IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis. Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and some biological agents. Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 in the pathogenesis of RA. TNF-α inhibitors are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs. Despite its effectiveness in a large patient population, up to two thirds of RA patients are found to be partially responsive to anti-TNF therapy. Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment. In this article, we review the mechanism of anti-IL-6 in the treatment of RA, provide the key efficacy and safety data from clinical trials of approved anti-IL-6, TCZ, as well as six candidate IL-6 blockers including sarilumab, ALX-0061, sirukumab, MEDI5117, clazakizumab, and olokizumab, and their future perspectives in the treatment of RA.

Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2

“…Targeting these pathways with specific drugs, such as tocilizumab, an anti–IL-6R antibody that has already been approved by FDA for other indications (82), or other agents that affect these pathways, such as metformin, ultimately sensitizes primary and metastatic tumors to anti-VEGF therapy in obesity. On the other hand, this study is consistent with recent evidence that weight management in BC patients may be an effective tool to improve prognosis (83).…”

Correlates of Elevated Interleukin-6 and 8-Hydroxy-2′-Deoxyguanosine Levels in Tracheal Aspirates from Very Low Birth Weight Infants Who Develop Bronchopulmonary Dysplasia

“…Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably in juvenile rheumatoid arthritis. 39 It is the only IL-6 pathway targeting agent approved by regulatory agencies for clinical use and may be a new approach to BPD prevention in high-risk preterm infants. However, more experimental and preliminary human studies are needed to prove its benefit before it can be used in preterm infants in the near future.…”

Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data

“…Clinical trials of TCZ demonstrate the therapeutic effectiveness of IL-6 receptor signaling inhibition in patients with rheumatoid arthritis (RA) with inadequate response to disease-modifying antirheumatic drugs (DMARDs), or tumor necrosis factor (TNF) α antagonists [2]. Currently TCZ has received approval in more than 75 countries worldwide for RA and more recently also for systemic juvenile idiopathic arthritis in children [3]. Efficacy and safety of TCZ as monotherapy or in combination with DMARDs in RA patients insufficiently responsive to DMARDs, or TNF-α-antagonist therapy have been shown [4;5].…”