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.

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

“…Recently it was shown that in AVS-patients who underwent AVR had lower levels of plasma IL-6 after surgery, indicating that neutralizing IL-6 may be beneficial for attenuation of AVS [69]. Monoclonal humanized mouse antibody inhibitor of IL-6 receptor (Tocilizumab; Actemra, Roche AG, Basel, Switserland) antagonizes IL-6 signaling by preventing IL-6 binding with its corresponding receptors which is currently approved to treat rheumatoid arthritis [70]. In vascular smooth muscle cells it was shown that in vitro neutralization of IL-6 using anti-IL-6 antibodies reduced BMP2 and RUNX2 expression leading to decreased calcification [71].…”

Anti-interleukin-6 receptor therapy with tocilizumab for refractory pseudophakic cystoid macular edema

“… 15 More recent studies noted efficacy of anti-IL-6R therapy in chronic cystoid macular edema secondary to other etiologies. 16 , 17 , 18 In a multicenter study of patients with refractory and noninfectious uveitic CME, treatment with TCZ showed a statistically significant reduction in macular thickness (432.7 ± 161.8 μm vs 259.1 ± 49.5 μm; p < 0.0001). Moreover, 21 of 23 eyes (91%) showed reduction in number of anterior chamber cells after 12 months of TCZ therapy, and resolution of vitritis was observed in 19 of 27 eyes (70.3%).…”

“…It demonstrated that ME could develop in up to 39% of patients on active mycophenolate treatment and that mycophenolate alone is not always sufficient in treating or preventing UME. 34 Additional immunomodulatory therapeutic agents, including anti-IL-6 tocilizumab, have been studied, 15 , 16 , 17 , 18 but these reports have been limited to cases of cystoid macular edema that occurred outside the context of post-cataract surgery. To the best of our knowledge, this is the first published case of a patient with refractory CME concerning for Irvine-Gass syndrome treated with anti-IL-6 therapy using tocilizumab.…”

“…Given the severity of our patient's CME, we also chose to begin concomitant therapy with methylprednisolone infusions with each cycle to allow for possible synergistic effects, though tocilizumab monotherapy has also shown efficacy for CME in previous studies. 16 , 17 , 18 …”

“…For example, Adán et al reported the use of tocilizumab infusions for the treatment for refractory uveitis-related CME, 15 and more recent studies noted efficacy of anti-IL-6 therapy in chronic CME of other etiologies. 16 , 17 , 18 In the STOP-UVEITIS study, an open-label and prospective randomized trial, infusion of tocilizumab at a dose of 4 or 8 mg/kg every four weeks for six months to treat active uveitis was effective in improving vitreous haze, CME, and visual acuity. 19 …”