controls, respectively [RR of success = 2.17 in complex fistula vs RR = 1.20 in simple fistula; p = 0.45]. Concerning safety, at Week 12, 17 patients developed at least one adverse event in the AFP group vs 8 in the controls [p = 0.07]., Conclusion: AFP is not more effective than seton removal alone to achieve FAP-CD closure., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Despite a high prevalence of Crohn's disease in women of childbearing age, disease-related factors that may impact fertility and perianal Crohn's disease after delivery remain unclear., Methods: Self-administered questionnaires related to childbirth were completed by women with Crohn's disease referred to a single gastroenterology unit. A survival analysis was performed for statistical purposes., Results: A total of 184 patients were assessed, including 63 nulliparous women. The cumulative probabilities of having a child were 30%, 51% and 72% at the ages of 25, 30 and 35 years, respectively. Women with colonic disease, prior abdominal surgery and perianal disease were less likely to experience childbirth. After a median follow-up of 165 weeks post-delivery, the cumulative probabilities of fistulizing perianal Crohn's disease occurrence were 8%, 12% and 21% at 1, 2 and 5 years following childbirth, respectively. Contrary to a prior history of perianal Crohn's disease and colonic location, mode of delivery was not associated with perianal fistula. An episiotomy in the group of women with prior anal lesions did not result in a higher rate of fistula recurrence., Conclusion: Perianal Crohn's disease is associated with fewer pregnancies, however perianal fistulas were less affected by obstetric events than their own natural history., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: In case of a loss of response to adalimumab, some patients with Crohn's disease may derive benefit from increasing the dosing frequency to 40 mg weekly. Efficacy and safety of adalimumab 80 mg weekly remain unknown., Methods: From February 2011 to September 2012, all adults who had active Crohn's disease, defined at least by Crohn's disease activity index >150 and 1 objective sign of inflammation, and required an adalimumab dose escalation to 80 mg weekly were enrolled in a prospective multicenter cohort study. Crohn's disease activity index and C-reactive protein levels were recorded during the first 14 weeks following adalimumab optimization and at 6 months. All adverse events were recorded., Results: Forty-two patients were included. The median age was 33 years, and the median disease duration was 8.6 years. Adalimumab was associated with steroids in 28% of cases and with immunomodulators in 10% of patients. Within the 14 weeks after adalimumab optimization, 14 patients (33.3%) achieved clinical remission (Crohn's disease activity index <150), and 23 patients (54.8%) had a clinical response. Clinical improvement was associated with a drop in the C-reactive protein level from 18 to 5 mg/L (P = 0.0008). After a median follow-up of 14.5 months, 5 patients underwent major abdominal surgery. Adverse events were reported in 13 patients (31%)., Conclusions: Adalimumab 80 mg weekly seems to be well-tolerated and may be effective in inducing clinical remission in patients with luminal Crohn's disease who failed to respond to 40 mg weekly or 80 mg every other week.

Background: Assessment of perianal Crohn's disease remains challenging. European Crohn's and Colitis Organisation (ECCO) recommend magnetic resonance imaging (MRI) as a gold standard, but both accuracy and advantages remain limited compared to systematic clinical assessment. The aim of this study was to define their actual diagnostic value., Methods: We performed a retrospective analysis of a prospective database of consecutive patients with perianal Crohn's disease assessed by magnetic resonance imaging and clinical examination from 2006 to 2012. At each outpatient visit, perianal activity (Perianal Disease Activity Index) and perianal phenotype (Cardiff-Hughes classification) were noted. MRI was interpreted according to Cardiff-Hughes and Van Assche classifications., Results: Overall, 122 combined evaluations were assessed in 70 patients. Radiological imaging failed to show superficial ulcerations in 20/21 patients (95%) and severe ulcerations in 13/15 patients (87%). It consistently failed to diagnose anal stenosis (n=21, 100%). For fistulising lesions, the global agreement between the two methods was 71/122 (58%) in assessing complex fistulas. Clinical assessment underestimated 44/68 (65%) of multiple or ramified fistula tracts. Clinical examination failed to diagnose half of the radiological abscesses., Conclusions: Current ECCO guidelines should be applied with some caution because of the low sensitivity of MRI for the diagnosis of non-fistulising perianal disease. Combining clinical and MRI assessments improves diagnostic accuracy., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients., Objective: We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms., Methods: We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed., Results: Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway., Conclusion: IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations., (Copyright © 2014. Published by Elsevier Inc.)

Background: The natural history of nonfistulising perianal Crohn's disease (PCD) remains unknown., Aim: To assess the long-term outcome of anorectal strictures., Methods: All outcomes of PCD patients with anorectal stricture followed in a single unit from 2005 to 2013 were reviewed, as well as subsequent therapeutic management. Cumulative incidence of stricture healing (disappearance of the anal stricture) was estimated using a Kaplan-Meier method and factor associated with an unfavourable course (persistent stricture S2, persistent stoma or proctectomy) with nonparametric test., Results: A total of 102 patients (M/F: 37/65) were included. The duration of CD at diagnosis was 8.9 years. After a median follow-up period of 2.8 years, 52 of the 88 followed patients (59%) achieved anorectal stricture healing. Two patients (2%) developed anal adenocarcinoma. Female gender [HR 2.05 (1.1-4.03), P = 0.0221], disease duration of CD of less than 10 years [HR 1.94 (1.01-3.63), P = 0.0271], and anal fistula at stricture diagnosis [HR 2.36 (1.21-5.05), P = 0.0106) were significantly associated with anorectal stricture healing in a multivariate analysis model. Twenty-eight patients (32%) had an unfavourable course at the end of follow-up. Gender and introduction or optimisation of TNFα antagonist treatment decreased the risk of unfavourable course in multivariate analysis. Conversely, the Luminal B2 phenotype at CD diagnosis was the only factor associated with unfavourable course., Conclusions: Anorectal stricture does not imply a nonreversible and complicated condition related to severe perianal Crohn's disease. However, both the diagnosis of cancer and sepsis drainage remain challenging in this situation., (© 2014 John Wiley & Sons Ltd.)

Background & Aims: Little is known about the long-term efficacy of infliximab for patients with fistulizing perianal Crohn's disease. We evaluated outcomes and predictors of outcomes in these patients., Methods: The medical records of 156 patients treated with infliximab for fistulizing perianal Crohn's disease at 2 referral centers from 1999 through 2010 were reviewed through September 2011. Cumulative probabilities of fistula closure and recurrence were estimated by using the Kaplan-Meier method. Predictors of outcomes were identified by using a Cox proportional hazards model., Results: When infliximab treatment began, only 17.9% of patients had a simple fistula; seton drainage was performed for 97 patients (62%). Concomitant immunosuppressants were given to 90 patients (56%). After a median follow-up period of 250 weeks, 108 patients (69%) had at least 1 fistula closure. Cumulative probabilities of first fistula closure were 40% and 65% at 1 and 5 years, respectively. Factors that predicted fistula closure were ileocolonic disease (hazard ratio [HR] = 1.88), concomitant immunosuppressants (HR = 2.58), duration of seton drainage <34 weeks (HR = 2.31), and long duration of infliximab treatment (HR = 1.76). Of the 108 patients with fistula closure, cumulative probabilities of first fistula recurrence were 16.6% and 40.1% at 1 and 5 years, respectively. Forty-four patients (28.9%) developed an abscess during follow-up. A number of infliximab infusions greater than 19 was associated with less abscess recurrence (HR = 0.33). At the maximal follow-up time, 55% of patients had fistula closure., Conclusions: About two-thirds of patients with fistulizing perianal Crohn's disease had fistula closure, and one-third had fistula recurrence after infliximab initiation. Combination therapy, duration of seton drainage less than 34 weeks, and long-term treatment with infliximab were associated with better outcomes., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Nonfistulizing perianal lesions, including ulcerations, strictures, and anal carcinoma, are frequently observed in Crohn's disease. Their clinical course remains poorly known. The management of these lesions is difficult because none of the treatments used is evidence-based. Ulcerations may be symptomatic in up to 85% of patients. Most ulcerations heal spontaneously but may also progress to anal stenosis or fistula/abscess. Topical treatments only improve symptoms, while complete healing can occur in patients with perianal ulcerations receiving infliximab therapy. Half of all patients with anal strictures will require permanent fecal diversion. Dilatation for symptomatic strictures should be performed on a highly selective basis in the absence of active rectal disease in order to avoid infectious complications. Anorectal strictures associated with rectal lesions should first be managed with medical therapy. Skin tags are usually painless and may hide other perianal lesions. Anal cancer is uncommon. Its treatment is similar to that recommended for anal cancer occurring in non-Crohn's disease patients. After reviewing the classification, clinical features, and epidemiology of each type of nonfistulizing perianal lesion (ulceration, stricture, skin tags, and anal cancer), we discuss the efficacy of medical treatment and surgery. This review article may help physicians in decision-making when managing potentially disabling lesions.

Background & Aims: Fibrin glue is a therapeutic for fistulas that activates thrombin to form a fibrin clot, which mechanically seals the fistula tract. We assessed the efficacy and safety of a heterologous fibrin glue that was injected into the fistula tracts of patients with Crohn's disease (ClinicalTrials.gov No. NCT00723047)., Methods: This multicenter, open-label, randomized controlled trial included patients with a Crohn's disease activity index < or =250 and fistulas between the anus (or low rectum) and perineum, vulva, or vagina, that drained for more than 2 months. Magnetic resonance imaging or endosonography was performed to assess fistula tracts and the absence of abscesses. Patients were stratified into groups with simple or complex fistulas and randomly assigned to receive fibrin glue injections (n = 36) or only observation (n = 41) after removal of setons. The primary end point was clinical remission at week 8, defined as the absence of draining, perianal pain, or abscesses. At week 8, a fibrin glue injection was offered to patients who were not in remission., Results: Clinical remission was observed in 13 of the 34 patients (38%) of the fibrin glue group compared with 6 of the 37 (16%) in the observation group; these findings demonstrate the benefit of fibrin glue (odds ratio, 3.2; 95% confidence interval: 1.1-9.8; P = .04). The benefit seemed to be greater in patients with simple fistulas. Four patients in the fibrin glue group and 6 in the observation group had adverse events., Conclusions: Fibrin glue injection is a simple, effective, and well-tolerated therapeutic option for patients with Crohn's disease and perianal fistula tracts., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: In Crohn's disease, anal ulcers and stricture can be disabling., Aim: To evaluate long-term outcome of non-fistulizing perianal Crohn's disease under infliximab., Methods: The medical records of 99 patients with non-fistulizing perianal Crohn's disease at first infliximab infusion were reviewed. Complete responses (ulcer healing or stricture regression) after induction infliximab therapy and at the maximal follow-up were assessed., Results: Ninety-four patients (94.9%) had ulcers, 22 (22.2%) had stricture and 31 (31.3%) had draining perianal fistulas at first infliximab infusion. After infliximab induction therapy, 40/94 (42.5%) patients with ulcers, 4/22 (18.2%) with stricture and 10/31 (32.2%) with fistulas had a complete response. Eight patients were lost to follow-up. After a median follow-up of 175 weeks (range, 13-459), complete response rates for ulcers, stricture and fistulas were 72.3% (68/94), 54.5% (12/22) and 54.8% (20/31) respectively. Long-term response for cavitating ulcer was positively associated with concomitant immunosuppressant use (P = 0.017) and older age (P = 0.049). Among the 12 patients with complete regression of stricture, 6 patients also had anal dilatation. Complete response was associated with perianal pain relief and disappearance of soiling. Three patients with ulcers developed an anal abscess., Conclusions: Infliximab therapy may be effective in inducing and maintaining response for ulcers.

Objectives: Three recently identified NOD2/CARD15 mutations have been described associated with an increased susceptibility Crohn's disease (CD). Our aim was to examine the potential association of these NOD2 mutations with CD and different subsets of CD phenotypes in our population., Methods: Two hundred and five well-defined CD patients from north-western France and 95 ethnically matched healthy controls were genotyped for mutations R702W, G908R and Leu1007insC by DNA sequencing. Allele and genotype frequencies of NOD2 variants were examined in the whole series of CD and in different subgroups of CD phenotypes defined by the clinical characteristics of the Vienna classification (age at diagnosis, location and behaviour) or by histological features (granuloma)., Results: Carriers of at least one NOD2/CARD15 variant were significantly more frequent in CD than in controls (38.0% versus 20.0%, P < 0.002), and the R702W allele was the most significant contributor to this NOD2 association with CD. Homozygotes and compound heterozygotes combined had a higher risk of CD (odds ratio = 12.0, P < 0.0026) than simple heterozygotes for any variant (odds ratio = 2.2, P < 0.013) compared with subjects with no variant. Univariate analysis revealed that carriage of at least one NOD2 mutation was significantly associated with ileal involvement (P < 0.03), and stricturing evolution (P < 0.0015). Granuloma was associated with an excess of the R702W allele (16.1% versus 8.0%, Pc < 0.035), and was correlated with a young age at diagnosis, whatever the NOD2/CARD15 genotype. Multivariate analysis demonstrated that carriage of NOD2/CARD15 mutants, especially R702W, was primarily and independently associated both with stricturing evolution of CD and the presence of granuloma., Conclusions: In our population, all NOD2/CARD15 mutant genotypes, especially compound heterozygosity, were found to increase the risk of CD, but R702W was the sole allele showing a significant association with CD. In addition, we confirm the positive and independent association of the R702W mutation with stricturing behaviour and describe a second one with the presence of granuloma.

Chemokines and their receptors are involved in the migration of different mononuclear cells. Among them macrophages-derived chemokines (MDC) and thymus-and activation regulated chemokine (TARC) belong to a new cluster of genes involve in Th2 lymphocytes homing. Cytokines appear to play a significant role in pathogenesis of inflammatory bowel diseases with an excessive Th1 response in chronic lesions of Crohn's disease (CD) and a Th2 pattern in both earlier mucosal CD lesions and in mucosa of ulcerative colitis (UC). Here we demonstrate that RNAm coding for MDC and TARC are expressed in mucosa from CD and UC patients. Using real-time fluorescent RT-PCR, MDC and TARC mRNA were increased in CD inflamed mucosa. Moreover MDC and TARC transcripts were increased in inflamed CD specimen compared to non-involved CD mucosa. These differences both discriminate CD from UC patients. Additionally, MDC protein was produced in isolated mononuclear cells from peripheral blood (PBMC) or mucosa (LPMC) from UC and CD patients: spontaneously, MDC production from PBMC was increased in CD compared to UC patients. MDC production from CD PBMC was also higher than that found in healthy controls. Together, these data indicate that MDC should be involved in the lymphocytes homing in mucosa from CD patients.

We report a case of multiple aseptic splenic abscesses occurring in a woman with Crohn's disease for three years. All microbiological samples were negative. The diagnosis was suspected on abdominal echography and CT scan and confirmed on histologic examination of the splenectomy specimen. The evolution was marked by recurrence of fever and inflammatory syndrome, associated to transitory morphological abnormalities of the accessory spleen. Aseptic splenic abscesses recurrence was suspected. This case allows us to consider aseptic splenic abscesses as an extra-intestinal manifestation and not as a splenic localisation of Crohn's disease.

Aim: Work-up of anoperineal lesions usually includes indices of clinical activity as well as diagnostic criteria of Crohn's disease but their prognostic implication remains unclear. This prospective study was conducted in order to evaluate the overall incidence of anoperineal lesions and their relation to the natural history of underlying intestinal Crohn's disease with special reference to the steroid-dependent state of the patients., Patients and Methods: One hundred and one patients (46 males, 55 females, aged 34 +/- 14 years; range: 15-79) were consecutively referred to our institution (May 1991 to May 1994) for intestinal symptoms related to Crohn's disease (mean duration 66 +/- 66 months). They all underwent a proctological examination regardless of perineal symptoms. The Cardiff classification was used to describe anoperineal lesions. Patients with anal lesions (64) differed from those without (37): male predisposition (53% vs. 32%, P<0.05), more frequent rectal involvement (75% vs. 24%, P<0.001) and more acute lesions observed at proctoscopic examination (42% vs. 16%, P<0.05). Age of onset, surgical past history of Crohn's disease, colonic or ileal involvement, or Harvey-Bradshaw score were not different between groups., Results: Patients with anal ulceration (43) as compared to patients having anal involvement without ulceration experienced pain more frequently (constant pain: 56 vs. 14%; defecatory pain: 35 vs. 19%) and a more severe evolution of intestinal (40 vs. 22%, P<0.05) and anal (42 vs. 12%, P<0.05) involvement. In those with an aggressive ulceration (U2, 28 patients), daily stool frequency (5.1 +/- 3 vs. 3.6 +/- 2.5, P<0.05) and clinical score (9 +/- 5 vs. 7 +/- 3) were more pronounced. Steroid therapy dependency occurred more frequently in the group with anal ulceration (35 vs. 16% and 40 vs. 17%, respectively, P<0.05). Similar associations were observed for cases of anal involvement (34 vs. 5%, P<0.01) and azathioprine was more frequently required (39 vs. 5%, P<0.01) than in those free of anal lesions. During follow-up, eight other patients required azathioprine (steroid dependence in six) and seven of them had anal lesions at referral. At the endpoint of the study, one out of two patients with anal lesions required azathioprine most often due to steroid dependency of the intestinal involvement (30/64 vs. 4/37, P<0.005)., Conclusion: Anal ulcerations are a reliable severity index of Crohn's disease in both short- and long-term prognosis but their link to the steroid status of the intestinal disease remains unclear.

The aim of this study was to determine whether the sensitivity of indium-111 (111In) scanning in the assessment of the activity and extent of Crohn's disease correlates with the severity of intestinal lesions as measured by the newly validated Crohn's disease endoscopic index of severity (CDEIS). Nineteen patients with active (CDAI > 200) colonic (N = 11) or ileocolonic (N = 8) Crohn's disease were assessed by colonoscopy and indium scanning. The intestine was divided into five segments in both studies (rectum, sigmoid and left colon, transverse colon, right colon, and ileum). Seventy of the 86 intestinal segments seen at colonoscopy presented macroscopic lesions of Crohn's disease. On third-hour scintigrams 111In uptake was observed in 52 segments, 51 of which were found to be abnormal at colonoscopy. Predictive positive and negative values of scanning with respect to disease extent assessment were equal to 98% and 44%, respectively. Complete agreement between endoscopic and scintigraphic findings was observed in only six of the 19 patients (32%). Segmental endoscopic indexes of severity (SEIS) were significantly (P < 0.001) lower in false negative (7.9 +/- 4.2) (mean +/- SD) than in true positive (18.0 +/- 9.7) segments as defined by scintigraphy. SEIS values above which 111In uptake was constantly observed did not differ in the different disease locations. When compared macroscopically abnormal intestinal segments according to their 111In uptake grade, the corresponding mean SEIS values increased significantly as the grade increased. Scintigraphic activity, as assessed by the fall in splenic activity, was equal to 23 +/- 11% (N = 19).(ABSTRACT TRUNCATED AT 250 WORDS)