IL-6 Blockade and its Therapeutic Success in Giant Cell Arteritis

Bench to Bedside Section Editors: Lynn K. Gordon, MD, PhD Jonathan Horton, MD, PhD IL-6 Blockade and its Therapeutic Success in Giant Cell Arteritis Sebastian Unizony, MD, Tanaz A. Kermani, MD, MS GIANT CELL ARTERITIS DEFINITION AND CLINICAL ASPECTS G iant cell arteritis (GCA) is a granulomatous inflammatory disease affecting the aorta and/or its major branches, with a predilection for the extracranial divisions of the carotid and vertebral arteries (1). It is the most common form of primary vasculitis among adults in Western countries with the highest incidence rates in Scandinavian countries (2). The disease generally occurs in individuals older than 50 years, increases with age, and is 2-3 times as likely to occur in women as in men (2,3). Clinical manifestations of GCA include constitutional symptoms (e.g., asthenia and weight loss), headaches, jaw claudication, shoulder and hip girdle pain and stiffness (i.e., polymyalgia rheumatica), fever, and elevated acutephase reactants. The most feared consequence of GCA pertains to vision loss due to arteritic anterior ischemic optic neuropathy (AAION), which occurs in up to 15%- 20% of cases (4-6). Although AAION is the most common cause of visual manifestations in GCA, other ocular manifestations have been reported including central or branch retinal artery occlusion, diplopia from ischemia of extraocular muscles or ocular motor nerves, and, rarely, posterior ischemic optic neuropathy or cortical blindness (5-7). Other clinical features may include scalp and tongue necrosis, large-artery complications (aortic aneurysm, aortic dissection, and ischemic manifestations from large-artery stenosis), stroke, myocardial infarction, and venous thromboembolism (4,8-15). The diagnosis of GCA is based on its clinical presentation and can often be confirmed with a temporal artery biopsy. The majority of patients with GCA also demonDivision of Rheumatology, Allergy and Immunology (SU), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and Division of Rheumatology (TAK), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. S. Unizony: Roche-GiACTA trial investigator; GSK-Scientific advisory board; Sanofi-Scientific advisory board; Galapagos- Consulting. T. A. Kermani: Roche-Consultant for GCA educational module by Med-IQ which received educational grant from Hoffmann-La Roche. Address correspondence to Sebastian Unizony, MD, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Yawkey 2C, Boston, MA 02114; E-mail: [e-mail] Unizony and Kermani: J Neuro-Ophthalmol 2018; 38: 551-560 strate changes suggesting arterial inflammation when noninvasive vascular imaging is used (e.g., vascular ultrasound, magnetic resonance angiography, computed tomography angiography, positron emission tomography). These vascular abnormalities, which are often subclinical, include circumferential arterial wall thickening, mural edema or contrast/radioactive isotope enhancement, as well as segments of luminal narrowing, occlusion, or aneurysmal dilatation (16) (Fig. 1). Most patients with GCA develop relapses despite prolonged treatment with corticosteroids (CS; e.g., prednisone) (17-19). Unfortunately, CS lead to drug-related toxicity in the great majority of cases (20-22). Until recently, no effective medications to maintain disease remission and spare the use of CS were available. Two recent randomized controlled trials (RCTs), however, have demonstrated that tocilizumab (TCZ), an interleukin (IL)6 receptor (IL-6R) antagonist, is effective in controlling disease activity off of CS in a sizable proportion of patients with GCA (23,24). GIANT CELL ARTERITIS PATHOGENESIS The etiology of GCA remains unknown. In contrast, the pathophysiology of the disease is partially understood. The main histopathological feature of GCA is a granulomatous inflammatory process rich in CD4+ T cells, macrophages, and giant cells that involves large- and medium-sized arteries. Studies have shown that dysregulation of the immune response in GCA leads to abnormal activation and maturation of arterial dendritic cells, which attract CD4+ T cells to the blood vessel wall in a process that actively involves endothelial cells of the vasa vasorum (25,26). Once the disease is well established, an imbalance among CD4+ T helper (Th)1, Th17 and regulatory T (Treg) cells is thought to drive the perpetuation of the inflammatory process (27- 31) (Fig. 2). Patients with new-onset GCA demonstrate Th1 and Th17 cell infiltrates in their arteries and an expansion of these cell subsets in the peripheral blood (27,29,30). Conversely, a series of Treg defects have been reported to occur at different stages of the disease (28,29). Although the Th17 axis seems to be sensitive to prednisone, some evidence suggests that the abnormalities described in both the Th1 and Treg subsets are resistant or less responsive to CS 551 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside FIG. 1. A. Computed tomography angiography shows circumferential wall thickening of the ascending thoracic aorta (arrows) in a patient with giant cell arteritis. B. Positron emission tomography demonstrates avid uptake of 18-fluorodeoxyglucose in the ascending and descending thoracic aorta (arrows) in a patient with active giant cell arteritis. therapy (27,28,32), possibly accounting for the high relapse rate seen after CS tapering. IL-6 AS AN INFLAMMATORY MEDIATOR IL-6 is a pleiotropic cytokine produced by T cells, B cells, macrophages, endothelial cells, fibroblasts, and muscle cells from different stimuli (e.g., IL-1, TNF-a, activation of tolllike receptors, prostaglandins, adipokines, and other cytokines) (33). It exerts its biological activity through binding to the IL-6 receptor (IL-6R), which may be expressed as a transmembrane protein or circulate in blood as a soluble form (34). A functional cell membrane IL-6R consists of 2 subunits: IL-6Ra (gp80 or CD126), an 80-kDa protein that binds to IL-6, and IL-6Rb (gp130 or CD130), a 130-kDa protein that is in charge of the signal transduction. Soluble forms of IL-6R are generated by differential splicing of IL-6R mRNA (e.g., monocytes and activated T cells) and cleavage and shedding of IL-6Ra (e.g., neutrophils). Although almost all cell types in the human body express IL-6Rb and can therefore respond to the complex formed by IL-6 and soluble IL-6R ("trans-signaling"), only 552 FIG. 2. Pathogenesis of giant cell arteritis. The key cellular and molecular players involved in the pathogenesis of GCA are shown. An imbalance among CD4+ T helper (Th)1, Th17, and regulatory T (Treg) cells leads to the formation of arterial granulomatous lesions. Interleukin (IL)-6 is a key inflammatory mediator in this process. IFN-g, interferon gamma; TGF-b, transforming growth factor beta; TNF a, tumor necrosis factor alpha. few specific cell types such as hepatocytes, megakaryocytes, and leucocytes (i.e., lymphocyte, neutrophils, monocytes, macrophages) express IL-6Ra and respond directly to the cytokine ("classic signaling") (33). IL-6 and IL-6R coupling primarily initiates the activation of Janus kinase (JAK), which in turn leads to tyrosine phosphorylation and activation of signal transducer and activator of transcription (STAT) 3. Activated STAT3 translocates to the cell nucleus and binds to the interferon-gamma activated sequence located within promoter elements of a great variety of target genes involved in cellular activation, differentiation, and survival (e.g., c-Fos, c-Myc, Bcl-2, Cyclin D, IL-12A, CXCL-10, IFNg, TNF-a, IL-1b, IL-21, IL-23, IL-23R, IL-17A, MCP1, Foxp3, IL-10, ICAM-1, VEGF-A, MMP-1, iNOS, COX2, etc). These events translate into modulation of the immune response among other functions (33). IL-6 is a main orchestrator of the innate and adaptive immunity. It is important for T-cell activation, B-cell differentiation, plasma cell survival, and granulocyte development (33,35,36). Of great relevance in the pathogenesis of GCA, IL-6 governs the proliferation, survival, and commitment of T cells and modulates their effector cytokine production. IL-6 is not only a key driver for the polarization Unizony and Kermani: J Neuro-Ophthalmol 2018; 38: 551-560 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside culating IL-6 have been associated with a stronger systemic inflammatory response, higher relapse rates, and prolonged CS treatments (47). Third, from a pathophysiologic perspective, 2 of the cell types involved in the pathogenesis of the disease, the Th17 and Treg cells, are subject to opposite regulation by IL-6 (see "Mechanisms of action of IL-6 blockade in giant cell arteritis"). Finally, the ultimate proof of the importance of IL-6 in the pathogenesis of GCA comes from the results of 2 RCTs that have unequivocally demonstrated that IL-6 blockade therapy is an effective treatment strategy (see "Giant cell arteritis treatment") (23,24). MECHANISMS OF ACTION OF IL-6 BLOCKADE IN GIANT CELL ARTERITIS FIG. 3. Key role of IL-6 in the biology of Th17 cells and Tregs. CD4+ T helper (Th)17 and regulatory T (Treg) cells develop from a common naive CD4+T-cell precursor under the influence of transforming growth factor-b (TGF-b). In the presence of interleukin (IL)-6, TGF-b-stimulated CD4+T cells differentiate into Th17 cells, whereas in the absence of IL-6, these TGF-b-stimulated precursors are induced to become Tregs. Foxp3, forkhead box P3; ROR-C, RAR-related orphan receptor. of CD4+ T cells toward the Th17 phenotype, but also suppresses the differentiation and function of Tregs (Fig. 3) (33,37). Moreover, IL-6 participates in the activation of monocytes and macrophages, and induces endothelial cells to acquire the proinflammatory phenotype that is necessary for trafficking of these and other leukocytes to the sites of inflammation. Due to its strategic location at the intersection of the innate and adaptive immune networks, the IL-6 system has the potential to perpetuate inflammatory responses if it becomes dysregulated. PIVOTAL ROLE OF IL-6 IN THE PATHOGENESIS OF GIANT CELL ARTERITIS Several observations highlight the pivotal role that IL-6 plays in the pathogenesis and clinical course of GCA. First, temporal artery biopsies from newly diagnosed patients demonstrate increased IL-6 mRNA and protein expression (38-40). In one study, a more intense IL-6 signal was associated with lower risk of ischemic complications including visual loss, leading to the hypothesis that this cytokine may have a protective effect in the ischemic manifestations through its promotion of angiogenesis and neovascularization (41). Second, elevated serum IL-6 levels have been reported in the peripheral blood of patients with active disease (42-46). In addition, higher concentrations of cirUnizony and Kermani: J Neuro-Ophthalmol 2018; 38: 551-560 Recent research has shown that one of the mechanisms by which IL-6 signaling inhibition may exert its therapeutic effects in GCA may involve the correction of abnormalities seen in the Treg compartment (Fig. 4). It has been established that considerable phenotypical and functional plasticity exists within the Treg and the Th17 cell subsets (48,49). Th17 cells and Tregs develop from a common naive CD4+T-cell precursor under the influence of transforming growth factor-b (TGF-b) (Fig. 3). In the presence of proinflammatory mediators (e.g., IL-6), TGF-b-stimulated CD4+T cells differentiate into Th17 cells, whereas in the absence of an inflammatory microenvironment, these TGF-b-stimulated precursors are induced to become Tregs (37). Under specific circumstances, fully differentiated Tregs may lose their suppressive function and become IL-17-producing cells (e.g., "pathogenic Tregs" and exFoxp3 Th17 cells) (50-52). One mechanism regulating the divergent fates between Tregs and Th17 cells involves the molecular antagonism of RARrelated orphan receptor (ROR)C by Foxp3 through the domain encoded by the exon 2 of the FOXP3 gene (53). Tregs that express a spliced variant of Foxp3 lacking exon 2 (Foxp3D2) are less suppressive (54) and more likely to become IL-17-producing Tregs. Patients with active GCA have a defective Treg population in peripheral blood that demonstrates decreased proliferation, overexpression of Foxp3D2, and increased production of IL-17 (IL-17+ Tregs) (28). These proinflammatory Tregs also express other markers commonly associated with the Th17 lineage (e.g., CD161) (51) and reside within the CD45RA2Foxp3low nonsuppressive T-cell subset characterized by Miyara et al (55). In addition, lymphocytes that express both Foxp3 and IL-17 have also been identified infiltrating inflamed GCA arteries (56). It is speculated that Foxp3D2 Tregs in GCA have lost their suppressive function, and have themselves become pathogenic as a source of IL17. Treatment with TCZ, in contrast to CS therapy, restores the proliferative capacity of Tregs and reverts their defective phenotype (i.e., Foxp3D2 and IL-17 expression) (Fig. 4) 553 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside FIG. 4. Defective Treg cells in GCA and mechanism of action of IL-6 blockade. Patients with active GCA demonstrate an expanded population of regulatory T (Treg) cells in peripheral circulation characterized by a low proliferative state (decreased expression of Ki-67). These defective Tregs express a spliced variant of the master transcription factor forkhead box P3 (Foxp3) lacking exon 2 (Foxp3D2) and produce interleukin (IL)-17. IL-6 blockade therapy with tocilizumab leads to normalization of this pathogenic phenotype and expression of Treg markers of activation, trafficking, and terminal differentiation. CCR4, C-C chemokine receptor type 4; CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IL6R, IL-6 receptor; Ki-67, antigen KI-67. (28). In addition, IL-6 blockade in patients with GCA is associated with increased numbers of activated Tregs (CD45RA2Foxp3high) and increased Treg expression of markers of trafficking (CCR4) and terminal differentiation (CTLA-4) (Fig. 4) (28). Although the function of IL-17- producing Tregs and Foxp3D2 Tregs in GCA remains to be determined, it is possible that the mechanism of action of IL-6 inhibition in this disease is in part mediated through upregulation of the Treg response and correction of Treg abnormalities related to the state of chronic inflammation and/or prolonged CS exposure. GIANT CELL ARTERITIS TREATMENT Until recently, CS have been the mainstay of treatment in GCA. Given the potential for serious complications such as vision loss, high-dose CS are initiated when there is clinical suspicion of this diagnosis while awaiting confirmation (57). Unfortunately, despite treatment, relapses are common resulting in the need to increase the dose of and prolong the treatment with CS (17-19). CS therapy, although effective in most cases, is associated with significant adverse effects (AE) (22,23). This problem prompted research looking for CS-sparing alternatives. Clinical trials in patients with GCA, however, have been challenging, given the lack of standardized measures and definitions of disease activity (58). Studies investigating the role of multiple immunosuppressive therapies such as azathioprine, cyclosporine A, cyclophosphamide, and TNF-a inhibitors (e.g., infliximab) have yielded disappointing results (57). Trials using methotrexate have demonstrated conflicting results with a metaanalysis aggregating these studies showing some possible modest effects, which are not clinically meaningful (59,60). A Phase II RCT of abatacept (cytotoxic T-lymphocyte antigen [CTLA-4] immunoglobulin that inhibits T-cell 554 activation) (61) and a small uncontrolled series using ustekinumab (monoclonal antibody against IL-12/23p40) (62) have shown encouraging preliminary results that need confirmation in larger and more rigorous studies. In contrast with the above-mentioned reports, 2 recent clinical trials have unequivocally demonstrated that IL-6 signaling inhibition is an efficacious strategy for the remission maintenance and CS-sparing in GCA (See "IL-6 blockade therapy in giant cell arteritis"). IL-6 Blockade Therapy in Giant Cell Arteritis IL-6 inhibition with TCZ has become part of the standard of care for treatment of GCA after evidence was gathered from a broad spectrum of research studies ranging from uncontrolled series to RCTs. Several initial case reports and case series reported efficacy of TCZ as a CS-sparing medication in patients with GCA, many of whom had failed other immunosuppressive therapies or had relapsing disease for which they were CS-dependent (63-68). A Phase II, single-center, randomized, double-blind, placebo-controlled trial was the first to demonstrate efficacy of TCZ in GCA (24). In this study, 30 patients with GCA (23 [77%] with newly diagnosed disease) were randomized to TCZ 8 mg/kg intravenously every 4 weeks for 13 infusions (N = 20) and oral prednisolone, or oral prednisolone and placebo (N = 10) (24). Prednisolone was tapered and discontinued using a standardized protocol. The primary outcome was complete remission (absence of any signs or symptoms of GCA with normal sedimentation rate and C-reactive protein at a prednisolone dose of 0.1 mg/kg/d) at Week 12. The primary endpoint was met in 85% of patients in the TCZ group compared with only 40% in the placebo group (P = 0.03) (24). TCZ also was superior to placebo in multiple other outcomes that were assessed. Relapse-free survival at Week 52 was 85% in the TCZ Unizony and Kermani: J Neuro-Ophthalmol 2018; 38: 551-560 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside group compared with 20% in the placebo group (P = 0.001) (24). Furthermore, 80% of patients in the TCZ group were able to discontinue prednisolone compared with only 20% in the placebo group (risk difference 60%, 95% CI 30-90). The mean time to discontinuation of prednisolone was 38 weeks (95% CI 35-42) in the TCZ group compared with 50 weeks (95% CI 46-54) in the placebo arm (P , 0.0001) (24). AEs were observed in 15 patients (75%) in the TCZ group (26 events; 7 serious AEs) and 7 patients (70%) in the placebo group (23 events; 10 serious AEs) (24). This included 3 gastrointestinal complications in the TCZ group and 3 serious cardiovascular events in the placebo group (24). There were 9 episodes of neutropenia in 4 patients treated with TCZ (24). Infectious AEs were observed in 10 patients in the TCZ group compared with 1 in the placebo arm (24). Of note, there were no episodes of vision loss in either the treatment or placebo arm during the study. The results of a Phase III, randomized, placebocontrolled trial confirmed and expanded the findings observed in previous studies (23). In this large, multicenter trial, 251 patients with newly diagnosed (47%) or relapsing GCA with active disease (GiACTA) were randomized in a 1:1:1:2 ratio to placebo plus 26-week prednisone taper (PBO + 26, N = 50), placebo plus 52-week prednisone taper (PBO + 52, N = 51), TCZ 162 mg every other week plus 26-week prednisone taper (TCZ Q2W, N = 50), or TCZ 162 mg weekly plus 26-week prednisone taper (TCZ QW, N = 100) (23). The prednisone taper was prespecified and standardized. The primary endpoint was sustained prednisone-free remission at Week 52 comparing TCZ QW and TCZ Q2W vs PBO + 26. Disease flares were determined by the investigators and defined as the recurrence of signs or symptoms of GCA and/or a sedimentation rate $30 mm per hour that required escape therapy with increased doses of prednisone. Disease remission was defined as the absence of flare and normalization of C-reactive protein levels (23). The primary endpoint of GiACTA was met in 56% of patients in the TCZ QW arm and in 53% of patients in the TCZ Q2W arm, compared with only 14% of patients in the PBO + 26 arm (P , 0.001 for both comparisons) (23). A key secondary endpoint was the comparison between the TCZ groups vs the PBO + 52 group, which better reflects the usual treatment of GCA. Sustained prednisone-free remission was achieved in only 18% of patients in the PBO + 52 group, again demonstrating superiority of TCZ QW and TCZ Q2W groups (P , 0.001 for both comparisons) (23). Other secondary endpoints of the GiACTA study included time to disease relapse, cumulative prednisone dose by Week 52, and patient reported quality of life measures (23). Relapses were observed in 23% of patients in the TCZ QW arm, 26% of patients in the TCZ Q2W arm, 68% of patients in the PBO + 26 arm, and 49% of patients Unizony and Kermani: J Neuro-Ophthalmol 2018; 38: 551-560 in the PBO + 52 arm (23). The hazard ratio for relapse was 0.23 (99% CI 0.11-0.46) for patients treated TCZ QW compared with PBO + 26 and 0.28 (99% CI 0.12-0.66) for the TCZ Q2W group compared with the PBO + 26 group. A prespecified subgroup analysis to assess the efficacy of TCZ in patients with new onset vs relapsed disease at baseline demonstrated a dose-response effect of TCZ in the relapsing subgroup, which obtained more benefits with weekly dosing as opposed to the every other week dosing. By contrast, such differential response was not observed in patients with newly diagnosed disease (23). Furthermore, the cumulative median prednisone dose over 52 weeks was 1,862 mg in each of the TCZ groups compared with 3,296 mg in the PBO + 26 group (P , 0.0001) and 3,818 mg in the PBO + 52 group (P , 0.0003) (23). Finally, compared with the PBO + 26 and the PBO + 52 groups, the TCZ QW group was associated with better patient-reported outcomes including the 36-Item Short Form Survey (SF-36), Functional Assessment of Chronic Illness Therapy fatigue score, and patient global assessment (23). In terms of safety, at least one AE was observed in the majority of patients in the GiACTA study: 98% TCZ QW, 96% TCZ Q2W, 96% PBO + 26, and 92% PBO + 52 (23). Most commonly observed AEs were infections. Serious AEs were seen in 15% of the patients in the TCZ QW group, 14% of the patients in the TCZ Q2W group, 22% of the patients in the PBO + 26 group, and 25% of the patients in the PBO + 52 group (23). One patient in the TCZ Q2W arm developed ischemic optic neuropathy, which resolved after treatment with high doses of prednisone (23). Grade 3 neutropenia was observed in 4% of subjects in each TCZ arm (23). There were 2 malignancies diagnosed during the study, both in the PBO groups. Finally, no gastrointestinal perforations or deaths occurred during the trial (23). CONCLUSIONS AND FUTURE PERSPECTIVES Until recently, therapies that could maintain disease remission and prevent the well-known toxicity associated with excessive CS exposures have been the greatest unmet need for the GCA population. Studies elucidating the role of IL-6 in the inflammatory cascade in general and in the pathogenesis of GCA in particular have been instrumental in the eventual success of IL-6 blockade for the treatment of this condition. Further research is now required to answer several outstanding questions pertaining to the duration of TCZ treatment, the use of CS in patients receiving TCZ (e. g., can TCZ be used in monotherapy?), and whether TCZ is effective in controlling arterial inflammation and preventing large-artery complications. These and other questions will fine tune the use of TCZ for GCA. In addition, IL-6 inhibition has made even more pressing the need for 555 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Bench to Bedside accurate biomarkers to monitor disease activity and response to treatment. More than 25 years passed from the initial observations that patients with GCA demonstrate an increased IL-6 signal to the demonstration of the efficacy of IL-6 blockade in rigorous clinical trials. We should do better. Fortunately, our understanding of the mechanisms of disease involved in GCA has improved and will likely continue to evolve in the future leading to the discovery of other important pathways and targeted treatment strategies. REFERENCES 1. 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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.