title: Personalized therapy with TNF-inhibitors in Crohn's disease: optimizing treatment outcomes by monitoring drug levels and anti-drug antibodies.
abstract: Therapeutic monoclonal antibodies (Abs) targeting the proinflammatory cytokine, TNF-α have revolutionized the treatment of inflammatory bowel disease (IBD), and raised treatment goals from symptom control to maintenance of clinical remission with mucosal healing. However, clinicians are challenged by a significant proportion of patients not responding to TNF-inhibitors or losing effect over time, and by the high costs of these drugs along with their potential side effects. The aim of this dissertation was therefore to examine if anti-TNF treatment outcomes can be improved by tailoring therapy on an individual patient basis by considering relevant prognostic variables. The main finding is that personalized treatment with TNF-inhibitors by use of an algorithm defined by measurements of anti-TNF drug and anti-drug Abs to guide interventions at therapeutic failure can be useful to secure optimal clinical, economic, and patient reported outcomes. Furthermore, the present studies have documented the key role of measurements of anti-TNF drug and anti-drug Abs to elucidate conditions related to pharmacokinetics and pharmacodynamics of these agents in individual patients, and to serve as prognostic markers of anti-TNF treatment outcomes. In addition, knowledge has been provided on how to interpret and integrate measurements of anti-TNF drug and anti-drug Abs in the clinical management of individual IBD patients taking into account potential pit-falls and biases. Hence, the studies forming the basis for this dissertation have yielded novel insights into the technical, temporal, and methodological complexities and challenges related to application of personalized anti-TNF treatment strategies based on measurements of anti-TNF drug and anti-drug Abs, and established measures to proactively address and accommodate these - both technically and clinically. Although not yet completely resolved, this dissertation has also laid a foundation for individually tailored anti-TNF therapy by use of algorithms based on measurements of anti-TNF drug and anti-drug Abs involving different clinical scenarios than treatment failure, for example in the context of drug withdrawal among selected subgroups in remission. Finally, this dissertation has demonstrated that personalized anti-TNF therapy cannot at this time be done on the basis of prognostic variables related to specific characteristics of individual patients, their disease and the anti-TNF treatment regimen, but that management decisions integrating knowledge of these factors can aid improving the overall benefit-risk ratio of anti-TNF treatment outcomes in individual patients. In conclusion, this dissertation has brought personalized anti-TNF therapy in IBD from bench to bedside.
authors.affiliation: steenholdt@dadlnet.dk.
authors.forename: Casper
authors.initials: C
authors.lastname: Steenholdt
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D016903:Drug Monitoring / Q000379:methods*; D005765:Gastrointestinal Agents / Q000493:pharmacokinetics; D006801:Humans; D007155:Immunologic Factors / Q000493:pharmacokinetics*; D000069285:Infliximab / Q000493:pharmacokinetics*; D057285:Precision Medicine / Q000379:methods*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab