In patients experiencing a loss of response to an anti-TNF with unfavourable pharmacokinetics (undetectable levels and anti-drug antibodies), the algorithms recommend a switch of the anti-TNF but this is frequently associated with the subsequent appearance of antibodies directed against the second anti-TNF. All patients with IBD in loss of response to a first optimised anti-TNF given in monotherapy at induction or 6 months later and with an undetectable level of anti-TNF and a high level of anti-drug antibodies were included. They were randomised to receive either AZA or nothing and induction by a second anti-TNF was performed at standard doses. They were followed up for 2 years after the switch, with assessments of activity and pharmacokinetics of the second anti-TNF at 6, 12, and 24 months. Non-primary responders after the switch were excluded. Failure was defined as disease worsening based on a Harvey–Bradshaw index >5 associated with a faecal calprotectin level >250 μg/g stool for Crohn's disease or a Mayo score >3 with an endoscopic sub-score >1 for ulcerative colitis and the need for a therapeutic change (dose intensification, change in treatment, addition of corticosteroids or AZA, use of surgery). Unfavourable pharmacokinetics were defined as appearance of low or undetectable levels of anti-TNF with anti-drug antibodies. Eighty-five patients (45 CD, mean age: 39.5 years, sex ratio M/F: 0.95) were included. The second anti-TNF was adalimumab (ADA) and infliximab (IFX) in 37 and 48 patients, respectively. Forty-five patients were randomised to receive AZA (2–2.5 mg/kg/day). Groups with or without AZA were comparable. At 12 and 24 months, survival rates without failure and without appearance of unfavourable pharmacokinetics were significantly higher in combination therapy (log rank <0.0001): 85% vs. 62% and 80% vs. 59% at 12 months, and 80% vs. 20% and 84% vs. 30% at 24 months, respectively. These rates were not different at 6 months (90% vs. 76% and 85% vs. 68%; p = 0.1). The results did not differ according to the type of anti-TNF. With ADA as reference to analyse failure during the follow-up, hazard ratios (HR) were for IFX of 1.2 [0.6–2.3], for ADA-AZA combination therapy of 0.1 [0–0.4] and for combotherapy IFX-AZA of 0.2 [0.1–0.4]. In univariate and multivariate analysis, only the use of combination therapy was significantly associated with favourable outcomes after anti-TNF switch. The type of IBD, the duration of the disease or the characteristics of the patient were not associated to outcomes. In case of a switch of anti-TNF because of a loss of response due to unfavourable pharmacokinetics with the presence of anti-drug antibodies, AZA must be associated with the second anti-TNF.
De nombreux modeles animaux d’inflammation intestinale ont ete developpes ces vingt dernieres annees. Leur nombre et la diversite des mecanismes a l’origine d’une inflammation intestinale illustrent la complexite du systeme immunitaire associe a l’intestin et de ses facteurs de regulation. Tous ces modeles ont permis d’ameliorer nos connaissances sur l’immunite et les interactions entre la flore et l’hote dans des conditions normales et inflammatoires. La comprehension de la pathogenie des maladies inflammatoires chroniques de l’intestin (MICI) chez l’homme a largement beneficie de toutes ces avancees. Les modeles animaux permettent aussi d’identifier de nouvelles cibles therapeutiques et constituent des outils indispensables pour tester l’efficacite et la toxicite de therapeutiques anti-inflammatoires et immuno-modulatrices innovantes.
The aim was to investigate the relation between urinary neopterin and the Crohn's Disease Activity Index (CDAI) and to compare its ability to discriminate active versus inactive CD with serum C-reactive protein (CRP).In all, 217 urinary samples for neopterin measurement were obtained in a cohort of 93 consecutive patients with CD and 66 samples in 33 healthy volunteers. Clinical parameters were recorded and blood samples for CRP were collected as well.Whereas patients with inactive CD showed similar levels of urinary neopterin excretion than healthy volunteers (163 +/- 8 versus 142 +/- 7 nmol/mol of creatinine, respectively; P = 0.1), urinary neopterin excretion from mild to severe active CD was significantly higher (302 +/- 15 nmol/mol of creatinine; P < 0.001). Serum CRP levels were higher in active CD (14.8 +/- 2.1 mg/L) compared with inactive CD (5.6 +/- 0.8 mg/L; P < 0.001). Urinary neopterin excretion, and to a lesser degree CRP, were positively and significantly correlated with CDAI (r = 0.64 and 0.43, respectively, P < 0.001). Based on the cutoff of 183 nmol/mol of creatinine for urinary neopterin, the sensitivity and specificity of urinary neopterin to discriminate between active and inactive CD were 73% and 82%, respectively, and the positive and negative predictive values were 80% and 78%, respectively.Urinary neopterin excretion is an objective, valuable, simple, and noninvasive biomarker to detect and follow fluctuations of CD activity. Further work is warranted to study its clinical value and relation to mucosal healing.
Depuis quelques annees, une autre voie de cancerogenese colique, distincte de celle des adenomes, est exploree. Il s’agit de celle des lesions festonnees. Ce terme regroupe 3 types de polypes caracterises par un aspect dentele des cryptes et comprenant les polypes hyperplasiques, les adenomes ou lesions festonnees sessiles et les adenomes festonnes traditionnels. Chaque lesion a ses propres caracteristiques morphologiques macro- comme microscopiques et genetiques qui sont importantes a connaitre dans le cadre du depistage colique et qui sont detaillees dans cette revue.
Background and aims We aimed to analyze circulating CD4 + T cell subsets and cytokines during the course of Crohn’s disease (CD). Methods and results CD4 + T cell subsets, ultrasensitive C-reactive protein (usCRP), and various serum cytokines (IL-6, IL-8, IL-10, IL-13, IL-17A, IL-23, TNFα, IFNγ, and TGFβ) were prospectively monitored every 3 months for 1 year, using multicolor flow cytometry and an ultrasensitive Erenna method in CD patients in remission at inclusion. Relapse occurred in 35 out of the 113 consecutive patients (31%). For patients in remission within 4 months prior to relapse and at the time of relapse, there was no significant difference in Th1, Th17, Treg, and double-positive CD4 + T cell subsets co-expressing either IFNγ and FOXP3, IL-17A and FOXP3, or IFNγ and IL-17A. On the contrary, in patients who remained in remission, the mean frequency and number of double-positive IL-17A + FOXP3 + CD4 + T cells and the level of usCRP were significantly higher ( p ≤ 0.01) 1 to 4 months prior to relapse. At the time of relapse, only the IL-6 and usCRP levels were significantly higher ( p ≤ 0.001) compared with those patients in remission. On multivariate analysis, a high number of double-positive IL-17A + FOXP3 + CD4 + T cells (≥1.4 cells/mm3) and elevated serum usCRP (≥3.44 mg/L) were two independent factors associated with risk of relapse. Conclusions Detection of circulating double-positive FOXP3 + IL-17A + CD4 + T cell subsets supports that T cell plasticity may reflect the inflammatory context of Crohn’s disease. Whether this subset contributes to the pathogenesis of CD relapse needs further studies.
In recent decades, the advent of biological therapy has changed the treatment of inflammatory bowel disease (IBD) and has opened new therapeutic endpoints such as mucosal healing (MH). MH incorporated with clinical remission presents a new concept: deep remission, which correlates with a decrease in hospitalization and surgery and improvement in the patient’s quality of life. Several techniques can be used to assess mucosal healing such as endoscopy which remains the gold standard. But considerable variations may exist in the interpretation of the definition of mucosal healing which may also be histological or evaluated by radiological or biological methods. Thus, it is important to study mucosal inflammation by endoscopic scores and by new, more sensitive techniques such as videocapsule endoscopy (VCE), magnetic resonance enterography (MRE), chromoendoscopy and confocal laser endomicroscopy (CLE). Biomarkers, such as fecal calprotectin (FC) were also studied in the evaluation of MH and showed positive results. These methods are currently the subject of validation studies.
