Management of loss of response to anti-TNF drugs: Change the dose or change the drug?

Abstract

The advent of biological therapy has dramatically changed our concept of treating refractory inflammatory bowel disease (IBD). Chimeric and more humanized anti-TNF Abs have shown to be highly efficacious in these illnesses, but all issues have not been resolved. Indeed, still 20–30% of patients with refractory Crohn's disease1–6 and 30–40%7 of those with refractory ulcerative colitis do not respond to anti-TNF treatment. Moreover, the long-term use of anti-TNF monoclonal antibodies is associated with immunogenicity, which interferes with efficacy, and with the risk of infectious complications. Secondary loss of response to monoclonal antibodies is a reality and clinicians should be prepared to optimize therapy. A rapidly declining response to a given drug in patients responding to the first doses is usually called tachyphylaxis. Underlying reasons for a rapid loss of response can be very diverse. First, the human body usually reacts to external activators of endogenous proteins by decreasing the expression of the target protein or by internalizing membrane bound receptors. Second, alternative pathways can be recruited to restore the bioactivity targeted by a given drug. Third, the bioavailability and/or pharmacokinetics of therapeutic compounds are highly variable among individuals and liable to dramatic changes over time. The last mechanism can also induce a gradual loss of response, which is more commonly observed with anti-TNF agents. We will focus on loss of response with the use of anti-TNF antibodies in IBD and suggest strategies to optimize therapy in these patients. Several strategies have been followed in drug development to improve the efficacy and tolerability of biological agents. Progress in protein engineering has resulted in the elimination of immunogenic non-human peptide sequences from anti-human antibodies, a technique called humanization.8 Third generation, humanized antibodies (± 95% human) and fourth generation, fully (100%) human antibodies, are usually associated with less …