Targeting IL-6 or IL-6 Receptor in Rheumatoid Arthritis: What's the Difference?

Interleukin-6 (IL-6) signaling is a critical target in inflammatory pathways. Today, tocilizumab (TCZ) and sarilumab (SAR), two IL-6 receptor-inhibiting monoclonal antibodies, are widely used in the treatment of rheumatoid arthritis (RA), with a favorable efficacy/safety profile. Successful introduction of such agents in the treatment of RA has encouraged the development of other agents targeting different points of the pathway. Sirukumab (SRK), a human anti-IL-6 monoclonal antibody, has been evaluated in clinical trials and showed largely similar clinical efficacy compared with TCZ and other IL-6 pathway-targeting agents. Furthermore, the drug safety profile seemed to reflect the profile of adverse effects and laboratory abnormalities seen in other inhibitors of the IL-6 pathway. However, increased death rates under SRK treatment compared with placebo raised safety concerns, which led to the decision by the FDA to decline the approval of SRK in August 2017. However, during the 18-week true placebo-controlled period, mortality rates were identical in the placebo- and SRK-treated patients. Comparisons after week 18 may be confounded by some factors, and also the 'crossover' design resulted in various treatment groups with varying drug exposure periods. The limited placebo exposure relative to SRK exposure makes interpretation of mortality rates difficult. We do not know whether the imbalance in mortality rates seen for SRK is a true safety signal or a result of bias due to the study design. Therefore, further long-term clinical data as well as basic research is needed to allow deeper insight into IL-6 signaling.