Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay

Lea C. Berkhout, Merel J. l'Ami, Jill Ruwaard, Margreet H. Hart, Pleuni Ooijevaar-de Heer, Karien Bloem, Michael T. Nurmohamed, Ronald F. van Vollenhoven, Maarten Boers, Daniel F. Alvarez, Catherine H. Smith, Gerrit J. Wolbink, Theo Rispens

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a “drug-tolerant” assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of >50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.
Original languageEnglish
Article numberaat3356
JournalScience Translational Medicine
Volume11
Issue number477
DOIs
Publication statusPublished - 2019

Cite this

Berkhout, Lea C. ; l'Ami, Merel J. ; Ruwaard, Jill ; Hart, Margreet H. ; Ooijevaar-de Heer, Pleuni ; Bloem, Karien ; Nurmohamed, Michael T. ; van Vollenhoven, Ronald F. ; Boers, Maarten ; Alvarez, Daniel F. ; Smith, Catherine H. ; Wolbink, Gerrit J. ; Rispens, Theo. / Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay. In: Science Translational Medicine. 2019 ; Vol. 11, No. 477.
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title = "Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay",
abstract = "Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a “drug-tolerant” assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of >50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.",
author = "Berkhout, {Lea C.} and l'Ami, {Merel J.} and Jill Ruwaard and Hart, {Margreet H.} and {Ooijevaar-de Heer}, Pleuni and Karien Bloem and Nurmohamed, {Michael T.} and {van Vollenhoven}, {Ronald F.} and Maarten Boers and Alvarez, {Daniel F.} and Smith, {Catherine H.} and Wolbink, {Gerrit J.} and Theo Rispens",
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Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay. / Berkhout, Lea C.; l'Ami, Merel J.; Ruwaard, Jill; Hart, Margreet H.; Ooijevaar-de Heer, Pleuni; Bloem, Karien; Nurmohamed, Michael T.; van Vollenhoven, Ronald F.; Boers, Maarten; Alvarez, Daniel F.; Smith, Catherine H.; Wolbink, Gerrit J.; Rispens, Theo.

In: Science Translational Medicine, Vol. 11, No. 477, aat3356, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay

AU - Berkhout, Lea C.

AU - l'Ami, Merel J.

AU - Ruwaard, Jill

AU - Hart, Margreet H.

AU - Ooijevaar-de Heer, Pleuni

AU - Bloem, Karien

AU - Nurmohamed, Michael T.

AU - van Vollenhoven, Ronald F.

AU - Boers, Maarten

AU - Alvarez, Daniel F.

AU - Smith, Catherine H.

AU - Wolbink, Gerrit J.

AU - Rispens, Theo

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AB - Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a “drug-tolerant” assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of >50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.

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