ABSTRACT
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.
Subject(s)
Adalimumab/pharmacokinetics , Anti-Inflammatory Agents/pharmacokinetics , Inflammatory Bowel Diseases/drug therapy , Adalimumab/administration & dosage , Adalimumab/therapeutic use , Adult , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Antibodies/blood , Area Under Curve , Cohort Studies , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
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.
Subject(s)
Crohn Disease/metabolism , Leukocyte L1 Antigen Complex/metabolism , Adolescent , Adult , Aged , Biomarkers/analysis , Biomarkers/metabolism , Colectomy , Crohn Disease/surgery , Feces/chemistry , Female , Follow-Up Studies , Humans , Leukocyte L1 Antigen Complex/analysis , Male , Middle Aged , Remission Induction , Young AdultABSTRACT
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.
Subject(s)
Azathioprine/therapeutic use , Immunosuppressive Agents/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab/administration & dosage , Adalimumab/therapeutic use , Adult , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Azathioprine/administration & dosage , Crohn Disease/drug therapy , Drug Therapy, Combination , Female , Humans , Immunosuppressive Agents/administration & dosage , Inflammatory Bowel Diseases/immunology , Infliximab/administration & dosage , Infliximab/therapeutic use , Male , Recurrence , Treatment Outcome , Tumor Necrosis Factor-alpha/immunologyABSTRACT
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.
Subject(s)
Crohn Disease/drug therapy , Remission Induction , Ustekinumab/blood , Ustekinumab/therapeutic use , Biomarkers/analysis , C-Reactive Protein/analysis , Feces/chemistry , Gastrointestinal Agents/blood , Gastrointestinal Agents/therapeutic use , Humans , Leukocyte L1 Antigen Complex/analysis , Predictive Value of Tests , Prospective Studies , Sensitivity and SpecificityABSTRACT
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.
Subject(s)
Colon/surgery , Crohn Disease/surgery , Ileum/surgery , Adult , Colectomy , Colon/pathology , Colonoscopy , Crohn Disease/pathology , Female , Humans , Ileum/pathology , Male , Microscopy, Confocal , Middle Aged , Pilot Projects , Prognosis , Recurrence , Risk Assessment , Young AdultABSTRACT
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 10â 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 (68/31â 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.
Subject(s)
Biopsy , Colonoscopy/methods , Colorectal Neoplasms/diagnosis , Gastroenterology , Image Enhancement/methods , Inflammatory Bowel Diseases/complications , Adult , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Biopsy/methods , Colitis, Ulcerative/complications , Colorectal Neoplasms/surgery , Crohn Disease/complications , Female , Follow-Up Studies , France , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/surgery , Male , Mesalamine/therapeutic use , Middle Aged , Narrow Band Imaging , Population Surveillance/methods , Predictive Value of Tests , Prospective Studies , Sensitivity and SpecificityABSTRACT
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).
Subject(s)
Crohn Disease/drug therapy , Crohn Disease/pathology , Gastrointestinal Agents/administration & dosage , Infliximab/administration & dosage , Adult , Belgium , Female , Follow-Up Studies , France , Humans , Male , Prospective Studies , Recurrence , Treatment OutcomeABSTRACT
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.
Subject(s)
Drug Hypersensitivity/etiology , Drug Tolerance , Inflammatory Bowel Diseases/drug therapy , Infliximab/adverse effects , Infliximab/therapeutic use , Adult , Female , Gastrointestinal Agents/administration & dosage , Gastrointestinal Agents/adverse effects , Gastrointestinal Agents/therapeutic use , Humans , Hypersensitivity, Immediate/chemically induced , Infliximab/administration & dosage , Male , Middle Aged , Treatment Outcome , Young AdultABSTRACT
BACKGROUND & AIMS: We investigated whether serum trough levels of vedolizumab, a humanized monoclonal antibody against integrin α4ß7, during the induction phase of treatment can determine whether patients will need additional doses (optimization of therapy) within the first 6 months. METHODS: We conducted an observational study of 47 consecutive patients with Crohn's disease (CD; n = 31) or ulcerative colitis (UC; n = 16) who had not responded to 2 previous treatment regimens with antagonists of tumor necrosis factor and were starting therapy with vedolizumab at 2 hospitals in France, from June 2014 through April 2016. All patients were given a 300-mg infusion of vedolizumab at the start of the study, Week 2, Week 6, and then every 8 weeks; patients were also given corticosteroids during the first 4-6 weeks. Patients not in remission at Week 6 were given additional doses of vedolizumab at Week 10 and then every 4 weeks (extended therapy or optimization). Remission at Week 6 of treatment was defined as CD activity score below 150 points for patients with CD and a partial Mayo Clinic score of <3 points, without concomitant corticosteroids, for patients with UC. Blood samples were collected each week and serum levels of vedolizumab and antibodies against vedolizumab were measured using an enzyme-linked immunosorbent assay. Median trough levels of vedolizumab and interquartile ranges were compared using the nonparametric Mann-Whitney test. The primary objective was to determine whether trough levels of vedolizumab measured during the first 6 weeks of induction therapy associated with the need for extended treatment within the first 6 months. RESULTS: Based on response to therapy at Week 6, extended treatment was required for 30 of the 47 patients (23 patients with CD and 7 patients with UC). At Week 2, trough levels of vedolizumab for patients selected for extended treatment were 23.0 µg/mL (interquartile range, 14.0-37.0 µg/mL), compared with 42.5 µg/mL in patients who did not receive extended treatment (interquartile range, 33.5-50.7; P = .15). At Week 6, trough levels of vedolizumab <18.5 µg/mL were associated with need for extended therapy (100% positive predictive value, 46.2%; negative predictive value; area under the receiver operating characteristic curve, 0.72) within the first 6 months. Among patients who required extended treatment at Week 10, all of those with trough levels of vedolizumab <19.0 µg/mL at Week 6 had achieved clinical remission 4 weeks later (secondary responders). CONCLUSIONS: In a prospective study of patients with CD or UC receiving induction therapy with vedolizumab, low trough levels of vedolizumab at Week 6 (<19.0 µg/mL) are associated with need for additional doses (given at Week 10 and then every 4 weeks). All patients receiving these additional doses achieved a clinical response 4 weeks later.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacokinetics , Gastrointestinal Agents/administration & dosage , Gastrointestinal Agents/pharmacokinetics , Inflammatory Bowel Diseases/drug therapy , Serum/chemistry , Adult , Female , France , Humans , Induction Chemotherapy , Male , Middle Aged , Prospective Studies , Time FactorsABSTRACT
BACKGROUND & AIMS: Ustekinumab, a human monoclonal antibody against the p40 subunit of interleukins-12 and -23, is effective in inducing and maintaining remission in patients with luminal Crohn's disease (CD). We assessed the efficacy and safety of subcutaneous ustekinumab in patients with anti-tumor necrosis factor (anti-TNF) refractory CD. METHODS: We performed a retrospective observational study, collecting data from the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif on 122 consecutive patients with active CD refractory to anti-TNF therapy who received at least 1 subcutaneous injection of ustekinumab from March 2011 to December 2014, in 20 tertiary centers in Europe. Subjects were followed for at least 3 months. The primary outcome was clinical benefit, defined as reductions in symptoms and biochemical markers of CD and complete weaning from steroids, without surgery or immunosuppressant therapies. RESULTS: Seventy-nine patients (65%) had a clinical benefit within 3 months of receiving ustekinumab. Concomitant immunosuppressant therapy at study inclusion increased the odds for a clinical benefit from ustekinumab (odds ratio, 5.43; 95% confidence interval, 1.14-25.77; P = .03). Over a median follow-up period of 9.8 months (interquartile range, 5.3-14.5 months), the cumulative probabilities that patients maintained the clinical benefit for 6 and 12 months after introduction of ustekinumab were 93% and 68%, respectively. CONCLUSIONS: Almost two-thirds of patients with CD refractory to at least 1 anti-TNF agent receive clinical benefit from ustekinumab therapy, not requiring steroids for up to 12 months afterward. While awaiting results from ongoing trials, ustekinumab can be considered for use in these patients.
Subject(s)
Crohn Disease/drug therapy , Immunologic Factors/therapeutic use , Ustekinumab/therapeutic use , Adult , Europe , Female , Humans , Immunologic Factors/adverse effects , Injections, Subcutaneous/adverse effects , Male , Retrospective Studies , Treatment Outcome , Tumor Necrosis Factor-alpha/therapeutic use , Ustekinumab/adverse effectsABSTRACT
BACKGROUND: Primary sclerosing cholangitis (PSC) is associated with ulcerative colitis and extensive colonic involvement or ileocolitis in Crohn's disease (CD). To our knowledge, no specific report of isolated ileitis associated with PSC in CD patients has been published in CD patients. AIM AND METHODS: We report three cases of patients with isolated Crohn's ileitis associated with PSC and in whom colonic inflammation was never documented. RESULTS: Patients were followed up 10-23 years and each patient underwent 6-7 ileocolonoscopies: inflammation was located only in the terminal ileum, which was confirmed on surgical specimens in two patients. Small-duct PSC led to diagnosis of CD ileitis in one patient, while small and large-ducts PSC were evidenced after CD diagnosis in the other 2. PSC were regularly followed for 9-10 years. CONCLUSIONS: Our three cases of PSC with isolated CD ileitis and long-term follow-up without any sign of colonic involvement argue against the concept that colonic mucosal inflammation is critical for the pathogenesis of PSC in inflammatory bowel disease.
Subject(s)
Cholangitis, Sclerosing/complications , Crohn Disease/complications , Ileitis/complications , Adult , Aged , Cholangitis, Sclerosing/diagnosis , Crohn Disease/diagnosis , Female , Humans , Ileitis/diagnosis , Middle AgedABSTRACT
OBJECTIVES: Fecal calprotectin (fCal) is widely used as marker of gut inflammation and is strongly associated with the severity of endoscopic lesions in Crohn's disease (CD). We analyzed the relationships between levels of fCal and high-sensitivity C-reactive protein (hsCRP) and the presence and severity of postoperative endoscopic recurrence in asymptomatic CD patients (Harvey-Bradshaw index≤3). METHODS: Blood and fecal samples were collected in consecutive asymptomatic CD patients (Harvey-Bradshaw index 0.85 ± 0.19, mean ± s.e.m.) who had undergone an ileocolonic resection. hsCRP and fCal were measured and a routine ileocolonoscopy was performed within 18 months (median 7 months) from resection, to detect endoscopic recurrence according to the Rutgeerts score. RESULTS: Eighty-six patients were included in this prospective multicenter observational cohort. fCal concentrations differed significantly in patients with endoscopic recurrence when compared with those in endoscopic remission (mean ± s.e.m.: 473 ± 78 µg/g vs. 115 ± 18 µg/g; P<0.0001). The area under the receiver operating characteristic (ROC) curve to discriminate between patients in endoscopic remission and recurrence was 0.86 for fCal and lower for hsCRP (0.70). The best cutoff point for fCal to distinguish between endoscopic remission and recurrence was 100 µg/g as determined by the ROC curve, and its sensitivity, specificity, positive and negative predictive values (NPVs), as well as overall accuracy were 95%, 54%, 69%, 93%, and 77%, respectively. CONCLUSION: Measurement of fCal concentrations is a promising and useful tool for monitoring asymptomatic CD patients after ileocolonic resection. Taking into account the high NPV of fCal, a threshold below 100 µg/g could avoid systematic ileocolonoscopies in 30% of patients from this population.
Subject(s)
C-Reactive Protein/metabolism , Colectomy , Crohn Disease/surgery , Feces/chemistry , Ileum/surgery , Leukocyte L1 Antigen Complex/metabolism , Adolescent , Adult , Aged , Asymptomatic Diseases , Cohort Studies , Crohn Disease/metabolism , Endoscopy, Gastrointestinal , Female , Humans , Male , Middle Aged , Prospective Studies , Recurrence , Remission Induction , Treatment Outcome , Young AdultABSTRACT
OBJECTIVES: Although anti-tumor necrosis factor (TNF) therapy is the treatment of choice for perianal fistulizing Crohn's disease (CD), the efficacy and safety of anti-TNF therapy in enterocutaneous fistula (ECF) remains unclear. METHODS: Between January 2008 and December 2009, we retrospectively reviewed the outcomes of all CD patients with ECF (excluding perianal fistula) treated with anti-TNF therapy followed up in Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID) centers. ECF closure and tolerance of anti-TNF therapy were studied using univariate and multivariate analyses. RESULTS: Forty-eight patients (twenty-six women; median age 34.6 (interquartile range=25.0-45.5) years) were included in this study. The median follow-up period was 3.0 (2.0-6.6) years. The fistula was located in the small bowel (n=38), duodenum (n=1), and colon (n=9). The fistula has been developed in ileocolonic anastomosis in 17 (35%) cases. Sixteen patients (33%) had complex fistulas with multiple tracts and eleven patients (23%) had a high ECF output (if wearing an ostomy bag). Complete ECF closure was achieved in 16 (33%) patients, of whom eight relapsed during the follow-up period. In multivariate analysis, complete ECF closure was associated with the absence of multiple ECF tracts and associated stenosis. An abdominal abscess developed in 15 (31%) patients. ECF resection was needed in 26 (54%) patients. One patient died after surgery owing to abdominal sepsis. CONCLUSIONS: In CD patients with ECF, anti-TNF therapy may be effective in up to one-third of patients, especially in the absence of stenosis and complex fistula. A careful selection of patients is mandatory to prevent treatment failure and improves the safety.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Colonic Diseases/drug therapy , Crohn Disease/drug therapy , Cutaneous Fistula/drug therapy , Duodenal Diseases/drug therapy , Intestinal Fistula/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Adult , Anastomosis, Surgical/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Colon/surgery , Colonic Diseases/etiology , Colonic Diseases/surgery , Crohn Disease/complications , Crohn Disease/surgery , Cutaneous Fistula/etiology , Cutaneous Fistula/surgery , Duodenal Diseases/etiology , Duodenal Diseases/surgery , Female , Follow-Up Studies , Humans , Ileum/surgery , Infliximab , Intestinal Fistula/etiology , Intestinal Fistula/surgery , Intestine, Small , Male , Middle Aged , Retrospective Studies , Time Factors , Treatment Outcome , Young AdultABSTRACT
A differential responsiveness of patients to ionizing radiation is observed after preoperative radiotherapy for rectal adenocarcinoma that might be related, in part, to an apoptosis defect. To establish if proteins of the apoptotic cascades [pro-apoptotic: active caspase 3, 8, and 9 and DIABLO (direct inhibitor of apoptosis-binding protein with low pI); anti-apoptotic: XIAP (X-linked inhibitor of apoptosis)] are involved, we analyzed their profile in radioresistant (SW480) and radiosensitive (SW48) human colorectal cell lines. We demonstrated that, after irradiation, the SW48 cells increased the expression of the pro-apoptotic proteins, whereas the SW480 cells increased the expression of the anti-apoptotic protein XIAP. Moreover, XIAP knockdown in SW480 cells enhanced the basal and radiation-induced apoptotic index; the propensity of the SW480 cells to undergo apoptosis after radiation was higher compared with SW48 cells. In a translational study of 38 patients with rectal carcinoma, we analyzed the apoptotic profile for tumor and noncancerous tissue for each biopsy specimen using IHC. According to their response to preoperative radiotherapy, patients were classified into two groups: responsive and nonresponsive. Although no difference in expression of caspase 3, 8, or 9 was observed in the tumor/normal tissue ratio between responsive and nonresponsive patients, the ratio decreased for DIABLO and increased for XIAP. In conclusion, inhibition of XIAP rescues cellular radiosensitivity and both DIABLO and XIAP might be potential predictive markers of radiation responsiveness in rectal adenocarcinoma.
Subject(s)
Adenocarcinoma/metabolism , Adenocarcinoma/radiotherapy , Biomarkers, Tumor/metabolism , Radiation Tolerance , Rectal Neoplasms/metabolism , Rectal Neoplasms/radiotherapy , X-Linked Inhibitor of Apoptosis Protein/metabolism , Adenocarcinoma/enzymology , Adenocarcinoma/pathology , Apoptosis/radiation effects , Apoptosis Regulatory Proteins , Carrier Proteins/metabolism , Caspase 3/metabolism , Caspase 8/metabolism , Cell Line, Tumor , Cell Survival/radiation effects , Gene Knockdown Techniques , Humans , Mitochondrial Proteins/metabolism , Prognosis , Radiation Tolerance/radiation effects , Radiation, Ionizing , Rectal Neoplasms/enzymology , Rectal Neoplasms/pathologyABSTRACT
BACKGROUND AND OBJECTIVES: Interaction of bacteria with the immune system within the intestinal mucosa plays a key role in the pathogenesis of inflammatory bowel disease (IBD). The aim of the current study was to develop a fluorescein-aided confocal laser endomicroscopy (CLE) method to visualise intramucosal enteric bacteria in vivo and to determine the involved mucosal area in the colon and ileum in patients with ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Initially, E coli strains expressing enhanced green fluorescent protein (pEGFP) were endomicroscopically imaged in mice. In addition, ex vivo and in vivo imaging of fluorescent human enteric bacteria was performed to specify the distinct endomicroscopic appearance of enteral bacteria. Targeted mucosal biopsies towards endomicroscopic identifiable intramucosal bacteria and negative mucosal areas were prospectively obtained during colonoscopy and correlated with bench-top fluorescence microscopy (FISH) to prove the endomicroscopic visualisation of intramucosal bacteria. Finally, a retrospective analysis as well as a prospective study was performed in patients with UC and CD to confirm the presence and distribution of intramucosal bacteria within the gut. RESULTS: Confocal endomicroscopy was able to identify intramucosal pEGFP E coli in mice and strains of enteric microflora in the mucosa of humans. Using FISH as the gold standard, evaluation of 21 patients showed that CLE had a sensitivity of 89% and specificity of 100% to identify intramucosal bacteria. In a retrospective study, 113 patients with CD and UC had intramucosal bacteria significantly more often than 50 control patients (66% vs 60% vs 14%, p<0.001). This result was confirmed in a prospective study in which 10 patients with CD and 10 with UC had a significantly wider distribution of involvement with intramucosal bacteria in the colon and terminal ileum compared with 10 controls (85.2% vs 75.9% vs 16.8%, p<0.0001). CONCLUSIONS: CLE is a new tool that can image intramucosal bacteria in vivo in patients with IBD. Intramucosal bacteria are found more frequently and with a wider distribution in patients with IBD than in patients with a normal intestine.
Subject(s)
Enterobacteriaceae/isolation & purification , Inflammatory Bowel Diseases/microbiology , Intestinal Mucosa/microbiology , Microscopy, Confocal/methods , Animals , Colitis, Ulcerative/microbiology , Colon/microbiology , Colonoscopy , Crohn Disease/microbiology , Escherichia coli/isolation & purification , Humans , Ileum/microbiology , In Situ Hybridization, Fluorescence , Male , Mice , Mice, Inbred C57BL , Prospective Studies , Retrospective StudiesABSTRACT
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 levelsâ >â 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 (nâ =â 61 patients, 42 Crohn's disease, 19 ulcerative colitis) or swapped for vedolizumab (nâ =â 40, 20 ulcerative colitis) or ustekinumab (nâ =â 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 (Pâ <â 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, Pâ <â 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; Pâ =â 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; Pâ =â 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.
Subject(s)
Biological Products , Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Adalimumab/therapeutic use , Biological Products/therapeutic use , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Humans , Inflammatory Bowel Diseases/drug therapy , Treatment Outcome , Ustekinumab/therapeutic useABSTRACT
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.
Subject(s)
Biosimilar Pharmaceuticals , Crohn Disease , Nijmegen Breakage Syndrome , Antibodies, Monoclonal/therapeutic use , Biosimilar Pharmaceuticals/therapeutic use , Gastrointestinal Agents/therapeutic use , Humans , Infliximab , Injections, Subcutaneous , Nijmegen Breakage Syndrome/drug therapy , Treatment OutcomeABSTRACT
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.
Subject(s)
Crohn Disease , Interleukin-17 , Humans , Interleukin-17/metabolism , Crohn Disease/pathology , Cytokines/metabolism , Interleukin-6/metabolism , T-Lymphocyte Subsets/metabolism , Th17 Cells/metabolism , Forkhead Transcription Factors/metabolism , RecurrenceABSTRACT
BACKGROUND & AIMS: Fibrin glue is a therapeutic for fistulas that activates thrombin to form a fibrin clot, which mechanically seals the fistula tract. We assessed the efficacy and safety of a heterologous fibrin glue that was injected into the fistula tracts of patients with Crohn's disease (ClinicalTrials.gov No. NCT00723047). METHODS: This multicenter, open-label, randomized controlled trial included patients with a Crohn's disease activity index < or =250 and fistulas between the anus (or low rectum) and perineum, vulva, or vagina, that drained for more than 2 months. Magnetic resonance imaging or endosonography was performed to assess fistula tracts and the absence of abscesses. Patients were stratified into groups with simple or complex fistulas and randomly assigned to receive fibrin glue injections (n = 36) or only observation (n = 41) after removal of setons. The primary end point was clinical remission at week 8, defined as the absence of draining, perianal pain, or abscesses. At week 8, a fibrin glue injection was offered to patients who were not in remission. RESULTS: Clinical remission was observed in 13 of the 34 patients (38%) of the fibrin glue group compared with 6 of the 37 (16%) in the observation group; these findings demonstrate the benefit of fibrin glue (odds ratio, 3.2; 95% confidence interval: 1.1-9.8; P = .04). The benefit seemed to be greater in patients with simple fistulas. Four patients in the fibrin glue group and 6 in the observation group had adverse events. CONCLUSIONS: Fibrin glue injection is a simple, effective, and well-tolerated therapeutic option for patients with Crohn's disease and perianal fistula tracts.
Subject(s)
Crohn Disease/complications , Fibrin Tissue Adhesive/therapeutic use , Rectal Fistula/therapy , Adult , Female , Fibrin Tissue Adhesive/adverse effects , Follow-Up Studies , Humans , MaleABSTRACT
Evidence that CD4(+) regulatory T cells can control Ag-specific CD8(+) T cell-mediated colitis in immunocompetent mice is poorly documented. To examine the potential of CD4(+) T cells to control colitis, we used our model of CD8(+) T cell-mediated colitis induced by intracolonic sensitization followed by challenge with the hapten 2,4-dinitrobenzene sulfonic acid. The defect of CD4(+) T cells in MHC class II-deficient (Abeta(degrees/degrees)) mice allowed priming of 2,4-dinitrobenzene sulfonic acid-specific IFN-gamma-producing CD8 colitogenic effectors and development of colitis in the otherwise resistant C57BL/6 strain. Cotransfer experiments in RAG2(degrees/degrees) mice and ex vivo studies showed that CD4(+)CD25(+) T cells completely prevented CD8(+) T cell-mediated colitis and controlled CD8(+) T cell activation, respectively. In the susceptible BALB/c strain, Ab depletion revealed that lack of CD4(+) regulatory T cells resulted in 1) acute colitis elicited by a suboptimal dose of hapten challenge and 2) more severe relapsing episodes of colitis induced by effector/memory CD8(+) T cell-mediated colitis at an optimal dose of hapten challenge, even when CD4 depletion was performed just before the second challenge. Oral administration of the probiotic strain Lactobacillus casei DN-114 001 alleviated colitis and increased the suppressive function of Foxp3(+)CD4(+) regulatory T cells of colon lamina propria. These data demonstrate that CD4(+) regulatory T cells exert a protective effect on colitis by controlling colitogenic effector/memory CD8(+) T cells during the effector (symptomatic) phase of acute and relapsing colitis, respectively. Probiotics with natural adjuvant effects on mucosal regulatory T cells may represent a valuable approach to alleviate the colitogenic effect of Tc1-type CD8(+) effectors.