Journal Article

Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial

Del Tedesco, Emilie, Williet, Nicolas, Flourie, Bernard, Roblin, Xavier, Nancey, Stéphane, Vedrines, Philippe, Boschetti, Gilles, Phelip, Jean-Marc, Berger, Anne-Emmanuelle, Peyrin-Biroulet, Laurent, Paul, Stephane, Duru, Gerard

2020

Overview

ObjectivesIn patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumour necrosis factor (anti-TNF), algorithms recommend a switch of anti-TNF without immunosuppressive drug. The aim of our study was to compare in these patients two strategies: either switch to a second anti-TNF alone or with addition of azathioprine (AZA). After randomisation outcomes (time to clinical and pharmacokinetic failure) were compared between the two groups during a 2-year follow-up period.DesignConsecutive IBD patients in immune-mediated LOR to a first optimised anti-TNF given in monotherapy were randomised to receive either AZA or nothing with induction by a second anti-TNF in both arms. Clinical failure was defined for Crohn’s disease (CD) as a Harvey-Bradshaw index ≥5 associated with a faecal calprotectin level >250 µg/g stool and for UC as a Mayo score >5 with endoscopic subscore >1 or as the occurrence of adverse events requiring to stop treatment. Unfavourable pharmacokinetics of the second anti-TNF were defined by the appearance of undetectable trough levels of anti-TNF with high antibodies (drug-sensitive assay) or by that of antibodies (drug-tolerant assay).ResultsNinety patients (48 CDs) were included, and 45 of them received AZA after randomisation. The second anti-TNF was adalimumab or infliximab in 40 and 50 patients, respectively. Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy (p<0.001; median time of clinical failure since randomisation 18 vs >24 months). At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22 versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy. Only the use of combination therapy was associated with favourable outcomes after anti-TNF switch.ConclusionIn case of immune-mediated LOR to a first anti-TNF, AZA should be associated with the second anti-TNF.Trial registration number03580876.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adalimumab - administration & dosage / Adalimumab - therapeutic use / Adult / Algorithms / Anti-Inflammatory Agents - administration & dosage / Anti-Inflammatory Agents - therapeutic use / Antibodies / Azathioprine / Azathioprine - administration & dosage / Azathioprine - therapeutic use / Clinical medicine / Crohn Disease - drug therapy / Crohn's disease / Drug dosages / Drug Therapy, Combination / Endoscopy / Female / Human health and pathology / Humans / IBD / Immunology / Immunomodulators / Immunosuppressive agents / Immunosuppressive Agents - administration & dosage / Immunosuppressive Agents - therapeutic use / Infectious diseases / Inflammatory bowel disease / Inflammatory Bowel Diseases - drug therapy / Inflammatory Bowel Diseases - immunology / Infliximab / Infliximab - administration & dosage / Infliximab - therapeutic use / Life Sciences / Male / Microbiology and Parasitology / Monoclonal antibodies / Patients / Pharmaceutical sciences / Pharmacokinetics / Pharmacology / Recurrence / Statistical analysis / TNF / Treatment Outcome / Tumor Necrosis Factor-alpha - antagonists & inhibitors / Tumor Necrosis Factor-alpha - immunology / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Vaccinology / Virology