Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response

Abstract

Antitumor necrosis factor α (anti-TNF) agents have dramatically influenced management of refractory inflammatory bowel disease (IBD). However, not all patients respond to treatment and some lose response or become intolerant over time. Immunogenicity, a well established phenomenon with anti-TNF agents, may have important clinical implications in patients with IBD. A comprehensive review of available evidence demonstrating how drug concentrations, immunogenicity, and other factors influence outcomes with anti-TNF agents was performed. PubMed, EMBASE, Biosis, Dialog, and Conference Papers Index were searched from 1 January 1995 to 7 April 2012 to identify clinical trials in adult and pediatric patients with IBD treated with anti-TNF agents for Crohn's disease or ulcerative colitis. Data on serum drug levels and immunogenicity and their relationship with clinical efficacy and safety outcomes were extracted and examined. Serum infliximab concentrations correlated with clinical efficacy and treatment outcomes in patients with IBD; this relationship is less well characterized with adalimumab and certolizumab pegol concentrations. In multiple studies, the presence and level of antibodies to infliximab correlated with loss of clinical efficacy and increased risk of infusion reactions. The incidence and clinical impact of antibody formation with adalimumab or certolizumab in IBD is becoming evident as more data become available. Current, enzyme-linked immunosorbent assay based anti-TNF antibody assays are suboptimal in that results are often inconclusive and comparisons between agents cannot be made. Measurement of anti-TNF agent drug concentrations and assessment of immunogenicity has the potential to positively impact clinical decision making during anti-TNF therapy for IBD. As assays are optimized, it is expected that the clinical impact of these determinations will be better characterized.

Keywords: Crohn’s disease; adalimumab; antitumor necrosis factor α; certolizumab; enzyme-linked immunosorbent assay; immunogenicity; inflammatory bowel disease; infliximab; ulcerative colitis.

Figure 1.

Concentrations versus time curve of infliximab in Crohn’s disease. Observed (dots) and simulated (lines) median concentration–time profiles of adult patients with Crohn’s disease (data from ACCENT I trial). Patients received treatment with infliximab 5 mg/kg at weeks 0, 2, and 6 and every 8 weeks thereafter. The serum infliximab concentrations are higher at early time points in the graph, corresponding with the induction phase of treatment (loading doses). After 14 weeks (100 days), infliximab serum concentrations tend to stabilize. ACCENT I, A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen. Reprinted with permission from Fasanmade et al. [2011].

Figure 2.

Enzyme-linked immunosorbent assay (ELISA). Although most commonly used for measuring antitumor necrosis factor α (TNF) levels and antidrug antibodies, ELISA has methodologic limitations that include risk of false-positive results because of nonspecific binding to immunoglobulins, and serum levels of the respective anti-TNF may interfere with the assay and produce inconclusive results potentially leading to underestimation of antidrug antibody levels.

Figure 3.

Radioimmunoassay (RIA). This assay provides greater sensitivity than enzyme-linked immunosorbent assay (ELISA). RIA measures functional serum drug levels via radiolabeled tumor necrosis factor α binding or by measuring antibody levels. RIA has less interaction with other immunoglobulins compared with ELISA.

Figure 4.

Suggested clinical algorithm for infliximab-treated patients with clinical symptoms. TNF, tumor necrosis factor. Reprinted with permission from Colombel et al. [2011].