Xavier Hébuterne

Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study

BACKGROUND Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a prospective observational cohort study. METHODS 19,486 patients with inflammatory bowel disease, of whom 11,759 (60.3%) had Crohns disease and 7727 (39.7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29-40). FINDINGS At baseline, 5867 (30.1%) of patients were receiving, 2809 (14.4%) had discontinued, and 10,810 (55.5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkins lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0.90 per 1000 (95% CI 0.50-1.49) patient-years in those receiving, 0.20/1000 (0.02-0.72) patient-years in those who had discontinued, and 0.26/1000 (0.10-0.57) patient-years in those who had never received thiopurines (p=0.0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5.28 (2.01-13.9, p=0.0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease. INTERPRETATION Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders. FUNDING Programme Hospitalier de Recherche Clinique National (AOM05157), Association François Aupetit, Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie.

A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease

Susceptibility to Crohns disease, a complex inflammatory disease, is influenced by common variants at many loci. The common exonic synonymous SNP (c.313C>T) in IRGM, found in strong linkage disequilibrium with a deletion polymorphism, has been classified as non-causative because of the absence of an alteration in the IRGM protein sequence or splice sites. Here we show that a family of microRNAs (miRNAs), miR-196, is overexpressed in the inflammatory intestinal epithelia of individuals with Crohns disease and downregulates the IRGM protective variant (c.313C) but not the risk-associated allele (c.313T). Subsequent loss of tight regulation of IRGM expression compromises control of intracellular replication of Crohns disease–associated adherent invasive Escherichia coli by autophagy. These results suggest that the association of IRGM with Crohns disease arises from a miRNA-based alteration in IRGM regulation that affects the efficacy of autophagy, thereby implicating a synonymous polymorphism as a likely causal variant.

Malnutrition is an independent factor associated with nosocomial infections

The aim of the present prospective study was to determine if malnutrition, measured using a simple validated score, is an independent risk factor for nosocomial infections (NI) in non-selected hospital in-patients. Between 29 and 31 May 2001, a survey on the prevalence of NI was conducted on all 1637 in-patients (61 (SD 25) years old) in a French university hospital as part of a national survey. Actual and usual body weights were recorded in all in-patients, and serum albumin levels were measured on all blood samples taken during the week before the study. Nutritional status was evaluated by using the nutritional risk index (NRI). Albumin values were obtained in 1084 patients, and complete weight information was obtained in 911. Therefore, NRI was calculated in 630 patients (61 (SD 20) years old): 427 (67.8 %) were malnourished. NI prevalence was 8.7 %: 4.4 % in non-malnourished patients, 7.6 % in moderately malnourished patients and 14.6 % in severely malnourished patients. In univariate analysis, the odds ratios for NI were 1.46 (95 % CI 1.2, 2.1) in moderately malnourished patients and 4.98 (95 % CI 4.6, 6.4) in severely malnourished patients. In multivariate analysis, age, immunodeficiency and NRI class influenced NI risk. Vascular and urinary catheters, and surgical intervention, were the extrinsic factors associated with NI, with odds ratios ranging from 2.0 (95 % CI 1.8, 2.6) for vascular catheters to 10.8 (95 % CI 8.8, 12.6) for association of the three factors. In conclusion, in non-selected hospitalized patients, malnutrition assessed with a simple and objective marker is an independent risk factor for NI. An early screening for malnutrition may therefore be helpful to reduce the high prevalence of NI.

ESPEN Guidelines on Parenteral Nutrition: Home Parenteral Nutrition (HPN) in adult patients

Home parenteral nutrition (HPN) was introduced as a treatment modality in the early 1970s primarily for the treatment of chronic intestinal failure in patients with benign disease. The relatively low morbidity and mortality associated with HPN has encouraged its widespread use in western countries. Thus there is huge clinical experience, but there are still few controlled clinical studies of treatment effects and management of complications. The purpose of these guidelines is to highlight areas of good practice and promote the use of standardized treatment protocols between centers. The guidelines may serve as a framework for development of policies and procedures.

Omega-3 Free Fatty Acids for the Maintenance of Remission in Crohn Disease: The EPIC Randomized Controlled Trials

CONTEXT Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. OBJECTIVE To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. DESIGN, SETTING, AND PATIENTS Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohns Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. INTERVENTIONS Patients with a Crohns Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. MAIN OUTCOME MEASURE Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. RESULTS For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease. CONCLUSION In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease. TRIAL REGISTRATION clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542.

Home parenteral nutrition in adults: a Europeanmulticentre survey in 1997

Abstract A retrospective survey on home parenteral nutrition (HPN) in Europe was performed fromJanuary to December 1997. Data were compared to a similar study performed in 1993. A questionnaire of HPN practice was designed by the members of the ESPEN-HAN group. This involvedadult patients (older than 16 years) newly registered in an HPN program between 1 January and 31 December 1997 and included: number of patients, underlying diseases and a 6–12 month outcome. Incidence and prevalence (at 1.1.1998) of adult HPN were calculated according to the estimated total population in 1997 for the countries in which more than 80% of HPN patients were reported. A total of 494 patients were registered in 73 centres from nine countries (Belgium (B), Denmark (D), France (F), Poland (P), Spain (S), Sweden (Sw), United Kingdom (UK), The Netherlands (N) and Germany (G). The underlying diseases for HPN in 494 patients were cancer (39%), Crohns (19%), vascular diseases (15%), radiation enteritis (7%), AIDS (2%), other diseases with intestinal failure (18%). Incidence (patients/million inhabitants/year) were in N (3), F. (2.9), D. (2.8), B. (2.6), UK (1.2), S (0.7) and P (0.36), respectively. Prevalence were in D. (12.7). U.K. (3.7), N. (33), F (3.6), B (3.0), P (1.1), S (0.65). After this 6–12 months follow-up (n=284), the mortality was respectively 4% in Crohns disease, 13% in vascular diseases, 16% in others, 21% in radiators enteritis, 34% in AIDS, 74% in cancer. Incidences and prevalences modestly increased in these seven European countries in 1997 in comparison to 1993. The percentages of underlying diseases in these countries remained similar except for ADS that significantly decreased (from 7% to 2%). Outcomes did not significantly differ in the 4-year period except for AIDS (34% instead of 88% mortality) and could have been related to newer, more efficacious therapy.

Long-term follow-up of patients on home parenteral nutrition in Europe: implications for intestinal transplantation

Background The indications for intestinal transplantation (ITx) are still debated. Knowing survival rates and causes of death on home parenteral nutrition (HPN) will improve decisions. Methods A prospective 5-year study compared 389 non-candidates (no indication, no contraindication) and 156 candidates (indication, no contraindication) for ITx. Indications were: HPN failure (liver failure; multiple episodes of catheter-related venous thrombosis or sepsis; severe dehydration), high-risk underlying disease (intra-abdominal desmoids; congenital mucosal disorders; ultra-short bowel), high morbidity intestinal failure. Causes of death were defined as: HPN-related, underlying disease, or other cause. Results The survival rate was 87% in non-candidates, 73% in candidates with HPN failure, 84% in those with high-risk underlying disease, 100% in those with high morbidity intestinal failure and 54%, in ITx recipients (one non-candidate and 21 candidates) (p<0.001). The primary cause of death on HPN was underlying disease-related in patients with HPN duration ≤2 years, and HPN-related in those on HPN duration >2 years (p=0.006). In candidates, the death HRs were increased in those with desmoids (7.1; 95% CI 2.5 to 20.5; p=0.003) or liver failure (3.4; 95% CI 1.6 to 7.3; p=0.002) compared to non-candidates. In deceased candidates, the indications for ITx were the causes of death in 92% of those with desmoids or liver failure, and in 38% of those with other indications (p=0.041). In candidates with catheter-related complications or ultra-short bowel, the survival rate was 83% in those who remained on HPN and 78% after ITx (p=0.767). Conclusions HPN is confirmed as the primary treatment for intestinal failure. Desmoids and HPN-related liver failure constitute indications for life-saving ITx. Catheter-related complications and ultra-short bowel might be indications for pre-emptive/rehabilitative ITx. In the early years after commencing HPN a life-saving ITx could be required for some patients at higher risk of death from their underlying disease.

Nutritional Deficiencies in Patients With Crohn's Disease in Remission

Background: Patients with Crohns disease (CD) are at risk of developing nutritional deficiencies, especially because of restrictive diets. The aim of our study was to assess food intake and the status for vitamins and trace elements in nonselected CD patients in clinical remission. Methods: A total of 54 consecutive CD patients (28 females, 26 males, 39 ± 2 years of age [mean ± SD]) in clinical remission for >3 months underwent body composition, resting energy expenditure, nutrient intake, and plasma concentration assessment, and were compared with 25 healthy controls (16 females, 9 males, 38 ± 3 years old). Results: According to the nutritional risk index, 37 patients (70%) were not malnourished, 12 were at moderate risk, and 4 were at severe risk for malnutrition. Fat mass was lower in patients in remission compared with controls (P = 0.04). The mean daily energy intake was comparable between patients (2218 ± 92 kcal/day) and controls (2066 ± 101 kcal/day), covering their needs. No significant difference was observed for macronutrient intake in comparison with controls; compared to controls, female CD patients had lower intakes of &bgr;‐carotene (P < 0.005), vitamins B1 (P < 0.05), B6 (P < 0.01), and C (P < 0.005), and magnesium (P < 0.01). They had significantly higher intakes of zinc (P < 0.01). Male CD patients had lower intakes of &bgr;‐carotene and vitamin C (P < 0.05). More than 50% of patients had low plasma concentrations of vitamin C (84%), copper (84%), niacin (77%), and zinc (65%). Conclusions: In CD patients in remission, macronutrient needs are usually covered by food intake. However, micronutrient deficiencies are frequent and call for specific screening and treatment.

Mast cells and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome

Background: A subset of patients with irritable bowel syndrome (IBS) have an increased number of mast cells (MCs) in the colonic mucosa. Psychological factors are believed to contribute to the course of IBS. Aims: To examine associations between fatigue, depression and MCs of the colonic mucosa in IBS. Methods: Colonic biopsies were taken from 50 Rome II IBS patients, 21 healthy controls and 11 depressed/fatigued patients without IBS. The cellularity of the lamina propria was determined as the number of inflammatory cells per high power field (hpf) through a 400× microscope. The Fatigue Impact Scale (FIS) and the short form Beck Depression Inventory (BDI) evaluated the severity of fatigue and depression. Results: IBS patients had a significant increase in the cellularity of the lamina propria compared with controls or with depressed patients (mean (SD) 94.5 (48–110) vs 68 (58–82) and 78 (87–90) cells per hpf, p = 0.005 and p = 0.05, respectively), in particular of MCs (9.3 (5.6–11.7) vs 4.0 (2.7–6.8) and 4.3 (2.8–7.8) cells per hpf, p = 0.001 and p = 0.005, respectively). Both the FIS and BDI scores were significantly higher in IBS or in depressed patients than in controls (p<0.001). In IBS, the FIS score correlated significantly with the cellularity of the lamina propria (r = 0.51, p<0.0001) and MCs (r = 0.64, p<0.0001). In IBS, the BDI score correlated significantly with MCs (r = 0.29, p = 0.03). Conclusions: Elevated MCs counts are a key feature of the low-grade inflammatory infiltrate in the caecal mucosa of IBS. Fatigue and depression are associated with mucosal cell counts, in particular MCs, suggesting that psychological factors are associated with the low-grade inflammatory infiltrate in IBS.

Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol

Objective To evaluate the efficacy of certolizumab pegol (CZP) in improving endoscopic lesions in patients with active ileocolonic Crohns disease (CD). Methods This phase IIIB multicentre open-label clinical trial enrolled 89 adult patients with active endoscopic disease (ulceration in ≥2 intestinal segments with a Crohns Disease Endoscopic Index of Severity (CDEIS) score ≥8 points). Patients received subcutaneous CZP 400 mg at weeks 0, 2 and 4 and every 4 weeks up to week 52. Endoscopic evaluations were performed at weeks 0, 10 and 54. The primary outcome was mean change in CDEIS score at week 10; secondary outcome measures included endoscopic response (decrease in CDEIS score >5 points), remission (CDEIS score <6), complete remission (CDEIS score <3) and mucosal healing (no ulcer) at weeks 10 and 54. Results In the intention-to-treat population (n=89) the mean±SD CDEIS score was 14.5±5.3 at baseline; the mean decrease in CDEIS score at week 10 was 5.7 (95% CI 4.6 to 6.8, p<0.0001). Rates of endoscopic response, endoscopic remission, complete endoscopic remission and mucosal healing at week 10 were 54%, 37%, 10% and 4%, respectively. At week 54 the corresponding rates were 49%, 27%, 14% and 8%, respectively. The safety profile was consistent with that of previous CZP trials. Conclusions Following CZP treatment in patients with active CD, endoscopic lesions were improved as shown by the decrease in mean CDEIS score and by endoscopic response and remission rates. These benefits were achieved as early as week 10 and were generally maintained through week 54. Clinical Trial Registration Number NCT00297648.