Interleukin-6 inhibition in the management of non-infectious uveitis and beyond

Abstract

Background: Uveitis consists of a spectrum of inflammatory disorders characterized by ocular inflammation. The underlying pathophysiology consists of a complex interplay of various inflammatory pathways. Interleukin 6 is an important mediator of inflammation in uveitis and constitutes focus of research toward development of newer biological therapies in the management of non-infectious uveitis.

Main body: Pan-blockade of the inflammatory pathways with steroids is generally the first step in the management of acute non-infectious uveitis. However, long-term therapy with steroids is associated with systemic and ocular side effects, thereby necessitating the need for development of steroid sparing agents. IL-6 is a cytokine produced by various immune cells, in response to molecular patterns and affects multiple inflammatory cells. In particular, IL-6 is involved in differentiation of CD-4 cells into Th-17 cells that have been shown to play a significant role in various immune-mediated diseases such as uveitis. This broad-spectrum immunomodulatory activity makes IL-6 an excellent target for immunomodulatory therapy. Tocilizumab was the first IL-6 inhibitor to demonstrate efficacy in humans. It inhibits IL-6 from binding to both membrane-bound and soluble receptor and can be administered via intravenous (IV) and subcutaneous (SC) routes. It has been FDA approved for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Following the approval in systemic diseases, its efficacy was demonstrated in various uveitis studies including a phase 2 clinical trial (STOP-Uveitis). Overall, tocilizumab has shown a good safety profile with the risk of malignancy consistent with that expected in patients with rheumatoid arthritis. However, tocilizumab therapy has been shown to increase the risk for gastrointestinal perforation and dose-dependent neutropenia. Following the success of tocilizumab, several other agents targeting the IL-6 pathway are in the pipeline. These include sirukumab, siltuximab, olokizumab, clazakizumab, and EBI-031 which target IL-6; Sarilumab and ALX-0061 act on the IL-6 receptor.

Conclusion: Studies have shown that IL-6 inhibitors can be effective in the management of NIU. In addition, the levels of IL-6 are elevated in other ocular vascular diseases such as retinal vein occlusion and diabetic macular edema. The roles of IL-6 inhibition may be broadened in the future to include the management of retinal vascular diseases and non-uveitic macular edema.

Keywords: Biological therapy; Immunomodulatory therapy; Interleukin-6; Interleukin-6 inhibition; Newer biologics; Non-infectious uveitis; Steroid-sparing therapy; Tocilizumab; Uveitis.

Fig. 1

IL-6 classic-signaling and IL-6 trans-signaling. IL-6 classic signaling requires membrane bound IL-6R and is restricted to hepatocytes, some epithelial cells and some leukocytes. IL-6 trans-signaling requires sIL-6R and is possible on all cells of the body since all cells express the gp130 protein. Adapted from “IL-6 trans-signaling via the soluble IL-6 receptor: Importance for the pro-inflammatory activities of IL-6.” by Rose-John S, Int J Biol Sci 2012; 8:1237-1247 [Copyright: Ivyspring International Publisher]

Fig. 2

Signaling, activation, and transduction pathways of IL-6. Adapted from “Hall of Fame among Pro-inflammatory Cytokines: Interleukin 6 Gene and Its Transcriptional Regulation Mechanisms.” by Luo Y, Zheng SG. Immunol. 2016; 7:604. [Copyright: © 2016 Luo and Zheng]

Fig. 3

Pro- and anti-inflammatory activities of IL-6. Anti-inflammatory activities of IL-6 include STAT3-dependent regeneration of epithelial cells and the induction of the hepatic acute-phase response. These activities are dependent on the membrane-bound IL-6R. Pro-inflammatory activities of IL-6 include recruitment of inflammatory cells, inhibition of apoptosis of inflammatory cells, and inhibition of regulatory T cell differentiation. Adapted from “Hall of Fame among Pro-inflammatory Cytokines: Interleukin-6 Gene and Its Transcriptional Regulation Mechanisms.” by Luo Y, Zheng SG. Immunol. 2016; 7:604. [Copyright: Ivyspring International Publisher]

Fig. 4

A case of an 18-year-old male subject with idiopathic panuveitis and macular edema who was a subject in the STOP-Uveitis Study, demonstrating changes in vitreous haze and central retinal thickness after treatment with intravenous infusions of 4 mg/kg tocilizumab. The subject was not on any other therapy while he was being treated with tocilizumab. [Adapted from Sepah YJ, Sadiq MA, Chu DS, et al. Primary (month-6) outcomes of the STOP-uveitis study: Evaluating the safety, tolerability, and efficacy of tocilizumab in patients with non-infectious uveitis. Am J Ophthalmology 2017; 183:71-80.]