Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Carl Turesson, Lund University,
- Second opponent: Associate Professor Diane van der Woude, Leiden University Medical Center,
- Third member and chair of the evaluation committee: Professor II Berit Flatø, University of Oslo
Chair of the Defence
Professor II Marte Lie Høivik, University of Oslo
Principal Supervisor
Senior Researcher, Silje Watterdal Syversen, Diakonhjemmet Hospital
Summary
TNF-inhibitors like infliximab have revolutionized treatment of patients with immune-mediated inflammatory diseases affecting the joints, the gut and the skin. However, a substantial proportion of patients do not respond adequately to treatment or lose response over time. Low serum drug concentrations and development of anti-drug antibodies are important reasons of treatment non-response.
The aims of the thesis were to examine clinical aspects of infliximab immunogenicity and the effect of proactive therapeutic drug monitoring using data from two large randomized controlled trials.
616 patients were randomized to receive infliximab treatment according to a proactive therapeutic drug monitoring regimen with regular assessments of serum drug and anti-drug antibody levels, or according to standard therapy.
Neutralizing anti-drug antibodies were detected in 24% of patients and were associated with disease worsening, infusion reactions and infliximab discontinuation. Patients with anti-drug antibodies in high levels had worse outcomes than patients with low levels, and low anti-drug antibody levels could sometimes be overcome by increasing the infliximab dose.
Factors associated with an increased risk of anti-drug antibodies were no immunosuppressive comedication, drug-holidays above 11 weeks, low infliximab doses, low serum infliximab levels, high disease activity, smoking, rheumatoid arthritis and the genetic variant HLA-DQ2.
Proactive therapeutic drug monitoring reduced the risk of having a disease worsening, both amongst patients with and without anti-drug antibodies, and also reduced the risk of infusion reactions. Proactive therapeutic drug monitoring may therefore be useful in patients receiving infliximab therapy, particularly those at risk of developing anti-drug antibodies who are especially prone to having a disease worsening or an infusion reaction.
Additional information
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