Rami Eliakim

Levels of Drug and Antidrug Antibodies Are Associated With Outcome of Interventions After Loss of Response to Infliximab or Adalimumab

BACKGROUND & AIMSnThere is controversy about whether levels of anti-tumor necrosis factor (TNF) and antidrug antibodies (ADAs) are accurate determinants of loss of response to therapy. We analyzed the association between trough levels of anti-TNF agents or ADAs and outcomes of interventions for patients with loss of response to infliximab or adalimumab.nnnMETHODSnWe performed a retrospective study of pediatric and adult patients with inflammatory bowel disease and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013. We examined the correlation between outcomes of different interventions and trough levels of drug or ADAs during loss of response. An additional subanalysis was performed including only patients with a definite inflammatory loss of response (clinical worsening associated with increased levels of C-reactive protein or fecal calprotectin, or detection of inflammation by endoscopy, fistula discharge, or imaging studies).nnnRESULTSnAmong 247 patients (42 with ulcerative colitis), there were 330 loss-of-response events (188 to infliximab and 142 to adalimumab). Trough levels of adalimumab greater than 4.5 mcg/mL and infliximab greater than 3.8 mcg/mL identified patients who failed to respond to an increase in drug dosage or a switch to another anti-TNF agent with 90% specificity; these were set as adequate trough levels. Adequate trough levels identified patients who responded to expectant management or out-of-class interventions with more than 75% specificity. Levels of antibodies against adalimumab >4 microgram per mL equivalent (mcg/mL-eq) or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity. Patients with high titers of ADAs had longer durations of response when anti-TNF agents were switched than when dosage was increased (Pxa0= .03; log-rank test), although dosage increases were more effective for patients with no or low titers of ADAs (Pxa0=xa0.02). An analysis of definite inflammatory loss-of-response events (nxa0= 244) produced similar results; patients with adequate trough levels had a longer duration of response when they switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class (Pxa0= .002; log-rank test).nnnCONCLUSIONSnThe results of this retrospective analysis suggest that trough levels of drug or ADAs may guide therapeutic decisions for more than two-thirds of inflammatory bowel disease patients with either clinically suspected or definite inflammatory loss of response to therapy.

Comparison of invasive and non-invasive tests diagnosis and monitoring of Helicobacter pylori infection in children.

Background: There are few reports which the tests used for diagnosing Helicobacter pylori infection and monitoring its eradication in children. Study Aims: Prospective evaluation of invasive (gastric histology, rapid urease test [RUT]) and non-invasive (stool antigen [FemtoLab H. pylori], urea breath test [UBT]) tests in the diagnosis of H. pylori infection and post-treatment eradication in children and adolescents. Methods: Ninety-two patients (50 male, 42 female) referred for upper gastrointestinal endoscopy were prospectively enrolled. UBT was performed and stool specimens collected for monoclonal enzyme immunoassay for H. pylori antigen (FemtoLab) 1 to 4 days before endoscopy. H. pylori in gastric biopsies was evaluated by RUT and staining with hematoxylin-eosin and giemsa. Eradication therapy was given to children with abdominal pain and H. pylori gastritis. FemtoLab H. pylori and UBT were repeated 6 weeks after the end of triple therapy. Results: Histology identified H. pylori in 49 of 92 (53%) subjects. Concordance between histology and RUT was found in 78 of 92 children. FemtoLab H. pylori was positive in 41 of 78 (52.6%) children with sensitivity, specificity, positive and negative predictive values of 97.5%, 94.7%, 95.1% and 97.3%, respectively. For UBT, these values were 100%, 96.9%, 97.5% and 100%, respectively. Twenty-six of 36 patients who received triple therapy returned for eradication evaluation. Tests for H. pylori antigen in stool were positive in 10 of 26 and for UBT in 11 of 26. Conclusion: Stool antigen (FemtoLab) and UBT were equally effective in diagnosing and confirming eradication of H. pylori infection in children.

The Hygiene Theory Harnessing Helminths and Their Ova to Treat Autoimmunity

The incidence of autoimmune diseases is increasing in Western countries, possibly due to the improved sanitary conditions and reduced exposure to infections in childhood (the hygiene hypothesis). There is an ongoing debate whether infection prevents or precipitates autoimmune diseases. Various helminths species used in several animal models were shown to limit inflammatory activity in a variety of diseases including inflammatory bowel disease, multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. At present the scientific data is based mostly on experimental animal models; however, there is an increasing body of evidence in a number of clinical trials being conducted. Herein we review several clinical trials evaluating the anti-inflammatory effects of helminths and assessing their association with different autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, and autoimmune liver diseases. We also describe the common pathways by which helminths induce immune modulation and the key changes observed in the host immune system following exposure to helminths. These common pathways include the inhibition of IFN-γ and IL-17 production, promotion of IL-4, IL-10 and TGF-β release, induction of CD4(+) T cell FoxP3+ expression, and generation of regulatory macrophages, dendritic cells, and B cells. Helminths products are becoming significant candidates for anti-inflammatory agents in this context. However, further research is needed for synthetic analogues of helminths potent products that mimic the parasite-mediated immunomodulation effect.

Wireless video capsule in pediatric patients with functional abdominal pain.

Objectives: Upper endoscopy (esophagogastroduodenoscopy [EGD]) has a limited role, if any, in the evaluation of functional abdominal pain (FAP). Nevertheless, children with intractable FAP are occasionally referred to EGD to rule out intestinal pathology. We evaluated the role of wireless video capsule endoscopy (VCE) in children referred for EGD with a diagnosis of FAP. Patients and Methods: Ten children older than 10 years of age were prospectively enrolled. Children were first studied with the PillCam SB (VCE; Given Imaging, Yokneam, Israel) followed by standard EGD within 2 weeks. After the completion of the study, a questionnaire of tolerance and content regarding the 2 procedures was completed by the patients. Results: Physical examinations and laboratory tests were within normal limits in all of the patients. Patients swallowed the endoscopic capsules without difficulty. There were no complications. VCE identified gastritis in 4 patients (confirmed by biopsies), whereas EGD detected erosive gastritis in only 1 of the 4 children. EGD detected no duodenal abnormalities. VCE detected Crohn disease in the small intestine and cecum in 1 patient. VCE was ranked by 8 patients as convenient and as a preferable procedure compared with EGD. Conclusion: The results of this small cohort suggest that in children with FAP, VCE is more sensitive than EGD for detection of macroscopic gastric and small bowel pathologies.

Association of Induction Infliximab Levels With Clinical Response in Perianal Crohn's Disease.

BackgroundnThe association of infliximab [IFX] trough levels with clinical and endoscopic outcomes in inflammatory bowel disease is well established. However, there is scarce data regarding the association of perianal fistula response with IFX. The aim of this study was to establish whether early induction infliximab levels and anti-infliximab antibodies [ATIs] are associated with perianal fistula response.nnnMethodsnConsecutive CD patients with perianal fistulae that were treated with IFX between 2008 and 2016 were included in the study. Response was defined as cessation or significant improvement of fistula drainage. Patients with unavailable IFX level or ATI measurements and/or missing clinical follow-up at Week 14 were excluded.nnnResultsnA total of 36 patients with perianal fistulae were included; 25/36 [69.4%] responded to treatment by Week 14. The median induction IFX levels at Weeks 2, 6 and 14 in the responders group at Week 14 were higher compared with those of the non-responders group [20/5.6 µg/mL, P = 0.0001; 13.3/2.55 µg/mL P = 0.0001; 4.1/0.14 µg/mL, P = 0.01]. On multivariate analysis, IFX leve at Weeks 2 and 6 were significantly associated with fistula response at Weeks 14 and 30. IFX drug levels of 9.25 µg/mL at Week 2 and 7.25 µg/mL at Week 6 were the best predictors of fistula response.nnnConclusionnHigh IFX trough levels during induction are associated with favorable fistula response to anti-TNF treatment. If validated in a larger prospective study, our findings may help guide anti-TNF treatment in patients with perianal CD, and suggest serum level-guided treatment escalation in non-responders or prompt changing of biologic treatment in non-responders.

Magnetic resonance enterography versus capsule endoscopy activity indices for quantification of small bowel inflammation in Crohn's disease.

Background: Video capsule endoscopy (VCE) and magnetic resonance enterography (MRE) are the prime modalities for the evaluation of small bowel (SB) Crohn’s disease (CD). Mucosal inflammation on VCE is quantified using the Lewis score (LS). Diffusion-weighted (DW) magnetic resonance imaging (MRI) allows for accurate assessment of SB inflammation without administration of intravenous contrast material. The Magnetic Resonance Index of Activity (MaRiA) and the Clermont index are quantitative activity indices validated for contrast-enhanced MRE and DW-MRE, respectively. The aim of this study was to compare the quantification of distal SB inflammation by VCE and MR-related activity indices. Methods: Patients with known quiescent SB CD were prospectively recruited and underwent MRE and VCE. LS, MaRIA and Clermont scores were calculated for the distal SB. Results: Both MRI-based indices significantly correlated with the LS and the Clermont index (r = 0.50, p = 0.001 and r = 0.53, p = 0.001, respectively). Both MaRIA and Clermont scores were significantly lower in patients with mucosal healing (LS < 135). The area under the curve (AUC) with both MR scores was moderate for prediction of any mucosal inflammation (LS ⩾ 135) and excellent for prediction of moderate-to-severe inflammation (LS ⩾ 790) (0.71 and 0.74 versus 0.93 and 0.91 for MaRIA and Clermont score, respectively). Conclusions: Modest correlation between VCE- and MRE-based quantitative indices of inflammation in patients with quiescent SB CD was observed. Between-modality correlation was higher in patients with endoscopically severe disease. DW-MRE gauged by Clermont score was at least as accurate as contrast-enhanced MRE for quantification of SB inflammation.

Association Between Fecal Calprotectin Levels and Small-bowel Inflammation Score in Capsule Endoscopy: A Multicenter Retrospective Study

BackgroundAccurate inflammation reporting in capsule endoscopy (CE) is important for diagnosis and monitoring of treatment of inflammatory bowel disease (IBD). Fecal calprotectin (FC) is a highly specific biomarker of gut inflammation. Lewis score (LS) was developed to standardize quantification of inflammation in small-bowel (SB) CE images.GoalsMulticenter retrospective study aiming to investigate correlation between LS and FC in a large group of patients undergoing CE for suspected or known small-bowel IBD, and to develop a model for prediction of CE results (LS) based on FC levels.StudyFive academic centers and a district general hospital offering CE in UK, Finland, Sweden, Canada, and Israel. In total, 333 patients were recruited. They had small-bowel CE and FC done within 3xa0months.ResultsOverall, correlation between FC and LS was weak (rs: 0.232, Pxa0<xa00.001). When two clinically significant FC thresholds (100 and 250xa0μg/g) were examined, the rs between FC and LS was 0.247 (weak) and 0.337 (moderate), respectively (Pxa0=xa00.307). For clinically significant (LSxa0≥xa0135) or negative (LSxa0<xa0135) for SB inflammation, ROC curves gave an optimum cutoff point of FC 76xa0μg/g with sensitivity 0.59 and specificity 0.41. Limitations: Retrospective design.ConclusionsLS appears to show low correlation with FC as well as other serology markers of inflammation. FC does not appear to be a reliable biomarker for significant small-bowel inflammation. Nevertheless, FC levelxa0≥xa076xa0μg/g may be associated with appreciable visual inflammation on small-bowel CE in patients with negative prior diagnostic workup.

Diffusion-weighted imaging in quiescent Crohn's disease: correlation with inflammatory biomarkers and video capsule endoscopy

AIMnTo investigate the role of restricted diffusion in quiescent Crohns disease (CD) patients and its association with inflammatory biomarkers and endoscopic disease.nnnMATERIAL AND METHODSnFifty-two quiescent CD patients prospectively underwent magnetic resonance enterography (MRE) and video capsule endoscopy (VCE) and were tested for the inflammatory biomarkers, faecal calprotectin (FCP) and C-reactive protein (CRP). Restricted diffusion in the distal ileum was qualitatively (absence/presence) and quantitatively (apparent diffusion coefficient [ADC]) assessed by two readers. The VCE-based Lewis score was calculated for the distal ileum. Restricted diffusion sensitivity and specificity for VCE ulcerations were assessed for patients with elevated (>100 μg/g) or normal (<100 μg/g) FCP. Receiver operating characteristic (ROC) curve was used to assess the ability of ADC to identify patients with concurrent VCE ulceration and elevated FCP.nnnRESULTSnThe sensitivity and specificity of restricted diffusion for patients with VCE ulceration were higher in patients with elevated FCP (reader 1: 71.4%, 80%, reader 2: 76.2%, 100%, respectively) compared to patients with normal FCP (reader 1: 46.2%, 61.5%; reader 2: 15.4%, 76.9%, respectively). The ADC had a high diagnostic accuracy for identifying patients that had concurrent VCE ulceration and elevated FCP (reader 1: AUC=0.819, reader 2: AUC=0.832).nnnCONCLUSIONnIn quiescent CD patients, the presence of restricted diffusion is suggestive of an active inflammation, associated with elevated FCP. Thus, DWI may serve as a clinical tool in the follow-up of these patients, implying subclinical inflammatory flares.

Capsule endoscopy in young patients with iron deficiency anaemia and negative bidirectional gastrointestinal endoscopy

Background Recent data imply young patients (age ≤50 years) undergoing small-bowel (SB) capsule endoscopy (CE) for iron deficiency anaemia (IDA) show higher diagnostic yield (DY) for sinister pathology. We aimed to investigate DY of CE in a large cohort of young IDA patients, and evaluate factors predicting significant SB pathology. Materials and methods This was a retrospective, multicentre study (2010–2015) in consecutive, young patients (≤50 years) from 18 centres/12 countries, with negative bidirectional gastrointestinal (GI) endoscopy undergoing SBCE for IDA. Exclusion criteria: previous/ongoing obscure-overt GI bleeding; age <19 or >50 years; comorbidities associated with IDA. Data retrieved: SBCE indications; prior investigations; medications; SBCE findings; final diagnosis. Clinical and laboratory data were analysed by multivariate logistic regression. Results Data on 389 young IDA patients were retrieved. In total, 169 (43.4%) were excluded due to incomplete clinical data; data from 220 (122F/98M; mean age 40.5u2009±u20098.6 years) patients were analysed. Some 71 patients had at least one clinically significant SBCE finding (DY: 32.3%). They were divided into two groups: neoplastic pathology (10/220; 4.5%), and non-neoplastic but clinically significant pathology (61/220; 27.7%). The most common significant but non-neoplastic pathologies were angioectasias (22/61) and Crohn’s disease (15/61). On multivariate analysis, weight loss and lower mean corpuscular volume(MCV) were associated with significant SB pathology (OR: 3.87; 95%CI: 1.3–11.3; pu2009=u20090.01; and OR: 0.96; 95%CI: 0.92–0.99; pu2009=u20090.03; respectively). Our model also demonstrates association between use of antiplatelets and significant SB pathology, although due to the small number of patients, definitive conclusions cannot be drawn. Conclusion In IDA patients ≤50 years with negative bidirectional GI endoscopy, overall DY of SBCE for clinically significant findings was 32.3%. Some 5% of our cohort was diagnosed with SB neoplasia; lower MCV or weight loss were associated with higher DY for SB pathology.

Structural bowel damage in quiescent Crohn’s disease ☆

BACKGROUNDnCrohns disease is associated with accumulation of progressive structural bowel damage (SBD) leading to the development of stenotic and penetrating complications. The data pertaining to the course of progression of SBD is scarce. The Lemann index (LI) is a novel tool for evaluation of SBD that incorporates pan-enteric clinical, endoscopic and imaging data.nnnAIMSnTo evaluate the progression of SBD in quiescent CD patients.nnnMETHODSnPatients with known quiescent small bowel Crohns disease (CD) for at least 3 months (CDAI<220) were prospectively recruited and underwent repeated magnetic resonance enterographies (MRE) and video capsule endoscopies (VCE). Patients were assessed for SBD on initial and follow-up evaluation using relevant clinicopathological data, MRE and VCE results. Significant structural bowel damage (SBD) was identified as LI>4.8, and progression of SBD as LI>0.3.nnnRESULTSnSixty one patients were enrolled in the study. Significant SBD was detected 13 (21.4%) on enrollment. Duration of disease (p=0.036) and history of CD-related surgery (p=0.0001) were associated with significant BD. Forty one patients underwent a follow-up MRE (14.8±2.5 months apart). LI was similar at baseline and follow-up. There was a negligible change in LI between the evaluations.nnnCONCLUSIONSnIn patients with quiescent Crohns disease, structural bowel damage was stable over a median of 14 months follow-up.