This month in Gastroenterology

Abstract

Interleukin-6 (IL-6) has a central role in regulating the immune response and inflammation. One of its mechanisms of action is mediated by forming a complex with soluble IL-6 receptor (sIL-6R), allowing it to activate cells lacking IL-6 receptors (IL-6R). In active Crohn’s disease (CD), serum concentrations of sIL-6R are increased and serum IL-6 and sIL-6R concentrations correlate with C-reactive protein (CRP) levels. Furthermore, the levels of IL-6 and sIL-6R in colonic organ cultures are elevated in patients with CD, especially in those with active inflammation. Several preclinical studies have also shown that blocking antibodies to IL-6 can reduce inflammation, disease severity, and cause lymphocyte apoptosis. These observations provided the basis for this pilot placebo-controlled study to investigate the efficacy, pharmacokinetics, and safety of MRA in patients with active Crohn’s disease. MRA (Chugai Pharmaceutical Co., Ltd., Tokyo, Japan) is a humanized anti-human IL-6R monoclonal antibody (mAb) that binds to both membrane-bound form and soluble form of human IL-6R with high affinity and specificity. It was constructed by grafting the complementarity-determining regions of the mouse anti-human IL-6R mAb into human IgG1 to re-create a properly functioning antigen-binding site in a reshaped human antibody. Patients with active Crohn’s disease were randomly assigned to receive biweekly intravenous infusion of either placebo, MRA, or MRA/placebo alternately for 12 weeks at a dose of 8 mg/kg. A reduction of the Crohn’s Disease Activity Index (CDAI) by 70 points was used as the study’s primary endpoint. The study by Ito et al. found that 80% of the patients given biweekly MRA had a significantly better clinical response rate as compared with 31% of the placebo-treated patients (Figure 1). Twenty percent of the patients (2 of 10) on this regimen went into remission as compared with 0% of the placebo-treated patients (0 of 13). The clinical response rate of the every 4-week regimen was 42% (5 of 12). No differences in endoscopic and histological examination were noted between MRA and placebo groups. The incidence of adverse events was similar in all the groups. Although preliminary, these data show that biweekly 8 mg/kg infusion of MRA is well tolerated, normalizes the acute-phase responses, and appears to be clinically effective in active Crohn’s disease. More studies are needed to corroborate these preliminary results and to determine optimal dosing and toxicity issues.