Time Course and Clinical Implications of Development of Antibodies Against Adalimumab in Patients With Inflammatory Bowel Disease

Casper Steenholdt; Madeline Therese Frederiksen; Klaus Bendtzen; Mark A Ainsworth; Ole Østergaard Thomsen; Jørn Brynskov

doi:10.1097/MCG.0000000000000375

Time Course and Clinical Implications of Development of Antibodies Against Adalimumab in Patients With Inflammatory Bowel Disease

Casper Steenholdt, Madeline Therese Frederiksen, Klaus Bendtzen, Mark A Ainsworth, Ole Østergaard Thomsen, Jørn Brynskov

Department of Clinical Medicine

15 Citations (Scopus)

Abstract

Background: Antibodies (Abs) against adalimumab (ADL) have been associated with low ADL levels and treatment failure. Aim: To characterize the temporal characteristics of anti-ADL Ab appearance and possible disappearance, and determine the clinical significance on drug efficacy and disease course. Methods: Cohort study including inflammatory bowel disease patients in whom anti-ADL Abs had been assessed by radioimmunoassay (RIA) and, in case of disappearance, by enzyme immunoassay, and functional reporter gene assay. Results: Anti-ADL Abs were evaluated in 133 serum samples from 72 patients. Seventeen patients (24%) tested positive after median of 194 days, interquartile range of 66 to 361. The proportion with anti-ADL Abs was 22% after 1 year, and 32% from 21 months onwards. Anti-ADL Abs generally persisted at repeat assessments during continued ADL therapy (n=8). Disappearance of anti-ADL Abs during therapy (n=3) was presumably caused by methodological biases due to detection of nonfunctional nonpersistent anti-ADL Abs by RIA, or false-negative measurement at reassessment by RIA and reporter gene assay. Anti-ADL Abs appeared pharmacologically active as judged by a median ADL concentration below limit of detection versus 7.4 μg/mL in anti-ADL Ab-negative samples (P<0.0001). Anti-ADL Abs associated with loss of response (odds ratio estimated 67, P<0.0001), and shorter treatment duration (P<0.0001). Conclusions: Abs against ADL appear in approximately one fourth of inflammatory bowel disease patients with decreasing frequency over time and usually within 1 year of therapy. Anti-ADL Abs generally persist during continued ADL therapy, and are associated with elimination of drug and treatment failure. Therefore, ADL cessation should be considered when anti-ADL Abs are detected and supported by clinical observations.

Original language	English
Journal	Clinical Gastroenterology and Hepatology
Volume	50
Issue number	6
Pages (from-to)	483-489
Number of pages	7
ISSN	1542-3565
DOIs	https://doi.org/10.1097/MCG.0000000000000375
Publication status	Published - Jul 2016

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Time Course and Clinical Implications of Development of Antibodies Against Adalimumab in Patients With Inflammatory Bowel Disease. / Steenholdt, Casper; Frederiksen, Madeline Therese; Bendtzen, Klaus et al.
In: Clinical Gastroenterology and Hepatology, Vol. 50, No. 6, 07.2016, p. 483-489.

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

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title = "Time Course and Clinical Implications of Development of Antibodies Against Adalimumab in Patients With Inflammatory Bowel Disease",

abstract = "Background: Antibodies (Abs) against adalimumab (ADL) have been associated with low ADL levels and treatment failure. Aim: To characterize the temporal characteristics of anti-ADL Ab appearance and possible disappearance, and determine the clinical significance on drug efficacy and disease course. Methods: Cohort study including inflammatory bowel disease patients in whom anti-ADL Abs had been assessed by radioimmunoassay (RIA) and, in case of disappearance, by enzyme immunoassay, and functional reporter gene assay. Results: Anti-ADL Abs were evaluated in 133 serum samples from 72 patients. Seventeen patients (24%) tested positive after median of 194 days, interquartile range of 66 to 361. The proportion with anti-ADL Abs was 22% after 1 year, and 32% from 21 months onwards. Anti-ADL Abs generally persisted at repeat assessments during continued ADL therapy (n=8). Disappearance of anti-ADL Abs during therapy (n=3) was presumably caused by methodological biases due to detection of nonfunctional nonpersistent anti-ADL Abs by RIA, or false-negative measurement at reassessment by RIA and reporter gene assay. Anti-ADL Abs appeared pharmacologically active as judged by a median ADL concentration below limit of detection versus 7.4 μg/mL in anti-ADL Ab-negative samples (P<0.0001). Anti-ADL Abs associated with loss of response (odds ratio estimated 67, P<0.0001), and shorter treatment duration (P<0.0001). Conclusions: Abs against ADL appear in approximately one fourth of inflammatory bowel disease patients with decreasing frequency over time and usually within 1 year of therapy. Anti-ADL Abs generally persist during continued ADL therapy, and are associated with elimination of drug and treatment failure. Therefore, ADL cessation should be considered when anti-ADL Abs are detected and supported by clinical observations.",

author = "Casper Steenholdt and Frederiksen, {Madeline Therese} and Klaus Bendtzen and Ainsworth, {Mark A} and Thomsen, {Ole {\O}stergaard} and J{\o}rn Brynskov",

year = "2016",

month = jul,

doi = "10.1097/MCG.0000000000000375",

language = "English",

volume = "50",

pages = "483--489",

journal = "Clinical Gastroenterology and Hepatology",

issn = "1542-3565",

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T1 - Time Course and Clinical Implications of Development of Antibodies Against Adalimumab in Patients With Inflammatory Bowel Disease

AU - Steenholdt, Casper

AU - Frederiksen, Madeline Therese

AU - Bendtzen, Klaus

AU - Ainsworth, Mark A

AU - Thomsen, Ole Østergaard

AU - Brynskov, Jørn

PY - 2016/7

Y1 - 2016/7

N2 - Background: Antibodies (Abs) against adalimumab (ADL) have been associated with low ADL levels and treatment failure. Aim: To characterize the temporal characteristics of anti-ADL Ab appearance and possible disappearance, and determine the clinical significance on drug efficacy and disease course. Methods: Cohort study including inflammatory bowel disease patients in whom anti-ADL Abs had been assessed by radioimmunoassay (RIA) and, in case of disappearance, by enzyme immunoassay, and functional reporter gene assay. Results: Anti-ADL Abs were evaluated in 133 serum samples from 72 patients. Seventeen patients (24%) tested positive after median of 194 days, interquartile range of 66 to 361. The proportion with anti-ADL Abs was 22% after 1 year, and 32% from 21 months onwards. Anti-ADL Abs generally persisted at repeat assessments during continued ADL therapy (n=8). Disappearance of anti-ADL Abs during therapy (n=3) was presumably caused by methodological biases due to detection of nonfunctional nonpersistent anti-ADL Abs by RIA, or false-negative measurement at reassessment by RIA and reporter gene assay. Anti-ADL Abs appeared pharmacologically active as judged by a median ADL concentration below limit of detection versus 7.4 μg/mL in anti-ADL Ab-negative samples (P<0.0001). Anti-ADL Abs associated with loss of response (odds ratio estimated 67, P<0.0001), and shorter treatment duration (P<0.0001). Conclusions: Abs against ADL appear in approximately one fourth of inflammatory bowel disease patients with decreasing frequency over time and usually within 1 year of therapy. Anti-ADL Abs generally persist during continued ADL therapy, and are associated with elimination of drug and treatment failure. Therefore, ADL cessation should be considered when anti-ADL Abs are detected and supported by clinical observations.

AB - Background: Antibodies (Abs) against adalimumab (ADL) have been associated with low ADL levels and treatment failure. Aim: To characterize the temporal characteristics of anti-ADL Ab appearance and possible disappearance, and determine the clinical significance on drug efficacy and disease course. Methods: Cohort study including inflammatory bowel disease patients in whom anti-ADL Abs had been assessed by radioimmunoassay (RIA) and, in case of disappearance, by enzyme immunoassay, and functional reporter gene assay. Results: Anti-ADL Abs were evaluated in 133 serum samples from 72 patients. Seventeen patients (24%) tested positive after median of 194 days, interquartile range of 66 to 361. The proportion with anti-ADL Abs was 22% after 1 year, and 32% from 21 months onwards. Anti-ADL Abs generally persisted at repeat assessments during continued ADL therapy (n=8). Disappearance of anti-ADL Abs during therapy (n=3) was presumably caused by methodological biases due to detection of nonfunctional nonpersistent anti-ADL Abs by RIA, or false-negative measurement at reassessment by RIA and reporter gene assay. Anti-ADL Abs appeared pharmacologically active as judged by a median ADL concentration below limit of detection versus 7.4 μg/mL in anti-ADL Ab-negative samples (P<0.0001). Anti-ADL Abs associated with loss of response (odds ratio estimated 67, P<0.0001), and shorter treatment duration (P<0.0001). Conclusions: Abs against ADL appear in approximately one fourth of inflammatory bowel disease patients with decreasing frequency over time and usually within 1 year of therapy. Anti-ADL Abs generally persist during continued ADL therapy, and are associated with elimination of drug and treatment failure. Therefore, ADL cessation should be considered when anti-ADL Abs are detected and supported by clinical observations.

U2 - 10.1097/MCG.0000000000000375

DO - 10.1097/MCG.0000000000000375

M3 - Journal article

C2 - 26166141

SN - 1542-3565

VL - 50

SP - 483

EP - 489

JO - Clinical Gastroenterology and Hepatology

JF - Clinical Gastroenterology and Hepatology

IS - 6

ER -

Time Course and Clinical Implications of Development of Antibodies Against Adalimumab in Patients With Inflammatory Bowel Disease

Abstract

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