Matthieu Allez

The First European Evidence-based Consensus on Extra-intestinal Manifestations in Inflammatory Bowel Disease.

This is the first European Crohn’s and Colitis Organisation [ECCO] consensus guideline that addresses extra-intestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. It has been drafted by 21 ECCO members from 13 European countries. Although this is the first ECCO consensus guideline that primarily addresses EIMs, it is partly derived from, updates, and replaces previous ECCO consensus advice on EIMs, contained within the consensus guidelines for Crohn’s disease1 [CD] and ulcerative colitis2 [UC]. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, topics were selected by the ECCO guidelines committee [GuiCom]. ECCO members were selected to form working groups. Provisional ECCO Statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds which included national representative participation by ECCO’s 35 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-based Medicine [www.cebm.net]. The ECCO Statements were finalised by the authors at a meeting in Vienna in October 2014 and represent consensus with agreement of at least 80% of participants. Complete consensus [100% agreement] was reached for most statements. The supporting text was then finalised under the direction of each working group leader [VA, SV, FC, MH] before being integrated by the two consensus leaders [MH, FC]. This consensus guideline is pictorially represented within the freely available ECCO e-Guide [http://www.e-guide.ecco-ibd.eu/].nnUp to 50% of patients with inflammatory bowel disease [IBD] experience at least one extra-intestinal manifestation [EIM], which can present before IBD is diagnosed.34,5,6 EIMs adversely impact upon patients’ quality of life and some, such as primary sclerosing cholangitis [PSC] or venous thromboembolism [VTE], can be life-threatening. The probability of developing EIMs increases with disease duration and in patients who already have one EIM.7 …

Paradoxical immune-mediated inflammation in inflammatory bowel disease patients receiving anti-TNF-α agents.

Reports of autoimmune diseases, including psoriasis- and dermatitis-like skin reactions with anti-tumor necrosis factor-α (TNF-α), are increasing, likely a reflection of the growing use of these agents. This paradoxical phenomenon can no longer be considered rare, with some studies providing incidence estimates of greater than 10%. This paradoxical inflammation has been reported in patients receiving treatment with anti-TNF-α agents for a variety of inflammatory conditions, including inflammatory bowel disease, psoriasis and rheumatoid arthritis and appears to be a class effect. Moreover, there have recently been reports of autoimmune arthralgia occurring in patients receiving anti-TNF-α agents. Further studies are necessary to determine the true incidence of this phenomenon and to identify those patients most likely to be at risk.

Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease: A Randomized Clinical Trial.

IMPORTANCEnCase reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease.nnnOBJECTIVEnTo evaluate the effect of autologous HSCT on refractory Crohn disease.nnnDESIGN, SETTING, AND PARTICIPANTSnParallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids.nnnINTERVENTIONSnAll patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (nu2009=u200923) or control treatment (HSCT deferred for 1 year [nu2009=u200922]). All were given standard Crohn disease treatment as needed.nnnMAIN OUTCOMES AND MEASURESnSustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) <150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging.nnnRESULTSnTwenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, -14.2% to 22.6%]; Pu2009=u2009.60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; Pu2009=u2009.01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; Pu2009=u2009.052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; Pu2009=u2009.054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died.nnnCONCLUSIONS AND RELEVANCEnAmong adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00297193.

Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease.

Background:Crohns disease (CD)–associated dysbiosis could predispose patients to relapse. Gut microbiota composition of patients from the prospective cohort study designed to identify predictive factors of clinical relapse after infliximab discontinuation (STORI Study) was investigated to determine the impact of dysbiosis in CD relapse. Methods:Fecal samples from 33 patients with CD in this cohort were collected at baseline, 2 months, 6 months, and at the end of the follow-up period (19 relapsers and 14 nonrelapsers). Healthy volunteers subjects (n = 29) were used as a control group. The fecal microbiota composition was assessed using quantitative PCR, and comparisons between the patient groups were made at different time points using the Wilcoxon test. The analysis of the time-to-relapse was performed according to the baseline median level of each bacterial signal. Results:Dysbiosis was observed in patients with CD compared with healthy subjects, and it was characterized by low mean counts of Firmicutes (Clostridium coccoides [P = 0.0003], C. leptum [P < 0.0001], and Faecalibacterium prausnitzii [P = 0.003]). Lower rates of Firmicutes were seen in relapsers compared with nonrelapsers. Moreover, a low rate of F. prausnitzii (P = 0.014) and a low rate of Bacteroides (P = 0.030) predicted relapse independently from high C reactive protein level (P = 0.0001). Conclusions:In this work, we report that CD-associated dysbiosis, characterized by a decrease in Firmicutes, correlates with the time-to-relapse after infliximab withdrawal. A deficit in some bacterial groups or species, such as F. prausnitzii, may represent a predictive factor for relapse. Restoring normobiosis in CD could be a new goal for optimal CD management.

Excess primary intestinal lymphoproliferative disorders in patients with inflammatory bowel disease

Background: It remains to be shown whether inflammatory bowel disease (IBD) is associated with an increased risk of primary intestinal lymphoproliferative disorders (PILD). We assessed this risk in the CESAME French nationwide prospective observational cohort. Methods: In all, 680 gastroenterologists enrolled 19,486 patients with IBD (Crohns disease in 60.3%) from May 2004 to June 2005. Follow‐up ended on 31 December 2007. Available biopsy samples and surgical specimens from patients with PILD (n = 14) were centralized for review. The reference incidence of PILD in the general population was obtained from the Côte dOr registry and was used as a comparator to assess the standardized incidence ratio (SIR). The influence of thiopurine exposure was explored in a nested case‐control study. Results: In the CESAME population the crude incidence of PILD was 0.12/1000 patient‐years, with a corresponding SIR of 17.51 (95% confidence interval [CI], 6.43–38.11; P < 0.0001). The risk was highest in patients exposed to thiopurines (SIR 49.52, 95% CI 13.49–126.8; P < 0.0001), while it did not reach statistical significance in patients naïve to thiopurines (SIR 4.83, 95% CI, 0.12–26.91; P = 0.37). The odds ratio associated with ongoing thiopurine exposure (vs. naïve) was 2.97 (95% CI, 0.30–infinity; P = 0.38). All 14 cases of PILD were non‐Hodgkins B‐cell LD, 78.6% occurred in males, 85.7% arose in IBD lesions, and 45.5% were Epstein–Barr virus‐positive. Eleven cases occurred in patients with Crohns disease. Mean (SD) age at PILD diagnosis was 55.1 (5.6) years and the median time since IBD onset was 8.0 years (interquartile range, 3.0–15.8). Conclusions: Patients with IBD have an increased risk of developing PILD. (Inflamm Bowel Dis 2012;)

Genotype/Phenotype Analyses for 53 Crohn’s Disease Associated Genetic Polymorphisms

Background & Aims Recent studies reported a role for more than 70 genes or loci in the susceptibility to Crohn’s disease (CD). However, the impact of these associations in clinical practice remains to be defined. The aim of the study was to analyse the relationship between genotypes and phenotypes for the main 53 CD-associated polymorphisms. Method A cohort of 798 CD patients with a median follow up of 7 years was recruited by tertiary adult and paediatric gastroenterological centres. A detailed phenotypic description of the disease was recorded, including clinical presentation, response to treatments and complications. The participants were genotyped for 53 CD-associated variants previously reported in the literature and correlations with clinical sub-phenotypes were searched for. A replication cohort consisting of 722 CD patients was used to further explore the putative associations. Results The NOD2 rare variants were associated with an earlier age at diagnosis (pu200a=u200a0.0001) and an ileal involvement (ORu200a=u200a2.25[1.49–3.41] and 2.77 [1.71–4.50] for rs2066844 and rs2066847, respectively). Colonic lesions were positively associated with the risk alleles of IL23R rs11209026 (ORu200a=u200a2.25 [1.13–4.51]) and 6q21 rs7746082 (ORu200a=u200a1.60 [1.10–2.34] and negatively associated with the risk alleles of IRGM rs13361189 (ORu200a=u200a0.29 [0.11–0.74]) and DEFB1 rs11362 (ORu200a=u200a0.50 [0.30–0.80]). The ATG16L1 and IRGM variants were associated with a non-inflammatory behaviour (ORu200a=u200a1.75 [1.22–2.53] and ORu200a=u200a1.50 [1.04–2.16] respectively). However, these associations lost significance after multiple testing corrections. The protective effect of the IRGM risk allele on colonic lesions was the only association replicated in the second cohort (pu200a=u200a0.03). Conclusions It is not recommended to genotype the studied polymorphisms in routine practice.

Diffusion‐weighted MRI in Crohn's disease: Current status and recommendations

Over the past years, technological improvements and refinements in magnetic resonance imaging (MRI) hardware have made high‐quality diffusion‐weighted imaging (DWI) routinely possible for the bowel. DWI is promising for the detection and characterization of lesions in Crohns disease (CD) and has been advocated as an alternative to intravenous gadolinium‐based contrast agents. Furthermore, quantification using the apparent diffusion coefficient may have value as a biomarker of CD activity and has shown promise. In this article we critically review the literature pertaining to the value of DWI in CD for detection, characterization, and quantification of disease activity and complications. Although the body of supportive evidence is growing, it is clear that well‐designed, multicenter studies are required before the role of DWI in clinical practice can be fully established. J. Magn. Reson. Imaging 2016;44:1381–1396.

Gastrointestinal cancers in inflammatory bowel disease: An update with emphasis on imaging findings.

Inflammatory bowel diseases (IBD) are associated with an increased risk of gastrointestinal cancers depending on the specific type of IBD, the extent of the disease and its location. Patients with IBD and extensive colonic involvement are at increased risk of colorectal cancer whereas patients with Crohn disease have an increased risk for small-bowel and anal carcinoma. These cancers preferentially develop on sites of longstanding inflammation. In regards to colon cancer, several key pathogenic events are involved, including chromosomal instability, microsatellite instability and hypermethylation. The risk for colon cancer in IBD patients correlates with longer disease duration, presence of sclerosing cholangitis, pancolitis, family history of colorectal cancer, early onset of the disease and severity of bowel inflammation. Identification of increased colorectal cancer risk in individual IBD patients has led to formal surveillance guidelines. Conversely, although an increased risk for other types of cancer has been well identified, no specific formal screening recommendations exist. Consequently, the role of the radiologist is crucial to alert the referring gastroenterologist when a patient with IBD presents with unusual imaging findings at either computed tomography (CT) or magnetic resonance (MR) imaging. This review provides an update on demographics, molecular, clinical and histopathological features of gastrointestinal cancers in IBD patients including colorectal carcinoma, small bowel adenocarcinoma, neuroendocrine tumors and anal carcinoma, along with a special emphasis on the current role of CT and MR imaging.

Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn's disease: a randomised controlled trial

Objective Anti-NKG2D (NNC0142-0002) is an antagonising human immunoglobulin G4 monoclonal antibody that binds to natural killer group 2 member D (NKG2D) receptors, which are expressed by T cells and innate lymphoid cells, and may be linked to mucosal damage in Crohns disease (CD). Design Seventy-eight patients (aged ≥18 and ≤75u2005years) with CD for ≥3u2005months, Crohns Disease Activity Index (CDAI) ≥220 and ≤450 and either C-reactive protein ≥10u2005mg/L or endoscopic evidence of inflammation, were randomised 1:1 to a single subcutaneous (SC) dose of 2u2005mg/kg anti-NKG2D or placebo. Primary endpoint was change in CDAI (ΔCDAI) from baseline to week 4. Prespecified significance level was 10% for CDAI endpoints. A futility analysis was instituted due to slow recruitment. Results Primary endpoint was not significantly different between anti-NKG2D and placebo (week 4 ΔCDAI=–16); however, there was a significant difference by week 12 (ΔCDAI=–55; p≤0.10). Significant improvements were noted in the non-failure to biologics subgroup (treated with anti-NKG2D (n=28)) from week 1 onward. Greater effects of anti-NKG2D were also observed in patients with baseline CDAI ≥330. Frequencies of adverse events (AEs) were comparable between anti-NKG2D and placebo. Most AEs were mild (49%) or moderate (43%). No antidrug antibodies were observed. Conclusions A single SC dose of 2u2005mg/kg anti-NKG2D did not reduce disease activity at week 4 versus placebo, but the difference was significant at week 12, and effects were evident in key subgroups. These data support further development of anti-NKG2D in IBD. Trial registration number NCT01203631.

Certolizumab pegol - A new therapeutic option for refractory disseminated pyoderma gangrenosum associated with Crohn's disease.

Abstract Systemic steroids, in association or not with cyclosporin, are indicated for the treatment of large or widespread Pyoderma gangrenosum (PG). We report the case of a 27-year-old woman with a 15-year history of severe Crohn’s disease, who developed a severe and disseminated PG, refractory to multiple lines of treatment. Infliximab and adalimumab were contraindicated, either because of allergy or of ineffectiveness on Crohn’s disease. The addition of certolizumab pegol to the baseline treatment, associating systemic steroids and tacrolimus, finally allowed the complete healing of PG. Oral prednisone was stopped and tacrolimus was decreased, without any cutaneous or digestive relapse. Certolizumab pegol could be an alternative therapy in the treatment of PG in case of intolerance or ineffectiveness of the other anti-tumor necrosis factor (anti-TNF) therapies.