B. Ungar

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.

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.

Early drug and anti‐infliximab antibody levels for prediction of primary nonresponse to infliximab therapy

Primary nonresponse, defined as lack of clinical benefit during the induction phase, occurs in up to 30% of IBD patients treated with infliximab. The mechanisms underlying primary nonresponse have not yet been clearly defined.

DOP062 Predictors of formation of antibodies to infliximab (ATI) and secondary loss of response in IBD patients treated with infliximab

DOP062 Predictors of formation of antibodies to infliximab (ATI) and secondary loss of response in IBD patients treated with infliximab B. Ungar1 *, U. Kopylov1, M. Yavzori1, E. Fudim1, O. Picard1, A. Lahat1, B. Avidan1, A. Lang1, B. Weiss2, Y. Chowers3, R. Eliakim1, S. Ben-Horin1. 1Chaim Sheba Medical Center, Gastroenterology, Ramat Gan, Israel, 2Chaim Sheba Medical Center Tel-Hashomer, Edmond & Lily Safra Children’s Hospita, Ramat Gan, Israel, 3Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Gastroenterology department, Haifa, Israel

Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and Drug Concentrations: The Poetic Study

OBJECTIVES: Adalimumab is usually self‐injected at home, making prospective serial‐sampling studies challenging and scarce. This has led to a gap in knowledge about evolution of anti‐adalimumab antibodies (AAAs) over time and its correlation with clinical and inflammatory outcomes. METHODS: A program for home visits by physicians at induction, every 3 months and at event of relapse, was established prospectively for Crohns disease (CD) patients. At each visit, patients’ clinical scores were determined and sera were obtained for C‐reactive protein, drug, and AAA levels. This cohort was compared to a parallel prospective cohort of infliximab‐treated CD patients. In a subgroup of 29 patients, trough and in‐between‐trough levels were compared, to elucidate the importance of timing of sampling during the injection cycle. RESULTS: Ninety‐eight CD patients starting adalimumab were prospectively followed (median follow‐up 44 weeks) and 621 serum samples were analyzed. Thirty‐three patients (32%) developed AAA; 18/33 (55%) of them as early as week 2, and 26/33 (79%) by week 14. Induction period AAAs were strongly associated with primary non‐response (odds ratio (OR) = 5.4, 95% confidence interval (CI): 1.6–17.8, p = 0.005). As compared to antibodies‐to‐infliximab (ATI), AAA formation rate over time was significantly lower (p = 0.01) and AAA were much more specific—85% of AAA events were associated with loss‐of‐response compared with 58% rate for ATI (p = 0.01). In 29 patients sampled serially during an injection cycle, levels of drug and AAA seemed comparable between four time‐points during a single cycle both in patients with or without AAA (n = 8, n = 21, respectively). CONCLUSIONS: When followed prospectively and serially, AAAs are found to arise earlier than previously appreciated and their impact may be more pronounced for primary rather than secondary, non‐response. Drug and AAA levels were similar both at trough and in‐between injections, enabling to simplify therapeutic drug monitoring of adalimumab.

Diffusion-weighted magnetic resonance enterography for prediction of response to tumor necrosis factor inhibitors in stricturing Crohn’s disease

Background and aimsDistinguishing between fibrotic and inflammatory strictures in Crohn’s disease (CD) is still challenging. The capacity of diffusion-weighted (DWI) magnetic resonance (MRE) to identify intestinal fibrosis was recently demonstrated; however, the therapeutic implications of this association have never been evaluated. The aim of the current study was to identify imaging features, including DWI, which can predict response to anti-inflammatory treatment in patients with stricturing CD.MethodsConsecutive CD patients with intestinal strictures that initiated treatment with anti-tumor necrosis alpha (anti-TNF) between June 2012 and April 2017 with MRE adjacent to treatment onset were retrospectively collected. The primary outcome was treatment failure, defined as drug discontinuation, CD-related surgery, or endoscopic dilatation of the stricture. Clinical, demographic, and imaging data were compared between patients who did and did not develop treatment failure within 12 months of anti-TNF treatment initiation.ResultsA total of 21 patients were included in the study; 9/21 (42.8%) developed treatment failure. None of the clinical/demographic parameters were associated with the risk of treatment failure. Among imaging parameters, only ADC value (<u20091u2009×u200910−3xa0mm2/s) was significantly associated with the risk of treatment failure (AUCu2009=u20090.81, 66% vs. 0%, pu2009=u20090.015).ConclusionsOur results suggest that ADC value on DWI MRE may predict the risk of treatment failure in stricturing CD. If replicated in larger studies, these results may guide therapeutic decisions and suggest avoiding anti-TNF treatment.

P122 The clinical and immunological significance of low level of infliximab in the absence of anti-infliximab antibodies in patients with IBD

P122 The clinical and immunological significance of low level of infliximab in the absence of anti-infliximab antibodies in patients with IBD B. Ungar1 *, A. Anafy1, M. Yavzori1, O. Picard1, E. Fudim1, U. Kopylov1, Y. Ron2, H. Yanai2, I. Dotan2, Y. Chowers3, R. Eliakim1, S. Ben-Horin1. 1Chaim Sheba Medical Center, Gastroenterology, Ramat Gan, Israel, 2Tel Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv, Israel, 3Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Gastroenterology department, Haifa, Israel