Adam S. Cheifetz

The incidence and management of infusion reactions to infliximab: a large center experience.

OBJECTIVE:To assess the incidence and management of infusion reactions to infliximab, a chimeric monoclonal antibody that targets human tumor necrosis factor-α, in patients with Crohns disease treated at a large infusion center.METHODS:A total of 165 consecutive patients who received 479 infliximab infusions in the Division of Clinical Immunology Infusion Center at Mount Sinai Medical Center from July, 1998 to January, 2001 were evaluated. Specific treatment protocols for initial and subsequent acute infusion reactions were followed and the outcomes documented.RESULTS:The overall incidence of infusion reactions to infliximab was 6.1% (29 of 479) of infusions, affecting 9.7% (16 of 165) of patients. Mild, moderate, or severe acute reactions occurred in 3.1% (15 of 479), 1.2% (six of 479), and 1.0% (five of 479) of infliximab infusions, respectively. Use of treatment protocols resulted in rapid resolution of all acute reactions to infliximab. With the prophylaxis protocol, all patients who experienced an initial mild or moderate acute reaction were able to receive additional infusions. Four patients experienced a total of five severe acute reactions. Three patients were retreated: two patients had no further problems, whereas one patient had a second severe acute reaction that rapidly resolved with treatment. Suggesting that acute infusion reactions are not type I hypersensitivity reactions, in 11 patients who experienced 14 acute infusion reactions, serum tryptase levels were normal. Delayed infusion reactions occurred in 0.6% (three of 479) of infusions.CONCLUSIONS:Infliximab infusions were accompanied by acute reactions in approximately 5% of infusions. These reactions did not seem to be true IgE-mediated type I hypersensitivity events. Using appropriate treatment protocols, these reactions were effectively treated and prevented upon retreatment in nearly all patients. Delayed reactions were rare, occurring in <1% of infusions.

The Risk of Retention of the Capsule Endoscope in Patients with Known or Suspected Crohn's Disease

OBJECTIVES:Capsule endoscopy (CE) allows visualization of the mucosa of the entire small bowel and is therefore a potentially important tool in the evaluation of patients with known or suspected Crohns disease (CD). However, small bowel strictures, which are not uncommon in Crohns, are considered to be a contraindication to CE for fear of capsule retention. Our goal was to determine the risk of capsule retention in patients with suspected or known CD.METHODS:We retrospectively reviewed the records of 983 CE cases performed at three private gastroenterology practices between December 2000 and December 2003, and selected those with suspected or proven Crohns.RESULTS:A total of 102 cases were identified in which CE was used in patients with suspected (N = 64) or known (N = 38) CD. Only one of 64 patients (1.6%) with suspected CD had a retained capsule. However, in five of 38 (13%) patients with known Crohns, the capsule was retained proximal to a stricture. Of the five cases of retained capsules, three strictures were previously unknown. In four cases, the obstructing lesions were resected without complications, leading to complete resolution of the patients underlying symptoms. One patient chose not to undergo surgery and has remained without an episode of small bowel obstruction for over 38 months.CONCLUSIONS:Capsule retention occurred in 13% (95% CI 5.6%–28%) of patients with known CD, but only in 1.6% (95% CI 0.2%–10%) with suspected Crohns. A retained capsule may indicate unsuspected strictures in Crohns that may require an unexpected, but therapeutic, surgical intervention. Patients and physicians should be aware of these potential risks when using CE in CD.

Impact of Antibodies to Infliximab on Clinical Outcomes and Serum Infliximab Levels in Patients With Inflammatory Bowel Disease (IBD): A Meta-Analysis

OBJECTIVES:Antibodies to infliximab (ATIs) have been associated with loss of clinical response and lower serum infliximab (IFX) levels in some studies of patients with inflammatory bowel disease (IBD). This has important implications for patient management and development of novel biologic therapies. The objective of this study was to perform a systematic review and meta-analysis of studies that reported clinical outcomes and IFX levels according to patients’ ATI status.METHODS:MEDLINE, Web of Science, CINAHL, Scopus, and EMBASE were searched for eligible studies. Quality assessment was undertaken using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. Raw data from studies meeting inclusion criteria was pooled for meta-analysis of effect estimates. Sensitivity analysis was performed for all outcomes. Funnel plot was performed to assess for publication bias.RESULTS:Thirteen studies met the inclusion criteria, and reported results in 1,378 patients with IBD. All included studies had a high risk of bias in at least one quality domain. The pooled risk ratio (RR) of loss of clinical response to IFX in patients with IBD who had ATIs was 3.2 (95% confidence interval (CI): 2.0–4.9, P<0.0001), when compared with patients without ATIs. This effect estimate was predominantly based on data from patients (N=494) with Crohns disease (RR: 3.2, 95% CI: 1.9–5.5, P<0.0001). Data only from patients with ulcerative colitis (n=86) exhibited a non-significant RR of loss of response of 2.2 (95% CI: 0.5–9.0, P=0.3) in those with ATIs. Heterogeneity existed between studies, in both methods of ATI detection, and clinical outcomes reported. Three studies (n=243) reported trough serum IFX levels according to ATI status; the standardized mean difference in trough serum IFX levels between groups was −0.8 (95% CI −1.2, −0.4, P<0.0001). A funnel plot suggested the presence of publication bias.CONCLUSIONS:The presence of ATIs is associated with a significantly higher risk of loss of clinical response to IFX and lower serum IFX levels in patients with IBD. Published studies on this topic lack uniform reporting of outcomes. High risk of bias was present in all the included studies.

Psoriasis associated with anti-tumour necrosis factor therapy in inflammatory bowel disease: a new series and a review of 120 cases from the literature

Aliment Pharmacol Ther 2011; 34: 1318–1327

Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease

Background:Inflammatory bowel disease (IBD) affects people during their prime reproductive years. The thiopurines (6-mercaptopurine and azathioprine), commonly used for induction and maintenance of remission, are U.S. Food and Drug Administration (FDA) pregnancy category D, raising concern for fetal risk. We performed a systematic review and meta-analysis to evaluate the effects of thiopurine exposure during pregnancy or at the time of conception on three measures of fetal risk in women and men with IBD. Methods:A systematic search of PubMed and Web of Science using a combination of Mesh and text terms was performed to identify studies reporting birth outcomes from IBD women and men exposed to thiopurines within 3 months of conception and/or during pregnancy. A meta-analysis was performed using the random effects model to pool estimates and report odds ratio (OR) for three outcomes in women: low birth weight (LBW), preterm birth, and congenital abnormalities and one in men: congenital abnormalities. Results:In women with IBD exposed to thiopurines, the pooled ORs for LBW, preterm birth, and congenital abnormalities were 1.01 (95% confidence interval [CI] 0.96, 1.06), 1.67 (95% CI 1.26, 2.20), and 1.45 (95% CI 0.99, 2.13), respectively. In men, the pooled OR for congenital abnormality was 1.87 (95% CI 0.67, 5.25). Conclusions:Thiopurine exposure in women with IBD was not associated with LBW or congenital abnormalities, but was associated with preterm birth. Exposure in men at the time of conception was not associated with congenital abnormalities.

Capsule endoscopy retention: is it a complication?

Background Capsule endoscopy has been found superior to barium x-rays and push enteroscopy in the investigation of obscure gastrointestinal bleeding and in the evaluation of suspected Crohns disease. Currently, small bowel obstruction and strictures are considered by many physicians to be a contraindication to capsule endoscopy for fear of capsule retention or impaction. The goal of this study was to reassess this conventional wisdom that capsule endoscopy is contraindicated in small bowel obstruction and to determine the safety and efficacy of capsule endoscopy in the evaluation of patients with suspected stricture or small bowel obstruction. Study A retrospective chart review was performed using a database of 568 capsule endoscopy cases performed between August 2001 and November 2003. Cases of suspected small bowel obstruction were selected and reviewed. Results Nineteen cases were identified in which capsule endoscopy was used in the setting of suspected small bowel obstruction. The diagnosis of suspected small bowel obstruction was based on symptoms alone in 8 cases and on symptoms plus abnormal radiographs in the remaining 11 cases. Capsule endoscopy made a definitive diagnosis in 5 of the 19 cases (26%): 2 Crohns strictures, 1 radiation induced stricture, 1 nonsteroidal anti-inflammatory drug induced stricture, and 1 MALT lymphoma. The capsule was retained proximal to a stricture in 4 cases, in which the obstructing lesions were electively resected without complications. There was no case in which administration of the capsule led to an acute small bowel obstruction. Conclusions Capsule endoscopy can be safely used to help identify the etiology and site of a small bowel obstruction. Retention of the capsule may indicate the presence of a lesion requiring surgery, but small bowel obstruction or strictures are not in themselves contraindications to the procedure. It is understood, however, that retention may lead to surgery in a patient who otherwise may have been treated medically without surgery for the same illness (eg, Crohns disease and nonsteroidal anti-inflammatory drug enteropathy).

Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study.

Background:Infliximab (IFX) is effective in the treatment of inflammatory bowel disease; however, the effect is often not durable. It is unknown if proactive therapeutic concentration monitoring (TCM) of IFX improves outcomes. Methods:This is a retrospective observational study examining the use of proactive TCM and titration of IFX to a target concentration for patients with inflammatory bowel disease in clinical remission at a tertiary care center. The primary aim was to describe the clinical course of patients who had proactive TCM. A secondary analysis was done to assess if this strategy was superior to the standard of care. Results:Forty-eight patients were identified as having proactive TCM. Fifteen percent had an initial undetectable trough concentration. Twenty-five percent (12 of 48) of patients escalated IFX after the first proactive TCM while 15% (7 of 48) of patients de-escalated IFX therapy over the study period. A control group of 78 patients was identified. Patients who had proactive TCM had a greater probability of remaining on IFX than controls (hazard ratio, 0.3; 95% confidence interval, 0.1–0.6; log rank test; P = 0.0006). The probability of remaining on IFX was greatest for patients who achieved a trough concentration >5 &mgr;g/mL (hazard ratio, 0.03; 95% confidence interval, 0.01–0.1; P < 0.0001 versus trough <5 &mgr;g/mL). Fewer patients in the proactive TCM group stopped IFX (10% versus 31%, P = 0.009). Conclusions:In this pilot observational study, proactive TCM of IFX frequently identified patients with low or undetectable trough concentrations and resulted in a greater probability of remaining on IFX.

Meta‐analysis: targeting the intestinal microbiota in prophylaxis for post‐operative Crohn’s disease

Aliment Pharmacol Ther 31, 802–809

The Utility of Capsule Endoscopy in Patients With Suspected Crohn's Disease

OBJECTIVES:In patients with suspected Crohns disease (CD), little is known about the test characteristics of capsule endoscopy (CE) in the diagnosis of this condition. We sought to determine the utility of CE for the subsequent diagnosis of CD in patients suspected to have this condition.METHODS:All patients who underwent CE at a single tertiary-care center for investigation of suspected small bowel CD, and who had a 12-month follow-up, were included in the study. All patients had undergone other investigations that were normal or equivocal. The test characteristics of CE were determined on the basis of capsule findings of small bowel ulcers and a subsequent new diagnosis of CD within 12 months of CE.RESULTS:The study included 102 patients with 12-month follow-up data. The majority (75%) met the established criteria to define “suspected Crohns disease” as an indication for CE. Most had undergone computed tomography scan or small bowel follow-through (92%) and colonoscopy (99%) before CE. There were abnormal CE findings suggestive of CD in 39 patients. The prevalence rate of a new diagnosis of CD by 12 months in the study population was 13%. Using the presence of more than 3 ulcers as the criterion for an abnormal CE study, the sensitivity of CE for the diagnosis of CD was 77%, the specificity was 89%, the positive predictive value (PPV) was 50%, and the negative predictive value (NPV) was 96%.CONCLUSIONS:In patients with suspected CD, CE has a high sensitivity and a NPV for this condition. The PPV varies depending on the patient population and the criteria for a CE diagnosis of CD.

The Crohn's disease activity index (CDAI) is similarly elevated in patients with Crohn's disease and in patients with irritable bowel syndrome

While the Crohns disease activity index (CDAI) is the gold standard for defining clinical endpoints in Crohns disease (Crohns) clinical trials, its ability to distinguish symptoms due to inflammation from those that are non‐inflammatory has been questioned.