1113747 research-article20222022 TAB0010.1177/1759720X221113747Therapeutic Advances in Musculoskeletal DiseaseJ Loricera, S Castañeda Therapeutic Advances in Musculoskeletal Disease Original Research Tocilizumab in visual involvement of Ther Adv Musculoskelet Dis 2022, Vol. 14: 1–16 giant cell arteritis: a multicenter study DOI: 10.1177/ https://doi.org/10.1177/1759720X221113747 https://doi.org/10.1177/1759720X221113747 1759720X221113747 of 471 patients © The Author(s), 2022. Article reuse guidelines: sagepub.com/journals- permissions Javier Loricera* , Santos Castañeda*, Clara Moriano*, Javier Narváez , Vicente Aldasoro, Olga Maiz, Rafael Melero, Ignacio Villa, Paloma Vela, Susana Romero-Yuste, José L. Callejas, Eugenio de Miguel, Eva Galíndez-Agirregoikoa, Francisca Sivera , Jesús C. Fernández-López, Carles Galisteo, Iván Ferraz-Amaro , Julio Sánchez-Martín, Lara Sánchez-Bilbao, Mónica Calderón-Goercke, Alfonso Casado, José L. Hernández†, Miguel A. González-Gay† and Ricardo Blanco† ; on behalf of the Tocilizumab in Giant Cell Arteritis Spanish Collaborative Group‡ Correspondence to: José L. Hernández Abstract Internal Medicine Division, Hospital Universitario Background: Visual involvement is the most feared complication of giant cell arteritis Marqués de Valdecilla, Avda. Valdecilla s/n, ES- (GCA). Information on the efficacy of tocilizumab (TCZ) for this complication is scarce and 39008 Santander, Spain controversial. Dpto. de Medicina y Objective: We assessed a wide series of GCA treated with TCZ, to evaluate its role in the Psiquiatría, Universidad de Cantabria, Servicio de prevention of new visual complications and its efficacy when this manifestation was already Medicina Interna, Hospital Universitario Marqués present before the initiation of TCZ. de Valdecilla, Instituto de Design: This is an observational multicenter study of patients with GCA treated with TCZ. Investigación Valdecilla (IDIVAL), Santander, Spain. Methods: Patients were divided into two subgroups according to the presence or absence of hernandezjluis@gmail. com visual involvement before TCZ onset. Visual manifestations were classified into the following Miguel A. González-Gay categories: transient visual loss (TVL), permanent visual loss (PVL), diplopia, and blurred Rheumatology Division, vision. Hospital Universitario Marqués de Valdecilla, Results: Four hundred seventy-one GCA patients (mean age, 74 ± 9 years) were treated with Instituto de Investigación Valdecilla (IDIVAL), Avda. TCZ. Visual manifestations were observed in 122 cases (26%), of which 81 were present at TCZ Valdecilla s/n, ES-39008 onset: PVL (n = 60; unilateral/bilateral: 48/12), TVL (n = 17; unilateral/bilateral: 11/6), diplopia Santander, Spain Cardiovascular (n = 2), and blurred vision (n = 2). None of the patients without previous visual involvement Pathophysiology and or with TVL had new episodes after initiation of TCZ, while only 11 out of 60 (18%) patients Genomics Research Unit, School of Physiology, with PVL experienced some improvement. The two patients with diplopia and one of the two Faculty of Health patients with blurred vision improved. Sciences, University of the Witwatersrand, Conclusion: TCZ may have a protective effect against the development of visual complications Johannesburg, Johannesburg, South or new episodes of TVL in GCA. However, once PVL was established, only a few patients Africa improved. miguelaggay@hotmail. com Ricardo Blanco Rheumatology Division, Keywords: giant cell arteritis, large-vessel vasculitis, tocilizumab, visual involvement Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Received: 26 February 2022; revised manuscript accepted: 29 June 2022. Valdecilla (IDIVAL), Avda. Valdecilla s/n, ES-39008 Santander, Spain. Introduction the involvement of the ophthalmic branches of rblancovela@gmail.com Javier Loricera Giant cell arteritis (GCA) is the most common the internal carotid artery.4 Lara Sánchez-Bilbao vasculitis that affects the elderly, especially in Mónica Calderón-Goercke Rheumatology Division, subjects of European descent. GCA mainly affects Early diagnosis and treatment of GCA are needed Hospital Universitario the extracranial branches of the external carotid since ocular complications are potentially irre- Marqués de Valdecilla, Instituto de Investigación artery.1–3 However, visual loss, the most feared versible.2–4 Permanent visual loss (PVL) may be Valdecilla (IDIVAL), complication of the disease, is generally due to preceded by transient visual loss (TVL).2 Visual Santander, Spain journals.sagepub.com/home/tab 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Musculoskeletal Disease Volume 14 Santos Castañeda involvement is usually unilateral,2,5 but may patients diagnosed with GCA and treated with Department of Rheumatology, Hospital become bilateral in 20–62% of cases, mainly dur- TCZ in real-life clinical practice from January Universitario de La ing the first 2 weeks of the disease.6,7 2014 to May 2020. Before TCZ onset, all of them Princesa, IIS-Princesa, Catedra UAM-Roche, had received high-dose GC, and 257 (54.6%) EPID-Future, UAM, High-dose glucocorticoids (GC), either orally or conventional synthetic and/or other biologic Madrid, Spain Clara Moriano intravenously, represent the cornerstone of GCA immunosuppressive agents. To reduce selection Department of therapy.2 Nevertheless, once blindness is estab- bias, we included all the patients who had received Rheumatology, Complejo lished, the prognosis is poor and only a few patients at least one dose of TCZ, regardless of the Asistencial Universitario de León, León, Spain recover some degree of visual acuity despite treat- outcome. Javier Narváez ment with GC.2,4,8,9 Before the use of GC, visual Department of Rheumatology, Hospital de manifestations develop in approximately 30–60% of The patients were recruited from the Bellvitge, Barcelona, Spain patients,3 but still occur in 5% of those treated with Rheumatology or Autoimmune Units of 57 refer- Vicente Aldasoro these agents.10,11 Therefore, the efficacy of other ral centers. They were diagnosed with GCA Department of Rheumatology, Complejo therapies in the prevention and management of vis- according to the criteria of the American College Hospitalario de Navarra, ual complications of GCA needs to be explored. of Rheumatology (ACR),20 and/or a positive Pamplona, Spain biopsy of the temporal artery, and/or the presence Olga Maiz Department of Interleukin (IL)-6 has been involved in the pathogen- of large vessel vasculitis in any of the following Rheumatology, Hospital esis of GCA.12 Tocilizumab (TCZ) is a monoclonal imaging techniques: 18F-fluorodeoxyglucose posi- Universitario de Donostia, San Sebastián, Spain antibody against the IL-6 receptor. Two placebo- tron emission tomography/computed tomogra- Rafael Melero controlled trials, one open-label trial, and several phy (18F-FDG PET/CT) scan, magnetic Department of clinical observation studies have demonstrated the resonance imaging angiography (MRI-A), com- Rheumatology, Complexo Hospitalario Universitario efficacy of TCZ in GCA patients to achieve GC-free puted tomography angiography (CT-A), or heli- de Vigo, Vigo, Spain remission.13–19 However, the time course of patients cal CT scan. Ignacio Villa Department of with visual symptoms at the start of TCZ has not Rheumatology, Hospital been documented in most previous studies.13,14,16 Patients were divided into two subgroups accord- Sierrallana, Torrelavega, Spain ing to the presence or absence of visual involve- Paloma Vela Two recent clinical studies have shown that TCZ ment throughout the course of the disease. Visual Department of can prevent the incidence of new visual manifesta- manifestations were classified as follows: TVL; Rheumatology, Hospital General Universitario de tions in patients with GCA.17,18 Despite these PVL, which can be partial or total, unilateral, or Alicante, Alicante, Spain promising data, three of the patients (5%) reported bilateral; diplopia; and blurred vision.2 Susana Romero-Yuste by Unizony et al.17 and one (0.5%) by Amsler Department of Rheumatology, Complejo et al.,18 developed visual symptoms after starting Subsequently, we evaluated the patients who had Hospitalario Universitario TCZ. New episodes of ocular involvement were any visual symptoms at the time of TCZ onset de Pontevedra, Pontevedra, Spain observed during treatment with TCZ in one and assessed their temporal clinical course. For José L. Callejas patient (0.7%) in the GiACTA trial and another this purpose, we divided these patients into three Unit of Systemic (6%) in the GUSTO trial.14,15 In contrast, Villiger groups according to the time elapsed between the Autoimmune Diseases, Hospital San Cecilio, et al. did not report the occurrence of new visual onset of visual symptoms and the initiation of Granada, Spain symptoms in patients on TCZ in a phase II clinical TCZ therapy. We considered the following time Eugenio de Miguel Department of trial.13 Therefore, additional data on the utility of points: (a) 1–10, (b) 11–30, and (c) more than Rheumatology, Hospital La this biological agent for the visual manifestations of 30 days. Paz, Madrid, Spain GCA are of potential interest. Eva Galíndez- Agirregoikoa Finally, we tried to compare the characteristics of Department of Keeping in mind these considerations, we patients with PVL who experienced visual Rheumatology, Hospital de Basurto, Bilbao, Spain assessed a series of patients with GCA treated improvement after starting TCZ with those who Francisca Sivera with TCZ, to evaluate its role in the prevention of did not. Department of visual complications and its efficacy for visual Rheumatology, Hospital Universitario de Elda, improvement when this manifestation was already Treatment of GCA was based on the classic phar- Alicante, Spain present before the initiation of this biologic agent. macological scheme, starting with high doses of Jesús C. Fernández-López GC (usually, an initial dose of 40–60 mg/day of Department of Rheumatology, Hospital prednisone or equivalent, gradually tapered in the Universitario Juan Canalejo, A Coruña, Spain Patients and methods following months). Conventional synthetic Carles Galisteo immunosuppressant (csIS) and biologic agents Department of Patients, enrollment criteria, and study protocol were used as GC sparing agents, mainly in Rheumatology, Hospital Parc Taulí, Barcelona, We set up an observational, national open-label, patients with a relapsing disease or in those with Spain retrospective, multicenter study, including 471 GC-adverse side effects. 2 journals.sagepub.com/home/tab J Loricera, S Castañeda et al. As indicated by the Spanish National Guidelines TVL, and/or PVL. TVL (‘amaurosis fugax’) was Iván Ferraz-Amaro Department of for the administration of biologic therapy in defined as a temporary loss of sight referred by Rheumatology, Complejo patients with rheumatic diseases, the presence of the patient, followed by recovery to baseline vis- Hospitalario Universitario de Canarias, Tenerife, infectious diseases, including tuberculosis and ual acuity and without abnormalities on ophthal- Spain hepatitis B or hepatitis C infection, was ruled out mologic examination. PVL was defined as partial Julio Sánchez-Martín before starting the biologic agent. A tuberculin or complete loss of sight in one or both eyes Department of Rheumatology, Hospital skin testing (PPD) and/or an interferon assay longer than 24 h. Patients with PVL were exam- Universitario 12 de (quantiFERON), as well as chest radiography, ined by an experienced ophthalmologist and Octubre, Madrid, Spain Alfonso Casado were performed to exclude latent tuberculosis. In underwent a thorough ophthalmic examination Department of positive cases, prophylaxis with isoniazid was ini- including best-corrected visual acuity (Snellen Ophthalmology, Hospital Universitario Marqués tiated at least 4 weeks before biological drug onset charts), refraction, intraocular pressure measure- de Valdecilla, Instituto de and was maintained for 9 months, according to ment with Goldmann applanation tonometer, Investigación Valdecilla (IDIVAL), Santander, Spain the national guidelines.21–27 In addition, the pres- anterior segment biomicroscopy, and dilated fun- *Javier Loricera, Santos ence of malignancies was also excluded, as previ- dus examination. The refractive error was Castañeda, and Clara ously described.21–27 recorded using an Autorefractometer Canon Moriano share first authorship. RK-F1 (Canon USA Inc., Lake Success, NY, †José L. Hernández, TCZ was prescribed at its standard dose, either USA). Diplopia was considered if there was Miguel A. González-Gay, intravenously (IV) (8 mg/kg/4 weeks) or subcuta- palsy of extrinsic ocular muscles on physical and Ricardo Blanco share senior authorship. neously (SC) (162 mg/week). It was started due examination and when it was a transient symptom ‡Tocilizumab in Giant to lack of efficacy and/or unacceptable adverse recalled by the patient. Stroke and/or transient Cell Arteritis Spanish side effects related to standard therapy. In many ischemic attacks were collected as cerebro­vascular Collaborative Group: Juan C. González Nieto cases, TCZ was prescribed off-label since it was disease. (H. Gregorio Marañón), indicated before its approval by the European Juan R. de Dios (H.U. Araba), Esther Fernández Medicines Agency (EMA) and the Food and Hypertension was considered when the systolic (H. Clínico Universitario Drug Administration (FDA) for the treatment of pressure was >130 mm Hg and/or the diastolic Virgen de la Arrixaca), Isabel de la Morena (H. GCA. Thus, written informed consent was pressure was >80 mm Hg. Dyslipidemia was Clínico Universitario obtained in these cases. defined if one of the following was present: total de Valencia), Patricia Moya (H. Sant Pau), cholesterol >200 mg/dl, triglycerides >150 mg/ Roser Solans i Laqué (H. The reporting of this study conforms to the dl, high-density lipoprotein (HDL) cholesterol Valle de Hebrón), Eva Pérez Pampín (H.U. de Strengthening the Reporting of Observational <40 mg/dl in men or <50 mg/dl in women, Santiago), José L. Andréu Studies in Epidemiology (STROBE) statement.28 or low-density lipoprotein (LDL) cholesterol (H.U. Puerta de Hierro), Marcelino Revenga (H. >130 mg/dl. CHADS2-score (a risk stratifica- Ramón y Cajal), Juan P. Treatment with antiplatelet, anticoagulant, anti- tion tool to predict the 1-year risk of ischemic Baldivieso Achá (H. U. de La Princesa), Eztizen hypertensive, and/or lipid-lowering drugs was stroke in a nonanticoagulated patient with non- Labrador (H. San Pedro), also documented. valvular atrial fibrillation) was calculated based Andrea García-Valle (Complejo Asistencial on the clinical information available at TCZ Universitario de onset.30 Palencia), Adela Gallego (Complejo Hospitalario Clinical definitions and laboratory data Universitario de Badajoz), Fever was present if the temperature was ⩾38°C. Serum C-reactive protein (CRP) >0.5 mg/dl and Carlota Iñíguez (H.U. Lucus Augusti), Cristina Constitutional symptoms included asthenia, erythrocyte sedimentation rate (ESR) in the first Hidalgo (Complejo anorexia, and weight loss >5% of the normal hour >20 mm in men or >25 mm in women were Asistencial Universitario de Salamanca), Noemí body weight over the last 6 months before dis- considered abnormal. Anemia was defined as a Garrido-Puñal (H. Virgen ease diagnosis. Headache had to be of recent hemoglobin level ⩽11 g/dl. del Rocío), Ruth López- González (Complejo onset and with different characteristics from pre- Hospitalario de Zamora), vious ones. Jaw claudication was present when In patients with PVL, improvement of visual José A. Román-Ivorra (H.U. y Politécnico La Fe), the patient reported pain on chewing, which symptoms was defined when the patient experi- Francisco Miguel Ortiz- improved after stopping. Polymyalgia rheumat- enced an improvement in ocular manifestations, Sanjuán (H.U. y Politécnico La Fe), Sara Manrique ica (PmR) was defined according to the classifi- whereas in patients with TVL it was considered as (H. Regional de Málaga), cation criteria proposed by the EULAR/ACR the absence of new episodes of visual loss. Paz Collado (H.U. Severo Ochoa), Enrique Raya (H. 2012.29 San Cecilio), Valvanera Pinillos (H. San Pedro), Francisco Navarro (H. A patient was considered to have visual involve- Data collection General Universitario ment whether one or more of the following mani- Data were extracted from the clinical records de Elche), Alejandro Olivé-Marqués (H. Trías i festations were present: diplopia, blurred vision, according to a specifically designed protocol, Pujol), Francisco J. Toyos (H.U. Virgen Macarena), journals.sagepub.com/home/tab 3 Therapeutic Advances in Musculoskeletal Disease Volume 14 María L. Marena Rojas reviewed for confirmation, and stored in a com- cardiovascular risk factors were more commonly (H. La Mancha Centro), Antoni Juan Más (H.U. puterized database. To minimize entry mistakes, present in patients with visual manifestations. It Son Llàtzer), Beatriz all data were double-checked. To maintain the was also the case for the presence of typical mani- Arca (H.U. San Agustín), Carmen Ordás-Calvo anonymity, all patient data were de-identified. festations of this vasculitis, such as headache or (H. Cabueñes), María The research project was carried out following jaw claudication. In contrast, patients with PVL D. Boquet (H. Arnau de Vilanova), Noelia the protocol and the standard procedures that had a lower frequency of PmR than those without Álvarez-Rivas (H.U. ensure compliance with the Declaration of visual manifestations. However, there were no Lucus Augusti), María L. Velloso-Feijoo (H.U. de Helsinki and Good Clinical Practice standards. significant differences in serum levels of acute- Valme), Cristina Campos phase reactants, ESR and CRP, between patients (H. General Universitario de Valencia), Íñigo with or without visual manifestations at TCZ Rúa-Figueroa (H. Statistical analysis onset. Doctor Negrín), Antonio García (H. Virgen de las Demographic and clinical characteristics in Nieves), Carlos Vázquez patients with GCA were described as (H. Miguel Servet), Pau Lluch (H. Mateu mean ± standard deviation (SD) or percentages Baseline features of patients with visual Orfila), Carmen Torres for categorical variables. For non-normally dis- involvement at TCZ onset (Complejo Asistencial de Ávila), Cristina Luna tributed continuous variables, data were expressed Visual manifestations were present at TCZ start (H.U. Nuestra Señora as the median and interquartile range (IQR). in 81 of the 122 patients with ocular involvement: de la Candelaria), Elena Becerra (H.U. Univariable differences between GCA patients unilateral PVL (n = 48), bilateral PVL (n = 12), de Torrevieja), Nagore according to visual involvement were assessed unilateral TVL (n = 11), bilateral TVL (n = 6), Fernández-Llanio (H. Arnáu de Vilanova), through Student’s t, Mann–Whitney U, chi- diplopia (n = 2), and blurred vision (n = 2). The Arantxa Conesa (H.U. de square, or Fisher’s exact tests according to nor- remaining 41 patients with previous visual symp- Castellón), Eva Salgado (Complejo Hospitalario mal distribution or number of subjects. Hazard toms had fully recovered. Anterior ischemic optic Universitario de ratios (HRs) were calculated through Cox pro- neuropathy (AION) was present in 41 of the 60 Ourense). portional hazards regression analysis. All the patients with PVL. Retrobulbar optic neuropathy analyses were performed using SPSS software, occurred in three (one of them also had AION); version 26 (IBM, Armonk, NY, USA), and Stata central retinal artery occlusion (CRAO) in two, software, version 17/SE (StataCorp, College while two other cases had papillitis/papillary Station, TX, USA). A p value < 0.05 was consid- edema. In 13 patients, this information was not ered statistically significant. available. Neither of the two patients complaining of diplopia showed palsy of extrinsic ocular mus- cles. Moreover, AION was observed in one of the Results two cases with blurred vision, while the ophthal- mological examination was normal in the other Baseline general features at TCZ onset one. Besides, one of the patients with TVL had an We included 471 patients (342 women/129 men) incipient AION. diagnosed with GCA and treated with TCZ. The mean age at TCZ onset was 74 ± 9 years. Ninety- one (19.3%) patients had a recent GCA diagnosis TCZ therapy and visual manifestations (within 6 weeks before TCZ use). One hundred After a mean of 20 ± 18 months on TCZ and and twenty-two (25.9%) cases had ever had vis- 25 ± 21 months of follow-up, none of the patients ual manifestations. Baseline characteristics of without visual symptoms at TCZ onset developed these subgroups, at TCZ onset, are summarized new ocular involvement. Moreover, none of those in Table 1. Figure 1 shows the previous treat- with TVL suffered new visual episodes after TCZ ments received by the patients. onset. In addition, 11 of 60 patients with PVL (18.3%) experienced visual improvement (Figure 2). Women outnumbered men in the groups of One of the cases with blurred vision and another patients with and without visual complications. with diplopia showed partial improvement, while However, it was significantly higher among the the other patient with diplopia recovered subgroup of patients without visual manifesta- completely. tions compared with those with visual involve- ment (Table 1). The 49 patients with PVL who did not experience visual improvement after TCZ onset remained At the time of TCZ onset, GCA patients with with the same visual symptoms, but did not visual involvement or PVL were older than those develop any new visual manifestations during the without visual manifestations. Overall, traditional follow-up period. 4 journals.sagepub.com/home/tab J Loricera, S Castañeda et al. Table 1. Main features of 471 patients with giant cell arteritis at TCZ onset. Overall GCA without GCA with GCA with P P (n = 471) visual visual PVL at TCZ visual versus PVL versus involvement involvement onset (n = 60) nonvisual nonvisual (n = 349) (n = 122) involvement involvement General features Age at diagnosis (mean ± SD) 72 ± 9 71 ± 9 75 ± 8 75 ± 9 0.001 0.001 Age at TCZ onset (mean ± SD) 74 ± 9 73 ± 9 76 ± 8 76 ± 9 <0.0001 0.005 Female/male (% of female) 342/129 (73) 265/84 (76) 77/45 (63) 41/19 (68) 0.006 0.21  Time from GCA diagnosis to TCZ 6 [2–18] 7 [2–22] 5 [1–12] 5 [1–10] 0.088 0.027 onset (months), median [IQR]  GCA fulfilling ACR 1990 criteria, n 344 (73) 235 (67) 109 (89) 53 (88) <0.0001 0.001 (%) Positive TAB, n (%) 201 (43) 146 (42) 55 (45) 33 (55) 0.53 0.34 Clinical phenotype of GCA Cranial, n (%) 217 (46) 138 (40) 79 (65) 40 (67) – – Extra-cranial, n (%) 80 (17) 80 (23) 0 (0) 0 (0) <0.0001 <0.0001 Mixed, n (%) 174 (37) 132 (38) 42 (34) 20 (33) – – Cardiovascular risk factors High blood pressure, n (%) 272 (58) 189 (54) 83 (68) 40 (67) 0.013 0.058 Dyslipidemia, n (%) 241 (51) 175 (50) 66 (54) 32 (53) 0.61 0.63 Diabetes, n (%) 81 (17) 50 (14) 31 (25) 16 (27) 0.007 0.016  Previous or current smoking 47 (10) 31 (9) 16 (13) 8 (13) 0.21 0.27 history, n (%) CHADS2 scorea, median [IQR] 1 [1–2] 1 [0–2] 2 [1–2] 2 [1–2] 0.001 0.004 Ischemic manifestations Headache, n (%) 259 (55) 167 (48) 92 (75) 42 (70) <0.0001 0.002 Jaw claudication, n (%) 112 (24) 63 (18) 49 (40) 26 (43) <0.0001 <0.0001 Cerebrovascular accident, n (%) 5 (1) 2 (1) 3 (2) 1 (2) 0.11 0.38 Systemic manifestations Fever, n (%) 57 (12) 47 (13) 10 (8) 4 (7) 0.12 0.20 Constitutional syndrome, n (%) 175 (37) 132 (38) 43 (35) 20 (33) 0.55 0.47 PmR, n (%) 284 (60) 218 (62) 66 (54) 29 (48) 0.094 0.022 Large-vessel involvement, n (%) 254 (54) 211 (60) 43 (35) 20 (33) <0.0001 <0.0001 Laboratory findings at the time of TCZ onset ESR, mm/first hour, median [IQR] 32 [12–57] 30 [11–54] 34 [15–67] 42 [12–67] 0.22 0.28 (Continued) journals.sagepub.com/home/tab 5 Therapeutic Advances in Musculoskeletal Disease Volume 14 Table 1. (Continued) Overall GCA without GCA with GCA with P P (n = 471) visual visual PVL at TCZ visual versus PVL versus involvement involvement onset (n = 60) nonvisual nonvisual (n = 349) (n = 122) involvement involvement CRP (mg/dl), median [IQR] 1.5 [0.5–3.4] 1.4 [0.5–3.0] 1.5 [0.4–4.7] 1.5 [0.4–3.6] 0.042 0.30 Hemoglobin (g/dl), mean ± SD 12.6 ± 1.5 12.7 ± 1.5 12.3 ± 1.6 11.9 ± 1.4 0.016 <0.0001 Treatment at TCZ onset Prednisone dose, mg/day, median [IQR] 20 [10–40] 20 [10–30] 30 [15–45] 40 [30–50] <0.0001 <0.0001 Methotrexate, n (%) 102 (22) 80 (25) 22 (18) 8 (13) 0.26 0.095 Leflunomide, n (%) 4 (1) 2 (1) 2 (2) 1 (2) 0.99 0.38 Azathioprine, n (%) 10 (2) 8 (2) 2 (2) 2 (3) 0.28 0.65 Hydroxychloroquine, n (%) 1 (0) 1 (0) 0 (0) 0 (0) 0.99 0.99 Antiplatelet, n (%) 216 (46) 142 (41) 74 (61) 36 (60) <0.0001 0.004 Anticoagulant, n (%) 56 (12) 40 (11) 16 (13) 8 (13) 0.70 0.68 Lipid-lowering drug, n (%) 234 (50) 168 (48) 66 (54) 33 (55) 0.38 0.32 Antihypertensive drugs, n (%) 266 (56) 185 (53) 81 (66) 37 (62) 0.016 0.16 TCZ schedule TCZmono/TCZcombo 353/118 257/92 96/26 49/11 0.27 0.19 TCZ route IV/SC, (% IV) 238/233 (50) 176/173 (50) 62/60 (51) 33/27 (55) 0.94 0.51 ACR, American College of Rheumatology; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GCA, giant cell arteritis; IQR, interquartile range; IV, intravenously; PmR, polymyalgia rheumatica; PVL, permanent visual loss; SC, subcutaneously; SD, standard deviation; TCZ, tocilizumab; TCZcombo, tocilizumab in combination with conventional synthetic immunosuppressants (besides glucocorticoids); TCZmono, tocilizumab in monotherapy (besides glucocorticoids). Statistical significance is expressed as bold characters. aCHADS2-score: stratification tool to predict the 1-year risk of ischemic stroke in a non-anticoagulated patient with non-valvular atrial fibrillation. To calculate the CHADS score, patients are assigned different points based on the risk factors for stroke (congestive heart failure: 1 point; hypertension: 1 point; age 75 years or older: 1 point; diabetes mellitus: 1 point; stroke/transient ischemic attack: 2 points). Comparison between PVL patients who regard, age was the only variable associated with experienced visual improvement after TCZ visual improvement following TCZ onset, since onset and those who did not the patients who had ocular improvement were Table 2 summarizes the main features of the younger than those who did not [70 ± 11 versus patients with PVL who experienced visual 77 ± 8 years, HR 0.93; 95% confidence interval improvement after starting TCZ and those who (CI): 0.87–0.99; p = 0.034]. did not. Although the time between the develop- ment of visual complications and the initiation of TCZ therapy was shorter in the 11 patients who Discussion experienced visual improvement [median 95 The present study provides data on visual involve- (IQR 21–180) days] when compared with the ment in 471 GCA patients treated with TCZ. Our remaining 49 patients with no improvement results suggest that TCZ might be useful for the [median 180 (IQR 40–450) days], the difference prevention and treatment of the visual manifesta- was not statistically significant (p = 0.26). In this tions of GCA. It is noteworthy that after the 6 journals.sagepub.com/home/tab J Loricera, S Castañeda et al. Figure 1. Flowchart summarizing the treatment of 471 patients with GCA treated with TCZ. ABA, abatacept; ADA, adalimumab; AZA, azathioprine; CsA, cyclosporine A; CsIS, conventional synthetic immunosuppressants; ETN, etanercept; GCA, giant cell arteritis; GOLI, golimumab; HCQ, hydroxychloroquine; IFX, infliximab; LFN, leflunomide; MM, mycophenolate mofetil; MTX, methotrexate; RTX, rituximab; SARI, sarilumab; SSZ, sulfasalazine; TCZ, tocilizumab. Figure 2. Efficacy of tocilizumab in giant cell arteritis patients with transient visual loss and permanent visual loss, according to the time between ocular involvement and tocilizumab onset. journals.sagepub.com/home/tab 7 Therapeutic Advances in Musculoskeletal Disease Volume 14 Table 2. Differences between patients with permanent visual loss who experienced visual improvement after TCZ onset and patients who did not improve: hazards ratios for visual improvement. Improvement No improvement p HR (95% CI) (n = 11) (n = 49) General features Age (years), mean ± SD 70 ± 11 77 ± 8 0.034 0.93 (0.87–0.99) Gender, female/male (% female) 9/2 (82) 32/17 (65) 0.15 0.92 (0.29–3.00) Time from visual symptoms to TCZ onset Median [IQR] 95 [21–180] 180 [40–450] 0.26 1.00 (0.99–1.00) ⩽10 days, n (%) 2 (18) 2 (4) 0.28 2.48 (0.48–12.76) 11–30 days, n (%) 1 (9) 9 (18) 0.67 1.68 (0.77–3.66) >30 days, n (%) 8 (73) 38 (78) 0.71 1.40 (0.37–5.32) Cardiovascular risk factors High blood pressure 6 (55) 34 (69) 0.45 0.56 (0.16–1.99) Dyslipidemia 8 (73) 24 (49) 0.16 3.03 (0.64–14.31) Diabetes 4 (36) 12 (24) 0.45 1.80 (0.51–6.43) Previous or current smoking history, n (%) 0 (0) 2 (4) 0.99 – CHADS2 score,a median [IQR] 2 [0–2] 2 [1–2] 0.28 0.79 (0.40–1.56) Ischemic manifestations Headache 7 (64) 35 (71) 0.71 0.72 (0.21–2.48) Jaw claudication 6 (55) 20 (41) 0.51 1.69 (0.51–5.57) Cerebrovascular accident 0 (0) 1 (2) 0.99 – Systemic manifestations Fever 0 (0) 4 (8) 0.99 – Constitutional syndrome 4 (36) 16 (33) 0.99 0.95 (0.28–3.24) PmR 4 (36) 25 (51) 0.51 0.52 (0.15–1.81) Large-vessel involvement 5 (45) 15 (31) 0.48 2.13 (0.65–7.01) Laboratory findings ESR, mm/first hours, median [IQR] 44 [31–69] 36 [12–66] 0.54 1.01 (0.99–1.03) CRP (mg/dl), median [IQR] 1.6 [0.4–4.1] 1.3 [1.0–2.3] 0.62 1.16 (0.87–1.21) Hemoglobin (g/dl), mean ± SD 11.7 ± 1.1 12.0 ± 1.5 0.61 0.83 (0.52–1.34) Pulses of IV MP at visual symptoms onset 7 (64) 35 (71) 0.72 0.73 (0.21–2.52) Concomitant therapy at TCZ onset Prednisone dose (mg/day), median [IQR] 40 [30–45] 40 [29–50] 0.86 1.00 (0.97–1.04) (Continued) 8 journals.sagepub.com/home/tab J Loricera, S Castañeda et al. Table 2. (Continued) Improvement No improvement p HR (95% CI) (n = 11) (n = 49) Methotrexate 2 (18) 6 (12) 0.63 1.84 (0.40–8.54) Other DMARDs 0 (0) 3 (6) – – Antiplatelet 5 (45) 31 (63) 0.30 0.49 (0.14–1.71) Anticoagulant 1 (9) 7 (14) 0.99 0.77 (0.90–6.80) Lipid-lowering drug 8 (73) 25 (51) 0.17 2.93 (0.62–13.81) Antihypertensive drug 6 (55) 31 (63) 0.71 0.65 (0.18–2.33) CI, confidence interval; CRP, C-reactive protein; DMARDs, disease-modifying antirheumatic drugs; ESR, erythrocyte sedimentation rate; HR, hazard ratio; IQR, interquartile range; IV, intravenously; MP, methylprednisolone; PmR, polymyalgia rheumatica; SD, standard deviation; TCZ, tocilizumab. Statistical significance is expressed as bold characters. p values refer to the difference between ‘improvement’ and ‘nonimprovement’ groups. aCHADS2-score: stratification tool to predict the 1-year risk of ischemic stroke in a non-anticoagulated patient with nonvalvular atrial fibrillation. To calculate the CHADS score, patients are assigned different points based on the risk factors for stroke (congestive heart failure: 1 point; hypertension: 1 point; age 75 years or older: 1 point; diabetes mellitus: 1 point; stroke/transient ischemic attack: 2 points). initiation of TCZ, no patient developed a new visual reported in other series.2 Once blindness is estab- impairment. Furthermore, none of the patients with lished, the visual prognosis is poor and only 15% TVL had more episodes and 18% of the cases with of patients recover an acceptable vision despite PVL experienced a total or partial improvement. the treatment with GC.2,4,8 Therefore, the pre- vention and therapeutic approach of visual We observed that GCA patients who had jaw impairment in GCA patients receiving GC remain claudication and headache had more commonly unmet needs, and new therapeutic targets are visual manifestations. On the contrary, patients required. Noteworthy, serum IL-6 levels and IL-6 with PmR or those in whom extracranial large- RNA expression within inflamed arteries are vessel vasculitis involvement was confirmed had increased in patients with GCA.10,36 TCZ is a less visual manifestations. The frequency of ocu- monoclonal antibody against both the soluble lar involvement in GCA varies widely, from 10% and membrane-bound forms of the IL-6 receptor, to 70%.2,3,8,31–33 GC represent the cornerstone of which has been recently approved for the treat- the therapy for GCA, and adequate doses quickly ment of GCA. The GiACTA trial confirmed the improve clinical manifestations and prevent most efficacy of TCZ to induce remission, prevent additional cranial ischemic events.2,34 Therefore, relapses, and reduce the GC adverse effects dele- GC therapy must be started as soon as GCA is terious burden in GCA patients.14 suspected to reduce the risk of blindness.9 In this regard, ocular complications have been reduced Nonetheless, data on the usefulness of TCZ for since the introduction of GC therapy in GCA. In the visual manifestations of GCA remain a population-based study from Olmsted County, scarce.17,18,37,38 Three clinical trials, two placebo- the frequency of blindness decreased from 19% controlled, phase II and III (GiACTA), and one observed between 1950 and 1969 to 6% in the open-label (GUSTO) trial have shown the effi- period of 1980–1985.35 Regrettably, relapse of cacy of TCZ in GCA.13–15 In the phase II trial, visual symptoms during the disease was described 25% of the patients who were randomized to in about 5% of patients treated with GC in mono- TCZ plus prednisone had visual impairment at therapy.10,11 The presence of new clinical mani- baseline.13 However, no data about their visual festations and especially the high relapse rate in outcomes during the follow-up were reported. At GCA despite GC, as well as the high morbidity the baseline visit of the phase III GiACTA trial, 4 associated with prolonged use of GC, has led to patients had unilateral blindness, 1 bilateral the search for new GC sparing agents. In our blindness, 2 ischemic optic neuropathy, 2 amau- series, before TCZ onset, visual manifestations rosis fugax, and 14 reported blurred vision.39 were observed in 122 (25.9%) cases throughout However, their clinical outcome throughout the the disease. This proportion was similar to that study was not reported. One patient assigned to journals.sagepub.com/home/tab 9 Therapeutic Advances in Musculoskeletal Disease Volume 14 TCZ (162 mg s.c. every other week) developed with PVL, whereas others such as PmR appeared AION at week 24, while the patient was on con- to be associated with a reduced risk of visual comitant prednisone (2 mg/day). On the other complications.1,2,5,8,31,40 hand, 6 of the 18 patients in the GUSTO trial had visual involvement at baseline. The results of Most of these observations were also confirmed in this trial have not yet been published, so data our cohort. Furthermore, we also observed that regarding this issue are unknown. We know that large-vessel involvement may be a protective fac- one of the patients developed AION 15 days after tor for the development of visual symptoms. GC pulse therapy, while the patient was treated Certainly, patients with a predominant extracra- with TCZ in monotherapy. This patient had cor- nial-large vessel vasculitis pattern of the disease onary heart disease and arterial hypertension as had a reduced risk of blindness.41,42 These find- associated cardiovascular comorbidity.15,18 ings contribute to reinforcing the fact that GCA is a T-cell-driven disease with two main pathogenic Recently, Unizony et al.,17 have attempted to evalu- pathways and phenotypes. Type 1 helper T cells ate the potential usefulness of TCZ to control the (Th1) response is associated with the production visual manifestations in 60 patients diagnosed with of interferon-gamma (IFN-γ), being responsible GCA from clinical practice. In that series, 27 (45%) for the ischemic manifestations, while Th17 cases had GCA-related visual manifestations before response and its related cytokines such as IL-6 starting TCZ. After TCZ onset, three patients had have been linked to the systemic inflammatory at least one flare with visual manifestations (amau- features.43 In this regard, some studies have rosis fugax, n = 1; blurred vision, n = 3). One of them shown an association between lower levels of was a patient without previous visual involvement acute-phase reactants and the development of before TCZ onset who had an episode of blurred visual symptoms in GCA.3,18,40,44 In our series, we vision after starting the biologic agent. No cases of did not observe such an association, probably AION occurred after starting TCZ. because most of our patients had already been followed up for a long period, and had received Twenty-one (11%) of 186 GCA patients treated previous treatment with high doses of GC and, with GC and TCZ reported by Amsler et al.18 had many of them, also with csIS. suffered from vision loss before inclusion. Fifty- four percent of eyes with visual loss showed stabi- Moreover, classic atherosclerosis risk factors lization of visual acuity, while 29% of eyes increase the risk of GCA ischemic ocular compli- experienced improvement while taking TCZ plus cations in several reports.33,45,46 The presence of GC. Two patients developed AION, one of them atherosclerosis risk factors at the time of diagnosis in the setting of the GUSTO clinical trial of GCA may influence the development of severe described above. The other was a 69-year-old ischemic manifestations of the disease.47 The male who developed AION in the left eye 2 weeks presence of a high CHADS2-score has also been after the first cranial symptoms appeared and reported as a predictor of PVL.45,48 In our series, 2 days after an episode of amaurosis fugax. He we observed that hypertension and diabetes were received immediate treatment with pulses of 1 g more frequent in patients with visual involve- of methylprednisolone for 3 days plus an IV infu- ment, as was the CHADS2-score. sion of TCZ at a dose of 8 mg/kg of body weight. Because the AION did not improve, he received Currently, the role of antiplatelet/anticoagulation three additional pulses of 500 mg of methylpred- therapy in reducing the risk of ischemic complica- nisolone followed by oral prednisolone. Two tions in GCA is controversial, and some authors weeks later, while still taking prednisone (75 mg/ disagree with the value of low-dose aspirin in day), he also lost vision in his right eye. GCA.49–51 In fact, in our series, the percentage of patients who received antiplatelet therapy was Our patients had a longer duration of disease and, lower in the group of patients with PVL and vis- consequently, had received GC, and in some ual improvement than in the group of patients cases, csIS for a longer period. All the included with PVL who did not improve, although statisti- patients in the GUSTO trial, as well as 80% in the cal significance was not reached. series by Unizony et al., had a new-onset GCA.15,17 In the present study, none of the patients with Some features of the disease such as amaurosis TVL developed PVL while on TCZ, whereas fugax or jaw claudication have been associated once PVL was established, only a few recovered 10 journals.sagepub.com/home/tab J Loricera, S Castañeda et al. Figure 3. Proposed algorithm for the use of tocilizumab in giant cell arteritis with and without visual involvement. GCA, giant cell arteritis; TCZ, tocilizumab. *If new visual involvement, in addition to additional tocilizumab we recommend increased glucocorticoids dose. the visual acuity. This was in accordance with in data collection. Although no quantification of studies from patients who only received GC.2 In changes in visual acuity of the subjects was this regard, improvement of PVL is rare, espe- assessed in this study, an experienced ophthal- cially if treatment is not started early. In a previ- mologist analyzed these modifications in the ous report,2 seven of eight patients who medical record. We acknowledge the limitation experienced partial improvement started treat- that, since our study was retrospective and per- ment with high-dose GC within 24 h of the onset formed in a real clinical practice setting, no sam- of visual symptoms. In our series, the number of ple size was calculated. In previous reports, TCZ patients with PVL who started TCZ within prevention of new visual involvement has been 10 days of the onset of visual symptoms is small described to range from 0.3% to 5%.17,18 Since in and none of them started TCZ within first 24 h. our study, 11 of 60 (18%) patients improved Considering the absence of recurrences in patients after TCZ treatment, the statistical power calcu- with TVL and the trend of a visual improvement lated to detect such therapy effect was 99%. On in patients with PVL who started TCZ within the the other hand, we recognize that the influence first 10 days after the onset of ocular manifesta- that steroids may have on the effect of TCZ was tions, as occurs with GC therapy, a prompt initia- not clearly established in our study. However, tion of TCZ seems to be essential for visual according to our results, no significant differ- recovery. Therefore, the key message of our study ences were found in prednisone dose at TCZ can be that TCZ seems to be particularly effective onset between patients with visual improvement to prevent the development of new ocular involve- and those without it. Furthermore, to our knowl- ment or PVL in those patients with previous edge, the present study represents the largest TVL. In addition, TCZ may also be useful in real-world study of the use of TCZ for GCA- patients with PVL as long as it is started immedi- related visual symptoms. ately after the onset of visual symptoms. According to these data, we propose the management algo- In conclusion, our results suggest that TCZ might rithm shown in Figure 3. Thus, we suggest that in be an effective therapy to control visual complica- patients with GCA and visual manifestations the tions and to prevent the development of new vis- combination of GC plus TCZ can be used as the ual manifestations in patients with GCA. first-line therapeutic scheme. Author’s note Our study has some limitations, mainly due to its This study was presented in part as an oral com- retrospective design. Furthermore, the multi- munication at the virtual EULAR meeting held in center design may be associated with some bias Frankfurt, Germany, in June 2021. journals.sagepub.com/home/tab 11 Therapeutic Advances in Musculoskeletal Disease Volume 14 Declarations José L. Callejas: Investigation; Supervision; Validation; Visualization; Writing – review & Ethics approval and consent to participate editing. This research project was approved by the Clinical Eugenio de Miguel: Formal analysis; Research Ethics Committee of Cantabria with the Supervision; Validation; Visualization; Writing – internal code 2018.080 (signed on 19 September review & editing. 2018). Eva Galíndez-Agirregoikoa: Investigation; Consent for publication Supervision; Validation; Visualization; Writing – This is a retrospective study and signed consent review & editing. for publication was not requested. To maintain Francisca Sivera: Formal analysis; Supervision; anonymity, all patient data were de-identified. Validation; Visualization; Writing – review & The research project was conducted following editing. standard protocol and procedures that ensure compliance with the Declaration of Helsinki and Jesús C. Fernández-López: Formal analysis; standards of good clinical practice. Supervision; Validation; Visualization; Writing – review & editing. All co-authors have given their consent for publi- Carles Galisteo: Investigation; Supervision; cation of the article. Validation; Visualization; Writing – review & editing. Author contribution(s) Javier Loricera: Conceptualization; Data cura- Iván Ferraz-Amaro: Formal analysis; Software; tion; Formal analysis; Investigation; Methodology; Supervision; Validation; Writing – review & Validation; Writing – original draft. editing. Santos Castañeda: Formal analysis; Julio Sánchez-Martín: Investigation; Investigation; Supervision; Validation; Writing – Supervision; Validation; Visualization; Writing – review & editing. review & editing. Clara Moriano: Investigation; Supervision; Lara Sánchez-Bilbao: Formal analysis; Validation; Visualization; Writing – review & Supervision; Validation; Visualization; Writing – editing. review & editing. Javier Narváez: Formal analysis; Supervision; Mónica Calderón-Goercke: Investigation; Validation; Visualization; Writing – review & Supervision; Validation; Visualization; Writing – editing. review & editing. Vicente Aldasoro: Conceptualization; Super­ Alfonso Casado: Conceptualization; Formal vision; Validation; Writing – review & editing. analysis; Funding acquisition; Methodology; Olga Maiz: Methodology; Supervision; Supervision; Validation; Visualization; Writing – Validation; Visualization; Writing – review & review & editing. editing. José L. Hernández: Formal analysis; Rafael Melero: Methodology; Supervision; Investigation; Supervision; Validation; Validation; Visualization; Writing – review & Visualization; Writing – review & editing. editing. Miguel A. González-Gay: Formal analysis; Ignacio Villa: Investigation; Supervision; Investigation; Supervision; Validation; Validation; Visualization; Writing – review & Visualization; Writing – review & editing. editing. Ricardo Blanco: Conceptualization; Formal Paloma Vela: Formal analysis; Supervision; analysis; Investigation; Supervision; Validation; Validation; Visualization; Writing – review & Writing – review & editing. editing. Susana Romero-Yuste: Formal analysis; Acknowledgements Supervision; Validation; Visualization; Writing – To all patients and members of the participating review & editing. hospitals. 12 journals.sagepub.com/home/tab J Loricera, S Castañeda et al. Funding Rubió, Sandoz, Sanofi, UCB and attendance at The authors disclosed receipt of the following conferences AbbVie, Astra-Zeneca, BMS, financial support for the research, authorship, Fresenius, Janssen, K. Pharma, Lilly, MSD, and/or publication of this article: This work was Novartis, Pfizer, Roche, Rubió, Sandoz, Sanofi, partially supported by RETICS Program UCB. E. de Miguel had consultation fees/partici- (RD16/0012/0009) (Instituto de Salud Carlos pation in company sponsored speaker’s bureau III, co-funded by the European Regional from AbbVie, Novartis, Pfizer, BMS, MSD, Development Fund) from ‘Instituto de Salud UCB, Roche, Grünenthal, and Janssen and Carlos III’ (ISCIII) (Spain). received support for attending meetings and/or travel from AbbVie, Novartis, Pfizer, BMS, Competing interests MSD, UCB, Roche, Grünenthal, and Janssen. E. The authors declared the following potential con- Galíndez-Agirregoikoa had consultation fees/par- flicts of interest with respect to the research, ticipation in company sponsored speaker’s bureau authorship, and/or publication of this article: from Celgene, AbbVie, Pfizer, Roche, Lilly, Disclosures that might be interpreted as consti- MSD, Janssen, and Bristol and received support tuting of possible conflict(s) of interest for the for attending meetings and/or travel from study: Celgene, AbbVie, Pfizer, Roche, Lilly, MSD, Janssen, and Bristol. F. Sivera received grants J. Loricera had consultation fees/participation in from Roche. Iván Ferraz-Amaro received grants/ company-sponsored speaker’s bureau from research supports from AbbVie, MSD, Janssen, Roche, Novartis, UCB Pharma, MSD, Celgene, and Roche and received consultation fees from and Grünenthal and received support for attend- company-sponsored speaker’s bureau associated ing meetings and/or travel from Janssen, AbbVie, with AbbVie, Pfizer, Roche, Sanofi, Sobi, Amgen, Roche, Novartis, MSD, UCB Pharma, Celgene, Celgene, and MSD and received support for Lilly, Pfizer, Galápagos. S. Castañeda is assistant attending meetings and/or travel from AbbVie, professor of the UAM-Roche, EPID-Future Pfizer, Roche, Sanofi, Sobi, Amgen, Celgene, and chair, Department of Medicine, Universidad MSD. Mónica Calderón-Goercke received sup- Autónoma de Madrid, Madrid, Spain, and port for attending meetings and/or travel from received support for attending meetings and/or Lilly, AbbVie, Pfizer. José L. Hernández received travel from Janssen, AbbVie, Roche, Novartis, grants from Amgen and had participation in com- MSD, UCB Pharma, Celgene, Lilly, Pfizer. V. pany-sponsored speaker’s bureau from Amgen, Aldasoro had consultation fees/participation in MSD, Bayer, and Esteve. Miguel A. Gonzalez- company sponsored speaker’s bureau from Gay has received grants/research supports from Janssen, BMS, MSD, Roche, Sanofi, Pfizer, AbbVie, MSD, Janssen, and Roche and had con- Novartis, Amgen, Lilly, AbbVie, Gebro, Nordic, sultation fees/participation in company-spon- Lacer, Alter, UCB, ASAC Pharma, Menarini and sored speaker’s bureau from AbbVie, Pfizer, Celgene and received support for attending meet- Roche, Sanofi, Lilly, Celgene, and MSD and ings and/or travel from Janssen, BMS, MSD, received support for attending meetings and/or Roche, Sanofi, Pfizer, Novartis, Amgen, Lilly, travel from AbbVie, Pfizer, Roche, Sanofi, Lilly, AbbVie, Gebro, Nordic, Lacer, Alter, UCB, Celgene, and MSD. R. Blanco received grants/ ASAC Pharma, Menarini, and Celgene. O. Maiz research supports from AbbVie, MSD, and received support for attending meetings and/or Roche, and had consultation fees/participation in travel from Janssen, AbbVie, Roche, Novartis, company-sponsored speaker’s bureau from MSD, UCB Pharma, Celgene, Lilly, Pfizer. P. AbbVie, Pfizer, Roche, Bristol-Myers, Lilly, Vela received grants/research supports from Janssen, and MSD and received support for AbbVie, Pfizer, BMS, Novartis, MSD, and Roche attending meetings and/or travel from AbbVie, and had consultation fees/participation in com- Pfizer, Roche, Bristol-Myers, Lilly, Janssen, and pany sponsored speaker’s bureau from Pfizer, MSD. BMS, Lilly, UCB, and MSD and received sup- port for attending meetings and/or travel from The other co-authors have declared no compet- Pfizer, BMS, Lilly, UCB, and MSD. S. Romero- ing interests. Yuste had consultation fees/participation in com- pany sponsored speaker’s bureau from AbbVie, Astra-Zeneca, BMS, Fresenius, Janssen, K. Availability of data and materials Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Not applicable. journals.sagepub.com/home/tab 13 Therapeutic Advances in Musculoskeletal Disease Volume 14 ORCID iDs 10. Kermani TA, Warrington KJ, Cuthbertson D, Javier Loricera https://orcid.org/0000-0003- et al. Disease relapses among patients with giant 4754-0277 cell arteritis: a prospective, longitudinal cohort study. J Rheumatol 2015; 42: 1213–1217. Javier Narváez https://orcid.org/0000-0002- 11. Restuccia G, Boiardi L, Cavazza A, et al. Flares 1614-8064 in biopsy-proven giant cell arteritis in northern Francisca Sivera https://orcid.org/0000- Italy: characteristics and predictors in a long-term 0002-3414-1667 follow-up study. Medicine 2016; 95: e3524. Iván Ferraz-Amaro https://orcid.org/0000- 12. Hernández-Rodríguez J, Segarra M, Vilardell 0003-0197-5267 C, et al. 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