Should Tocilizumab Be Used Routinely in New Patients With a Diagnosis of Giant Cell Arteritis?

Myelinated nerve fibers (MNF) are characterized as whitish, relatively sharply demarcated, feather-like structures located in the retinal nerve fiber layer. MNF are located quite frequently in contiguity with the optic nerve head. This may lead to a diagnostic dilemma by preventing clear visualization of the optic disc margins. We herein describe the utility of multicolor imaging (MCI) in identifying optic disc anatomy in a case of MNF contiguous to the disc. MCI and infrared reflectance were superior to color fundus photography in delineating disc margins. Our pilot study describes the efficacy of MCI in delineating optic disc anatomy in a case of MNF.

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Should Tocilizumab Be Used Routinely in New Patients With a Diagnosis of Giant Cell Arteritis? Alfredo Sadun, MD, Lynn Gordon, MD Giant cell arteritis (GCA) is the most common vasculitis in the elderly, and left untreated can result in devastating visual loss. Corticosteroids have been the mainstay of treatment for decades, but carry a host of serious and potentially life-altering complications. Tocilizumab, an interleukin-6 inhibitor, can reduce steroid-related complications and allow for a more rapid steroid taper in patients with GCA. Two experts discuss whether tocilizumab should be routinely used for treatment of this condition. Pro: Alfredo A. Sadun, MD, PhD I have been diagnosing GCA in patients who present with visual problems for over 40 years. And, I have learned 2 big lessons: 1) Just when I think I know the presentation, GCA has a new wrinkle in store for me, and 2) I hate prednisone. Although I worry about the long-term treatment with prednisone, I hate blindness more, and so, I have kept on using it. Finally, the choice will not be so hard. GCA is a dangerous and challenging disease involving granulomatous inflammation in the walls of medium- and large-sized arteries. A patient with GCA presents to the ophthalmologist with acute visual loss or, less often, diplopia, with the looming prospect of bilateral severe and permanent visual loss. When the patient who presents with sudden visual loss is older than 65 years, has jaw claudication, scalp tenderness, myalgia, malaise, fatigue, and weight loss, and demonstrates several key abnormal blood values (high erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelets), then the diagnosis is straightforward and relatively easy (1,2). But, some patients are atypical in presentation, and this requires biopsy of temporal arteries and much concern and anxiety before the diagnosis and decision to treat can be made. Corticosteroids (usually prednisone) are the mainstay of successful management and usually prevent the patient from losing further vision; yet, the remission of GCA often requires years of prednisone with the attendant risk of severe side effects (2-5). This has the consequence of high morbidity and mortality (6). It has long been known that interleukin-6 plays a major role in the acute pathogenesis of GCA (7,8). Tocilizumab is a humanized immunoglobulin monoclonal antibody that binds to the alpha chain of the interleukin-6 receptor and blocks signaling (9). Several case studies and series successfully demonstrated the utility of tocilizumab in the treatment of GCA (10-12). Department of Ophthalmology, UCLA, Los Angeles, California. The authors report no conflicts of interest. Sadun and Gordon: J Neuro-Ophthalmol 2019; 40: 117-121 Consequently, Villiger et al (13) performed and published a Phase 2, randomized, double-blind, placebo-controlled trial of tocilizumab for the induction and maintenance of remission in GCA. Twenty patients with GCA were randomly assigned to receive tocilizumab and prednisone, and these were compared with 10 patients with GCA receiving placebo and prednisone. The primary outcome was set to be the proportion of patients who achieved complete remission of disease at a prednisone dose of less than 0.1 mg/kg per day at 12 weeks. At 12 weeks, 85% of those on tocilizumab vs 40% of those with placebo reached this endpoint (13). Equally importantly, 35% of patients on tocilizumab vs 50% of those on placebo had serious corticosteroid-associated side effects. In short, corticosteroids could be more rapidly tapered, and the cumulative prednisone levels reduced. This led to a prospective, randomized, placebo-controlled Phase 3 clinical trial of tocilizumab for GCA (GiACTA) that was published in 2017 in the New England Journal of Medicine (14). Stone et al assessed 251 patients to receive 1 of 2 doses of tocilizumab vs placebo, both in combination with prednisone that was tapered over either 26 or 52 weeks. They concluded that tocilizumab in either weekly or every other week subcutaneous administration, combined with 26 weeks of tapering prednisone, kept patients with GCA in remission better than either 26 or 52 weeks' prednisone tapering alone (14). One important and unambiguous finding was that patients in the tocilizumab groups received about half the cumulative dose of prednisone compared with the placebo-controlled groups (14). This is key. The average patient with GCA is treated with corticosteroids for over 2 years (15,16) and with a cumulative dose of over 5,000 mg of prednisone (17). For a variety of reasons, there is a current trend toward longer treatment with a larger cumulative dose of corticosteroids in GCA (18,19). However, for every 1,000 mg of additional cumulative dosing of prednisone, the hazard ratio 117 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point for adverse events (AEs) increases (17). These AEs include diabetes, fractures from osteopenia, and hip replacements (17,18). There are, of course, several concerns that come with the use of tocilizumab for GCA. Neutropenia occurred in 4% of the patients on tocilizumab, and this is consistent with other studies using this agent, such as in the treatment of rheumatoid arthritis (20). Patients on tocilizumab require careful laboratory monitoring; however, this is required for patients with GCA anyway as measures of disease activity dictate prednisone dosing (21-23). It is a little early to completely appreciate the long-term complications with tocilizumab treatment. And, there is the issue of cost: Tocilizumab is expensive, at $25,000-$40,000 per year, depending on dosing. These things will change. As tocilizumab becomes the standard of care, biosimilars and other anti-interleukin-6 therapies will become available, and some costs will come down. Better protocols will be developed that will accom- modate different patient populations. Patients with diabetes or other comorbidities for which corticosteroid treatment is particularly challenging may be afforded a steroid-reduced treatment regimen through tocilizumab. Should tocilizumab be used in all cases of GCA? Of course not; treatment protocols in medicine are rarely universal, and for the patient with a known history of diverticulitis, tocilizumab may not be the right choice. What is clear, however, is that for the treatment of GCA, tocilizumab is a game changer. This is great news. We have seen patients with GCA on corticosteroids avoid bilateral visual loss only to succumb to the myriad of serious side effects that comes with prolonged prednisone therapy. When an patient on prednisone dies, we are reminded that there is a great toll that comes from exposing elderly patients, whose health is in a delicate balance, to prolonged corticosteroid use. We now have an effective tool to mitigate this risk while preserving vision in GCA. Con: Lynn K. Gordon, MD, PhD In July 2017, the New England Journal of Medicine published the results of a prospective, randomized, placebocontrolled Phase 3 clinical trial (GiACTA) of the use of tocilizumab in GCA (14). The results of this study were revolutionary in that it was the first steroid-sparing agent that was successful in GCA, and this engendered much enthusiasm about the use of tocilizumab as adjunctive initial therapy in GCA. However, multiple questions remain about the clinical settings in which tocilizumab should be used, at what dose and frequency, along with what systemic steroid dose, how to taper systemic steroids while on tocilizumab therapy, and how long to use this therapy in patients with GCA (24- 27). Furthermore, the long-term safety profile had not been completely identified. The premise of my position is that tocilizumab should not universally be used in the treatment of GCA. Instead, traditional systemic steroid therapy alone should be the first-line agent used for patient who presents with neuro-ophthalmic symptoms of GCA if the patient is able to both comply with and tolerate the therapy. Why is this my recommendation? At the first glance, it seems obvious that tocilizumab should be initiated at the time of steroid therapy to decrease the total systemic steroid dose. Tocilizumab blocks the IL-6 pathway, which has been identified as clinically relevant both in human GCA and in animal models of disease, therefore targeting one of the well-defined proximate inflammatory pathways in GCA pathogenesis (28,29). Chronic use of high-dose steroids in the range used for control of GCA symptoms often results in untoward side effects which are potentially reduced through use of a steroid-sparing agent (3,19). We also understand that 118 GCA is a serious cause of morbidity and potential mortality. In addition to vision loss or stroke being present in up to 25% of patients with GCA, over the long term, they can develop aortic disease and aortic aneurysm (30-32). The quality of life for patients on weekly tocilizumab and a 52-week steroid taper was significantly higher and AEs significantly lower than those patients on steroids without tocilizumab, providing validation for use of tocilizumab in this disease (33). Tocilizumab is therefore helpful in certain cases, but there are limitations that preclude my recommending it in all cases of new-onset GCA. Previous trials with other potential steroid-sparing agents were largely unsuccessful, except for a single trial using azathioprine in a small number of patients (34). There are conflicting results using methotrexate as a steroid-sparing agent (35-37). There were technical issues with these trials as the steroid dosage and tapering protocol used in those trials was suboptimal and not what a neuro-ophthalmologist might recommend. For example, high disease recurrence rates in studies with early alternate day therapy or quick reduction in daily steroid dose may have occurred because of the manner in which steroids were used (14,37,38). To be clear, some of these limitations were also observed in the GiACTA trial, therefore limiting enthusiasm for tocilizumab in all cases of GCA. There were 4 arms of the GiACTA study, 3 of which included a 26-week prednisone taper, 1 with weekly tocilizumab, 1 with every other week tocilizumab, and 1 with placebo in place of tocilizumab. Only 1 group, which did not receive tocilizumab, underwent a 52-week prednisone taper. They also excluded those who may have received, Sadun and Gordon: J Neuro-Ophthalmol 2019; 40: 117-121 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point within 6 weeks before baseline, high-dose intravenous methylprednisolone at doses above 100 mg/day, which are commonly used for patients with neuro-ophthalmic symptoms of GCA (14). Patients at entry to the trial may have been on moderate, not high, doses of oral prednisone at as low as 20 mg per day, which is low for patients in an acute phase of GCA onset in a neuro-ophthalmology practice. Thus, the conclusions from this trial may not be entirely relevant in considering with the patient who presents to the neuro-ophthalmologist with an acute arteritic anterior optic neuropathy from GCA. Sustained remission at 52 weeks was achieved in w53-56% of patients receiving tocilizumab every other week or weekly, and these patients had a cumulative prednisone dose that was less than patients who did not take tocilizumab. There are known adverse effects of tocilizumab which are potentially limiting in patients with GCA. Patients on tocilizumab require laboratory monitoring for disease activity and relapse as well as elevation in alanine aminotransferase (2%) or neutropenia (4%) (21-23,39). A report on disease flares in the GiACTA study demonstrated relapses, the majority of which occurred while on prednisone at doses less than 20 mg, in about 38% of patients in the first 52 weeks of the study (38). In addition, 1 patient developed an anterior ischemic optic neuropathy on every other week tocilizumab, suggesting that the steroid taper in this patient may have been too rapid to prevent this complication in the setting of lower dose tocilizumab. Only 14%-18% in patients who tapered prednisone at the 26- or 52-week timepoint obtained remission at 52 weeks. The high rate of relapse may reflect a quicker prednisone taper than is typically recommended by neuro-ophthalmologists. The authors also highlighted the need for careful patient monitoring when using tocilizumab, as it blocks the traditional acute-phase reactants; therefore, CRP and ESR levels are not reliable in predicting a relapse. Although there are real risks for serious AEs in use of tocilizumab in GCA, the safety profile remains good in comparison with patients treated with glucocorticoids (25,40). One must however ensure that the patients are screened for tuberculosis and viral infections before starting the medication and while on medicine must be monitored for serious infection, diverticulitis, and hypersensitivity reactions. In addition, once tocilizumab is discontinued, there remains a significant risk of relapse. Guidelines for treatment of GCA were approved in 2018 and published in 2019 from the Swedish Society of Rheumatology (41). These guidelines embrace use of corticosteroids as first-line therapy for GCA and suggest the adjunctive use of tocilizumab when all 5 or solely the last criteria are met: 1) relapse during or after completion of treatment with glucocorticoid, 2) large vessel involvement as defined by biopsy or imaging with MRI, positron emission tomography-CT, or CT angiography, 3) clinically active GCA, 4) elevated ESR and CRP, and 5) obvious side effects of or great risk of side effects from glucocorticoids. A majority of the patients neuro-ophthalmologists manage are at risk of adverse steroid side effects and therefore may often meet the Swedish recommendation on the last criterion alone. However, one must then consider how and when to use tocilizumab in the neuro-ophthalmic presentations of GCA. There are financial and practical limitations to the use of tocilizumab. The annual cost of tocilizumab in the United States is at least 30 times the cost of prednisone. However, cost should not be the only or even the most significant consideration when selecting appropriate therapy for patients. Tocilizumab use requires a weekly or alternate week subcutaneous injection, which can be challenging for elderly patients. Finally, the long-term consequences of therapy with tocilizumab are not yet known. It is not clear how long to continue therapy and whether termination of therapy would require addition of systemic steroids. It is clear that there is a role for tocilizumab in the therapy of GCA; however, it is not yet clear that it should be used as initial therapy along with systemic corticosteroids. Patients with GCA who respond quickly to steroids, do not develop significant steroidassociated adverse effects, and are able to taper the steroids to a level with an acceptable safety profile likely do not require tocilizumab. Rebuttal: Alfredo A. Sadun, MD, PhD Dr. Gordon makes several important points. Patients on tocilizumab do need to be monitored for neutropenia and other AEs. Of course, all patients with GCA need to be carefully monitored for disease activity, relapse, and the common and serious adverse effects of corticosteroids, anyway. Tocilizumab is expensive, as we have both pointed out. Tocilizumab requires subcutaneous injections every week or 2 (although some regimens allow less frequent use). However, although this can be challenging in the elderly, it is not as challenging as Sadun and Gordon: J Neuro-Ophthalmol 2019; 40: 117-121 the daily insulin injections that are needed to control the steroid-induced diabetes, which is more prevalent without tocilizumab. I want to re-emphasize that tocilizumab reduces the cumulative dose of prednisone by half. It probably reduces the devastating complications of corticosteroids by more than half. With this new IL-6 receptor blocking strategy, we will have, in patients with GCA, fewer cases of diabetes, osteopenia, fractures, etc. Those who have been treating GCA cases for many years know the medical nightmares 119 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point associated with GCA management, medical nightmares that are well worth mitigating. Dr. Gordon and I agree that there is a major role for tocilizumab in the therapy of most patients with GCA. Of course, clinical practice requires customizing therapy to the particular needs of each patient. But, I am very pleased to say that tocilizumab is a game changer in the management of GCA. Rebuttal: Lynn Gordon, MD, PhD There is much agreement between the 2 of us about the use of tocilizumab, which as targeted therapy against IL-6, may have an important role in managing patients with GCA. The question becomes: when should tocilizumab become a firstline agent along with systemic corticosteroids? The answer to that question remains unknown in terms of evidence-based medical decisions. Can patients develop severe adverse side effects through use of high-dose corticosteroids? Absolutely yes. Would it be beneficial to reduce the total dose of corticosteroids in any patient with GCA? Probably yes, depending on the morbidity of other therapeutic agents. So, why not recommend starting tocilizumab for every patient with GCA? The goal as a physician is always to treat the patient and reduce disease morbidity. Morbidity can be from side effects of the medication, the natural history of disease, or disease recurrence. Some patients on tocilizumab therapy experienced recurrence, which could lead to severe and irreversible morbidity, including permanent vision loss. Could a slower corticosteroid tapering regimen have mitigated or prevented recurrences for those patients? Perhaps, but then, there would not have been as large of a reduction in total steroid dose. The risks of long-term therapy with tocilizumab are still unknown. I would recommend proceeding with caution and using this new and exciting therapy in patients in whom it is difficult to reduce corticosteroids or there are contraindications for long-term high-dose corticosteroid use. Perhaps, after additional experience with tocilizumab, it may become a first-line therapy. Conclusions: Andrew G. Lee, MD, and Gregory Van Stavern, MD The addition of tocilizumab to the armamentarium of GCA treatment is exciting. The safety profile is reasonable, and it is backed by high-quality evidence of efficacy. However, the long-term side effects remain unknown, and the cost of the medication is high (particularly since insurance coverage is variable). Some patients with GCA respond well to corticosteroids and can be tapered off of treatment within 1-2 years without any major complications, while others clearly require longer term treatment with a higher risk of steroidrelated morbidity. It is now becoming clear that there are several distinct subtypes of GCA: 1) cranial arteritis with severe ischemic complications (visual loss and cerebral ische- mia); 2) large vessel arteritis; 3) aortitis leading to aortic dissection, aneurysm, and aortic rupture; and 4) a systemic inflammatory syndrome with nonstenosing vasculitis and "isolated" polymyalgia rheumatica. These subtypes can only be separated at this time by clinical and radiologic findings, but as differentiating biomarkers for these subtypes emerge, it may turn out that each requires a specific, targeted treatment regimen. GCA is still best managed on an individualized, patient-by-patient basis, but the addition of tocilizumab is indeed a game changer and provides an evidence-based treatment alternative for selected patients with this condition. REFERENCES 7. Emilie D, Liozon E, Crevon MC, Lavignac C, Portier A, Liozon F, Galanaud P. Production of interleukin 6 by granulomas of giant cell arteritis. Hum Immunol. 1994;39:17-24. 8. Roche NE, Fulbright JW, Wagner AD, Hunder GG, Goronzy JJ, Weyand CM. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum. 1993;36:1286-1294. 9. Mihara M, Kasutani K, Okazaki M, Nakamura A, Kawai S, Sugimoto M, Matsumoto Y, Ohsugi Y. 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