Casper Steenholdt1, Klaus Bendtzen2, Jørn Brynskov3, Ole Ø Thomsen3, Lars K Munck4, Lisbet A Christensen5, Gitte Pedersen6, Jens Kjeldsen7, Mark A Ainsworth3. 1. Department of Gastroenterology, Herlev Hospital, Herlev, Denmark steenholdt@brygge.dk. 2. Institute for Inflammation Research, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark. 3. Department of Gastroenterology, Herlev Hospital, Herlev, Denmark. 4. Department of Medical Gastroenterology, Køge Hospital, Køge, Denmark. 5. Department of Hepatology and Gastroenterology V, Aarhus Hospital, Aarhus, Denmark. 6. Department of Gastroenterology, Hvidovre Hospital, Hvidovre Denmark. 7. Department of Medical Gastroenterology S, Odense Hospital, Odense, Denmark.
Abstract
BACKGROUND AND AIMS: Intensification of the infliximab (IFX) regimen is recommended if the treatment effect is inadequate. However, the rationale for this is not well defined as the underlying mechanisms vary. The aim of this study was to explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes. METHODS: We performed a post hoc analysis of a randomized clinical trial including 42 Crohn's disease patients with IFX treatment failure, all treated with an intensified IFX regimen (5mg/kg every 4 week) for 12 weeks. Trough serum IFX and anti-IFX Ab concentrations were measured by a homogeneous mobility shift binding assay (HMSA) and a functional cell-based reporter gene assay (RGA) at treatment failure and the end of the trial. RESULTS: Twenty-one patients (50%) regained clinical response on the intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA, 8.8 versus 3.0 μg/mL, p = 0.035; HMSA, 9.9 versus 4.7 μg/mL, p = 0.040), and differentiated patients by clinical outcome (RGA, area under receiver operating characteristic curve [AUC] 0.75 [0.53-0.97], p = 0.035; HMSA, AUC 0.74 [0.53-0.95], p = 0.042). All responders exhibited an IFX increase ≥2.6 μg/mL (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in six patients (15%) became undetectable. CONCLUSION: Increase in IFX levels following treatment intensification was associated with improved clinical outcomes, indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification, suggesting lowered production or the formation of immune complexes.
RCT Entities:
BACKGROUND AND AIMS: Intensification of the infliximab (IFX) regimen is recommended if the treatment effect is inadequate. However, the rationale for this is not well defined as the underlying mechanisms vary. The aim of this study was to explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes. METHODS: We performed a post hoc analysis of a randomized clinical trial including 42 Crohn's diseasepatients with IFX treatment failure, all treated with an intensified IFX regimen (5mg/kg every 4 week) for 12 weeks. Trough serum IFX and anti-IFX Ab concentrations were measured by a homogeneous mobility shift binding assay (HMSA) and a functional cell-based reporter gene assay (RGA) at treatment failure and the end of the trial. RESULTS: Twenty-one patients (50%) regained clinical response on the intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA, 8.8 versus 3.0 μg/mL, p = 0.035; HMSA, 9.9 versus 4.7 μg/mL, p = 0.040), and differentiated patients by clinical outcome (RGA, area under receiver operating characteristic curve [AUC] 0.75 [0.53-0.97], p = 0.035; HMSA, AUC 0.74 [0.53-0.95], p = 0.042). All responders exhibited an IFX increase ≥2.6 μg/mL (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in six patients (15%) became undetectable. CONCLUSION: Increase in IFX levels following treatment intensification was associated with improved clinical outcomes, indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification, suggesting lowered production or the formation of immune complexes.
Authors: Konstantinos Papamichael; Adam S Cheifetz; Gil Y Melmed; Peter M Irving; Niels Vande Casteele; Patricia L Kozuch; Laura E Raffals; Leonard Baidoo; Brian Bressler; Shane M Devlin; Jennifer Jones; Gilaad G Kaplan; Miles P Sparrow; Fernando S Velayos; Thomas Ullman; Corey A Siegel Journal: Clin Gastroenterol Hepatol Date: 2019-03-27 Impact factor: 11.382
Authors: Helena Edlund; Casper Steenholdt; Mark A Ainsworth; Eva Goebgen; Jørn Brynskov; Ole Ø Thomsen; Wilhelm Huisinga; Charlotte Kloft Journal: AAPS J Date: 2016-10-13 Impact factor: 4.009
Authors: Casper Steenholdt; Jørn Brynskov; Ole Ø Thomsen; Lars K Munck; Jan Fallingborg; Lisbet A Christensen; Gitte Pedersen; Jens Kjeldsen; Bent A Jacobsen; Anne Sophie Oxholm; Jakob Kjellberg; Klaus Bendtzen; Mark A Ainsworth Journal: Dig Dis Sci Date: 2015-02-12 Impact factor: 3.199
Authors: Casper Steenholdt; Mehmet Coskun; Sine Buhl; Klaus Bendtzen; Mark A Ainsworth; Jørn Brynskov; Ole H Nielsen Journal: Medicine (Baltimore) Date: 2016-04 Impact factor: 1.889
Authors: Thomas Langford; Zehra Arkir; Anastasia Chalkidou; Kate Goddard; Lamprini Kaftantzi; Mark Samaan; Peter Irving Journal: JMIR Res Protoc Date: 2018-10-19