Objectives In 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.
Design Consecutive 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).
Results Ninety 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.
Conclusion In case of immune-mediated LOR to a first anti-TNF, AZA should be associated with the second anti-TNF.
Trial registration number 03580876.
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Contributors XR, SP, GD, EDT, PV, A-EB, GB, SN and BF performed the research; XR, SP, LP-B, EDT and BF designed the research study. SP, GD and NW analysed the data. XR, GB, SN, LP-B, J-MP, SP and BF wrote the paper. All authors approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests XR was speaker for MSD, Abbvie and Takeda and participated in an advisory board member for MSD, Takeda, Janssen and Pfizer. SP was speaker for Theradiag and MSD. EDT was speaker for Ferring, MSD and Abbvie. GB, Berger, Phelip, Vedrines and Duru. LP-B received Honoraria from Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, HAC-Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera and Samsung Bioepis. SN was speaker for MSD, Hospira and HAC Pharma and participated in an advisory board member for Hospira. BF was speaker for Hospira, Abbvie and MSD.
Patient consent for publication Not required.
Ethics approval This study was approved by the Ethics Committee Board of Montbrison Hospital and the Centre National Informatique et Liberté (number: 1849323).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.