Sa1866 LOW DRUG CONCENTRATIONS AND ANTI-DRUG ANTIBODY FORMATION TO THE PRIOR ANTI-TNF PREDISPOSES PATIENTS WITH INFLAMMATORY BOWEL DISEASE TO DEVELOP ANTI-DRUG ANTIBODIES TO THE SUBSEQUENT ANTI-TNF

2020 ◽  
Vol 158 (6) ◽  
pp. S-457
Author(s):  
Adam S. Cheifetz ◽  
Maria T. Abreu ◽  
Sarah N. Flier ◽  
Konstantinos Papamichail ◽  
Florian Rieder ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Antibody Formation ◽  
Drug Concentrations ◽  
Inflammatory Bowel

scholarly journals A156 SERUM TUMOUR NECROSIS FACTOR-α ANTAGONIST DRUG CONCENTRATIONS IN PATIENTS WITH PYODERMA GANGRENOSUM ASSOSCIATED WITH INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 162-163
Author(s):  
M Mikail ◽  
A Wilson
Keyword(s):  
Inflammatory Bowel Disease ◽  
Pyoderma Gangrenosum ◽  
Bowel Disease ◽  
Complete Resolution ◽  
Therapeutic Drug ◽  
Drug Concentrations ◽  
Median Serum ◽  
Inflammatory Bowel ◽  
Factor Α ◽  
Necrosis Factor

Abstract Background The utility of therapeutic drug monitoring for guiding the dosing of tumor necrosis factor-α antagonists (TNFAs) in luminal inflammatory bowel disease (IBD) is well-established and well-accepted. TNFAs, specifically infliximab and adalimumab, have become integral to the management of the rare, neutrophilic dermatosis, pyoderma gangrenosum (PG) in IBD. Little is known regarding the target serum TNFA concentrations to guide dosing to achieve resolution of PG in IBD. Aims To describe the serum TNFA concentrations (infliximab or adalimumab) associated with the resolution of PG lesions in patients with IBD. Methods Patients with IBD and associated PG treated with one of infliximab or adalimumab (collectively known as TNFAs) seen at two academic hospitals affiliated with Western University were identified. Serum TNFA concentrations were assessed at the time of PG treatment. Results Nine patients were identified. All patients had IBD-associated PG. Seven patients were treated with infliximab and 2 patients were treated with adalimumab. All patients received standard dosing. Eight patients had complete resolution of their PG, while one had near complete resolution at the time of last follow-up. A median serum infliximab concentration of 3.00 (IQR, 3.52) µg/ml at week 14 and a median serum adalimumab concentration of 2.02 (IQR, 0.98) µg/ml at week 12 were seen at the time of PG treatment. Conclusions Herein, we report low serum TNFA concentrations despite PG healing in a cohort of IBD patients. This is lower than what is in patients for successful TNFA treatment in luminal and fistulising IBD. Funding Agencies NoneNone.

scholarly journals A208 HLA-DQA1*05 GENOTYPE PREDICTS ANTI-DRUG ANTIBODY FORMATION AND LOSS OF RESPONSE DURING INFLIXIMAB THERAPY FOR INFLAMMATORY BOWEL DISEASE

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 80-81
Author(s):  
C Peel ◽  
Q Wang ◽  
A Pananos ◽  
R Kim ◽  
A Wilson
Keyword(s):  
Inflammatory Bowel Disease ◽  
At Risk ◽  
Genetic Variation ◽  
Bowel Disease ◽  
Antibody Formation ◽  
Adverse Drug Events ◽  
Treatment Discontinuation ◽  
Carrier Status ◽  
Loss Of Response ◽  
Inflammatory Bowel

Abstract Background The underlying mechanism for immunogenicity in anti-TNFa-exposed patients with inflammatory bowel disease is poorly understood. Anti-drug antibodies are a leading contributor to infliximab loss of response and adverse drug events. Currently, it is not feasible to identify patients at risk of antibody formation prior to initiating infliximab. The genetic variation HLADQA1*05(rs2097432) has been linked to infliximab antibody formation in a cohort of patients with Crohn’s disease. Aims Due to the wide variation in the frequency of HLADQA1* 05 across ethnic groups, we aim to independently evaluate the association between HLADQA1*05and infliximab antibody formation, infliximab loss of response, treatment discontinuation and adverse drug events, in a Canadian inflammatory bowel disease cohort. Methods In a retrospective cohort study, infliximab-exposed patients with inflammatory bowel disease (n=262) were screened for the genetic variation, HLADQA1*05A>G(rs2097432). The risk of infliximab anti-drug antibody formation, infliximab loss of response, adverse events, and discontinuation were assessed in wild type (GG) and variant-carrying (AG or AA) individuals. Results Forty percent of all participants were HLADQA1*05A>Gvariant carriers, with 79% of participants with infliximab antibodies carrying at least one variant allele. The risk of infliximab antibody formation was higher in HLADQA1*05A>Gvariant carriers in an IBD population (adjusted HR=7.29, 95%CI=2.97–17.191, p=1.46x10-5) independent of age, sex, weight, dose and co-immunosuppression with an immunomodulator. Variant carrier status was associated with an increased risk of infliximab loss of response (adjusted HR=2.34, 95%CI=1.41–3.88, p=0.001) and discontinuation (adjusted HR=2.27, 95%CI=1.46–3.43, p=2.53x10-4) though not with infliximab-associated adverse drug events. Conclusions HLADQA1*05 is independently associated with a high risk of infliximab antibody formation in addition to infliximab loss of response and treatment discontinuation. As a result, we propose that pre-emptive genetic screening for the HLADQA1* 05A>Gvariant would be useful in order to predict individuals at risk of developing immunogenicity. There may be a role for genotype-guided application of combination therapy in inflammatory bowel disease. Funding Agencies NoneWolfe Medical Research Chair in Pharmacogenomics (MOP-89753 to RBK), the Academic Medical Organization of Southwestern Ontario (INN18-005 to RBK and AW; S17-004 to AW), and Lawson Health Research Institute (IRF-05-19 to AW)

A Genetic Variation in the Neonatal Fc-Receptor Affects Anti-TNF Drug Concentrations in Inflammatory Bowel Disease

2016 ◽  
Vol 111 (10) ◽  
pp. 1438-1445 ◽  
Author(s):  
Thomas Billiet ◽  
Erwin Dreesen ◽  
Isabelle Cleynen ◽  
Willem-Jan Wollants ◽  
Marc Ferrante ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Genetic Variation ◽  
Bowel Disease ◽  
Fc Receptor ◽  
Neonatal Fc Receptor ◽  
Drug Concentrations ◽  
Inflammatory Bowel

Immunogenicity of Tumor Necrosis Factor Antagonists and Effect of Dose Escalation on Anti-Drug Antibodies and Serum Drug Concentrations in Inflammatory Bowel Disease

2020 ◽  
Author(s):  
Robert Battat ◽  
Dana Lukin ◽  
Ellen J Scherl ◽  
Suresh Pola ◽  
Anand Kumar ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Dose Escalation ◽  
Bowel Disease ◽  
Primary Outcome ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
Therapeutic Drug ◽  
Drug Concentrations ◽  
Inflammatory Bowel ◽  
The Impact

Abstract Background Infliximab and adalimumab concentrations are associated with important outcomes in inflammatory bowel disease (IBD). Antibodies to infliximab (ATI) and adalimumab (ATA) are associated with reduced drug concentrations and worse outcomes. Because the efficacy of dose escalation to overcome antibodies is unclear, we assessed the impact of this strategy to overcome immunogenicity in IBD. Methods Infliximab and adalimumab dosing, drug, and antibody concentrations were extracted from a database of patients with IBD having specimens collected for therapeutic drug monitoring. The primary outcome compared proportions with either infliximab ≥5 μg/mL or adalimumab ≥7.5 μg/mL and undetectable antibodies between dose-escalated and non-escalated patients. Area under the receiver operating characteristic curve analyses determined antibody concentrations below which dose escalation was associated with the primary outcome. Results The study included 63,176 patients treated with infliximab and 46,429 patients treated with adalimumab. We detected ATI and ATA in 23.6% (n = 14,900) of patients treated with infliximab and 19.6% (n = 9101) of patients treated with adalimumab. In patients with ATI, infliximab dose escalation (n = 453) yielded higher proportions achieving the primary outcome (47.5% vs 30.9%; P < 0.001), greater drug concentration increases (5.9 μg/mL vs 0.2 μg/mL; P < 0.001), and ATI reductions (4.3 U/mL vs 1.9 U/mL; P = 0.002) compared to no escalation (n = 204). An ATI threshold of 8.55 U/mL was associated with achieving the primary outcome with dose escalation (area under the curve = 0.66). For patients with ATI ≤8.55 U/mL (n = 274), higher proportions (59.1% vs 29.6%; P < 0.001) achieved the primary outcome compared with those with ATI >8.55 U/mL (n = 179). No patients treated with adalimumab achieved the primary outcome (0/390), regardless of dose escalation (n = 87). Conclusion Dose escalation increased drug concentrations and eliminated antibodies with infliximab but not adalimumab. Initial ATI ≤8.55 U/mL was associated with increased efficacy of dose escalation using this assay.

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