Use of infliximab and anti-infliximab antibody measurements to evaluate and optimize efficacy and safety of infliximab maintenance therapy in Crohn's disease.

BACKGROUND

Infliximab (IFX) is a therapeutic monoclonal antibody (Ab) against TNF-α, which is used to induce and maintain remission in patients with moderate to severe Crohn's disease. Despite its effectiveness, approximately one third of patients experience primary treatment failure, and another one third later lose effect of maintenance therapy. IFX is well tolerated but may result in potentially life-threatening side effects such acute severe infusion reactions. Determining optimal therapy after therapeutic failure is complicated. Recent studies have indicated, that measurements of IFX and anti-IFX Ab concentrations in individual patients may be helpful in this process.

AIM

The aim of this PhD thesis was to investigate the clinical utility of measuring IFX and anti-IFX Ab by novel radioimmunoassay (RIA) techniques. Specifically, the aim was to investigate if these measurements could aid in evaluating and optimizing efficacy and safety of IFX therapy in patients with Crohn's disease.

METHODS

An experimental study for comparison of analytical properties of assays for measuring IFX and anti-IFX Ab was applied. In addition, three observational, retrospective, single centre cohort studies of all patients with Crohn's disease treated with IFX were carried out.

RESULTS

Serum levels of IFX and anti-IFX Ab measured by RIA strongly associated with clinical response types to IFX maintenance therapy. Cut-off values providing optimal discrimination of patients with loss of response or maintained remission were established. An algorithm for evaluating and optimizing therapy in individual patients with loss of treatment response based on IFX and anti-IFX Ab levels was proposed. Acute severe infusion reactions appeared not to be true IgE-mediated anaphylactic reactions, but rather associated with development of anti-IFX IgG Ab. Risk was increased during episodic therapy, but absence of anti-IFX Ab prior to a reinitiation series did not exclude reactions and assessments hereof could not be used for risk stratification. Several factors may potentially interfere with associations of IFX and anti-IFX Ab with clinical outcome including use of different analytical techniques, different cut-off values for reporting of positive test results, differences in timing of measurements, and transiency of anti-IFX Ab.

CONCLUSIONS

Monitoring serum levels of IFX and anti-IFX Ab by novel RIA techniques appears promising for evaluating and optimizing efficacy and safety of IFX therapy in Crohn's disease. Previous conflicting reports on the importance of tests are potentially biased by use of different types of assays, different cut-off values for binary classification of test results, and inconsistent timing of measurements. Prospective validation of proposed treatment algorithms in larger cohorts is warranted.