Higher Mucosal Healing with Tumor Necrosis Factor Inhibitors in Combination with Thiopurines Compared to Methotrexate in Crohn’s Disease

  • Abhinav Vasudevan
  • Ajay Raghunath
  • Shane Anthony
  • Cian Scanlon
  • Miles P. Sparrow
  • Peter R. Gibson
  • Daniel R. van Langenberg
Original Article



The differential impact of anti-tumor necrosis factor (anti-TNF) therapy with methotrexate versus thiopurine co-therapy on endoscopic remission remains uncertain.


To compare rates of endoscopic remission based on methotrexate or thiopurine co-therapy used with anti-TNF therapy in Crohn’s disease.


A retrospective observational study at two tertiary centers between 2010 and 2016 compared endoscopic remission rates and persistence on anti-TNF therapy in combination with methotrexate versus thiopurines for at least 3 months.


Of 412 patients on anti-TNF therapy, 278 (67%) received immunomodulator co-therapy for ≥ 3 months and 269 (65%) had complete data for analysis. Methotrexate was used in 77 (29%) and thiopurines in 192 (71%) patients plus either infliximab (156, 58%) or adalimumab (113, 42%), with median follow-up of 2.8 years. The methotrexate group had greater prior immunomodulator intolerance (62% vs 20%, p < 0.01). Endoscopic remission rates were higher in those treated with thiopurine compared to methotrexate co-therapy at 12 m (58% vs 17%, p < 0.01) and at last review (59% vs 40%, p = 0.03). Endoscopic remission rates were higher with thiopurines than methotrexate when combined with adalimumab (49% vs 6%, p < 0.01) but not with infliximab (65% vs 54%, p = 0.09). In multivariate analysis, thiopurine co-therapy, elevated baseline CRP, and therapeutic anti-TNF drug levels were each associated with longer persistence of co-therapy (each p < 0.05). There were no significant differences in adverse events, malignancy or infection rates.


In this cohort, anti-TNF and thiopurine co-therapy resulted in higher rates of mucosal healing than methotrexate, the difference is most pronounced with adalimumab and conversely with low-dose methotrexate.


Infliximab Adalimumab Azathioprine Mercaptopurine Endoscopy 


Compliance with ethical standards

Conflict of interest

AV receives financial support through an Australian Government Research Training Program Scholarship. He has received financial support to attend educational conferences from Ferring, Shire, Norgine and Takeda. MPS has received educational grants or research support from Ferring and Orphan. He has received speaker’s fees from Janssen, Abbvie, Ferring, Takeda and Hospira. He has served on advisory boards for Janssen, Takeda, Pfizer, Celgene, Abbvie and MSD. PRG has served as consultant or advisory board member for AbbVie, Ferring, Janssen, Merck, Nestle Health Science, Danone, Allergan, Pfizer, Celgene and Takeda. His institution has received speaking honoraria from AbbVie, Janssen, Ferring, Takeda, Fresenius Kabi, Mylan and Pfizer. He has received research grants for investigator-driven studies from AbbVie, Janssen, Falk Pharma, Danone and A2 Milk Company. His Department financially benefits from the sales of a digital application and booklets on the low FODMAP diet. He has published an educational/recipe book on diet. DvL has served as a speaker and/or received travel support from Takeda, Ferring and Shire. He has consultancy agreements with Abbvie, Janssen and Pfizer. He received research funding grants for investigator-driven studies from Ferring, Shire and AbbVie. For the remaining authors, none were declared.

Ethics approval

The study was approved by the hospital ethics committee at each center and has therefore been performed in accordance with the ethical standards laid down in the 1975 Declaration of Helsinki and its later amendments.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Gastroenterology and Hepatology, Eastern HealthBox Hill HospitalBox HillAustralia
  2. 2.Eastern Health Clinical SchoolMonash UniversityBox HillAustralia
  3. 3.Department of Gastroenterology, Alfred HealthMonash UniversityMelbourneAustralia

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