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

Abstract

Tocilizumab (TCZ) is the first humanized antiinterleukin-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 longterm 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 longterm 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 TOCILIZUMAB: THE FIRST INTERLEUKIN-6 RECEPTOR-NEUTRALIZING BIOLOGICInterleukin-6 (IL-6) is a multifunctional cytokine that plays an important role in both acute and chronic inflammatory responses. Consequently, the dysregulated or persistent production of IL-6 can lead to the development of inflammatory disorders [1]. Elevated levels of IL-6 in serum, synovial fluid, and various tissues have been correlated with disease activity in patients with rheumatoid arthritis (RA) [2], juvenile idiopathic arthritis (JIA) [3,4], Castleman's disease [5,6], systemic sclerosis (SSc) [7], giant cell arteritis (GCA) [8,9], adult-onset Still's disease (AOSD) [10], familial Mediterranean fever (FMF) [11,12], Schnitzler's syndrome [13,14], polychondritis [15], and amyloidosis [1]. These associations suggest a pathogenetic role for IL-6 in multiple inflammatory conditions and form the basis of the rationale for the development of anti-IL-6 therapies.Tocilizumab (TCZ) is the first humanized monoclonal antibody targeting the IL-6 receptor subunit alpha (IL-6Ra) [16], and its mechanism of action has been described in detail in previous reviews [17,18]. Briefly, TCZ targets both membrane-bound and soluble IL-6Ra, which prevents t...

Translating IL-6 biology into effective treatments

“…Consistent with expectations for a biologic DMARD for RA, serious infections, including serious bacterial infections, are among the most common serious adverse events reported in clinical trials, post-marketing surveillance studies, short-term studies and open-label extension studies. The overall rate of serious infections in patients with long-term exposure to IL-6 pathway inhibitors is in line with rates seen in studies with a short duration of exposure 58,145,159,161,[164][165][166][167][168][169] .…”

Targeting miR‐223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds

“…It was reported that IL6 À/À mice exhibited delayed aseptic skin wound healing (Gallucci et al, 2000;Lin et al, 2003) and recombinant murine IL-6 improved skin wound healing in glucocorticoidtreated mice (Gallucci et al, 2001). In contrast, excess IL-6 causes inflammatory diseases; therefore, IL-6 receptor antibody (Tocilizumab) has been used as therapeutic agent against Castleman disease and rheumatic diseases in the clinic (Rubbert-Roth et al, 2018;Yoshizaki et al, 2018). Taken together, it appears that precise regulation of IL-6 levels is necessary at inflamed sites to regulate inflammation and tissue repair.…”

Pandemic Coronavirus Disease (COVID-19): Challenges and A Global Perspective

“…A humanized monoclonal antibody viz. tocilizumab competitively binds to IL-6 receptors and subsequently prevents the binding of IL-6 to its receptor [130]. Notably, the blocking of the IL-6…”