Targeting IL-6 or IL-6 Receptor in Rheumatoid Arthritis: What Have We Learned?

Abstract

The use of different pathways in the treatment of rheumatoid arthritis has led to a significant decrease in the number of treatment-resistant patients. In this context, interleukin (IL)-6 inhibition has filled an important gap in rheumatoid arthritis treatment with its effectiveness and safety in both monotherapy and combinations. The process of IL-6 inhibition initiated with IL-6 receptor blockers has prompted questions regarding the potential impact and safety of different inhibitions of this pathway, such as the direct blockade of IL-6. Following the termination of the development of sirukumab because of mortality data in early studies, the investigation of olokizumab, which targets a different region of the IL-6 cytokine, has renewed the hope in this area and the safety concerns have been largely alleviated by the open-label extension data. In addition, the efficacy and safety of tocilizumab and sarilumab have led to a rapid investigation of biosimilars and new potent IL-6 receptor blockers. A comprehensive understanding of mechanisms of this pathway with further long-term clinical data and basic research may provide a decisive impact on selecting the appropriate mechanism as the first choice in personalized treatments.

Fig. 1

Interleukin (IL)-6 signaling cascade. Interleukin-6 demonstrates its biological activities only by binding to its specific receptor, IL-6R. This cytokine-receptor complex then associates with the IL-6R β-subunit, gp130, leading to intracellular signaling. Classical IL-6 receptor signaling occurs in cells that express IL-6R and gp130. IL-6 receptor can be proteolytically cleaved from the cell membrane by ADAM17, generating sIL-6R. This mechanism of trans-signaling allows IL-6 to act on cells that lack IL-6R. Both modes of IL-6 receptor signaling lead to gp130 activation of Janus kinases 1 and 2 and tyrosine kinase 2, and a series of proximal tyrosine residues that activate the STAT1, STAT3, MAPK, and PI3K cascade. In addition to the JAK/STAT pathway, IL-6 signaling also stimulates SFK-dependent signaling, which probably leads to the activation of different transcriptional regulators including YAP. Phosphorylation of the tyrosine motif 759 in the cytoplasmic tail of gp130 is important for negative regulation of IL-6 signal transduction. SHP2 and SOCS3 bind to this phosphotyrosine and attenuate the IL-6 downstream JAK/STAT signaling. In trans-presentation, mIL-6Rα in complex with IL-6 is presented by dendritic cells and sensed by gp130 molecules expressed on T cells. ADAM17 a disintegrin and metallopeptidase domain 17, IL-6 interleukin-6, IL-6R interleukin-6 receptor, Jak Janus kinase, MAPK mitogen-activated protein kinase, mIL-6R membrane bound IL-6R, PI3K phosphatidylinositol-4,5-bisphosphate 3-kinase, SFK Src-family kinase, SHP2 Src homology 2-containing protein tyrosine phosphatase 2, sIL-6R soluble IL-6R, SOCS3 suppressor of cytokine signaling 3, STAT signal transducer and activator of transcription, Tyk2 Tyrosine kinase 2, Tyr759 tyrosine residue 759, YAP YES-associated protein

Fig. 2

Interleukin-6 inhibitors can bind to different antigenic sites on interleukin (IL)-6. Sirukumab and clazakizumab bind to site 1 and interfere with the binding of IL-6 to the IL-6 receptor (IL-6R)-α in the IL-6–IL-6R–gp130 trimolecular complex and prevents dimerization. Olokizumab binds to site 3 and blocks hexamer formation by disrupting the interaction of IL-6 and the IL-6–IL-6R dimer with the signal-transducing β-receptor subunit gp130 part of the receptor complex