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

doi:10.1007/s10620-018-5020-9

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^*

^*Corresponding author for this work

Department of Clinical Medicine

4 Citations (Scopus)

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 (r_P = − 0.17, p = 0.45; r_S = − 0.38, p = 0.08), or 6-MeMP and ADL (r_P = − 0.23, p = 0.31; r_S = − 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.

Original language	English
Journal	Digestive Diseases and Sciences
Volume	63
Issue number	6
Pages (from-to)	1583-1591
Number of pages	9
ISSN	0163-2116
DOIs	https://doi.org/10.1007/s10620-018-5020-9
Publication status	Published - 2018

Keywords

Adalimumab
Inflammatory bowel disease
Interactions
Personalized therapy
Therapeutic drug monitoring
Thiopurine

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10.1007/s10620-018-5020-9

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Holmstrøm, R. B., Mogensen, D. V., Brynskov, J., Ainsworth, M. A., Nersting, J., Schmiegelow, K., & Steenholdt, C. (2018). Interactions Between Thiopurine Metabolites, Adalimumab, and Antibodies Against Adalimumab in Previously Infliximab-Treated Patients with Inflammatory Bowel Disease. Digestive Diseases and Sciences, 63(6), 1583-1591. https://doi.org/10.1007/s10620-018-5020-9

Interactions Between Thiopurine Metabolites, Adalimumab, and Antibodies Against Adalimumab in Previously Infliximab-Treated Patients with Inflammatory Bowel Disease. / Holmstrøm, Rikke B.; Mogensen, Ditte V.; Brynskov, Jørn et al.

In: Digestive Diseases and Sciences, Vol. 63, No. 6, 2018, p. 1583-1591.

Research output: Contribution to journal › Journal article › Research › peer-review

Holmstrøm, RB, Mogensen, DV, Brynskov, J, Ainsworth, MA, Nersting, J, Schmiegelow, K & Steenholdt, C 2018, 'Interactions Between Thiopurine Metabolites, Adalimumab, and Antibodies Against Adalimumab in Previously Infliximab-Treated Patients with Inflammatory Bowel Disease', Digestive Diseases and Sciences, vol. 63, no. 6, pp. 1583-1591. https://doi.org/10.1007/s10620-018-5020-9

@article{02b3404c346b41ccb859741773e5a11a,

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

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, Inflammatory bowel disease, Interactions, Personalized therapy, Therapeutic drug monitoring, Thiopurine",

author = "Holmstr{\o}m, {Rikke B.} and Mogensen, {Ditte V.} and J{\o}rn Brynskov and Ainsworth, {Mark A.} and Jacob Nersting and Kjeld Schmiegelow and Casper Steenholdt",

year = "2018",

doi = "10.1007/s10620-018-5020-9",

language = "English",

volume = "63",

pages = "1583--1591",

journal = "Digestive Diseases and Sciences",

issn = "0163-2116",

publisher = "Springer",

number = "6",

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TY - JOUR

T1 - Interactions Between Thiopurine Metabolites, Adalimumab, and Antibodies Against Adalimumab in Previously Infliximab-Treated Patients with Inflammatory Bowel Disease

AU - Holmstrøm, Rikke B.

AU - Mogensen, Ditte V.

AU - Brynskov, Jørn

AU - Ainsworth, Mark A.

AU - Nersting, Jacob

AU - Schmiegelow, Kjeld

AU - Steenholdt, Casper

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Adalimumab

KW - Inflammatory bowel disease

KW - Interactions

KW - Personalized therapy

KW - Therapeutic drug monitoring

KW - Thiopurine

U2 - 10.1007/s10620-018-5020-9

DO - 10.1007/s10620-018-5020-9

M3 - Journal article

C2 - 29564674

AN - SCOPUS:85044198535

SN - 0163-2116

VL - 63

SP - 1583

EP - 1591

JO - Digestive Diseases and Sciences

JF - Digestive Diseases and Sciences

IS - 6

ER -

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

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Keywords

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