Comments on Tocilicizumab Use in Giant Cell Arteritis

Letters to the Editor Abhimanyu S. Ahuja, BS Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida Mays A. El-Dairi, MD Majda Hadziahmetovic, MD Sidney M. Gospe, III, MD, PhD Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina Comments on Tocilicizumab Use in Giant Cell Arteritis W e read with interest the recent Point–Counterpoint discussion regarding the use of tocilizumab in giant cell arteritis (GCA) by Gordon and Sadun. We have encountered many patients with GCA in our practice in the past few years who were initiated on therapy with tocilizumab within weeks of their diagnosis. The evidence cited for this practice is always the Giant-Cell Arteritis Actemra (GiACTA) study, published in the New England Journal of Medicine in 2017, the same study on which Gordon and Sadun base their main conclusions (1). However, we would like to raise a number of critical points regarding the study methodology that were not discussed. First, the inclusion criteria for GiACTA trial did not specify that participants should have a new diagnosis of GCA. Thus, patients were enrolled in the study if they had a new diagnosis of GCA within past 6 weeks or had a refractory (nonremitting or refractory relapsing) GCA, with evidence of active disease within 6 weeks of study onset while they were treated with 20–60 mg of daily oral prednisone. Of the 251 enrolled patients, half (52%) had relapsing disease. The mean disease duration at baseline in each of the 4 study arms was reported as: 307 6 564, 258 6 501, 365 6 570, and 255 6 436 days. These data by themselves are very confusing: when reporting data with bimodal distribution of disease duration, SD is not a useful measure. If half of the enrolled patients had disease diagnosed within 6 weeks of enrollment yet the mean number of days from the onset of diagnosis was minimum 255 days for all groups, the second group (those who were not diagnosed within 6 weeks of disease onset) would have had GCA for many months (over 2 years in many cases) before being enrolled in this trial. We know that most patients with GCA should be weaned off steroids completely within 12–18 months from the time of their diagnosis (2) and European League Against e534 The authors report no conflicts of interest. REFERENCES 1. Ahuja AS, El-Dairi MA, Hadziahmetovic M, Gospe SM III. Paracentral acute middle maculopathy as a manifestation of giant cell arteritis. J Neuroophthalmol. 2021;41:e153–e156. 2. Pichi F, Fragiotta S, Freund KB, Au A, Lembo A, Nucci P, Sebastiani S, Gutierrez Hernandez JC, Interlandi E, Pellegrini F, Dolz-Marco R, Gallego-Pinazo R, Orellana-Rios J, Adatia FA, Munro M, Abboud EB, Ghazi N, Cunha Souza E, Amer R, Neri P, Sarraf D. Cilioretinal artery hypoperfusion and its association with paracentral acute middle maculopathy. Br J Ophthalmol. 2019;103:1137–1145. Rheumatism recommends tapering prednisone to a target of 15–20 mg daily within 2–3 months and 5 mg or less after 1 year (3). Thus, at least half of the patients enrolled in GiACTA should have already been weaned off the steroids completely. On top of that, only 62% of patients in the GiACTA study had biopsy-proven GCA, with the remaining patients diagnosed using evidence of large vessel vasculitis on any of the following modalities: traditional angiography, computed tomography or magnetic resonance angiography or positron-emission tomography. Findings of inflammation and vessel wall abnormalities on these studies are not specific to GCA and are often subtle and difficult to interpret. The first set of formal guidelines on the use of imaging in large vessel vasculitis were not published until 2018 (4), 5 years after the start of the GiACTA trial. In this document, computed tomography and positron-emission tomography are not recommended for diagnosis of cranial GCA and for magnetic resonance imaging, specific sequences to be used are outlined the need for an expert interpreter is recognized. Thus, it is possible that at least some participants included in GiACTA study had a diagnosis other than GCA. Finally, the definition of a disease flare is critical to determining the efficacy and steroid-sparing benefit of tocilizumab and in GiACTA flare was “. . .Determined by the investigator and defined as the recurrence of signs or symptoms of GCA and/or ESR $30 mm/hour attributable to GCA.” Disease flares in GCA are most commonly characterized by headache and polymyalgia rheumatica symptoms. Ischemic complications such as permanent vision loss are very rare in relapsing disease (5–7). This makes the diagnosis of a flare challenging and subjective and GiACTA study definition means that a patient with any vague complaint could have been considered as having a disease flare and treated with steroids for a dose and duration determined by the individual investigator. Also, erythrocyte sedimentation rate of 30 mm/hour would be within the range of normal for any patient over 60 years. In neuro-ophthalmology Letters to the Editor: J Neuro-Ophthalmol 2022; 42: e533-e538 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor clinics we often see patients who have been suspected of having a flare of GCA, but in reality, have other causes for their visual symptoms such as cataracts that are accelerated by long-term steroid therapy or ocular surface disease. Tocilizumab is a potentially exciting therapeutic option and the GiACTA study demonstrates that it can be beneficial in tapering off steroids more quickly without disease relapse in some patients. However, this study does have important limitations: half of the enrolled subjects were enrolled many months after the time of diagnosis when most patients should be completely weaned off or be on a very low dose of steroids and the definition of relapse which shaped study conclusions was vague. Thus, we believe there is still a critical lack of evidence that tocilizumab is indicated in all patients with a new diagnosis of GCA. Laura Donaldson, MD, PhD Kirill Zaslavsky, MD, PhD Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Edward Margolin, MD Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Division of Neurology, Department of Medicine, Faculty of Medicine, Reply to Should Tocilizumab Be Used Routinely in New Patients With a Diagnosis of Giant Cell Arteritis? T he authors would like to thank Donaldson et al for their comments in response to our point counter-point publication that discussed the pros and cons of the routine use of tocilizumab in new patients with a diagnosis of giant cell arteritis (1). They raise some important limitations about the GiACTA study, a randomized prospective clinical trial (2). Many of their points were reasonable and, indeed, consistent with our own published considerations. However, they are incorrect in stating that the 2017 New England Journal of Medicine (NEJM) publication was the basis for our “main conclusions.” Our initial point counter-point publication was rooted not solely on the Letters to the Editor: J Neuro-Ophthalmol 2022; 42: e533-e538 University of Toronto, Toronto, Ontario, Canada The authors report no conflicts of interest. REFERENCES 1. Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Schett G, Schulze-Koops H, Spiera R, Unizony SH, Collinson N. Trial of tocilizumab in giant-cell arteritis. New Engl J Med. 2017;377:317–328. 2. Salvarani C, Pipitone N, Versari A, Hunder GG. Clinical features of polymyalgia rheumatica and giant cell arteritis. Nat Rev Rheumatol. 2012;8:509–521. 3. Hellmich B, Agueda A, Monti S, Buttgereit F, de Boysson H, Brouwer E, Cassie R, Cid MC, Dasgupta B, Dejaco C, Hatemi G, Hollinger N, Mahr A, Mollan SP, Mukhtyar C, Ponte C, Salvarani C, Sivakumar R, Tian X, Tomasson G, Turesson C, Schmidt W, Villiger PM, Watts R, Young C, Luqmani RA. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020;79:19–30. 4. Dejaco C, Ramiro S, Duftner C, Besson FL, Bley TA, Blockmans D, Brouwer E, Cimmino MA, Clark E, Dasgupta B, Diamantopoulos AP, Direskeneli H, Iagnocco A, Klink T, Neill L, Ponte C, Salvarani C, Slart RHJA, Whitlock M, Schmidt WA. EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice. Ann Rheum Dis. 2018;77:636–643. 5. Kermani TA, Warrington KJ, Cuthbertson D, Carette S, Hoffman GS, Khalidi NA, Koening CL, Langford CA, MaksimowiczMcKinnon K, McAlear CA, Monach PA, Seo P, Merkel PA, Ytterberg SR; Vasculitis Clinical Research Consortium. Disease relapses among patients with giant cell arteritis: a prospective, longitudinal cohort study. J Rheumatol. 2015;42:1213–1217. 6. Aiello PD, Trautmann J, McPhee T, Kunselman AR, Hunder GG. Visual prognosis in giant cell arteritis. Ophthalmology. 1993;100:550–555. 7. Alba MA, García-Martínez A, Prieto-González S, Tavera-Bahillo I, Corbera-Bellalta M, Planas-Rigol E, Espígol-Frigolé G, Butjosa M, Hernández-Rodríguez J, Cid MC. Relapses in patients with giant cell arteritis: prevalence, characteristics, and associated clinical findings in a longitudinally followed cohort of 106 patients. Medicine (Baltimore). 2014;93:194–201. findings of the GiACTA study but also on several additional studies, basic science as well as clinical, that both preceded and followed the trial reported in the NEJM article. Specifically, we commented on the limitations of the GiACTA trial. For example, in Gordon's section, the following statement was made: “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.” The authors' last statement is quite in agreement with our conclusions. They state that: “Thus we believe there is still a critical lack of evidence that tocilizumab is indicated in all patients with a new diagnosis of GCA.” That sentiment was articulated in our publication and summed up in the conclusions, authored by Lee and Van Stavern: “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.” e535 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.