Guillaume Bouguen

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES:The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a “treat-to-target” clinical management strategy using an evidence-based expert consensus process.METHODS:A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7–10 on a 10-point rating scale (where 10=agree completely).RESULTS:The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn’s disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0–1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target.CONCLUSIONS:Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients’ quality of life.

Long-term Outcome of Perianal Fistulizing Crohn's Disease Treated With Infliximab

BACKGROUND & AIMS Little is known about the long-term efficacy of infliximab for patients with fistulizing perianal Crohns disease. We evaluated outcomes and predictors of outcomes in these patients. METHODS The medical records of 156 patients treated with infliximab for fistulizing perianal Crohns 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 Crohns 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.

Successive treatment with cyclosporine and infliximab in steroid-refractory ulcerative colitis

OBJECTIVES:Rescue therapy with either cyclosporine (CYS) or infliximab (IFX) is an effective option in patients with intravenous steroid-refractory attacks of ulcerative colitis (UC). In patients who fail, colectomy is usually recommended, but a second-line rescue therapy with IFX or CYS is an alternative. The aims of this study were to investigate the efficacy and tolerance of IFX and CYS as a second-line rescue therapy in steroid-refractory UC or indeterminate colitis (IC) unsuccessfully treated with CYS or IFX.METHODS:This was a retrospective survey of patients seen during the period 2000–2008 in the GETAID centers. Inclusion criteria included a delay of <1 month between CYS withdrawal (when used first) and IFX, or a delay of <2 months between IFX (when used first) and CYS, and a follow-up of at least 3 months after inclusion. Time-to-colectomy, clinical response, and occurrence of serious adverse events were analyzed.RESULTS:A total of 86 patients (median age 34 years; 49 males; 71 UC and 15 IC) were successively treated with CYS and IFX. The median (±s.e.) follow-up time was 22.6 (7.0) months. During the study period, 49 patients failed to respond to the second-line rescue therapy and underwent a colectomy. The probability of colectomy-free survival (±s.e.) was 61.3±5.3% at 3 months and 41.3±5.6 % at 12 months. A case of fatal pulmonary embolism occurred at 1 day after surgery in a 45-year-old man. Also, nine infectious complications were observed during the second-line rescue therapy.CONCLUSIONS:In patients with intravenous steroid-refractory UC and who fail to respond to CYS or IFX, a second-line rescue therapy may be effective in carefully selected patients, avoiding colectomy within 2 months in two-thirds of them. The risk/benefit ratio should still be considered individually.

Recent advances in cytokines: Therapeutic implications for inflammatory bowel diseases

Inflammatory bowel diseases (IBDs) are complex and chronic disabling conditions resulting from a dysregulated dialogue between intestinal microbiota and components of both the innate and adaptive immune systems. Cytokines are essential mediators between activated immune and non-immune cells, including epithelial and mesenchymal cells. They are immunomodulatory peptides released by numerous cells and these have significant effects on immune function leading to the differentiation and survival of T cells. The physiology of IBD is becoming a very attractive field of research for development of new therapeutic agents. These include cytokines involved in intestinal immune inflammation. This review will focus on mechanisms of action of cytokines involved in IBD and new therapeutic opportunities for these diseases.

Feasibility of endoscopic assessment and treating to target to achieve mucosal healing in ulcerative colitis.

Background:Mucosal healing (MH) as a treatment target for ulcerative colitis is of growing interest because it is associated with improved clinical outcomes. However, the feasibility and probability of reaching MH in clinical practice is unknown. We therefore evaluated the feasibility of “treating to target” according to endoscopic findings to reach MH. Methods:All endoscopic outcomes of patients with ulcerative colitis followed in a single inflammatory bowel disease unit from 2011 to 2012 were reviewed and subsequent therapeutic management. Cumulative incidence of MH and histologic healing (HH) were estimated using a Kaplan–Meier method. Results:A total of 60 patients underwent at least 2 consecutive endoscopic assessments, of whom 45 and 48 patients had endoscopic and histologic evidence of active disease, respectively. After a median follow-up of 76 weeks, 27 of 45 (60%) patients with endoscopic disease activity at baseline achieved MH and 24 (50%) of 48 patients with histologic disease activity at baseline had HH. The cumulative probabilities of MH were 26%, 52%, and 70% at 26, 52, and 76 weeks, respectively. The cumulative probabilities of HH at weeks 26, 52, and 76 from the time of initial procedure were 19%, 41%, and 57%, respectively. Any adjustment in medical therapy in case of persistent endoscopic activity was associated with both MH and HH. Conclusions:Repeated assessment of endoscopic disease activity with adjustment of medical therapy to the target of MH is feasible in clinical practice in patients with ulcerative colitis, and seems to be of benefit.

Nonfistulizing perianal Crohn's disease: Clinical features, epidemiology, and treatment

Nonfistulizing perianal lesions, including ulcerations, strictures, and anal carcinoma, are frequently observed in Crohns 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-Crohns 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.

A systematic review of measurement of endoscopic disease activity and mucosal healing in Crohn's disease: recommendations for clinical trial design.

Background:Crohns disease (CD) is a chronic idiopathic inflammatory disorder of the gastrointestinal tract. Recently, mucosal healing has been proposed as a goal of therapy because clinical symptoms are subjective. Evaluative indices that measure endoscopic disease activity are required to define mucosal healing for clinical trials. The primary objective of this systematic review was to assess the existing evaluative indices that measure disease activity in CD and evaluate their role as outcome measures in clinical trials. Methods:A systematic literature review was performed using MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and DDW abstracts to identify randomized controlled trials and controlled clinical trials that used a relevant evaluative index from inception to February 2013. The data obtained from these trials were reviewed and summarized. Results:The initial literature searches identified 2300 citations. After duplicates were removed, 1454 studies remained. After application of the apriori inclusion and exclusion criteria, 109 articles were included and 3 were identified with handsearches. In total, 9 evaluative indices for CD were identified and reviewed. The Crohns Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score in Crohns Disease (SES-CD) are indices with the most extensively described operating properties. Conclusions:Both the endoscopic evaluative instrument selected and the definition chosen for mucosal healing affect the validity of assessing endoscopic disease activity during a clinical trial for CD. Currently, the CDEIS and SES-CD have the most data regarding operating properties; however, further validation is required.

Efficacy of adalimumab in patients with Crohn's disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study

Objective The efficacy of anti-tumour necrosis factors (anti-TNFs) in patients with Crohns disease (CD) and symptomatic small bowel stricture (SSBS) is controversial. The aim of this study was to estimate the efficacy of adalimumab in these patients and to identify the factors predicting success. Design We performed a multicentre, prospective, observational cohort study in patients with CD and SSBS. The included patients underwent magnetic resonance enterography at baseline and subsequently received adalimumab. The primary endpoint was success at week 24, defined as adalimumab continuation without prohibited treatment (corticosteroids after the eight week following inclusion, other anti-TNFs), endoscopic dilation or bowel resection. The baseline factors independently associated with success were identified using a logistic regression model, leading to a simple prognostic score. Secondary endpoints were prolonged success after week 24 (still on adalimumab, without dilation nor surgery) and time to bowel resection in the whole cohort. Results From January 2010 to December 2011, 105 patients were screened and 97 were included. At week 24, 62/97 (64%) patients had achieved success. The prognostic score defined a good prognosis group with 43/49 successes, an intermediate prognosis group with 17/28 successes and a poor prognosis group with 1/16 successes. After a median follow-up time of 3.8 years, 45.7%±6.6% (proportion±SE) of patients who were in success at week 24 (ie, 29% of the whole cohort) were still in prolonged success at 4 years. Among the whole cohort, 50.7%±5.3% of patients did not undergo bowel resection 4 years after inclusion. Conclusions A successful response to adalimumab was observed in about two-thirds of CD patients with SSBS and was prolonged in nearly half of them till the end of follow-up. More than half of the patients were free of surgery 4 years after treatment initiation. Clinical Trial registration number NCT01183403; Results.

Colorectal Adenomatous Polyposis Associated with MYH Mutations: Genotype and Phenotype Characteristics

PurposeRecent literature reports that several digestive diseases are associated with mutations in the base excision repair gene MYH. This study was designed to establish the prevalence of germ-line MYH mutations in a series of 56 consecutive patients with no detectable APC mutation and describe the phenotype of those with MYH mutations.MethodsMYH mutations were screened by DNA sequencing after polymerase chain reaction amplification of each exon. Clinical, endoscopic, and surgical data were collected for the tested patients.ResultsMYH mutations were identified only in the group of patients with attenuated adenomatous polyposis with ten or more adenomatous polyps. The prevalence of MYH mutations was 34.4 percent (11 cases) in this subgroup of 30 patients. There were two homozygotes and eight compound heterozygotes. Only one patient had a monoallelic mutation. At least one of two mutational hot spots was identified in ten patients. Three patients presented with a family history of adenomatous polyposis in siblings, without vertical transmission. The median number of colorectal adenomatous polyps was 53 without preferential localization. Colorectal cancer was associated with polyposis in seven patients. Gastric and duodenal adenomas were diagnosed in one case. Ten of 11 patients underwent colectomy.ConclusionsMYH mutations have been observed in one-third of patients with attenuated polyposis. The phenotype of the disease is similar to attenuated familial adenomatous polyposis. Upper gastrointestinal endoscopy also should be recommended. However, its transmission shows evidence of a recessive pattern.

One-year effectiveness and safety of vedolizumab therapy for inflammatory bowel disease: a prospective multicentre cohort study

We recently showed that vedolizumab is effective in patients with Crohns disease (CD) and ulcerative colitis (UC) with prior anti‐TNF failure in a multicentre compassionate early‐access programme before marketing authorisation was granted to vedolizumab.