Tocilizumab, A Humanized Anti-IL-6R Antibody, as an Emerging Therapeutic Option for Rheumatoid Arthritis: Molecular and Cellular Mechanistic Insights

Abstract

Pro-inflammatory cytokines play a major role in the initiation and maintenance of joint inflammation and destruction in rheumatoid arthritis (RA). The therapeutic success of biologics targeting tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin (IL)-6 receptor (IL-6R) has broadened the treatment options for RA. These agents have potential overlapping and discriminating biologic effects, as well as different pharmacological features. Tocilizumab (TCZ) is a humanized monoclonal antibody that binds and neutralizes IL-6R, resulting in the inhibition of various IL-6-mediated biological activities, including inflammation-related, immunomodulatory and tissue/matrix remodelling effects. Randomized, double-blind, controlled phase III studies and a number of early clinical observational studies have shown that treatment with TCZ results in rapid and sustained improvement in the signs and symptoms of RA among different patient populations. These studies have established the efficacy and safety of TCZ. Here, we review the pleiotropic functions of IL-6 and how it impinges on many aspects of RA pathogenesis, and highlight the clinical experience to date with TCZ as an emerging new treatment option for RA.

Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

“…Recognising that lack of replication and effect heterogeneity does not preclude at least one of these effects being genuine, we performed MR analyses using the most significant SNP across studies and report the findings with caution. Some proteins that are targets of approved drugs were found in this analysis, such as IL6R (targeted by tocilizumab) on rheumatiod arthritis 32 , and CHD, the latter being supported by treatment trials of therapies targeting IL1B 33 , which is upstream of IL6R ( Supplementary Table 12).…”

Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder

“…In both diseases, increased serum IL-6 levels have been shown to promote synovitis and induce progressive bone resorption and cartilage degeneration. 16 Interleukin 6 also mediates inflammation, demyelination, and astrogliosis in the central nervous system.…”

“…14 Interleukin 6 promotes AQP4-ab production and secretion from B-cell-derived plasmablasts, whereas the blockade of IL-6 receptor signaling by an anti-IL-6 receptor antibody reduces the survival of plasmablasts in vitro. 15 Tocilizumab, a humanized monoclonal antibody against the IL-6 receptor approved for treatment of rheumatoid arthritis, 16 recently showed beneficial clinical and paraclinical effects in single patients with NMO and in one prospective cohort for treatment periods of 12 to 24 months. [17][18][19][20][21][22] The aim of this retrospective multicenter study was to evaluate the long-term safety and efficacy of tocilizumab in patients with highly active NMO.…”

Effects of tocilizumab on neutrophil function and kinetics

“…Anti-IL-6R therapy is an important intervention in inflammatory diseases and has been used successfully in diseases such as rheumatoid arthritis [8,31]. However, concerns have been raised about its effects on circulating neutrophil numbers and function.…”