Anti-Interleukin-6 Antibody as Treatment for Giant Cell Arteritis

Bench to Bedside 61. Langford CA, Cuthbertson D, Ytterberg SR, Khalidi N, Monach PA, Carette S, Seo P, Moreland LW, Weisman M, Koening CL, Sreih AG, Spiera R, McAlear CA, Warrington KJ, Pagnoux C, McKinnon K, Forbess LJ, Hoffman GS, Borchin R, Krischer JP, Merkel PA. A randomized, double-blind trial of abatacept (CTLA4Ig) for the treatment of giant cell arteritis. Arthritis Rheumatol. 2017;69:837-845. 62. Conway R, O'Neill L, O'Flynn E, Gallagher P, McCarthy GM, Murphy CC, Veale DJ, Fearon U, Molloy ES. Ustekinumab for the treatment of refractory giant cell arteritis. Ann Rheum Dis. 2016;75:1578-1579. 63. Unizony S, Arias-Urdaneta L, Miloslavsky E, Arvikar S, Khosroshahi A, Keroack B, Stone JR, Stone JH. Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (Hoboken). 2012;64:1720-1729. 64. Evans J, Steel L, Borg F, Dasgupta B. Long-term efficacy and safety of tocilizumab in giant cell arteritis and large vessel vasculitis. RMD Open. 2016;2:e000137. 65. Loricera J, Blanco R, Hernandez JL, Castaneda S, Mera A, Perez-Pampin E, Peiro E, Humbria A, Calvo-Alen J, Aurrecoechea E, Narvaez J, Sanchez-Andrade A, Vela P, Diez E, Mata C, Lluch P, Moll C, Hernandez I, Calvo-Rio V, OrtizSanjuan F, Gonzalez-Vela C, Pina T, Gonzalez-Gay MA. Tocilizumab in giant cell arteritis: multicenter open-label study of 22 patients. Semin Arthritis Rheum. 2015;44:717-723. 66. Oliveira F, Butendieck RR, Ginsburg WW, Parikh K, Abril A. Tocilizumab, an effective treatment for relapsing giant cell arteritis. Clin Exp Rheumatol. 2014;32:S76-S78. 67. Regent A, Redeker S, Deroux A, Kieffer P, Ly KH, Dougados M, Liozon E, Larroche C, Guillevin L, Bouillet L, Espitia O, Costedoat-Chalumeau N, Soubrier M, Brihaye B, Lifermann F, Lefevre G, Puechal X, Mouthon L, Toussirot E. Tocilizumab in giant cell arteritis: a multicenter retrospective study of 34 patients. J Rheumatol. 2016;43:1547-1552. 68. Seitz M, Reichenbach S, Bonel HM, Adler S, Wermelinger F, Villiger PM. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly. 2011;141:w13156. Anti-Interleukin-6 Antibody as Treatment for Giant Cell Arteritis Yaping Joyce Liao, MD, PhD G iant cell arteritis (GCA) is the most common cause of vasculitis in adults with an annual incidence of 19.8 per 100,000 (1). It is associated with large- and mediumvessel granulomatous inflammation, which leads to thrombosis and ischemia (2). Vision loss is the most feared neurologic consequence of GCA and can occur due to arteritic anterior ischemic optic neuropathy (A-AION), central or branch retinal artery occlusion, cilioretinal artery occlusion, posterior ischemic optic neuropathy, retinal or orbital ischemia, and stroke (3-5). Vision loss from A-AION is typically severe and irreversible (4), and vision can deteriorate in 27% of patients within the first week despite high-dose IV corticosteroid treatment (6). In a study of 840 patients with GCA, the incidence of visual complications was 20.9/1,000 person-years compared with 6.9/1,000 person-years in the reference population or a rate ratio of 3.0 (95% CI 2.3-3.8) (7). In a study of 274 patients with biopsy-proven GCA, 29% had visual manifestations, and 19% had permanent (partial or complete) visual loss (8). In another study of 204 cases of GCA, 23% had visual changes, and 4% suffered complete vision loss (9). Diagnosis of GCA is based on clinical suspicion, elevated systemic inflammatory markers (C-reactive protein and Departments of Ophthalmology and Neurology, Stanford University School of Medicine, Palo Alto, California. The author reports no conflicts of interest. Address correspondence to Yaping Joyce Liao, MD, PhD, Stanford University, Palo Alto, CA 94303-5353; E-mail: [e-mail]. 558 erythrocyte sedimentation rate), and should be confirmed pathologically on temporal artery biopsy, which shows transmural inflammation, medial smooth muscle cell damage, and multinucleated giant cells (10). The mainstay of GCA treatment in the past 6 decades is chronic, high-dose corticosteroid treatment (11-13), which is limited because it has many short- and long-term side effects, and some patients continue to exhibit symptoms or develop recurrence of inflammation (12,14-16). On the cellular level, corticosteroid therapy is limited because it only reduces CD4+ T helper (TH) 17- but not TH1-mediated tissue-destructive immune responses (2). Although the cause is unknown, GCA is associated with polyclonal activation of the CD4+ T cells and macrophages, and there is, thus far, no evidence of an antibody-mediated process (17). In GCA pathogenesis, T cells interact with endothelial cells in the tunica adventitia in an antigenspecific manner, which lead to activation of TH1 and TH17 cells and increased chemokine and cytokine production, including interferon g (IFNg), tumor necrosis factor a (TNFa), and interleukins (IL-6 and IL-17) (2,18). In GCA, there is significantly increased level of plasma vascular endothelial growth factor (VEGF), a cytokine that increases vasopermeability (19). In these patients, increased VEGF has been shown to upregulate Notch receptor ligand Jagged1 in the endothelial cells. This tilts the local T cell repertoire toward the TH1 and TH17 fates and may be one of the earliest triggers of vasculitis and thrombosis (19). Joyce Liao: J Neuro-Ophthalmol 2018; 38: 551-560 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside The accompanying article by Unizony and Kermani (20) highlights the role of IL-6 in GCA pathogenesis and discusses the consideration of anti-IL-6 therapy as treatment of GCA. IL-6 is a key cytokine in the development of GCA as well as other autoimmune diseases, and plays an important role in the regulation of TH17/Treg imbalance (20,21). Patients with GCA exhibit a hypoproliferating Treg compartment enriched in IL-17-secreting Tregs (22). Tocilizumab (TCZ) is the first humanized anti-IL-6 receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis, Castleman disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, GCA (23,24). As a result of this success, anti-IL-6 therapies, delivered intravenously or subcutaneously, are being explored in a variety of autoimmune diseases (25). TCZ is the first Food and Drug Administration-approved treatment for GCA after the demonstration of efficacy and safety in clinical trials (23,24). In one study of 251 patients with GCA, subcutaneous TCZ (162 mg) weekly or every other week combined with a 26-week prednisone taper was significantly better in terms of the rate of sustained glucocorticoid-free remission compared with 26-week or 52-week prednisone tapering plus placebo (23). There also is evidence that TCZ can help reduce chronic corticosteroid treatment associated with adverse events. At the cellular level, treatment with TCZ, in contrast to corticosteroid therapy, corrects the Treg abnormalities observed in patients with GCA by increasing the proliferation and activation of Tregs (22). As we evaluate patients with GCA and weigh the pros and cons of different therapeutic options, there are some important considerations. First, because vision loss from GCA often is devastating, there is a tendency to be aggressive in the treatment course to prevent this complication. However, it is important to remember that visual prognosis is generally poor in GCA despite high-dose corticosteroid treatment (26-28). Subsequent therapeutic decision should not be made based on the severity of vision loss in the first eye. Second, it is also important to remember that although symptom relapse in GCA may occur after initiation of steroid therapy, the new onset of vision loss is actually rare. In a retrospective study of 245 patients, the incidence of vision loss after initiation of treatment was estimated to be 1% at 5 years (27). In a 2014 prospective study of 106 patients with GCA, 64% experienced at least 1 relapse (51% polymyalgia rheumatica symptoms, 31% cranial symptoms, and 18% systemic complaints), but only 1 patient (,0.1%) developed vision loss (15). In a 2015 prospective study of 128 patients with GCA, 34% had clinical relapse (42% headache, 51% polymyalgia rheumatic symptoms, and 12% ischemia), and 5% had new, transient visual symptom, but none had vision loss (16). Third, with increased awareness of the visual complications of GCA, the frequency of visual loss may be declining. For example, in a 55-year study of 204 patients with GCA, the incidence of Joyce Liao: J Neuro-Ophthalmol 2018; 38: 551-560 A-AION in the 1980-2004 cohort was significantly lower compared with that of the 1950-1979 group (6% vs 15%, P = 0.03) (29). Choosing the right treatment for patients with GCA remains challenging. Although there is now an approved alternative to corticosteroids, our experience with TCZ is still limited compared with more than 6 decades of experience with corticosteroids. TCZ has promising efficacy in GCA, but there have been several reports of clinically significant, albeit rare, side effects such as severe neutropenia, recurrent pneumonia, cytomegalovirus, and other infections (30-32). Further research into the pathogenesis of GCA and the development of new therapies that can reverse vision loss and prevent relapse are critically needed. ACKNOWLEDGMENTS The author is grateful to Dr. Cornelia Weyand for her thoughtful comments. REFERENCES 1. Chandran AK, Udayakumar PD, Crowson CS, Warrington KJ, Matteson EL. The incidence of giant cell arteritis in Olmsted County, Minnesota, over a 60-year period 1950-2009. Scand J Rheumatol. 2015;44:215-218. 2. Weyand CM, Liao YJ, Goronzy JJ. The immunopathology of giant cell arteritis: diagnostic and therapeutic implications. J Neuroophthalmol. 2012;32:259-265. 3. Gonzalez-Gay MA, Garcia-Porrua C, Llorca J, Hajeer AH, Branas F, Dababneh A, Gonzalez-Louzao C, Rodriguez-Gil E, Rodriguez-Ledo P, Ollier WE. 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