PMID- 31523783 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220410 IS - 1869-5760 (Print) IS - 1869-5760 (Electronic) IS - 1869-5760 (Linking) VI - 9 IP - 1 DP - 2019 Sep 16 TI - Interleukin-6 inhibition in the management of non-infectious uveitis and beyond. PG - 17 LID - 10.1186/s12348-019-0182-y [doi] LID - 17 AB - 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. FAU - Karkhur, Samendra AU - Karkhur S AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. AD - Department of Ophthalmology, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, India. FAU - Hasanreisoglu, Murat AU - Hasanreisoglu M AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. AD - Department of Ophthalmology, School of Medicine, Gazi University, Ankara, Turkey. FAU - Vigil, Erin AU - Vigil E AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. AD - University of Texas Southwestern Medical Center, Dallas, TX, USA. FAU - Halim, Muhammad Sohail AU - Halim MS AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. FAU - Hassan, Muhammad AU - Hassan M AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. FAU - Plaza, Carlos AU - Plaza C AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. AD - Department of Ophthalmology, Hospital Universitario de Leon, Leon, Spain. FAU - Nguyen, Nam V AU - Nguyen NV AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. AD - University of Nebraska, Lincoln, USA. FAU - Afridi, Rubbia AU - Afridi R AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. FAU - Tran, Anh T AU - Tran AT AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. FAU - Do, Diana V AU - Do DV AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. FAU - Sepah, Yasir J AU - Sepah YJ AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. FAU - Nguyen, Quan Dong AU - Nguyen QD AD - Byers Eye Institute, Spencer Center for Vision Research, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA. ndquan@stanford.edu. LA - eng PT - Journal Article PT - Review DEP - 20190916 PL - Germany TA - J Ophthalmic Inflamm Infect JT - Journal of ophthalmic inflammation and infection JID - 101553216 PMC - PMC6745304 OTO - NOTNLM OT - Biological therapy OT - Immunomodulatory therapy OT - Interleukin-6 OT - Interleukin-6 inhibition OT - Newer biologics OT - Non-infectious uveitis OT - Steroid-sparing therapy OT - Tocilizumab OT - Uveitis COIS- The authors declare that they have no competing interests. EDAT- 2019/09/17 06:00 MHDA- 2019/09/17 06:01 PMCR- 2019/09/16 CRDT- 2019/09/17 06:00 PHST- 2019/03/04 00:00 [received] PHST- 2019/08/02 00:00 [accepted] PHST- 2019/09/17 06:00 [entrez] PHST- 2019/09/17 06:00 [pubmed] PHST- 2019/09/17 06:01 [medline] PHST- 2019/09/16 00:00 [pmc-release] AID - 10.1186/s12348-019-0182-y [pii] AID - 182 [pii] AID - 10.1186/s12348-019-0182-y [doi] PST - epublish SO - J Ophthalmic Inflamm Infect. 2019 Sep 16;9(1):17. doi: 10.1186/s12348-019-0182-y.