Interactions Between Thiopurine Metabolites, Adalimumab, and Antibodies Against Adalimumab in Previously Infliximab-Treated Patients with Inflammatory Bowel Disease

  • Rikke B. Holmstrøm
  • Ditte V. Mogensen
  • Jørn Brynskov
  • Mark A. Ainsworth
  • Jacob Nersting
  • Kjeld Schmiegelow
  • Casper Steenholdt
Original Article
  • 86 Downloads

Abstract

Background

Interactions between thiopurines and infliximab presumably contribute to superior effect of infliximab–thiopurine combination therapy in patients with inflammatory bowel disease (IBD). We examined whether principal cytotoxic thiopurine metabolites influence adalimumab (ADL) and anti-ADL antibodies (Abs).

Methods

Ninety-eight IBD patients previously treated with infliximab (96%) in whom trough ADL and anti-ADL Abs had been assessed as part of their clinical care were included. Thiopurine metabolites [6-thioguanine nucleotides (6-TGN) and methylated mercaptopurine metabolites (6-MeMP)] were determined at similar time points.

Results

ADL–thiopurine combination therapy was not associated with reduced anti-ADL Ab positivity compared to ADL monotherapy: 8/31 (26%) versus 19/67 (28%), p = 1.00. Concentrations of thiopurine metabolites were similar in anti-ADL Ab-positive and negative patients (6-TGN median 109 pmol/8 × 108 RBC vs. 112, p = 0.80; 6-MeMP 448 RBC vs. 720, p = 0.94). ADL trough levels did not differ between anti-ADL Ab-negative patients on ADL–thiopurine combination therapy and those on monotherapy (9.5 μg/mL vs. 7.6, p = 0.31). ADL levels were also comparable between patients on ADL mono- and combination therapy after stratification for 6-TGN/6-MeMP quartiles. There were no correlations between levels of 6-TGN and ADL (rP = − 0.17, p = 0.45; rS = − 0.38, p = 0.08), or 6-MeMP and ADL (rP = − 0.23, p = 0.31; rS = − 0.35, p = 0.11). Anti-ADL Ab positivity was associated with ADL treatment failure (OR 6 [2–20], p < 0.01). Higher trough ADL (9.6 μg/mL vs. 7.3, p < 0.05), but not concomitant thiopurine treatment, metabolite levels, or dosage, was associated with clinical remission.

Conclusion

Effectiveness of ADL therapy associated with circulating ADL levels and anti-ADL Ab formation. In this study, there appeared no direct interactions between thiopurine metabolites and ADL or anti-ADL Abs.

Keywords

Adalimumab Thiopurine Personalized therapy Therapeutic drug monitoring Interactions Inflammatory bowel disease 

Notes

Acknowledgments

This study was kindly supported by grants from Danish Colitis and Crohn’s Disease Society and Direktør Jacob Madsen og hustru Olga Madsens Fond.

Author’s contribution

CS was involved in study design; RH, DM, and CS collected the data; RH and CS analyzed the data; all authors interpreted the data; RH and CS drafted the manuscript; and all authors were involved in manuscript revision and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

Within the last 2 years: C Steenholdt has no interests to declare. J Brynskov has served as advisory board member for Abbvie, Janssen, and Takeda; and as primary investigator for Abbvie and Janssen. RB Holmstrøm, DV Mogensen, MA Ainsworth, J Nersting, and K Schmiegelow have no interests to declare.

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Copyright information

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

Authors and Affiliations

  1. 1.Department of GastroenterologyCopenhagen University Hospital HerlevHerlevDenmark
  2. 2.Pediatric Oncology Research Laboratory, RigshospitaletUniversity Hospital of CopenhagenCopenhagenDenmark

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