Ther Clin Risk Manag. 2008 Aug; 4(4): 767–775.
Published online 2008 Aug. doi: 10.2147/tcrm.s3470

Interleukin-6 inhibitors in the treatment of rheumatoid arthritis

Stephanie Hennigan and Arthur Kavanaugh
Division of Rheumatology, Allergy, Immunology, The University of California, San Diego, CA, USA

Abstract
Recent developments in understanding the immunopathogenesis of rheumatoid arthritis (RA), combined with progress in biopharmaceutical development, have facilitated the introduction of novel immune modulating therapies for this progressive debilitating disorder. Efficacy achieved with certain agents, particularly the TNF inhibitors, has spurred the development of additional biologic agents targeting other components of the dysregulated immune response relevant to the etiology and sustenance of immune driven systemic inflammation characteristic of RA. Among these other potential targets is IL-6, a cytokine with effects on numerous cell types, including those involved in the pathogenesis of RA. Based on its activities, IL-6 appeared to be a viable target for autoimmune disease. Inhibitors of IL-6 were successful in animal models of autoimmune disease paving the way for subsequent studies in humans. The greatest experience to date has been with tocilizumab, a humanized monoclonal antibody specific for the IL-6 receptor (IL-6R). Beginning with open label studies, and progressing through larger and more rigorous controlled trials, tocilizumab has been shown to have significant Efficacy in patients with RA. Additional studies analyzing its effects in varied populations of RA patients, as well as greater detail concerning its longer-term tolerability and safety, will help define the ultimate role of tocilizumab and other future inhibitors of IL-6 activity as potential therapies for RA.

Keywords: rheumatoid arthritis, IL-6, tocilizumab, biologic agents

Introduction to targeted treatments in rheumatoid arthritis: TNF and IL-6
Rheumatoid arthritis (RA) is a chronic, inflammatory disease characterized by progressive, symmetric joint inflammation and subsequent destruction. Left untreated, RA is associated with significant patient morbidity and accelerated mortality. Treatment with traditional disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX) can be efficacious for a number of RA patients. However, appreciation of the severity of the disease has led to elevation in the goals of treatment of RA. The desire for more complete control of disease, coincident with advances in understanding the underlying immunopathogenesis of RA, and progress in biopharmaceutical development, has spawned the introduction of novel biologic agents. Perhaps the greatest success has come with targeting those inflammatory cytokines that exhibit key roles in the activation and continuation of the destructive process occurring in the rheumatoid synovium. To date, the most notable clinical success in the treatment of RA has been achieved through inhibition of tumor necrosis factor alpha (TNFα). Patients receiving anti-TNF agents have not only exhibited significant improvement in arthritis signs and symptoms, but also better quality of life, less functional disability, and abrogation of joint damage (Gartlehner et al 2006). Despite these benefits, as with DMARDs not all patients respond or maintain Efficacy to desired standards. Therefore, new therapies for RA are needed.

Interleukin-6 (IL-6) is a pleiotropic cytokine that is abundant in both the synovium and serum of RA patients. Locally in the joint, the major source of IL-6 may be synovial fibroblasts, with additional amounts released by activated macrophages and lymphocytes (Yoshizaki et al 1998). Originally identified as a B-cell differentiation factor, IL-6 is now known to regulate a diverse array of activities may underlie both systemic as well as local symptoms of RA. For example, IL-6 initiates the acute-phase response inducing the hepatic synthesis of acute phase proteins including C-reactive protein (CRP), serum amyloid, haptoglobin, and fibrinogen among others (Cronstein 2007). IL-6 can also activate vascular endothelial cells, upregulating expression of certain chemokines and adhesion molecules, and facilitating leukocyte recruitment directly to sites of inflammation (Lipsky 2006). Excess production of IL-6 also contributes to the anemia of chronic disease common in active RA by increasing hepcidin production, and induces thrombocytosis through increased megakaryocyte differentiation (Ishibashi et al 1993; Andrews 2004. Its ability to induce B-cell differentiation may lead to hypergammaglobulinemia as well as the production of autoantibodies such as rheumatoid factor (RF) and autoantibodies to citrullinated peptides (Yoshizaki et al 1998). Additionally, IL-6 may prompt synovial fibroblast differentiation and osteoclast activation, contributing to pannus formation and cartilage and bone destruction (Kudo et al 2003; Park and Pillinger 2007).

Dysregulation of IL-6 may provide an explanation for some of the common clinical manifestations associated with active RA, including fever, weight loss, fatigue, and poor appetite (Yoshizaki et al 1998). Significant correlations between elevated levels of IL-6 and disease activity parameters including duration of morning stiffness and the Ritchie articular index have also been reported (Madhok et al 1993a). Furthermore, treatment of RA patients with methotrexate or gold therapy results in decreased levels of IL-6 in patients with concomitant improvement in additional measures of disease activity (Madhok et al 1993b; Straub et al 1997).

Given its many possible contributions to the pathogenesis of rheumatoid inflammation, IL-6 would appear to be an attractive therapeutic target in RA. Tocilizumab, a monoclonal antibody (mAb) specific for the IL-6 receptor (IL-6R) is the first biologic agent targeting IL-6 that has progressed to late phase clinical trials.

Tocilizumab: pharmacology, mechanism of action, and pharmacokinetics
IL-6 mediates cell signaling by binding its cognate receptor (IL-6R; CD126). However, in order to transduce a signal, the combination of IL-6/IL-6R must also bind a ubiquitous transmembrane protein, glycoprotein (gp) 130 (CD130). The binding of IL-6R complexed with IL-6 results in homodimerization of gp130 and signal transduction through Janusactivated kinase (JAK)/signal transducers and activators of transcription (STAT) pathways (Heinrich et al 2003). IL-6R is expressed on several cell types. However, IL-6 may also bind IL-6R in its soluble form. This complex can then bind gp130, which is expressed on a much wider variety of cell types. The presence of soluble IL-6R allows cell activation through gp130, a process known as trans-signaling, in tissues that do not constitutively express IL-6R (Rose-John 2003). This may help explain the diverse activities mediated by IL-6 in systemic inflammatory diseases such as RA.

Tocilizumab, previously known as myeloma receptor antibody (MRA), is a humanized, IgG1 IL-6 receptor monoclonal antibody that binds with high affinity to the 80 kDa component of IL-6R. This binding subsequently inhibits dimerization of the IL-6/IL-6R complex with membrane-bound gp130, preventing signaling.

The pharmacokinetics of tocilizumab were first established in a small, open-label study (Nishimoto et al 2003). Fifteen patients with active RA who had previously failed at least one DMARD or immunosuppressant received tocilizumab intravenously at doses of 2, 4, or 8 mg/kg biweekly for 6 weeks. The half-life of tocilizumab increased in a dose-dependent manner, as well as with repeated dosing. After the third dose of 8 mg/kg, half-life reached a maximum of ∼240 hours. Serum tocilizumab concentrations were detectable during the entire study period in 4 of 5 patients in the 2 mg/kg group, 3 of 5 patients in the 4 mg/kg group, and all patients in the 8 mg/kg group, and decreased in a nonlinear manner. Those patients with detectable blood levels of tocilizumab maintained marked improvement in serum acute phase reactants such as CRP and amyloid A.

Interleukin-6 inhibitors in the treatment of rheumatoid arthritis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2621374/

　

Inhibiting the PI3K/AKT/NF-κB signal pathway with nobiletin for attenuating the development of osteoarthritis: in vitro and in vivo studies

Osteoarthritis (OA), an age-related degenerative disease, is characterized by progressive degradation of the articular cartilage. There is increasing evidence that nobiletin (NOB) exerts special biological functions in a variety of diseases. However, whether it protects against OA remains unknown. In this study, we investigated the anti-inflammatory and chondroprotective effects of NOB on IL-1β-induced human OA chondrocytes and in the surgical DMM mice OA models. In vitro, NOB treatment completely suppressed the overproduction of pro-inflammatory mediators, including PGE2, NO, COX-2, iNOS, TNF-α and IL-6 in IL-1β-induced human OA chondrocytes. Moreover, NOB exerted a potent inhibitory effect on the expression of MMP-13 and ADAMTS-5 as well as the degradation of aggrecan and collagen-II, which leads to the degradation of the extracellular matrix. Furthermore, NOB dramatically suppressed the IL-1β-stimulated phosphorylation of PI3K/Akt and activation of NF-κB in human OA chondrocytes. In addition, treatment with NOB not only prevented the destruction of cartilage and the thickening of subchondral bone but also relieved synovitis in mice OA models. In conclusion, our study suggests that NOB holds novel therapeutic potential for the treatment of OA.

Inhibiting the PI3K/AKT/NF-κB signal pathway with nobiletin for attenuating the development of osteoarthritis: in vitro and in vivo studies - Food & Function (RSC Publishing)
https://pubs.rsc.org/en/content/articlelanding/2019/fo/c8fo01786g#!divAbstract