Op0060 clinical Consequences of Infliximab Immunogenicity and the Impact of Therapeutic Drug Monitoring: Secondary Analyses of a Randomised Clinical Trial

Abstract

BackgroundNeutralising anti-drug antibodies (ADAb) are a problem in treatment with TNF-inhibitors (TNFi). Prospective data are needed to better understand how ADAb formation impacts safety and treatment outcomes of TNFi. Proactive therapeutic drug monitoring (TDM) allows for timely detection of ADAb and this strategy may have a role in reducing the negative clinical consequences of ADAb.ObjectivesTo explore the temporal relation between anti-infliximab antibody formation and treatment outcomes and adverse events, and to assess the impact of TDM as a strategy to reduce these consequences.MethodsPatients with immune mediated inflammatory diseases on infliximab therapy (n=615; 181 spondyloarthritis, 120 rheumatoid arthritis, 72 psoriatic arthritis, 114 ulcerative colitis, 83 Crohns disease and 45 psoriasis) were included in the Norwegian Drug Monitoring (NOR-DRUM) trials (1, 2) and randomised to TDM or standard infliximab therapy. Patients were followed for 30 and 52 weeks in the NOR-DRUM A (induction therapy) and NOR-DRUM B (maintenance therapy) trials, respectively. Neutralising ADAb were assessed with a drug sensitive automated fluorescence assay at each infusion. In this sub-study, we assessed the risk of; failure to achieve remission (analysis A), disease worsening during maintenance therapy (analysis B), treatment discontinuation (analysis C) and adverse events (analysis D) in patients developing ADAb compared to patients without ADAb using logistic- or cox regression and Kaplan-Meier survival analyses, stratified by TDM or standard therapy. Regression analyses were adjusted for potential confounders (Table 1). Remission and disease worsening were defined by disease specific composite scores (1, 2).ResultsADAb were detected in 147/615 (24 %) patients. Patients with ADAb had higher risk of not achieving remission 30 weeks after initiating infliximab therapy (odds ratio (OR) 2.4, 95 % confidence interval (CI) 1.3-4.2, P<0.01) (Table 1, Figure 1A) and of having a disease worsening during 52 weeks of infliximab maintenance therapy (hazard ratio (HR) 2.1, CI 1.4-3.3, P<0.001) (Figure 1B). ADAb formation was not significantly associated with adverse events in general, but the risk of infusion reactions was highly increased in patients with ADAb (HR 29, CI 11-78, P<0.001). The risk of infliximab treatment discontinuation was increased in ADAb positive patients (HR 6.5, CI 4.7-8.9, P<0.001). Patients developing ADAb in the TDM group had lower risk of disease worsening or an infusion reaction than patients with ADAb in the standard infliximab therapy group (Table 1, Figure 1B and C). Patients with ADAb discontinued infliximab treatment more often in the TDM group than in the control group (Table 1, Figure 1D).ConclusionFormation of ADAb led to poorer clinical outcomes both during induction and maintenance therapy with infliximab and increased the risk of infusion reactions. Early detection of ADAb by proactive TDM reduced the negative consequences of ADAb, both on infliximab effectiveness and safety, highlighting the role of proactive TDM in optimising TNFi therapy.References[1]Syversen SW et al. Jama. 2021;326(23)[2]Syversen SW et al. Jama. 2021;325(17)Table 1.Treatment and safety outcomes related to ADAb formation and TDMAnalysis A) Non-remissionOR (CI)PADAb2.4 (1.3-4.2)<0.01TDM1.0 (0.7-1.5)0.9Analysis B) Disease worseningHR (CI)PADAb2.1 (1.4,3.2)<0.01TDM0.4 (0.3-0.6)<0.001Analysis C) Infusion reactionHR (CI)PADAb29 (11-78)<0.001TDM0.3 (0.1-0.7)<0.01Analysis D) Treatment discontinuationHR (CI)PADAb6.5 (4.7-8.9)<0.001TDM1.4 (1.0-1.8)0.03Results from multivariable logistic (A)- or cox (B-D) regression models including the covariates: ADAb, TDM, age, sex, diagnosis, comedication. Results shown in table are risk of A) non-remission week 30, B) disease worsening during 52 weeks of maintenance therapy, C) infusion reactions and D) infliximab treatment discontinuation for patients developing ADAb and for patents in the TDM group.Figure 1.Acknowledgements:NIL.Disclosure of InterestsMarthe Kirkesæther Brun: None declared, Kristin Hammersbøen Bjørlykke Speakers bureau: Janssen, Grant/research support from: Olympus travel grant, Johanna Elin Gehin: None declared, David J Warren: None declared, Rolf A. Klaasen: None declared, Joseph Sexton: None declared, Øystein Sandanger: None declared, Tore K. Kvien Speakers bureau: Grünenthal, Sandoz, UCB, Consultant of: AbbVie, Amgen, Celltrion, Gilead, Novartis, Pfizer, Sandoz, UCB, Grant/research support from: AbbVie, Amgen, BMS, Galapagos, Novartis, Pfizer, UCB, Cato Mørk Speakers bureau: Novartis Norway, LEO Pharma, ACO Hud Norge, Cellgene, Abbvie, and Galderma Nordic AB, Jørgen Jahnsen Speakers bureau: AbbVie, Boerhinger Ingelheim, BMS, Celltrion, Giliad, Hikma, Janssen Cilag, Novartis, Orion Pharma, Pfizer, Roche, Takeda and Sandoz, Consultant of: AbbVie, Boerhinger Ingelheim, BMS, Celltrion, Giliad, Hikma, Janssen Cilag, Novartis, Orion Pharma, Pfizer, Roche, Takeda and Sandoz, Nils Bolstad: None declared, Kristin Kaasen Jørgensen Speakers bureau: Roche, BMS, Celltrion and Norgine, Espen A Haavardsholm Speakers bureau: Pfizer, UCB, Consultant of: AbbVie, Boehringer-Ingelheim, Eli Lilly, Gilead, Guro Løvik Goll Speakers bureau: AbbVie, Boehringer Ingelheim, Novartis, Pfizer, Orion Pharma, Eli Lilly, Roche, Sandoz, Silje Watterdal Syversen: None declared.

Therapeutic Drug Monitoring: A Tool to Optimize Treatment of Inflammatory Joint Diseases

“…12,13 By implementing TDM, adverse events related to anti-drug antibody formation (eg, infusion reactions) can be avoided by change of therapy. 6,7,9,11 In NOR-DRUM A, 16 patients (8%) in the standard therapy group compared to 5 patients (2.5%) in the TDM group experienced an infusion-related reaction (hazard ratio 17.02, 95% CI 6.98-41.47]). 9,11 It is still not known whether infections and other adverse events are dependent on serum drug levels of TNFi.…”

“…7,9 The formation of immune-complexes also increases the risk of drug reactions. 7,9 Assays for serum drug levels and anti-drug antibodies exist for use in clinical practice for nearly all biologics used in rheumatology (TNFi, interleukin [IL] 6 receptor, T cell costimulatory, and IL-17 inhibitors), but the access to these assays vary widely. Assays and guidance regarding the interpretation of results are most widely available for TNFi.…”

“…7,8 Neutralizing anti-drug antibodies block and inactivate the target binding site of the drug and accelerate drug clearance, with subsequent loss of response. 7,9 The formation of immune-complexes also increases the risk of drug reactions. 7,9 Assays for serum drug levels and anti-drug antibodies exist for use in clinical practice for nearly all biologics used in rheumatology (TNFi, interleukin [IL] 6 receptor, T cell costimulatory, and IL-17 inhibitors), but the access to these assays vary widely.…”

“…Although changing the therapy if the patient is in remission might seem contradictory to the treat-to-target principle, patients with no effective drug present and high levels of anti-drug antibodies are using a costly drug with limited potential effect and are at risk of disease worsening or antibody-mediated adverse events. 9 Assessment of serum drug levels and anti-drug antibodies may also be triggered by a specific event or concern, an approach designated as reactive TDM. Triggers can include treatment failure, adverse events such as infusion or injection reactions, or suspected nonadherence.…”

“…If levels of anti‐drug antibodies are present in low levels, immunogenicity may be suppressed by increasing the dose or adding co‐medication such as methotrexate. If anti‐drug antibodies are detected in high levels, the immunogenicity process is irreversible, indicating a need for switching to an alternative therapy 7,9 . Although changing the therapy if the patient is in remission might seem contradictory to the treat‐to‐target principle, patients with no effective drug present and high levels of anti‐drug antibodies are using a costly drug with limited potential effect and are at risk of disease worsening or antibody‐mediated adverse events 9 …”