Yulia Ron

Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response

Background: Intensifying infliximab therapy is often practiced in Crohns disease (CD) patients losing response to the drug but there are no data if halving the interval is superior to doubling the dose. We aimed to assess the efficacy of infliximab dose intensification by interval‐halving compared with dose‐doubling. Methods: A multicenter retrospective study of CD patients losing response to infliximab was undertaken. The clinical outcome of patients whose infusion intervals were halved (5 mg/kg/4 weeks) was compared with patients treated by dose‐doubling (10 mg/kg/8 weeks). Results: In all, 168 patients were included from 18 centers in Europe, USA, and Israel. Of these, 112 were intensified by dose‐doubling and 56 received interval‐halving strategy. Early response to dose‐escalation was experienced by 86/112 (77%) patients in the dose‐doubling group compared with 37/56 patients (66%) in the interval‐halving group (odds ratio [OR] 1.7, 95% confidence interval [CI] 0.8–3.4, P = 0.14). Sustained clinical response at 12 months postescalation was maintained in 50% of patients in the dose‐doubling group compared with 39% in the interval‐halving group (OR 1.5, 95% CI 0.8–2.9, P = 0.2). On multivariate analysis, predictors of long‐term response to escalation were a nonsmoking status, CD diagnosis between 16–40 years of age, and normal C‐reactive protein (CRP). Conclusions: Dose intensification leads to a sustained regained response in 47% of CD patients who lost response to standard infliximab dose, but halving the infusion intervals is probably not superior to dose‐doubling. Given the costs and patient inconvenience incurred by an additional infusion visit, the dose‐doubling strategy may be preferable to the interval‐halving strategy. (Inflamm Bowel Dis 2012;)

The decline of anti-drug antibody titres after discontinuation of anti-TNFs: implications for predicting re-induction outcome in IBD

Anti‐drug antibodies can be elicited by infliximab and adalimumab, but the rate of their decay after therapy is stopped is unknown.

Infliximab-Related Infusion Reactions: Systematic Review

Objective: Administration of infliximab is associated with a well-recognised risk of infusion reactions. Lack of a mechanism-based rationale for their prevention, and absence of adequate and well-controlled studies, has led to the use of diverse empirical administration protocols. The aim of this study is to perform a systematic review of the evidence behind the strategies for preventing infusion reactions to infliximab, and for controlling the reactions once they occur. Methods: We conducted extensive search of electronic databases of MEDLINE [PubMed] for reports that communicate various aspects of infusion reactions to infliximab in IBD patients. Results: We examined full texts of 105 potentially eligible articles. No randomised controlled trials that pre-defined infusion reaction as a primary outcome were found. Three RCTs evaluated infusion reactions as a secondary outcome; another four RCTs included infusion reactions in the safety evaluation analysis; and 62 additional studies focused on various aspects of mechanism/s, risk, primary and secondary preventive measures, and management algorithms. Seven studies were added by a manual search of reference lists of the relevant articles. A total of 76 original studies were included in quantitative analysis of the existing strategies. Conclusions: There is still paucity of systematic and controlled data on the risk, prevention, and management of infusion reactions to infliximab. We present working algorithms based on systematic and extensive review of the available data. More randomised controlled trials are needed in order to investigate the efficacy of the proposed preventive and management algorithms.

Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis.

Infliximab is effective as salvage therapy for patients with steroid refractory acute severe ulcerative colitis (UC). Although current data suggest that the pharmacokinetics of infliximab are influenced by inflammatory burden in patients with acute severe UC, data comparing infliximab trough levels in patients with acute severe UC vs. moderately severe UC are scarce.

Significance of low level infliximab in the absence of anti-infliximab antibodies.

AIM To evaluate the prevalence of double negative (DN) sera and the mechanisms responsible for DN status. METHODS Sera of inflammatory bowel disease patients treated with infliximab (IFX) were tested for drug/antibodies to infliximab (ATI) trough levels and the proportion of DN results was compared between a commercially available double antigen ELISA (with labeled IFX as the detection antibody) and an anti-lambda ELISA (with anti-human lambda chain detection antibody). Repeat testing with lower than customary serum dilution (1:10) was performed. Patients with DN status were matched with IFX+/ATI- controls and were followed-up for subsequent development of non-transient ATI to investigate if DN status precedes ATI. RESULTS Of 67 sera obtained at time of loss of response, only 6/67 (9%) were DN by anti-lambda ELISA compared to 27/67 (40%) with double antigen ELISA (P < 0.001, Fishers Exact test). Of the latter 27 sera, 22% were also DN by anti-lambda ELISA, whereas 44% were actually IFX positive (IFX+ATI-), 30% were ATI positive (IFX-ATI+) and 4% were double positive (IFX+ATI+). Re-testing using a 1:10 dilution converted most DN results into IFX+ and /or ATI+ status. Patients with DN status had shorter survival free of non-transient ATI compared with matched controls (log rank test, P < 0.001). In 9/30 (30%) of these patients, non transient ATI occurred before and after the event at which the DN serum was obtained, supporting the view that a DN result may represent a particular time-point along the two curves of ATI titer rise and infliximab drug level decline. CONCLUSION DN status may result from false negative detection of IFX or ATI by double antigen ELISA, suggesting a transitional state of low-level immunogenicity, rather than non-immunological clearance.

Adolescent transition clinic in inflammatory bowel disease: quantitative assessment of self-efficacy skills

Objectives There is no model for the process of transition of adolescents with inflammatory bowel diseases (IBD) to the adult care protocol. We recently established a transition clinic where 17-year-old to 18-year-old IBD patients are seen by a multidisciplinary team including pediatric and adult gastroenterologists with expertise in IBD treatments, an IBD nurse, and a psychologist. We quantitatively describe this model and its benefits, and correlate demographic and transition parameters to self-efficacy in IBD adolescent patients before and after transition. Patients and methods All adolescent IBD patients enrolled in our transition clinic between January 2013 and December 2015 were included. They completed a self-efficacy questionnaire (‘IBD-yourself’) before and after the transition. The scores were correlated to demographic, disease, and transition parameters. Results Thirty of the 36 enrolled patients (mean age: 19±1.8 years, range: 17–27) had Crohn’s disease. Twenty-seven patients completed the transition protocol, which included an average of 3–4 meetings (range: 2–8) over 6.9±3.5 months. Self-efficacy scores in all domains of the questionnaire were significantly higher after completion of the transition. The weighted average score of the questionnaire’s domains was 1.85±0.3 before and 1.41±0.21 after transition (P<0.0001). Age, sex, disease duration, duration of transition, and the number of meetings in the clinic correlated with the questionnaire’s scores in the domains of coping with IBD, knowledge of the transition process, and medication use. Conclusion A well-planned adolescent IBD transition clinic contributes significantly toward improved self-efficacy in IBD. We recommend its implementation in IBD centers to enable a personalized transition program tailored to the needs of adolescents with IBD in specific domains.

Comparative Study of Two Cohorts of Newly Diagnosed Crohn's Disease Demonstrates Change in Therapeutic Strategies

Background: There has been a paradigm shift in the treatment of Crohns disease (CD) involving the rapid introduction of biologics and/or immunomodulators after diagnosis. We wished to assess whether this was applied to patients with newly diagnosed CD in a tertiary inflammatory bowel disease referral centre in Israel. Methods: Newly diagnosed CD patients were stratified into 2 groups: the early group was diagnosed between 2005 and 2007 and the late group was diagnosed between 2010 and 2012. Baseline demographics, medical and surgical treatments, disease course and complications during those 2 periods were analyzed. Results: Each group included 60 patients. Significantly higher rates of immunomodulators and biologics were administered to patients in the late group compared to the early group (81.7 and 36.7% compared to 56.7 and 18.3%, p = 0.004 and p = 0.021, respectively). On the other hand, steroid therapy was less prevalent in the late (36.7%) group compared to that of the early group (56.7%), p = 0.059. Medical and surgical CD outcomes, including exacerbations/hospitalizations and surgeries, were comparable for both groups. Conclusions: There was a change in treatment strategy between 2005-2007 and 2010-2012, as reflected in higher proportions of biologics/immunomodulators for patients with newly diagnosed CD. This was associated with a steroid-sparing effect.

Su1121 Anti-TNF and Anti-Drug Antibodies Levels Predict the Outcomes of Interventions After Loss of Response to Adalimumab and Infliximab

Background: Anti-TNFalpha agents are commonly used for ulcerative colitis (UC) therapy in the event of non-response to conventional strategies or as colon-salvaging therapy. The objectives were to assess the appropriateness of biological therapies for UC patients and to study treatment discontinuation over time, according to appropriateness of treatment, as a measure of outcome. Methods: We selected adult ulcerative colitis patients from the Swiss IBD cohort who had been treated with anti-TNFalpha agents. Appropriateness of the firstline anti-TNFalpha treatment was assessed using detailed criteria developed during the European Panel on the Appropriateness of Therapy for UC. Treatment discontinuation as an outcome was assessed for categories of appropriateness. Results: Appropriateness of the first-line biological treatment was determined in 186 UC patients. For 64% of them, this treatment was considered appropriate. During follow-up, 37% of all patients discontinued biological treatment, 17% specifically because of failure. Time-to-failure of treatment was significantly different among patients on an appropriate biological treatment compared to those for whom the treatment was considered not appropriate (p=0.0007). Discontinuation rate after 2 years was 26% compared to 54% between those two groups. Patients on inappropriate biological treatment were more likely to have severe disease, concomitant steroids and/or immunomodulators. They were also consistently more likely to suffer a failure of efficacy and to stop therapy during follow-up. Conclusion: Appropriateness of first-line anti-TNFalpha therapy results in a greater likelihood of continuing with the therapy. In situations where biological treatment is uncertain or inappropriate, physicians should consider other options instead of prescribing anti-TNFalpha agents.

Effectiveness and Safety of Vedolizumab in Anti-TNF-Naïve Patients With Inflammatory Bowel Disease—A Multicenter Retrospective European Study

Background Vedolizumab (VDZ) is effective for treatment of ulcerative colitis (UC) and Crohns disease (CD). In GEMINI trials, anti-tumor necrosis factor (anti-TNF)-naïve patients had a superior response compared with anti-TNF-exposed patients. In real-world experience (RWE), the number of included anti-TNF-naïve patients was low. We aimed to evaluate the effectiveness and safety of VDZ in anti-TNF-naïve patients in an RWE setting. Methods This retrospective multicenter European pooled cohort study included consecutive active anti-TNF-naïve IBD patients treated with VDZ. The primary end point was clinical response at week 14. Patients with follow-up beyond week 14 and those discontinuing VDZ at any time were included for maintenance outcomes analysis. Results Since January 2015, 184 anti-TNF-naïve patients from 23 centers initiated VDZ treatment (Crohns disease [CD], 50; ulcerative colitis [UC], 134). In CD, 42/50 (82%) patients responded by week 14 and 32 (64%) were in clinical remission; 26/50 (52%) achieved corticosteroid-free remission (CSFR). At last follow-up (44 weeks; interquartile range [IQR], 30-52 weeks), 27/35 (77.1%) patients with available data responded to treatment; 24/35 (68.6%) were in clinical remission, 21/35 (60%) were in CSFR. For UC, 116/134 (79.1%) responded to treatment by week 14, including 53 (39.5%) in clinical remission; 49/134 (36.6%) achieved CSFR. At last follow-up (42.5 weeks; IQR, 30-52 weeks), 79/103 (76.7%) patients responded to treatment, 69/103 (67.0%) were in remission, and 61/103 (59.2%) were in CSFR. Adverse effects were reported in 20 (11%) of the patients, leading to treatment discontinuation in 6 (3.3%). Conclusions VDZ is similarly effective in ant-TNF-naïve CD and UC patients. The efficacy is higher than reported in anti-TNF-experienced patients and is comparable to that of anti-TNF biologics in this population.

Evaluation of a new pan-enteric video capsule endoscopy system in patients with suspected or established inflammatory bowel disease – feasibility study

Background and study aims  Inflammatory bowel disease (IBD) affects the small bowel and colon. Endoscopic evaluation of these organs is essential. The new pan-enteric Crohn’s capsule (PCC) system is customized for complete coverage of IBD lesions in the entire bowel, allowing assessment and follow-up of disease severity and extent. The aim of this study was to evaluate the functionality of the PCC system in patients with suspected or established IBD. Patients and methods  This was a prospective five-center feasibility study assessing the performance of PCC. Subjects ingested PCC after patency assurance with standard bowel preparation plus boosts. The primary endpoint was successful procedure, that is, video creation and report generation in accordance with methodology. Secondary endpoints were subjective coverage of the entire bowel, duration of reading time, video quality and occurrence of adverse events. Results  Forty-one patients were included in the study with a mean age of 40.8 years ± 15.5, 46 % of whom were males. Seventy-one percent of patients had established Crohn’s disease (CD) and 53 % had active disease. Cleansing was graded good/excellent in 95 %. All 41 videos met the primary endpoint. There was no retention, 83 % reached the toilet while still recording. Thirty-one percent of patients with CD had proximal disease. Bowel coverage was graded 6.7 ± 0.6 and 6.1 ± 1.3 (1 – 7, unconfident – confident), image quality 6.1 ± 0.8 (1 – 7, poor – excellent), and reading time 3.7 ± 1.4 (1 – 7, very short to very long). Conclusions  The PCC system is a minimally invasive system allowing extensive evaluation of the entire bowel in patients with IBD.