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Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped.

BACKGROUND & AIMS It is important to determine whether infliximab therapy can be safely interrupted in patients with Crohns disease who have undergone a period of prolonged remission. We assessed the risk of relapse after infliximab therapy was discontinued in patients on combined maintenance therapy with antimetabolites and identified factors associated with relapse. METHODS We performed a prospective study of 115 patients with Crohns disease who were treated for at least 1 year with scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months. Infliximab was stopped, and patients were followed up for at least 1 year. We associated demographic, clinical, and biologic factors with time to relapse using a Cox model. RESULTS After a median follow-up period of 28 months, 52 of the 115 patients experienced a relapse; the 1-year relapse rate was 43.9% ± 5.0%. Based on multivariable analysis, risk factors for relapse included male sex, the absence of surgical resection, leukocyte counts >6.0 × 10(9)/L, and levels of hemoglobin ≤145 g/L, C-reactive protein ≥5.0 mg/L, and fecal calprotectin ≥300 μg/g. Patients with no more than 2 of these risk factors (approximately 29% of the study population) had a 15% risk of relapse within 1 year. Re-treatment with infliximab was effective and well tolerated in 88% of patients who experienced a relapse. CONCLUSIONS Approximately 50% of patients with Crohns disease who were treated for at least 1 year with infliximab and an antimetabolite agent experienced a relapse within 1 year after discontinuation of infliximab. However, patients with a low risk of relapse can be identified using a combination of clinical and biologic markers.

Infliximab Pharmacokinetics in Inflammatory Bowel Disease Patients

Infliximab, a chimeric monoclonal antibody, has profoundly modified the treatment of several inflammatory diseases, but no satisfactory description of its pharmacokinetics is available. The objective of this study is to describe the pharmacokinetics of infliximab and to explore the sources of its interindividual variability. Thirty-three chronic inflammatory bowel disease patients were studied. Infliximab serum concentrations, obtained during therapeutic drug monitoring, were analyzed using a population approach. Influence of sex, weight, age, concomitant immunosuppressive treatment, and development of antibodies toward infliximab (ATI) on pharmacokinetic parameters was investigated. A two-compartment model with first-order distribution and elimination constants allowed a satisfactory description of infliximab serum concentrations. Mean population distribution and elimination half-lives were 4.3 and 18.5 days, respectively. Weight and sex were found to significantly influence volume of distribution of the central compartment, which increased with weight and was higher in men. Clearance was 2.7 times higher, and elimination half-life was 34% lower in the presence of ATI. In two patients, an increase in infliximab dose or a decrease in dosing interval lead to a decrease in infliximab clearance toward its value in patients without ATI. Infliximab pharmacokinetics are similar to those of other monoclonal antibodies, notably with an elimination half-life of approximately 3 weeks. Both body weight and sex were found to influence infliximab pharmacokinetics, and its clearance increased thrice in the presence of ATI.

Motor activity recorded in the unprepared colon of healthy humans.

A manometric method was developed to study the motor activity in the unprepared human colon, and the results in eight healthy subjects were compared with those obtained in the same subjects after bowel cleansing with a non-absorbable solution containing polyethylene glycol 4000 (PEG). A tube assembly (4.5 m long, 12 lumen) was introduced through the nose and passed through the gastrointestinal tract. Two manometric recordings were performed one month apart, one without any preparation and the other after bowel cleansing with PEG. There was no obvious qualitative difference between the recordings performed in the uncleansed and PEG cleansed colon. Moreover, in the unprepared colon motility indices were close to those measured in the cleansed colon. The number of high amplitude propagated contractions (mean (SEM)) was, however, higher in the cleansed colon (8.6 (2.8) v 5.4 (1.8)/subject/9 h in the unprepared colon; p < 0.04). It is concluded that in healthy subjects taking a regular diet, motor activity is not different between the uncleansed and cleansed colon with PEG, except for the high amplitude propagated contractions, which occur more frequently in the cleansed colon.

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.

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.

Right and left colonic transit after eating assessed by a dual isotopic technique in healthy humans

Propulsion of colonic contents after eating in the whole colon was studied in 15 volunteers by scintigraphy with injection of 111In-diethylenetriamine-pentaacetic acid and 99mTc-sulfur colloid into the colon through a nasogastric tube. The radionuclide was injected into the cecoascending colon (n = 7), the hepatic flexure (n = 6), the splenic flexure (n = 9), and the descending colon (n = 4). Changes of activity in the regions distal from and proximal to the injection points were determined before and after a 1000-kcal meal. Isotopic movements were also analyzed when a simultaneous injection of the two markers in the right and left parts of the colon was achieved (n = 11). During fasting, no significant change of activity was seen. After eating, radioactivity injected into the cecoascending and the hepatic flexure was transferred distally (P less than 0.01 and P = 0.07); radioactivity injected into the splenic flexure was transferred both distally (P = 0.07) and proximally (P less than 0.02); and no significant change of activity was seen proximally from or distally to the descending colon. Both antegrade and retrograde isotopic movements increased after eating (P less than 0.01), but the number of antegrade movements was significantly greater (P less than 0.05). This study confirms the colonic propulsive effect of eating and shows that this response is different in the right and left parts of the colon.

864 Close Monitoring of CRP and Fecal Calprotectin is Able to Predict Clinical Relapse in Patients With Crohn's Disease in Remission After Infliximab Withdrawal. a Sub-Analysis of the Stori Study

Close Monitoring of CRP and Fecal Calprotectin is Able to Predict Clinical Relapse in Patients With Crohns Disease in Remission After Infliximab Withdrawal. a Sub-Analysis of the Stori Study Nicolas de Suray, Julia Salleron, Gwenola Vernier-Massouille, Jean-Charles Grimaud, Yoram Bouhnik, David Laharie, Jean-Louis Dupas, Helene PillantLe Moult, Laurence Picon, Michel Veyrac, Mathurin Flamant, Guillaume Savoye, Raymond Jian, Martine De Vos, Eric Piver, Jean-Frederic Colombel, Edouard Louis

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

ABSTRACT Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohns disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a one-compartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.

A robust estimation of infliximab pharmacokinetic parameters in Crohn's disease.

Pharmacokinetic studies on infliximab, an anti-TNF-αmonoclonal antibody, in Crohn’s disease reported different pharmacokinetic (PK) parameters [1–4]. These discrepancies could be explained by (i) the inclusion of patients at distance of treatment initiation, (ii) the large intra-individual variability observed during long (>6 months) patient follow-up, or/and (iii) the inclusion of patients both with and without antibodies toward infliximab (ATI). We report here an analysis of infliximab pharmacokinetics in inflammatory bowel disease (IBD) patients that took into account these drawbacks. This is an update of our previous study [3], and we retrospectively analyzed 133 patients treated by infliximab for IBD between 2006 and 2012 in Tours university hospital, in whom trough and peak infliximab concentrations were available during treatment initiation and ATI not detected during the first 6 months. These patients received 5 mg/kg infliximab at weeks 0, 2, 8, and 14. Median [range] body weight was 60 kg [41– 120], and 79 (59 %) were women. Infliximab concentrations were measured using a validated ELISA technique [5]. Infliximab pharmacokinetics was described using a population approach (MONOLIX 4.3.2, Lixoft, Saclay, France). A two-compartment model was used. Central (V1) and peripheral (V2) volumes of distribution, and systemic (CL) and intercompartment clearances (Q) were estimated. Interindividual and residual models used were, respectively, exponential and mixed additive-proportional. Body weight (coded as a median-centered power function, βweight being the power parameter for body weight) and gender were tested as covariates for V1 and CL. All parameters were estimated with satisfactory accuracy, and no obvious model misspecification was observed. Typical parameters (relative standard error) were V1=2.6 L (4 %), CL=0.014 L/h (6 %), V2=4.5 L (1 %), and Q=0.083 L/h (3%). Interindividual standard deviations for V1 and CL (relative standard error) were ωV1=27 % (8 %) and ωCL=47 % (7 %), respectively. Additive and proportional (relative standard error) standard deviations were σadd=2.3 mg/L (16 %) and σprop=0.21 (6%), respectively. Central volume of distribution (V1) increased with body weight (βweight=0.22, p=0.00013). Both V1 and CL were higher in men than in women: typical V1 was 3.2 L in men and 2.6 L in women, and typical CL was 0.019 L/h in men and 0.014 L/h inwomen. Distribution and elimination half-liveswere T1⁄2-α=0.5 days and T1⁄2-β=16.1 days, respectively. Compared to other PK studies of infliximab in IBD patients (Table 1), our T1⁄2-α estimate was similar to that reported by Fasanmade et al. (0.2 days [2]) but lower than that reported by others (approximately 3 days [1, 3, 6]). Of note, our T1⁄2-α estimate was similar to values reported in rheumatoid arthritis (0.3 days [7]) and ankylosing spondylitis (0.3 days [8, 9]). Among PK studies of infliximab in IBD, this study is the first to analyze patients from their first infusion of infliximab, with a short follow-up of less than 6 months and after exclusion of ATI+ patients. Our study has nevertheless limitations. First, our data were scarce, consisting in trough and peak concentrations. Second, the ATI assay used for this cohort was unable to detect ATI in the presence of concentrations of infliximab >2 mg/L, which probably led to an underestimation of the proportion of immunized patients. * David Ternant david.ternant@univ-tours.fr

Successful autologous stem cell transplantation in Gaucher disease patient with multiple myeloma.

To the editor: In the first book of the Bible, God fashions a woman from one of Adam’s ribs: ‘‘while Adam was sleeping, . . . [he] took one of the ribs. . . and the rib taken from man. . . made a woman’’ (Genesis 2:21–22). Were stem cells present at this ancient origin point, in Adam’s rib? The recent discovery of stem cells in bone marrow and their therapeutic application in stem cells regenerative medicine would support the hypothesis that the development of science represents a quite predictable phenomenon proceeding from the potency of Adam’s rib. Likewise, the biomedical research appears to represent a continuous discovery of historical and prehistorical milestones. Stem cells represent by far the most recurrent word in all kinds of writings, in either scientific papers or mass-media communications. PubMed data reveal that over the past 10 years, more than 130,000 papers have been published on this topic in English international journals, with about 19,000 appearing just in the last year. These data reflect the great impact of stem cells on the scientific community and on worldwide expectations for disease prevention and treatment. We are now in an era of post-modern regenerative medicine. However, regeneration of tissue and organs has been a well-known phenomenon since ancient times. The story of Prometheus, the super hero chained to a rock for defying Zeus by stealing fire from Mount Olympus for the benefit of human beings, subjected to daily tearing at his liver by an eagle, attests to the early recognition of the extraordinary regenerative capacity of the human liver. This process has remained an intriguing mystery over the millennia. Alexander Maximow is given the credit for introducing the term ‘‘stem cells’’ in the medical literature in a lecture read before the Berlin Society of Hematology and published in 1909. In 1963, McCulloch and Till provided evidence that self-renewing stem cells are present in the bone marrow of mice. Hematopoietic stem cell transplant was first applied in 1959, when bone marrow cells were transplanted to a patient suffering from acute leukaemia from his identical twin [1]. Since then, bone marrow transplantation has been used to treat a number of acquired as well as congenital diseases. In addition, different stem cells have been identified in several organs and tissues and classified according to their differentiation potential: that is, toti-, multi-, pluri-, and uni-potent. A further designation of stem cells refers to adult or embryonic stem cells. Recently, a new type of stem cells has been identified, the induced pluripotent stem cells (iPS) derived from adult cells [2]. These cells are of particular interest in that they can help by filling the present gap among the various positions in the ongoing bioethical debate on the research opportunities and clinical uses of stem cells. The rib, in particular, represents an anatomic type of long bone with a wide, spongious component rich in hematopoietic bone marrow, containing multipotent, pluripotent, and unipotent stem cells [3]. Totipotent so far have not been identified in bone marrow. As with the making of new life from Adam’s rib, new tissues and organs are now being made in both experimental and clinical work by using hematopoietic bone marrow from cell cultures. Given this creation of new tissues and organs via hematopoietic bone marrow, the question arises about the implication of these observations for science. Carefully reading Genesis 2 [4], one is impressed by the fact that man and woman originated via two different modalities: Man ‘‘from the dust of the ground, [God] breathed into his nostrils the breath of life; and man became a living soul’’ (Genesis 2:7); Woman ‘‘from the rib taken from [from] man [Adam]’’ while he was sleeping (Genesis 2:21–22). The analogy between Adam’s sleep and anaesthesia (as in surgical procedures, for bone marrow transplantation) is striking. Also striking, is that the two events—the origin of man and of woman—are not comparable. Adam’s origin is not discussed at present, as nowadays, it seems to belong to the sphere of divinity and as such is inaccessible to scientific knowledge, whereas woman’s origin is a suitable subject for science. The recent discovery (or rediscovery) of stem cells in bone marrow and their application in regenerative medicine would seem to support the hypothesis that the development of science could be predicted from the story of Adam’s rib. Surprisingly, the progress of science, in turn, may lead us to look again into the narrative of our evolutionary ancestry. FRANCESCO CALLEA MICHELE CALLEA Department of Pathology and Laboratory Medicine Children’s Hospital Bambino Gesù, Rome, Italy; Institute for Maternal and Child Health – IRCCS Burlo Garofolo, Trieste, Italy Conflict of interest: Nothing to report. Published online 11 February 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.22005