Relationships of circulating CD4+ T cell subsets and cytokines with the risk of relapse in patients with Crohn's disease.

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 TGFß) 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.

Subcutaneous injection of infliximab CT-P13 results in stable drug levels within 14-day treatment cycle in Crohn's disease.

The new subcutaneous (sc) formulation of the infliximab (IFX) biosimilar CT-P13 results in homogeneous serum trough concentrations of IFX at steady state. The present study aimed to investigate in Crohn's disease (CD) patients the intra-individual variations of IFX drug levels at multiple time-points during 2 consecutive cycles of maintenance therapy with CT-P13 sc. PATIENTS AND METHODS: CD patients in clinico-biological remission under maintenance therapy with intravenous (iv) IFX/CT-P13 were switched to CT-P13 sc 8 weeks (W) after the last infusion. They were treated with CT-P13 sc, 120 mg every 2 W. Assessments were performed from 8 W after starting CT-P13 sc and patients had to attend 6 visits on 2 consecutive cycles of treatment (cycles A and B). Visits were scheduled on days 4-6 (visit 1), days 7-9 (visit 2) and day 14 (visit 3) of each cycle, where days 1 and 14 were the days of sc injection of CT-P13. At each visit, peripheral blood was collected to measure serum IFX levels and anti-drug antibodies. RESULTS: Twenty patients underwent 120 evaluations. Large intra-individual variations of serum drug levels of IFX were observed. When pooling the 120 evaluations, the mean drug level was 11.3 ± 4.9 µg/ml, and the median drug level was 10.9 µg/ml (IQR 7.5-15.5). During each cycle, the median drug levels were similar between visits 1 and 2 as well as between visits 1 and 3 and between visits 2 and 3. In cycle A, median drug levels were 11.1 µg/ml (7.8-14.5), 12.0 µg/ml (7.2-16.1) and 11.0 µg/ml (7.5-15.1) at V1, V2 and V3, respectively. Similar results were obtained in cycle B, where median drug levels were 11.6 µg/ml (7.9-14.9), 11.4 µg/ml (8.1-15.2) and 10.9 µg/ml (7.9-15.6) at V1, V2 and V3, respectively. In univariate analysis, we failed to identify factors predictive of low drug levels. CONCLUSIONS: IFX drug levels are quite stable within 14-day treatment cycle, without trough levels in CD patients in remission during the maintenance therapy with CT-P13 sc. In patients with inactive CD under maintenance therapy with CT-P13 sc, therapeutic drug monitoring of IFX can be performed at any time between two CT-P13 sc injections.

Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels.

BACKGROUND: In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma-either ADA dose optimization or switching to vedolizumab or ustekinumab. METHODS: Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 µg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. RESULTS: Adalimumab was optimized (n = 61 patients, 42 Crohn's disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn's disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P < 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (>24 months) than in the optimization group (13.3 months, P < 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 µg/g (HR, 3.53; 95% CI, 1.16-10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13-0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. CONCLUSION: In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

Early detection of anti-drug antibodies during initiation of anti-tumour necrosis factor therapy predicts treatment discontinuation in inflammatory bowel disease.

BACKGROUND: Anti-drug antibodies develop mostly during the induction therapy with anti-tumour necrosis factor (TNF) drugs and can be revealed by means of a drug-tolerant assay. AIM: To investigate whether the early detection of anti-drug antibodies during the induction therapy was predictive of treatment discontinuation. METHODS: In a prospective study, consecutive patients with inflammatory bowel disease (IBD), who should start an anti-TNF, were enrolled and followed regularly during 24 months or less in case of non- or loss of response (LOR) or adverse events requiring treatment discontinuation. Anti-TNF levels and anti-drug antibodies were measured at week 2 for adalimumab (ADA) and weeks 2 and 6 for infliximab (IFX) using a drug-tolerant assay. RESULTS: One hundred and eight patients were enrolled (54 under ADA). At week 2, antibodies to ADA and to IFX were detected in 76% and 67% of patients. Time to treatment discontinuation was significantly shorter (P < 0.001) in patients with antibodies to ADA ≥2.0 µg/mL-eq (6.0 vs 24 months, HR = 18.51, 95% CI [4.35-78.71]) or with antibodies to IFX ≥4.0 µg/mL-eq (5.5 vs >24 months, HR = 13.89, 95% CI [4.08-47.31]) at week 2 compared to patients without positive antibodies. Antibodies to ADA and to IFX were predictive of treatment failure within 24 months with a sensitivity of 79% and 62%, and specificities and positive predictive values of 100%. In multivariate analysis, antibodies to ADA or to IFX at week 2 were the only factors associated with treatment discontinuation. CONCLUSIONS: The prevalence of antibodies to anti-TNF is high when detected early using a drug-tolerant assay, and their appearance predicts further treatment discontinuation.

Comparison of short- and long-term effectiveness between ustekinumab and vedolizumab in patients with Crohn's disease refractory to anti-tumour necrosis factor therapy.

BACKGROUND: The best option between vedolizumab and ustekinumab after anti-tumour necrosis factor (TNF) failure remains unclear in Crohn's disease. AIMS: To compare the short- and long-term effectiveness of vedolizumab and ustekinumab in Crohn's disease patients with prior anti-TNF exposure. METHODS: All Crohn's disease patients treated with ustekinumab or vedolizumab after exposure to at least one anti-TNF agent were included from two referral centres. Primary endpoint was corticosteroid-free clinical remission defined as Crohn's disease activity index <150 at week 54. Deep remission (corticosteroid-free clinical remission and faecal calprotectin <100 µg/g) was assessed at week 14. Propensity-matched analyses were applied to make the two groups comparable. RESULTS: Overall, 312 patients (ustekinumab = 224 and vedolizumab = 88) were included. After propensity score analysis, ustekinumab was more effective to achieve corticosteroid-free clinical remission at week 54 (49.3% vs 41.2%, P = 0.04) and deep remission at Week 14 (25.9% vs 3.8%, P = 0.02) than vedolizumab. The rate of primary nonresponders (6.7% vs 14.8%, P = 0.034) and the long-term risk of drug discontinuation due to therapeutic failure (HR = 1.53 [1.04-2.07], P = 0.029) were lower in patients treated with ustekinumab compared with vedolizumab. Predictors of ustekinumab failure were complicated phenotype (odds ratio [OR] = 2.35 [1.31-4.22]; P = 0.004) and anti-TNF primary non-response (OR = 2.55 [1.27-5.12]; P = 0.008). We did not find any predictor of corticosteroid-free clinical remission in patients treated with vedolizumab. Vedolizumab was less effective than ustekinumab in patients >35 years old (OR = 0.41 [0.19-0.87]), with noncomplicated phenotype (OR=0.42 [0.18-0.96]), no prior bowel resection (OR = 0.49 [0.24-0.96]), and no steroids at baseline (OR=0.47 [0.23-0.97]). CONCLUSION: Ustekinumab was more effective to achieve early and long-term effectiveness than vedolizumab in Crohn's disease patients who previously failed response to anti-TNF agents.

Low Levels of Fecal Calprotectin 3 Months After Surgery Predict Subsequent Endoscopic Postoperative Remission in Crohn's Disease.

BACKGROUND/AIMS: In Crohn's disease (CD) few data are available on the usefulness of monitoring fecal calprotectin (FC) in the early postoperative setting. We assessed prospectively the accuracy of FC measured 3 months after surgery to predict the risk of endoscopic postoperative recurrence (POR) within 1 year after resection. METHODS: In 55 consecutive CD patients who had undergone ileocolonic resection samples were collected 3 months after surgery for measuring serum CRP and FC. Endoscopic POR was assessed by ileocolonoscopy within 6-12 months (median 7 months). Receiver operating characteristic (ROC) curves were generated to assess accuracy of the markers, to determine the best threshold and to calculate sensitivity, specificity, positive and negative predictive values. RESULTS: In contrast with median CRP levels, median FC concentrations measured 3 months after surgery were significantly higher in patients who later experienced endoscopic POR (Rutgeerts ≥ i2) compared with those who stayed in endoscopic remission within the following 6-12 months (205 µg/g IQR [106-721] vs. 103 µg/g IQR [60-219], p = 0.008). Area under the ROC curve for FC was 0.71. The best cutoff value of FC to identify patients in subsequent endoscopic remission 3 months after surgery was 65 µg/g (96% sensitivity, 31% specificity, 50% positive and 91% negative predictive values). In multivariate analysis, FC < 65 µg/g at 3 months was the only factor associated with subsequent endoscopic remission. CONCLUSION: FC measured 3 months after surgery below 65 µg/g is an accurate marker to identify CD patients who will later stay in endoscopic remission within 1 year after resection.

No Difference of Adalimumab Pharmacokinetics When Dosed at 40 mg Every Week or 80 mg Every Other Week in IBD Patients in Clinical Remission After Adalimumab Dose Intensification.

INTRODUCTION: The pharmacokinetic equivalence of dose intensification with adalimumab (ADA) 80 mg every other week (EOW) compared to weekly 40 mg has only been supported by modeling systems. AIM OF THE STUDY: To compare the trough levels of ADA (TLA) and the occurrence of anti-ADA antibodies (AAA) between these two treatment regimens. PATIENTS AND METHODS: This was a prospective study including all consecutive patients with inflammatory bowel disease (IBD) who had reached a longstanding and deep remission under treatment with ADA 40 mg once a week. In these patients, the ADA regimen was changed from 40 mg/week to 80 mg EOW. TLA and AAA levels using a drug-tolerant assay were monitored before and ten weeks after from the change in the ADA regimen and the results compared by a Wilcoxon paired test. RESULTS: Sixty-two patients (60% CD, mean age 35 years) were included. Before and ten weeks after the changes of ADA regimen, the median TLA were (6.9 µg/mL versus 7.0 µg/mL, respectively; P = 0.34) and the AAA levels (3.4 µg/ml-eq versus 3.0 µg/ml-eq, respectively; P = 0.25.) were quite similar. Likewise, quartiles of TLA (Kendall test r = 0.91; P < 0.001) and AAA (r = 0.78; P < 0.001) did not differ before and after ADA regimen. When stratifying all the patients into 4 groups based on drug/antibody levels (immunogenic, subtherapeutic, therapeutic, or supratherapeutic), no patient needed for returning to the previous weekly regimen. In terms of acceptability, more than 60% of patients preferred an injection EOW compared once a week. CONCLUSIONS: In IBD patients who achieved a deep clinical remission under ADA 40 mg once a week, the pharmacokinetic of ADA was similar when ADA regimen was changed to 80 mg EOW. Given the patient's preference for the latter regimen, a modification of injection regimen should be systematically proposed.

Effectiveness And Safety Of Ustekinumab Intensification At 90 Mg Every Four Weeks In Crohn's Disease: A Multicenter Study.

INTRODUCTION: The approved maintenance regimens for ustekinumab in Crohn's disease (CD) are 90 mg every 8 or 12 weeks. Some patients will partially respond to ustekinumab or will experience a secondary loss of response. It remains poorly known if these patients may benefit from shortening the interval between injections. METHODS: All patients with active CD, as defined by Harvey-Bradshaw score ≥ 4 and one objective sign of inflammation (CRP > 5 mg/L and/or fecal calprotectin > 250 µg/g and/or radiologic and/or endoscopic evidence of disease activity) who required ustekinumab dose escalation to 90mg every 4 weeks for loss of response or incomplete response to ustekinumab 90mg every 8 weeks were included in this retrospective multicenter cohort study. RESULTS: One hundred patients, with a median age of 35 years (Interquartile Range (IQR), 28 - 49) and median disease duration of 12 (7 - 20) years were included. Dose intensification was performed after a median of 5.0 (2.8 - 9.0) months of ustekinumab treatment and was associated with corticosteroids and immunosuppressants in respectively 29% and 27% of cases. Short-term clinical response and clinical remission were observed in respectively 61% and 31% after a median of 2.4 (1.3 - 3.0) months. After a median follow-up of 8.2 (5.6-12.4) months, 61% of patients were still treated with ustekinumab, and 26% in steroid-free clinical remission. Among the 39 patients with colonoscopy during follow-up, 14 achieved endoscopic remission (no ulcers). At the end of follow-up, 27% of patients were hospitalized, and 19% underwent intestinal resection surgery. Adverse events were reported in 12% of patients, including five serious adverse events. CONCLUSION: In this multicenter study, two-thirds of patients recaptured response following treatment intensification with ustekinumab 90 mg every 4 weeks.

Infliximab induces clinical resolution of sacroiliitis that coincides with increased circulating FOXP3+ T cells in a patient with IPEX syndrome.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency due to mutations of FOXP3, a master transcription factor of regulatory T cells (Treg). IPEX syndrome leads to fatal course in most cases during early childhood or severe multi-organ immune-mediated disorders in patients who survive. Currently hematopoietic stem cell transplantation represents the only known effective cure for IPEX syndrome. However, older patients with a mild disease not severe enough to justify transplantation, raise concerns regarding the appropriate therapeutic management, which is therefore based on supportive and replacement therapies combined with pharmacological immunosuppression. Herein, we report the case of a 22-year-old man with an incomplete IPEX syndrome without endocrine disorders having suffered from severe enteropathy since his birth treated with a combination of various immunosuppressant agents. He developed severe exacerbation of inflammatory low back pain in relation to sacroiliitis. Eventually, infliximab was initiated to control his back pain with rapid resolution as well as digestive improvement and also reduced biological inflammatory markers. In parallel, flow cytometry analysis revealed an increase in the frequency of circulating FOXP3+ CD4+ Treg cells. Altogether these data highlight that anti-TNF may represent a promising therapeutic option in patients with IPEX syndrome.

Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial.

OBJECTIVES: In patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumour necrosis factor (anti-TNF), algorithms recommend a switch of anti-TNF without immunosuppressive drug. The aim of our study was to compare in these patients two strategies: either switch to a second anti-TNF alone or with addition of azathioprine (AZA). After randomisation outcomes (time to clinical and pharmacokinetic failure) were compared between the two groups during a 2-year follow-up period. DESIGN: Consecutive IBD patients in immune-mediated LOR to a first optimised anti-TNF given in monotherapy were randomised to receive either AZA or nothing with induction by a second anti-TNF in both arms. Clinical failure was defined for Crohn's disease (CD) as a Harvey-Bradshaw index ≥5 associated with a faecal calprotectin level >250 µg/g stool and for UC as a Mayo score >5 with endoscopic subscore >1 or as the occurrence of adverse events requiring to stop treatment. Unfavourable pharmacokinetics of the second anti-TNF were defined by the appearance of undetectable trough levels of anti-TNF with high antibodies (drug-sensitive assay) or by that of antibodies (drug-tolerant assay). RESULTS: Ninety patients (48 CDs) were included, and 45 of them received AZA after randomisation. The second anti-TNF was adalimumab or infliximab in 40 and 50 patients, respectively. Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy (p<0.001; median time of clinical failure since randomisation 18 vs >24 months). At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22 versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy. Only the use of combination therapy was associated with favourable outcomes after anti-TNF switch. CONCLUSION: In case of immune-mediated LOR to a first anti-TNF, AZA should be associated with the second anti-TNF. TRIAL REGISTRATION NUMBER: 03580876.

Concentrations of Ustekinumab During Induction Therapy Associate With Remission in Patients With Crohn's Disease.

Ustekinumab is approved for treatment of Crohn's disease (CD).1,2 Few data are available to assess the usefulness of monitoring inflammatory biomarkers and therapeutic drug monitoring to predict response to ustekinumab. We conducted a prospective study to assess the relationships between these parameters and the clinical outcome at week 16 in active CD patients receiving ustekinumab.

Usefulness of confocal laser endomicroscopy for predicting postoperative recurrence in patients with Crohn's disease: a pilot study.

BACKGROUND AND AIMS: Confocal laser endomicroscopy (CLE) has been shown to predict relapse in inflammatory bowel disease, but its value in the detection of postoperative recurrence in Crohn's disease (CD) is unknown. The aims of this pilot study performed in patients with CD after ileocolonic resection were to compare the macroscopic appearance of the neoterminal ileum, according to the endoscopic Rutgeerts score, with the microscopic findings provided by CLE 6 to 12 months after surgery and to assess the predictive values of CLE-generated parameters for predicting further recurrence in patients with postoperative endoscopic remission. METHODS: In 25 consecutive patients with CD within 6 to 12 months of surgery, the neoterminal ileum was examined by standard white-light endoscopy (Rutgeerts scale) followed by CLE (Watson grade). Only patients without endoscopic recurrence (Rutgeerts i0 and i1) were then followed endoscopically and clinically (median follow-up 38 months). RESULTS: At the time of the first postoperative colonoscopy, 18 patients (72%) were in endoscopic remission, and 7 (28%) experienced an endoscopic recurrence (Rutgeerts ≥i2). The Rutgeerts score was significantly correlated with the Watson score (ρ = 0 .73; P < .0001). The Watson scores at baseline were significantly higher in patients with further endoscopic recurrence (median 2.0; interquartile range [IQR] 1.5-2.0) than in those with endoscopic remission (median 1.0; IQR 1.0-1.0; P = .032) and were significantly higher in patients with clinical relapse (medium 2.0, IQR 2.0-2.0) compared with those in clinical remission (median 1.0; IQR 1.0-1.0; P = .036). CONCLUSIONS: CLE could be useful in monitoring patients with CD after intestinal resection. Further studies with a larger population are necessary to confirm these preliminary results.

Efficacy and Safety of Infliximab Tolerance Induction in Patients with Inflammatory Bowel Diseases who Experienced Acute Infusion Reactions.

BACKGROUND AND AIMS: One of the reasons for the failure of infliximab (IFX) is immediate hypersensitivity reactions (IHR). We aimed to report the efficacy and safety of a tolerance induction protocol in inflammatory bowel diseases (IBD) patients who had previously experienced IHR during IFX infusions. PATIENTS AND METHODS: We reported all cases of IBD patients who had previously experienced IHR due to IFX and who were submitted to a standardized protocol of tolerance induction to IFX from 2010 to 2015. RESULTS: IHR occurred in a majority of patients (69%) during the first 3 infusions and for half of them after a period of IFX withdrawn. Skin prick tests were negative and only 2 intradermal tests were positive. Basophil activation tests and antidrug antibody measurements were performed in 8 out of 16 patients and were positive in 3 and 4 patients respectively. Induction of tolerance was successful in 69% of patients and IFX was pursued with clinical efficacy > 1 year in 7 patients (44%). Allergologic investigations were not predictive of tolerance induction success. CONCLUSION: A majority of IHR to IFX infusions occurred during the beginning or restarting of treatment and was related to a nonallergic hypersensitivity. Induction of tolerance to IFX is feasible and effective and may safely allow retreatment of IFX in almost 70% of IBD patients.

Soluble Mucosal Addressin Cell Adhesion Molecule 1 and Retinoic Acid are Potential Tools for Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease Treated with Vedolizumab: A Proof of Concept Study.

BACKGROUND AND AIMS: Vedolizumab [VDZ], a humanized monoclonal antibody targeting α4ß7 integrin, is effective in induction and maintenance therapy in patients with inflammatory bowel disease [IBD] who have not adequately responded to standard therapies, and high vedolizumab trough levels [VTLs] have been associated with clinical remission. The α4ß7 integrin binds to endothelial MAdCAM-1 and is upregulated by retinoic acid [RA]. The aim of this study was to determine the relationships between soluble MAdCAM-1 [sMAdCAM-1] and RA concentrations during clinical remission with VDZ maintenance therapy. METHODS: In a retrospective study performed in IBD patients treated with VDZ, we measured VTL, sMAdCAM-1 and RA concentrations. RESULTS: Among the 62 included patients [38 Crohn's disease], 24 relapsed and 38 stayed in remission from Weeks 10 to 30 after VDZ initiation. During this maintenance therapy, the median values of VTLs and RA were 15.4 µg/mL and 0.97 ng/mL, respectively, whereas sMAdCAM-1 was undetectable [<0.41 ng/mL] in 67.3% of samples. The positive predictive value [PPV] of undetectable sMAdCAM-1 for clinical remission was 80.0%, with a corresponding sensitivity of 74.6%. On multivariate analysis, undetectable sMAdCAM-1 and high VTLs [>19 µg/mL] were independently associated with clinical remission [OR = 7.5, p = 0.006 and OR = 2.2, p = 0.045, respectively]. The combination of sMAdCAM-1 < 0.41 ng/mL and VTL > 19 µg/mL was the best pharmacokinetic profile, with a PPV of 95.2%. Median values of sMAdCAM-1 and RA were significantly higher [p = 0.0001] before VDZ therapy than during the follow-up [sMAdCAM-1: 40.5 vs < 0.41 ng/mL; RA: 1.7 vs 0.97 ng/mL]. Only RA > 1.86 ng/mL before VDZ therapy was predictive of clinical remission during the follow-up (Area Under a Receiver Operating Characteristic curve [AUROC] = 80.7%). CONCLUSIONS: Undetectable sMAdCAM-1 appears strongly associated with clinical remission during VDZ maintenance therapy. Combination of undetectable sMAdCAM-1 with high VTL is also potentially interesting for therapeutic drug monitoring. Baseline RA concentrations are predictive of clinical remission. These findings need to be confirmed in further prospective studies.

Is the Pharmacokinetic Profile of a First Anti-TNF Predictive of the Clinical Outcome and Pharmacokinetics of a Second Anti-TNF?

AIM: The aim of this study was to evaluate prospectively the clinical outcomes and pharmacokinetics of a second anti-TNF according to the pharmacokinetics of the first anti-TNF in patients with inflammatory bowel disease (IBD). METHODS: In patients in loss of response (LOR) to a first optimized anti-TNF and switched to a second anti-TNF, pharmacokinetics of anti-TNF were measured at the switch time, 30 weeks later, at the time of LOR, or at the end of the study (102 weeks). RESULTS: At the switch time, patients (n = 59) belonged to 4 groups according to the pharmacokinetics of the first anti-TNF: group 1 (n = 18), therapeutic trough levels; group 2 (n = 13) undetectable trough levels with antibodies against anti-TNF; group 3 (n = 13) without antibodies against anti-TNF; and group 4 (n = 15) subtherapeutic trough levels. After switching, the failure rates at week 30 and during the follow-up were as follows, respectively: in group 1 with therapeutic levels, 50% and 78%, despite therapeutic levels of the second anti-TNF in 83% of cases; in group 2 with undetectable levels and antibodies, 15% and 69% with undetectable levels of the second anti-TNF and antibodies in 85% of cases; in group 3 with undetectable levels without antibodies, 0% and 31% with therapeutic levels in 77% of cases; in group 4 with subtherapeutic levels, 13% and 33% with therapeutic levels in 73% of cases. Clinical remission rates were significantly lower (P ≤ 0.05) in groups 1 and 2 with therapeutic or undetectable levels with antibodies than in the 2 other groups. CONCLUSION: In the case of LOR with therapeutic levels of the first anti-TNF or undetectable levels with antibodies, the switch to a second anti-TNF results in pharmacokinetic profile similar to the first one and again in LOR in most of the patients.

IBD-INFO Questionnaire: A Multicenter French Up-to-Date Survey of Patient Knowledge in Inflammatory Bowel Disease.

Background: It has been demonstrated in many chronic conditions, including inflammatory bowel disease (IBD), that better patient knowledge about pathology and treatment improves the course and management of disease. The aim of this study was to develop an updated self-questionnaire to assess patients' level of knowledge of IBD. Methods: The IBD-INFO included 3 parts: an original part (Q1) and 2 parts from the translation of the preexisting questionnaires Crohn's and Colitis Knowledge score (CCKNOW) (Q2) and Crohn's and Colitis Pregnancy Knowledge score (CCPKNOW) (Q3). The reliability and discriminatory ability of the questionnaire were validated in 3 groups of non-IBD volunteers with various theoretical knowledge levels. The final questionnaire (64 validated questions) was then tested on 364 in- and out- IBD patients from 4 French university hospitals. The score for each part of the questionnaire was calculated, and factors associated with low scores were identified by univariate and multivariate logistic regression analyses. Results: The scores obtained by the 3 non-IBD volunteer groups differed significantly (P < 0.0001), and the IBD-INFO questionnaire showed excellent internal reliability and consistency (α = 0.98). The median total score obtained by the IBD patients was 27/64 (range, 0-59), and scores for Q1, Q2, and Q3 were, respectively, 10/23 (range, 0-21), 11/24 (range, 0-23), and 4/17 (range, 0-16). In multivariate analysis, lack of a university degree, not being a member of a patient association, not receiving anti-tumor necrosis factor alpha (anti-TNFα) treatment, duration of IBD ≤3 years, male sex, and age >38 years were independent risk factors of a poor IBD-INFO knowledge score. The areas of knowledge least mastered were vaccination, IBD-related cancers, treatments, and pregnancy. Conclusions: Using the IBD-INFO, an updated self-administered questionnaire built to assess IBD patients' knowledge, several risk factors have been highlighted that allow better targeting of patients and areas requiring an improvement in the level of information.

Outcomes 7 Years After Infliximab Withdrawal for Patients With Crohn's Disease in Sustained Remission.

BACKGROUND & AIMS: Little is known about long-term outcomes of patients with Crohn's disease (CD) after infliximab withdrawal. We aimed to describe the long-term outcomes of patients with CD in clinical remission after infliximab treatment was withdrawn. METHODS: We performed a retrospective analysis of data from the 115 patients included in the infliximab discontinuation in patients with CD in stable remission on combined therapy with antimetabolites (STORI) study, performed at 20 centers in France and Belgium from March 2006 through December 2009. The STORI cohort was a prospective analysis of risk and factors associated with relapse following withdrawal of maintenance therapy with infliximab, maintained on antimetabolites, while in clinical remission. We collected data from the end of the study until the last available follow-up examination on patient surgeries, new complex perianal lesions (indicating major complications), and need for and outcomes of restarting therapy with infliximab or another biologic agent. The de-escalation strategy was considered to have failed when a major complication or infliximab restart failure occurred. RESULTS: Of the 115 patients initially included, data from 102 patients (from 19 of the 20 study centers) were included in the final analysis. The median follow-up time was 7 years. Twenty-one percent of the patients did not restart treatment with infliximab or another biologic agent and did not have a major complication 7 years after infliximab withdrawal (95% CI, 13.1-30.3). Among patients who restarted infliximab, treatment failed for 30.1% 6 years after restarting (95% CI, 18.5-42.5). Overall, at 7 years after stopping infliximab therapy, major complications occurred in 18.5% of patients (95% CI, 10.2-26.8) whereas 70.2% of patients had no failure of the de-escalation strategy (95% CI, 60.2-80.1). Factors independently associated with major complications were upper-gastrointestinal location of disease, white blood cell count ≥ 5.0 × 109/L, and hemoglobin level ≤12.5 g/dL at the time of infliximab withdrawal. Patients with at least 2 of these factors had a more than 40% risk of major complication in the 7 years following infliximab withdrawal. CONCLUSIONS: In a long-term follow-up of the STORI cohort (7 years) one fifth of the patients did not restart infliximab or another biologic agent and did not develop major complications. Seventy percent of patients had no failure of the de-escalation strategy (no major complication and no failure of infliximab restart).

Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy?

BACKGROUND: Colonoscopy with pan-chromoendoscopy (CE) is superior to standard colonoscopy in detecting neoplasia in patients with IBD. Performing random biopsies in unsuspicious mucosa after CE remains controversial. METHODS: Consecutive patients with IBD who underwent surveillance colonoscopy using CE were prospectively included. The standardised procedure used CE, performed targeted biopsies or endoscopic resection on suspicious lesions and then quadrant random biopsies every 10 cm. A panel of five expert pathologists reviewed histological slides with dysplasia. Logistic regression model was used to evidence the factors associated with neoplasia in any or in random biopsies. RESULTS: 1000 colonoscopes were performed in 1000 patients (495 UC, 505 Crohn's colitis). In 82 patients, neoplasia was detected from targeted biopsies or removed lesions, and among them dysplasia was detected also by random biopsies in 7 patients. Importantly, in 12 additional patients dysplasia was only detected by random biopsies. Overall, 140 neoplastic sites were found in 94 patients, 112 (80%) from targeted biopsies or removed lesions and 28 (20%) by random biopsies. The yield of neoplasia by random biopsies only was 0.2% per-biopsy (68/31 865), 1.2% per-colonoscopy (12/1000) but 12.8% per-patient with neoplasia (12/94). Dysplasia detected by random biopsies was associated with a personal history of neoplasia, a tubular appearing colon and the presence of primary sclerosing cholangitis (PSC). CONCLUSIONS: Despite their low yield, random biopsies should be performed in association with CE in patients with IBD with a personal history of neoplasia, concomitant PSC or a tubular colon during colonoscopy. TRIAL REGISTRATION NUMBER: IRB 001508, Paris 7 University.

Distinct Thresholds of Infliximab Trough Level Are Associated with Different Therapeutic Outcomes in Patients with Inflammatory Bowel Disease: A Prospective Observational Study.

BACKGROUND: Several studies have reported a strong correlation between infliximab (IFX) trough levels (trough levels of infliximab [TLI]) and clinical remission (CR). We aimed to determine threshold values of TLI associated with the occurrence of CR, with or without normal inflammatory biomarkers, including serum C-reactive protein (CRP) and fecal calprotectin (fCal). METHODS: We included prospectively all consecutive patients with inflammatory bowel disease under IFX therapy (5 mg/kg every 8 wk) for at least 6 months. Disease activity (using the Crohn's Disease Activity Index or Mayo score) was recorded, and TLI, CRP, and fCal were measured before IFX infusion. RESULTS: Two hundred thirteen patients (131 Crohn's disease) were included. The median TLIs were higher in patients who achieved CR compared with those in patients who did not (2.6 versus 1.2 µg/mL, P < 0.01). The median TLI were higher in patients achieving CR with CRP normalization or CR with fCal <250 µg/g in comparison with patients with persistent elevated CRP or fCal (3.5 versus 1.6 µg/mL, P < 0.01 and 4.9 versus 1.8 µg/mL, P < 0.001, respectively). Finally, the median TLIs were higher in patients achieving CR with normal CRP and fCal <50 µg/g in comparison with patients without strictly normal biomarkers (5.9 versus 2.1 µg/mL, P < 0.001). The more the expected level of response to IFX was stringent, the more the median TLI and optimal thresholds were high. CONCLUSIONS: Threshold values of TLI differ according to therapeutic outcomes expected in patients with inflammatory bowel disease under maintenance therapy with IFX.

Dietary patterns, digestive symptoms, and health-related quality of life in women reporting minor digestive symptoms.

OBJECTIVE: Digestive symptoms are reported to result from a wide range of dietary components. Dietary pattern analysis is a useful method when considering the entire diet, rather than individual foods or nutrients, providing an opportunity to take interactions into account. The aim of the present study was to investigate, using a dietary pattern approach, the relationship between diet, digestive symptoms, and health-related quality of life (HRQoL) in women reporting minor digestive symptoms. METHODS: Analysis was performed on dietary and digestive symptoms data collected in France. Women (N = 308, ages 18-60 y) reporting a bowel movement frequency within the normal range (3-21 stools/wk) but with minor digestive symptoms in the previous month were studied. Dietary data was collected using three 24-h recalls. K-means was used to divide the dietary data into clusters. The frequency of digestive symptoms (abdominal discomfort or pain, bloating, flatulence, borborygmi) and bowel movements were evaluated over a 2-wk period. HRQoL was also assessed. RESULTS: Four dietary clusters were identified and characterized as unhealthy, balance, healthy, and convenience. No differences were found in the frequency of digestive symptoms according to dietary cluster, except for flatulence (P = 0.030), which was more prevalent in the unhealthy and convenience clusters. No significant differences were observed in HRQoL according to dietary clusters. CONCLUSIONS: Results from the present study demonstrated that even within a relatively homogeneous sample of French women, distinct dietary patterns can be identified but without significant differences in digestive symptoms (except for flatulence) or HRQoL.