A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases

Abstract

Tocilizumab (TCZ) is the first humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, and more recent studies in patients with RA have provided evidence characterizing the role of intravenous TCZ as monotherapy in early disease and led to the introduction of a subcutaneous formulation of TCZ. In addition, recently published open-label extension and observational studies continue to support the long-term efficacy and safety of TCZ in both clinical trial and real-world settings. Given the involvement of IL-6-mediated signaling in inflammatory disorders, TCZ is also being investigated in other immunological diseases. In particular, a phase 2 trial on the safety and efficacy of subcutaneous TCZ in adults with systemic sclerosis shows clinically relevant improvements in skin sclerosis and lung function in these patients. Another anti-IL-6 receptor agent, sarilumab, targeting the IL6 receptor alpha subunit, was recently approved for the treatment of patients with RA, although long-term data for this biologic are not yet published. In this article we review the placement of TCZ in current treatment guidelines; recent clinical trial data, including quality of life in patients with RA; recent updates to the TCZ safety profile; recent investigations of TCZ in other immunological diseases; and the clinical development of other novel IL-6-targeted agents.

Keywords: Interleukin-6; Rheumatoid arthritis; Tocilizumab.

Figures

Fig. 1

Interleukin-6 (IL-6) signaling. IL-6 binds to and forms a complex with the IL-6 receptor and glycoprotein 130 (gp130), resulting in the homodimerization of gp130 and subsequent activation of the signaling system via classic signaling or trans-signaling pathways. The humanized anti-IL-6 receptor monoclonal antibody tocilizumab targets both soluble and membrane-bound IL-6 receptors, thus inhibiting the binding of IL-6 to both receptors. JAK Janus-activated kinase, MAPKs mitogen-activated protein kinases, SHP-2 Src-homology 2 domain-containing protein tyrosine phosphatase, STAT signal transducer and activator of transcription. Reproduced with permission from Tanaka et al. [1]. Copyright Cold Spring Harbor Laboratory Press

Fig. 2

Global clinical development of tocilizumab (TCZ) and approval by regulatory authorities for the treatment of inflammatory disorders. DMARD Disease-modifying antirheumatic drug, EU European Union, GCA giant cell arteritis, IR inadequate responder, LTE long-term extension, MTX methotrexate, OL open-label, pJIA polyarticular juvenile idiopathic arthritis, RA rheumatoid arthritis, SC subcutaneous, sJIA systemic juvenile idiopathic arthritis,TNFi tumor necrosis factor inhibitor, US United States of America