Laurent Peyrin-Biroulet

Development of the Crohn's disease digestive damage score, the Lemann score.

Crohns disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohns disease (IPNIC) group. This instrument, called the Crohns Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be “diagnostic modality driven”: for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patients disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011)

Clinical implications of mucosal healing for the management of IBD

Mucosal healing (MH) has emerged as an important treatment goal for patients with IBD. Historically, the therapeutic goals of induction and maintenance of clinical remission seemed insufficient to change the natural history of IBD. Evidence has now accumulated to show that MH can alter the course of IBD, as it is associated with sustained clinical remission, and reduced rates of hospitalization and surgical resection. In patients with ulcerative colitis, MH may represent the ultimate therapeutic goal because inflammation is limited to the mucosa. In patients with Crohns disease, which is a transmural disease, MH could be considered as a minimum therapeutic goal. This Review focuses on the definition of MH and discusses the ability of each available IBD medication to induce and maintain MH. The importance of achieving MH is also discussed and literature that demonstrates improvement of disease course with MH is reviewed. Finally, we discuss how best to integrate the treatment end point of MH into clinical practice for the management of patients with IBD.

PPARγ as a new therapeutic target in inflammatory bowel diseases

The peroxisome proliferator activated receptor γ (PPARγ) is a nuclear receptor highly expressed in the colon and playing a key role in bacterial induced inflammation. Regulation of colon inflammation by this receptor has been well demonstrated in many experimental models of colitis but also in patients with ulcerative colitis, characterised by impaired expression of PPARγ confined to their colon epithelial cells. Recent data showing that PPARγ was the major functional receptor mediating the common aminosalicylate activities in inflammatory bowel diseases (IBD) have also reinforced the roles of this receptor in the control of intestinal inflammation. The aims of this review are to discuss the potential roles of PPARγ in the physiopathology of IBD, as well as the emerging therapeutic strategies targeting this receptor. Current evidence suggests that Crohn’s disease (CD) and ulcerative colitis (UC) result from a complex interplay between genetic and environmental factors, leading to an abnormal innate and adaptive immune response of the gut directed against luminal constituents in genetically determined patients. Identification of cytoplasmic receptors of bacterial peptidoglycan, namely nucleotide oligomerisation domain (NOD)2/caspase recruitment domain (CARD)15 and NOD1/CARD4, as CD susceptibility genes reinforced the pivotal role of the interactions between enteric microbes and the intestinal immune system in the physiopathology of IBD.1–3 Furthermore, recent advances in our laboratory and others also indicate the involvement of another key receptor, PPARγ, which regulates colon inflammation. This represents a new target in the development of therapeutic molecules in IBD. PPARγ is a nuclear receptor discovered in mammals in 1993 as an orphan receptor.4 Until recently, PPARγ was known as a receptor mainly expressed by adipose tissue and involved in the regulation of insulin resistance. PPARγ is activated by antidiabetic thiazolidinedione drugs.5 In 1998, the first studies were published reporting a potential link between this receptor and …

Iron deficiency anaemia

Anaemia affects roughly a third of the worlds population; half the cases are due to iron deficiency. It is a major and global public health problem that affects maternal and child mortality, physical performance, and referral to health-care professionals. Children aged 0-5 years, women of childbearing age, and pregnant women are particularly at risk. Several chronic diseases are frequently associated with iron deficiency anaemia--notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease. Measurement of serum ferritin, transferrin saturation, serum soluble transferrin receptors, and the serum soluble transferrin receptors-ferritin index are more accurate than classic red cell indices in the diagnosis of iron deficiency anaemia. In addition to the search for and treatment of the cause of iron deficiency, treatment strategies encompass prevention, including food fortification and iron supplementation. Oral iron is usually recommended as first-line therapy, but the most recent intravenous iron formulations, which have been available for nearly a decade, seem to replenish iron stores safely and effectively. Hepcidin has a key role in iron homoeostasis and could be a future diagnostic and therapeutic target. In this Seminar, we discuss the clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron deficiency anaemia, and outstanding research questions for treatment.

3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management

This paper is the first in a series of two publications relating to the European Crohn’s and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn’s disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn’s disease. Surgical management as well as special situations including management of perianal Crohn’s disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].

Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury

The colonic epithelium self-renews every 3 to 5 d, but our understanding of the underlying processes preserving wound healing from carcinogenesis remains incomplete. Here, we demonstrate that Nod-like receptor pyrin domain-containing protein 6 (NLRP6) suppresses inflammation and carcinogenesis by regulating tissue repair. NLRP6 was primarily produced by myofibroblasts within the stem-cell niche in the colon. Although NLRP6 expression was lowered in diseased colon, NLRP6-deficient mice were highly susceptible to experimental colitis. Upon injury, NLRP6 deficiency deregulated regeneration of the colonic mucosa and processes of epithelial proliferation and migration. Consistently, absence of NLRP6 accelerated colitis-associated tumor growth in mice. A gene-ontology analysis on a whole-genome expression profiling revealed a link between NLRP6 and self-renewal of the epithelium. Collectively, the integrity of the epithelial barrier is preserved by NLRP6 that may be manipulated to develop drugs capable of preventing adenoma formation in inflammatory bowel diseases.

Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn's disease in the SONIC trial

Background and aims The Crohns Disease Activity Index (CDAI) has been criticised due to heavy weighting on subjective clinical symptoms. C-reactive protein (CRP) and endoscopic lesions are objective measures of inflammation. We investigated the relationships between clinical disease activity, CRP normalisation and mucosal healing in Crohns disease (CD). Methods The Study of Biologic and Immunomodulator Naive Patients in CD trial compared infliximab to azathioprine and to infliximab plus azathioprine in 508 CD patients. Mucosal healing was defined as the absence of mucosal ulceration at the week 26 ileocolonoscopy in a patient who had evidence of ulceration at the baseline ileocolonoscopy. Results 188 patients who had evaluable ileocolonoscopy with evidence of mucosal ulceration at baseline, CDAI scores and CRP values at baseline and week 26 were analysed. Seventy-two of 136 patients (53%) who had a CDAI<150 at week 26 achieved mucosal healing, and 38 of 90 patients (42%) achieved both CRP normalisation (CRP<0.8 mg/dL) and mucosal healing while in clinical remission. The positive predictive value (PPV) and negative predictive value (NPV) of CDAI to detect mucosal healing using 150 as a cut-off for CDAI were 65% and 53%, respectively. The PPV and NPV of CDAI to detect mucosal healing and CRP normalisation using 150 as a cut-off for CDAI were 79% and 42%, respectively. Conclusions Half the patients under azathioprine and/or infliximab in clinical remission have endoscopic and/or CRP evidence of residual active CD, whereas other patients with endoscopic and CRP normalisation have persistent clinical symptoms. Clinical symptoms as scored by CDAI are not a reliable measure of the underlying inflammation.

Diffusion-weighted magnetic resonance without bowel preparation for detecting colonic inflammation in inflammatory bowel disease

Objective Magnetic resonance imaging (MRI) enables accurate assessment of inflammatory bowel diseases (IBD), but its main limitation is the need for bowel preparation. Diffusion-weighted imaging is feasible in Crohns disease. We evaluated the accuracy of MRI in combination with diffusion-weighted imaging (DWI-MRI) without oral or rectal preparation in assessing colonic inflammation in both ulcerative colitis and Crohns disease. Design This was an observational study of a single-centre cohort. Patients All patients who underwent DWI-MRI-colonography without bowel preparation between January 2008 and February 2010 in our centre were analysed. Results Among the 96 patients (ulcerative colitis=35; Crohns disease=61) who had DWI-MRI-colonography, 68 had concomitant endoscopy. In ulcerative colitis a segmental magnetic resonance score (MR-score-S) >1 detected endoscopic inflammation with a sensitivity and specificity of 89.47% and 86.67%, respectively (AUROC=0.920, p=0.0001). In the Crohns disease group, a MR-score-S >2 detected endoscopic inflammation in the colon with a sensitivity and specificity of 58.33% and 84.48%, respectively (AUROC=0.779, p=0.0001). The MR-score-S demonstrated better accuracy for the detection of endoscopic inflammation in the ulcerative colitis group than in the Crohns disease group (p=0.003). In ulcerative colitis, the proposed total magnetic resonance score (MR-score-T) correlated with the total modified Baron score (r=0.813, p=0.0001) and the Walmsley index (r=0.678, p<0.0001). In Crohns disease, the MR-score-T correlated with the simplified endoscopic activity score for Crohns disease (r=0.539, p=0.001) and the Crohns disease activity index (r=0.367, p=0.004). The DWI hyperintensity was a predictor of colonic endoscopic inflammation in ulcerative colitis (OR=13.26, 95% CI 3.6 to 48.93; AUROC=0.854, p=0.0001) and Crohns disease (OR=2.67, 95% CI 1.25 to 5.72; AUROC=0.702, p=0.0001). The accuracy of the DWI hyperintensity for detecting colonic inflammation was greater in ulcerative colitis than in Crohns disease (p=0.004). Conclusions DWI-MRI-colonography without bowel preparation is a reliable tool for detecting colonic inflammation in ulcerative colitis.

Impact of azathioprine and tumour necrosis factor antagonists on the need for surgery in newly diagnosed Crohn's disease

Objective The aim of the study was to assess whether azathioprine and antitumour necrosis factor (TNF) treatment decrease the long-term need for surgery in patients with Crohns disease. Methods This was an observational study of a referral centre cohort. The cumulative incidence of the first Crohns disease-related major abdominal surgery was estimated using the Kaplan–Meier method, and independent predictors of surgery were identified using Cox proportional hazards regression with propensity scores adjustment. Receiver operating characteristic (ROC) analysis was used to identify optimal cut-offs for duration of maintenance treatments. The electronic charts of 296 incident cases of Crohns disease from Nancy University Hospital, France, diagnosed between 2000 and 2008, were reviewed through January 2010. Results The median follow-up time per patient was 57 months. Seventy-six patients (26%) underwent at least one major abdominal surgical procedure. The cumulative probabilities of the first Crohns disease-related major abdominal surgery were 6.5, 25.9 and 44.3 at 1, 5 and 9 years, respectively. In the ROC analysis, the duration of anti-TNF and azathioprine treatment had significant cut-off values (≤475 days ∼16 months and ≤45 days ∼1.5 months, respectively) with positive likelihood ratios (PLRs) of 1.52 (p<0.0001) and 1.51 (p=0.003) for the first Crohns disease-related major abdominal surgery. Using multivariate Cox proportional hazards regression analysis (after propensity score adjustment), independent positive predictors of major abdominal surgery were stricturing (HR=12.01; 95% CI 5.97 to 24.17) or penetrating (HR=10.77; 95% CI 4.87 to 23.80) disease behaviour at diagnosis, duration of anti-TNF treatment of <16 months (HR=3.86; 95% CI 1.77 to 8.45) and duration of azathioprine treatment of <1.5 months (HR=2.00; 95% CI 1.20 to 3.34). Conclusions Non-complicated inflammatory disease behaviour and long-term anti-TNF treatment are associated with a lower risk for surgery whereas azathioprine only modestly lowers this risk.

Opportunistic infections with anti-tumor necrosis factor-α therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials.

OBJECTIVES:Several anti-tumor necrosis factor-α (TNFα) antibodies have demonstrated efficacy in Crohns disease (CD) and ulcerative colitis (UC). These drugs carry the theoretical risk of opportunistic infection, but no systematic review and meta-analysis has examined this issue specifically.METHODS:MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through to November 2012). Randomized controlled trials (RCTs) recruiting adults with active or quiescent CD or UC comparing anti-TNFα therapy with placebo were eligible. Dichotomous data were pooled to obtain a relative risk (RR) of opportunistic infection, with a 95% confidence interval (CI). The number needed to harm (NNH) was estimated from the reciprocal of the risk difference from the meta-analysis.RESULTS:The search strategy identified 20,563 citations, 21 of which were eligible, reporting 22 separate RCTs with between 2 and 56 weeks of follow-up. In total, there were 39 (0.9%) opportunistic infections among 4,135 patients allocated to anti-TNFα therapy, compared with 9 (0.3%) among 2,919 assigned to placebo. Among patients receiving active therapy these included eight cases of Mycobacterium tuberculosis, eight cases of herpes simplex infection, six cases of oral or esophageal candidiasis, six cases of herpes zoster infection, two cases of varicella-zoster virus infection, two cases of cytomegalovirus or Epstein–Barr virus infection, and one case of Nocardia infection. The RR of developing an opportunistic infection was significantly higher with anti-TNFα therapy (2.05; 95% CI 1.10–3.85, NNH=500; 95% CI 200–1,567). The RR of tuberculosis infection was 2.52 (95% CI 0.62–10.21).CONCLUSIONS:Anti-TNF therapy doubles the risk of opportunistic infections in inflammatory bowel disease patients. This underlines the importance of adherence to guidelines for their prevention and management.