Jérôme Filippi

Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial

BACKGROUND Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication. METHODS In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152). FINDINGS 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI -7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. INTERPRETATION Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. FUNDING Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.

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.

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.

A multicenter experience with infliximab for ulcerative colitis: outcomes and predictors of response, optimization, colectomy, and hospitalization.

OBJECTIVES:The objective of this study was to evaluate short- and long-term outcomes of infliximab in ulcerative colitis (UC), including infliximab optimization, colectomy, and hospitalization.METHODS:This was a retrospective multicenter study. All adult patients who received at least one infliximab infusion for UC were included. Cumulative probabilities of event-free survival were estimated by the Kaplan–Meier method. Independent predictors were identified using binary logistic regression or Cox proportional-hazards regression, and results were expressed as odds ratios or hazard ratios (HRs), respectively.RESULTS:Between January 2000 and August 2009, 191 UC patients received infliximab therapy. Median follow-up per patient was 18 months (interquartile range=25–75th, 8–32 months). Primary non-response was noted in 42 patients (22.0%). “Hemoglobin at infliximab initiation ≤9.4 g/dl” (odds ratio=4.35; 95% confidence interval (CI)=1.81–10.42) was a positive predictor of non-response to infliximab. Infliximab optimization was required in 36 (45.0%) of 80 patients on scheduled infliximab therapy. The only predictor of infliximab optimization was “infliximab indication for acute severe colitis” (HR=2.75; 95% CI=1.23–6.12). Thirty-six patients (18.8%) underwent colectomy. Predictors of colectomy were: “no clinical response after infliximab induction” (HR=7.06; 95% CI=3.36–14.83), “C-reactive protein at infliximab initiation >10 mg/l” (HR=5.11; 95% CI=1.77–14.76), “infliximab indication for acute severe colitis” (HR=3.40; 95% CI=1.48–7.81), and “previous treatment with cyclosporine” (HR=2.53; 95% CI=1.22–5.28). Sixty-nine patients (36.1%) were hospitalized at least one time and UC-related hospitalizations rate was 29 per 100 patient-years (95% CI=24–35 per 100 patient-years). Predictors of first hospitalization were: “no clinical response after infliximab induction” (HR=3.87; 95% CI=2.29–6.53), “infliximab indication for acute severe colitis” (HR=3.13, 95% CI=1.65–5.94), “disease duration at infliximab initiation ≤50 months” (HR=2.14, 95% CI=1.25–3.66), “hemoglobin at infliximab initiation ≤11.8 g/dl” (HR=1.77; 95% CI=1.03–3.04), and “previous treatment with methotrexate” (HR=0.30; 95% CI=0.09–0.97).CONCLUSIONS:Primary non-response to infliximab was noted in one fifth of patients and increased by seven and four the risks of colectomy and hospitalization, respectively. Infliximab optimization, colectomy, and hospitalization were required in half, one fifth, and one third of patients, respectively. Infliximab indication for acute severe colitis increased by three the risks of infliximab optimization, colectomy, and UC-related hospitalization.

Impact of mucosal healing on long‐term outcomes in ulcerative colitis treated with infliximab: a multicenter experience

Mucosal healing can be achieved with infliximab (IFX).

Diagnostic accuracy of a rapid urine-screening test (Multistix8SG) in cirrhotic patients with spontaneous bacterial peritonitis.

Objective To assess the diagnostic accuracy of a rapid urine-screening test (Multistix8SG) for spontaneous bacterial peritonitis (SBP) in cirrhotic patients. Methods Seventy-two consecutive patients (44 males, 28 females; mean age 61.6 years) with cirrhosis and ascites were included in the study. A diagnostic paracentesis was performed on hospital admission in all patients and 2 days after antibiotic treatment in the case of SBP (polymorphonuclear [PMN] count over 250/mm3 in ascitic fluid). Each fresh sample of ascitic fluid was also tested using the Multistix8SG urine test, and the results were scored as negative, trace or positive. Results Nine of the 72 patients had SBP and the Multistix8SG urine test was positive. After 48 h of antibiotic therapy, the PMN count of three of these nine patients was still above 250/mm3 and the Multistix8SG test remained positive. In three other patients with SBP, the PMN count dropped below 250/mm3 and the Multistix8SG test result had become negative. Two of the nine SBP patients died before 48 h, and paracentesis was not performed in the ninth case. In the other 63 patients, the PMN count in ascitic fluid was below 250/mm3; the Multistix8SG test revealed 17 trace results and 46 negative results. At the threshold of 250 PMN/mm3 in ascitic fluid, this test had a sensitivity and a specificity of 100%. Conclusion A positive Multistix8SG urine test result in ascitic fluid appears to be an indication for antibiotic treatment.

Sarcopenia is prevalent in patients with Crohn's disease in clinical remission

Background: Patients with Crohns disease (CD) are prone to osteoporosis. A loss of muscle mass, called sarcopenia, is responsible for an increased risk of disability. Many factors associated with osteopenia also decrease muscle mass. The aim of the present study was to measure the prevalence of sarcopenia in CD patients in remission and uncover its relationship with osteopenia. Methods: In all, 82 CD patients (43 female / 39 male; 36 ± 14 years; body mass index [BMI] 21.1 ± 3.4) and 50 healthy volunteers (30F/20M; 39 ± 13 years; BMI 22.2 ± 2.5) were studied. Body composition was assessed using dual‐energy x‐ray absorptiometry. Sarcopenia was defined as an appendicular skeletal muscle index (ASMI) below 5.45 kg/m2 for women and 7.26 for men. Osteopenia was defined as a T‐score for bone mineral density (BMD) (g/cm2) below −1.0. Results: In all, 60% of CD patients were found to be sarcopenic and 30% osteopenic, compared to 16% and 4% of controls, respectively (P < 0.01). ASMI was significantly lower in patients than in controls (6.0 ± 1.1 versus 6.5 ± 1.2; P < 0.05). Sarcopenic patients had significantly (P < 0.01) lower BMI (20.0 ± 3.5 versus 22.7 ± 2.8 kg/m2), lean mass (41.5 ± 9.1 versus 48.1 ± 9.1 kg), and BMD (1.09 ± 0.12 versus 1.15 ± 0.08 g/cm2) than nonsarcopenic patients; 91% of sarcopenic patients were also osteopenic. ASMI correlated with BMD (r = 0.46; P < 0.01) and BMI (r = 0.38; P < 0.01). Conclusions: The prevalence of sarcopenia is high in young CD patients and strongly related to osteopenia. These 2 phenomena may share similar mechanisms. Simultaneous screening for sarcopenia and osteopenia may be useful in CD patients.

Muscle performance in patients with Crohn's disease in clinical remission.

Background: Because patients with Crohns disease (CD) often show increased energy expenditure, nutritional deficiencies, and general fatigue, all which may persist after a flare, we hypothesized that CD could alter muscle mass and function. This study aimed to assess muscle strength and endurance in CD patients in clinical remission and the influencing factors. Methods: Forty‐one outpatients (17 men and 24 women; age, 37 ± 10 yr), in remission (CD Activity Index < 150) for >3 months, and 25 age‐matched healthy controls (10 men and 15 women; age, 37 ± 13 yr) were evaluated. Evaluation included a sit‐up test, hand‐grip strength test, hand‐grip endurance test, lower limb strength test, and lower limb endurance test (LE), as well as a measure of physical activity. Results: No significant difference was found between CD and control groups regarding weight, height, body mass index, fat mass, and fat‐free mass. Strength performance was lower in CD subjects compared with controls, particularly for lower limb indexes: lower limb strength test (−24.6%, P < 0.001), LE (−25.8%, P < 0.001), and sit‐up test (−25.1%, P < 0.001). Previous disease severity, disease duration, the cumulative dose of glucocorticosteroids, current inflammation, and global habitual physical activity did not affect muscle performance. A recent use of steroids improved LE. Conclusions: CD patients in clinical remission have decreased muscle function that may affect their quality of life. This pattern is reflected by reduced strength and endurance indexes, particularly for lower limbs. The reasons for these changes need further study. Strength training should be assessed in these patients.

Does Anti-TNF Therapy Reduce the Requirement for Surgery in Ulcerative Colitis? A Systematic Review

Infliximab has demonstrated its efficacy in moderate to severe ulcerative colitis. The Active Ulcerative Colitis Trial (ACT) -1 and 2 have demonstrated the beneficial impact of infliximab on the short-term colectomy rate. However, data evaluating this outcome beyond one year remains scarce. To provide evidence on the potential impact of infliximab on the long-term colectomy rate in patients suffering from ulcerative colitis, data was reviewed from randomized and controlled studies, referral centre studies and population-based studies, in adult and pediatric populations. In the pre-biologic era, 9-33%, 50% and 29% of adult patients with ulcerative colitis underwent colectomy in clinical trials, referral center studies and population-based cohorts, respectively. In the pediatric population, 9-61% and 8-20% underwent colectomy in referral centers and population-based cohorts, respectively. Between 10 and 36% of adult patients treated with infliximab for ulcerative colitis underwent colectomy in clinical trials, referral center studies and population-based cohorts. In the pediatric population treated with infliximab, long-term data is lacking, with colectomy rates ranging from 16 to 28%. Whether infliximab proves to be a disease modifying treatment in ulcerative colitis in the long term remains to be elucidated and will require further long-term prospective studies.

Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia.

The acute phase of Crohns disease (CD) is characterized by a large afflux of polymorphonuclear leukocytes (PMNL) into the mucosa and by the release of TNF-alpha. Conversion of inactive TNF-alpha into an active form requires the cleavage of a transmembrane TNF-alpha precursor by the TNF-alpha-converting enzyme (ADAM17), a protease mainly regulated by the tissue inhibitor of metalloproteinase 3 (TIMP3). The aim of the present study was to investigate in an in vitro model of PMNL transepithelial migration and in the intestinal mucosa of patients with CD the expression and regulation of ADAM17 and TIMP3 in intestinal epithelial cells (IEC). ADAM17 and TIMP3 expression was analyzed by Western blotting, RT-PCR, confocal microscopy, and immunohistochemistry by using the T84 model and digestive biopsies. ADAM17 expression in IEC was increased at a posttranscriptional level during the early phase (from 2 to 4 h) of PMNL transepithelial migration whereas TIMP3 was only increased 24 h later. TNF-alpha induced an early upregulation of ADAM17 in T84 cells, whereas PMNL adhesion, H(2)O(2), or epithelial tight junction opening alone did not affect the amount of ADAM17. Immunohistochemistry of intestinal biopsies revealed that strong expression of ADAM17 was associated with a high activity of CD. In contrast, TIMP3 was very poorly expressed in these biopsies. ADAM17 and TIMP3 profiling did not correlated with the NOD2/CARD15 status. The ADAM17 activity was higher both in the early phase of PMNL transepithelial migration and in active CD. These results showed early posttranscriptional upregulation of ADAM17 in IEC linked to PMNL transepithelial migration and a high activity of CD.