1020917 research-article20212021 TAB0010.1177/1759720X211020917Therapeutic Advances in Musculoskeletal DiseaseD Prieto-Peña, P Bernabeu Therapeutic Advances in Musculoskeletal Disease Original Research Tocilizumab in refractory Caucasian Ther Adv Musculoskel Dis 2021, Vol. 13: 1–12 Takayasu’s arteritis: a multicenter study DOI: 10.1177/ https://doi.org/10.1177/1759720X211020917 https://doi.org/10.1177/1759720X211020917 1759720X211020917 of 54 patients and literature review © The Author(s), 2021. Article reuse guidelines: sagepub.com/journals- permissions Diana Prieto-Peña, Pilar Bernabeu, Paloma Vela, Javier Narváez , Jesús C. Fernández-López, Mercedes Freire-González, Beatriz González-Álvarez, Correspondence to: Roser Solans-Laqué, José L. Callejas Rubio, Norberto Ortego, Carlos Fernández-Díaz, Miguel A. González-Gay Rheumatology Division, Esteban Rubio, Salvador García-Morillo, Mauricio Minguez, Cristina Fernández-Carballido, Research Group on Eugenio de Miguel, Sheila Melchor, Eva Salgado, Beatriz Bravo, Susana Romero-Yuste, Genetic Epidemiology and Atherosclerosis in Juan Salvatierra, Cristina Hidalgo, Sara Manrique, Carlos Romero-Gómez, Systemic Diseases and in Patricia Moya , Noelia Álvarez-Rivas, Javier Mendizabal, Francisco Ortiz-Sanjuán, Metabolic Bone Diseases of the Musculoskeletal Iván Pérez de Pedro, José L. Alonso-Valdivielso , Laura Perez-Sanchez, Rosa Roldán, System, IDIVAL, Hospital Nagore Fernandez-Llanio, Ricardo Gómez de la Torre, Silvia Suarez, Universitario Marqués de Valdecilla, Avenida María Jesús Montesa Cabrera, Mónica Delgado Sánchez, Javier Loricera, Belén Atienza-Mateo, Valdecilla s/n, Santander, Santos Castañeda, Miguel A. González-Gay* and Ricardo Blanco* 39008, Spain School of Medicine, Universidad de Cantabria, Abstract Santander, Spain Cardiovascular Objective: To assess the efficacy and safety of tocilizumab (TCZ) in Caucasian patients with Pathophysiology and refractory Takayasu’s arteritis (TAK) in clinical practice. Genomics Research Unit, School of Physiology, Methods: A multicenter study of Caucasian patients with refractory TAK who received TCZ. Faculty of Health The outcome variables were remission, glucocorticoid-sparing effect, improvement in imaging Sciences, University of the Witwatersrand, techniques, and adverse events. A comparative study between patients who received TCZ as Johannesburg, South Africa monotherapy (TCZMONO) and combined with conventional disease modifying anti-rheumatic miguelaggay@hotmail. drugs (cDMARDs) (TCZCOMBO) was performed. com Diana Prieto-Peña Results: The study comprised 54 patients (46 women/8 men) with a median [interquartile Javier Loricera range (IQR)] age of 42.0 (32.5–50.5) years. TCZ was started after a median (IQR) of 12.0 (3.0– Belén Atienza-Mateo Ricardo Blanco 31.5) months since TAK diagnosis. Remission was achieved in 12/54 (22.2%), 19/49 (38.8%), Department of 23/44 (52.3%), and 27/36 (75%) patients at 1, 3, 6, and 12 months, respectively. The prednisone Rheumatology, Research Group on dose was reduced from 30.0 mg/day (12.5–50.0) to 5.0 (0.0–5.6) mg/day at 12 months. An Genetic Epidemiology and Atherosclerosis in improvement in imaging findings was reported in 28 (73.7%) patients after a median (IQR) Systemic Diseases and in of 9.0 (6.0–14.0) months. Twenty-three (42.6%) patients were on TCZMONO and 31 (57.4%) on Metabolic Bone Diseases of the Musculoskeletal TCZCOMBO: MTX (n = 28), cyclosporine A (n = 2), azathioprine (n = 1). Patients on TCZCOMBO were System, IDIVAL, Hospital Universitario Marqués younger [38.0 (27.0–46.0) versus 45.0 (38.0–57.0)] years; difference (diff) [95% confidence de Valdecilla, Santander, interval (CI) = -7.0 (-17.9, -0.56] with a trend to longer TAK duration [21.0 (6.0–38.0) versus 6.0 Spain (1.0–23.0)] months; diff 95% CI = 15 (-8.9, 35.5), and higher c-reactive protein [2.4 (0.7–5.6) Pilar Bernabeu Paloma Vela versus 1.3 (0.3–3.3)] mg/dl; diff 95% CI = 1.1 (-0.26, 2.99). Despite these differences, similar Department of Rheumatology, Hospital outcomes were observed in both groups (log rank p = 0.862). Relevant adverse events were General de Alicante, reported in six (11.1%) patients, but only three developed severe events that required TCZ Alicante, Spain Javier Narváez withdrawal. Department of Conclusion: TCZ in monotherapy, or combined with cDMARDs, is effective and safe in patients Rheumatology, Hospital de Bellvitge, Barcelona, Spain with refractory TAK of Caucasian origin. Jesús C. Fernández-López Mercedes Freire- González Keywords: biological therapy, Caucasian, cDMARDs, Takayasu’s arteritis, Tocilizumab Department of Rheumatology, Complejo H. Universitario de A Received: 7 February 2021; revised manuscript accepted: 10 May 2021. Coruña, A Coruña, 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 13 Beatriz González- Introduction Caucasian population. As already mentioned, Álvarez María Jesús Montesa Takayasu’s arteritis (TAK) is a large-vessel vas- patients of Caucasian ethnicity usually have dif- Cabrera culitis (LVV) characterized by the affection of the ferent demographic and clinical features which Mónica Delgado Sánchez aorta and its main branches. This may lead to the may influence treatment outcomes. Department of development of severe vascular complications, Rheumatology, Hospital Nuestra such as stenosis, aneurysms, and aortic dissec- Taking all these considerations into account, our Señora de la tion.1 TAK mainly affects young females of Asian aim was to assess the efficacy and safety of TCZ Candelaria, Tenerife, Spain descent; however, TAK is increasingly being rec- for the management of refractory TAK in Roser Solans-Laqué ognized among individuals of Caucasian origin Caucasian patients from a real-world clinical Department of from both European countries and the United setting. Internal Medicine, Hospital Vall States.2–5 d’Hebron, Barcelona, Spain José L. Callejas Rubio Epidemiology studies have revealed an estimated Patients and methods Norberto Ortego incidence of 2–3 cases per million people per year Juan Salvatierra Autoimmune Disease in the United States.5 The reported incidences in Study design Unit, Hospital San Europe range from 0.4 to 1.5 per million people We conducted an observational, multicenter Cecilio, Granada, Spain year while the prevalence varies from 4.7 to 33 study in patients diagnosed with TAK who Carlos Fernández- per million people.4,6 received at least one dose of TCZ in a real-world Díaz clinical setting from January 2014 to May 2020. Department of Rheumatology, H. Clinical manifestations and outcomes in Preliminary partial data on eight patients were Universitario de La Caucasian patients with TAK diagnosis appear to previously reported.13 Princesa, IIS-Princesa, Madrid, Spain differ from those originally observed in patients of Esteban Rubio Asian origin. Caucasian patients are usually older Patients were diagnosed with TAK at the Salvador García- at diagnosis, with nearly 25% of patients aging Rheumatology or Autoimmune Units of 26 Morillo Autoimmune Disease 40–50 years. Cardiovascular comorbidities are national referral centers. TAK diagnosis was Unit, Hospital Virgen more frequent among these patients, which may based on the American College of Rheumatology del Rocío, Sevilla, Spain potentially increase the risk for developing vascu- (ACR) 1990 criteria20 or Ishikawa criteria modi- Mauricio Minguez lar complications.3,5 The pattern of vascular affec- fied by Sharma et al.21 Vascular affection was con- Cristina Fernández- tion also seems to be different in Caucasian firmed in every patient by at least one imaging Carballido Department of patients. Supra-aortic vessels are more likely technique, including 18F-fluorodexyglucose posi- Rheumatology, affected in Caucasian individuals, whereas tron emission tomography/computed tomogra- Hospital San Juan de Alicante, Alicante, abdominal vascular involvement is more frequent phy (18F-FDG PET/CT) (Figure 1), magnetic Spain in patients of South-Asian descent.3,7 Disturbingly, resonance imaging angiography (MRI-A), and Eugenio de Miguel Department of a recent study showed that Caucasian patients computed tomography angiography (CT-A). Rheumatology, with TAK diagnosis have a significantly higher Hospital Universitario La Paz, Madrid, Spain mortality than other ethnic groups.8 The initial management of TAK was based on the Sheila Melchor classic pharmacological therapy strategy starting Department of The mainstay treatment of TAK remains a com- on a high dose of glucocorticoids, usually with an Rheumatology, Hospital Universitario bination of glucocorticoids and conventional dis- initial dose of prednisone between 40 and 60 mg/ 12 de Octubre, ease modifying anti-rheumatic drugs day, which was gradually tapered. cDMARDs Madrid, Spain (cDMARDs).9 Nonetheless, relapses are com- and/or biologic therapy were added in patients Eva Salgado Department of mon in TAK despite treatment with cDMARDs.10 with relapsing disease, or in those cases with Rheumatology, A recent French study involving 318 patients with adverse side effects related to glucocorticoid Complejo H. Universitario de TAK showed that 50% of patients experience a therapy. Ourense, Ourense, relapse and vascular complications in the first Spain 10 years from diagnosis. As indicated by the Spanish National Guidelines Beatriz Bravo Department of for the administration of biologic therapy in Rheumatology, Tocilizumab (TCZ), a humanized monoclonal patients with rheumatic diseases, the presence of Hospital Virgen de las Nieves, Granada, Spain antibody directed against the interleukin 6 (IL-6) infectious diseases had to be ruled out, including Susana Romero- receptor, seems to be a promising therapeutic tuberculosis and hepatitis B or hepatitis C infec- Yuste Department of option for refractory TAK. Up to now, the main tions, before the onset of biologic therapy. To Rheumatology, evidence for the efficacy of TCZ in TAK comes exclude latent tuberculosis, a tuberculin skin test- Complejo H. Universitario from retrospective studies,11–17 one small rand- ing (PPD) and/or an interferon assay (quantiF- de Pontevedra, omized clinical trial,18 and one open trial;19 how- ERON), as well as a chest radiograph, were Pontevedra, Spain ever, none of these studies were focused on performed. In positive cases, prophylaxis with 2 journals.sagepub.com/home/tab D Prieto-Peña, P Bernabeu et al. Cristina Hidalgo Department of Rheumatology, Complejo Universitario de Salamanca, Salamanca, Spain Sara Manrique Carlos Romero-Gómez Autoimmune Disease Unit, Hospital Regional de Málaga, Málaga, Spain Patricia Moya Department of Rheumatology, Hospital Sant Pau, Barcelona, Spain Noelia Álvarez-Rivas Department of Rheumatology, Hospital Universitario San Agustín, Avilés, Spain Javier Mendizabal Department of Rheumatology, Complejo Hospitalario de Navarra, Pamplona, Spain Francisco Ortiz- Figure 1. PET/CT images of a 43 years-old woman with Takayasu’s arteritis showing an intense FDG uptake Sanjuán along the thoracic aorta (arrows) and the brachiocephalic trunk, subclavian and axillary arteries (head arrows). Department of Courtesy of Dr. Martínez-Rodríguez. Rheumatology, Hospital Universitario CT, computed tomography; FDG, fluorodeoxyglucose; PET, positron emission tomography. y Politécnico La Fe, Valencia, Spain Iván Pérez de Pedro Autoimmune Disease isoniazid was initiated at least 4 weeks before the was present. Constitutional symptoms included Unit, Hospital Carlos onset of the biological agent and was maintained asthenia, anorexia, and weight loss greater than Haya, Málaga, Spain for 9 months. The presence of malignancies was 5% of the normal body weight over the last José L. Alonso- Valdivielso also excluded in all the patients.22 6 months before disease diagnosis. Fever was con- Department of sidered to be present if temperature was ⩾38°C. Rheumatology, Hospital Universitario de TCZ was prescribed as intravenous (IV) infusions Headache if head pain was of recent development Burgos, Burgos, Spain at a standard dose (8 mg/kg/4 weeks) or as subcu- or had different characteristics than usual. Visual Laura Perez-Sanchez taneous (SC) (162 mg/week) injections. It was manifestations include blurred vision, diplopia, Rosa Roldán Department of started due to a lack of efficacy and/or unaccepta- amaurosis fugax, unilateral or bilateral hemianop- Rheumatology, Hospital ble adverse side-effects related to previous ther- sia, and permanent unilateral or bilateral blind- Universitario Reina Sofía, Córdoba, Spain apy. Since TCZ is an off-label indication for TAK ness. The definition of other clinical manifestations Nagore Fernandez- in Europe, written informed consent was requested has been previously reported.13 Llanio Department of and obtained from all the patients before starting Rheumatology, Hospital therapy. Patients were treated with TCZ as mono- A full blood cell count, renal and liver function Arnau de Vilanova, Valencia, Spain therapy or combined with cDMARDs. tests, as well as CRP and ESR were obtained at Ricardo Gómez de la the time of TCZ onset and then at each follow-up Torre visit. Normalization of CRP was considered when Silvia Suarez Autoimmune Disease Clinical definitions and laboratory data it was under 0.5 mg/dl and normalization of ESR Unit, Hospital Remission was defined as the absence of new when it was less than 25 mm/first hour. Universitario Central de Asturias, Oviedo, Spain symptoms and the disappearance of all previous Santos Castañeda symptoms of TAK, along with the normalization Follow-up imaging techniques were performed Department of of c-reactive protein (CRP) and erythrocyte sedi- based on each physician criteria. Changes from Rheumatology, H. Universitario de La mentation rate (ESR). Relapse was defined as the baseline in imaging results were qualitatively eval- Princesa, IIS-Princesa, recurrence of signs or symptoms of TAK after a uated by a radiologist or nuclear medicine expert Madrid, Spain remission period of at least 6 months. at each referral center. Imaging vascular improve- Cátedra UAM-ROCHE, EPID-Future, Universidad ment was defined as the partial or complete Autónoma Madrid (UAM), Limb claudication was defined as pain, tightness, enhancement of the vessel wall thickness, steno- Madrid, Spain *Miguel A. Gonzalez- heaviness, cramping and/or weakness in one or sis, or occlusions, along with the absence of new Gay and Ricardo both of arms and/or legs. Chest pain was consid- vascular lesions at the follow-up imaging tech- Blanco share senior authorship. ered when pressure, pain, or heaviness in the chest nique as compared with the baseline. journals.sagepub.com/home/tab 3 Therapeutic Advances in Musculoskeletal Disease 13 Adverse events were recorded and severe infec- excluded from the analysis (Figure 2). In conse- tion was considered to be present when a life- quence, we assessed 54 patients (46 women/8 threatening infection, fatal, or requiring men), with a median (IQR) age of 42.0 (32.5– hospitalization occurred, intravenous antibiotics 50.5) years old at TCZ onset. The median time were required, or the infectious process led to from TAK diagnosis to TCZ therapy was 12.0 persistent or significant disability. (3.0–31.5) months. The main clinical manifesta- tions at TCZ onset were constitutional symptoms In a further step, a comparative study was per- (59.3%) and limb claudication (55.6%). The formed between patients who received TCZ as most common pattern of vascular affection was monotherapy (TCZMONO) and combined with type IIa (31.5%), which involves the ascending cDMARDs (TCZCOMBO). aorta, aortic arch, and its branches. In contrast, type III (7.4%) and type IV (7.4%), which pre- dominantly affects abdominal vessels, were the Data collection and ethics less frequent patterns of vascular inflammation. Information was retrieved from the patient’s clinical The main general features, laboratory data, previ- records, including data on clinical and laboratory ous therapies, and treatment at baseline are parameters, angiographic classification,23 previous shown in Table 1. A total of forty-two (77.8%) administered treatment for the management of patients were previously treated with at least one TAK, clinical response to TCZ, and the develop- cDMARD, mainly methotrexate (MTX) (n = 37), ment of side effects while patients were undergoing followed by azathioprine (n = 10), cyclophospha- TCZ therapy. All data were stored in a computer- mide (n = 8), mycophenolate mofetil (n = 6), and ized database. The study was approved by the cyclosporine A (n = 2). Twelve patients (22.2%) Cantabria Institutional Review Board (approval also received at least one biologic agent before number 2018-110). It was carried out in accord- TCZ onset: infliximab (n = 10), adalimumab ance with the protocol and with the standard work (n = 2), abatacept (n = 2), etanercept (n = 1), and procedures that ensure compliance with the rituximab (n = 1) (Figure 2). Declaration of Helsinki and Good Clinical Practice standards, regulated by (EU) 2016/679 of the TCZ was administered IV to 40 (74.1%) patients European Parliament and of the Council of 27 April and SC to 14 (25.9%). The maintenance dose of 2016 on data protection (RGPD) that entered into TCZ ranged from 8 mg/IV/kg/4 weeks to 4 mg/IV/ force on 25 May 2018. Retrospective data have kg/8 weeks, and from 162 mg/SC/week to 162 mg/ been obtained during routine clinical practice with SC/every other week. the informed consent of the patients to be treated in a service that performs assistance and research tasks. TCZMONO was administered to 23 (42.6%) patients and TCZCOMBO to 31 (57.4%) patients. In the TCZCOMBO group, the combined drugs Statistical analysis used were: MTX (n = 28), cyclosporine A (n = 2), Statistical analysis was performed using SPSS and azathioprine (n = 1). Baseline features of Statistics for Windows, version 18.0 (SPSS Inc, these subgroups of patients are summarized in Chicago, IL, USA). All continuous variables were Table 1. Patients on TCZCOMBO were signifi- tested for normality and results were expressed as cantly younger than those on TCZMONO. No mean ± standard deviation (SD) or as a median other statistically significant differences were and interquartile range (IQR) as appropriate. The found between both groups, but a trend to longer comparison of continuous variables among time disease duration and higher levels of acute phase periods was performed using the Wilcoxon signed reactants was observed in patients on TCZCOMBO. rank test. A p-value < 0.05 was considered as sta- tistically significant in all the calculations. Efficacy outcomes Remission was achieved in 12/54 (22.2%), 19/49 Results (38.8%), 23/44 (52.3%), and 27/36 (75%) patients at 1, 3, 6, and 12 months, respectively. Patients’ characteristics The improvement of laboratory parameters and Sixty patients with TAK diagnosis who received reduction of prednisone dose throughout follow- TCZ were initially enrolled in the study. Six up is shown in Table 2 and Figure 3. The percent- patients were non-Caucasians and were therefore age of patients who achieved remission was similar 4 journals.sagepub.com/home/tab D Prieto-Peña, P Bernabeu et al. Figure 2. Flow chart of patients who met the inclusion/exclusion criteria for the study showing the immunosuppressive therapy prescribed prior to Tocilizumab therapy. in patients receiving TCZMONO and TCZCOMBO TCZ. At the end of follow-up, TCZ was discon- (log rank p = 0.862) (Figure 4). The age-adjusted tinued in 18 patients. TCZ was stopped in six hazard ratio (HR) at 12 months = 1.33; 95% con- patients due to prolonged remission after a median fidence interval (CI) = 0.30–5.90; p = 0.71. (IQR) of 57.0 (52.0–76.5) months. None of these patients experienced a relapse after a median A follow-up imaging technique was performed in (IQR) of 37.5 (24.0–63.5) months from TCZ 38 (70.4%) patients after a median (IQR) of 9.0 withdrawal. Other reasons for TCZ discontinua- (6.0–14.0) months. Improvement in imaging tion were inefficacy (n = 4), pregnancy (n = 4), findings was reported in 28 (73.7%) patients, adverse reactions (n = 3), and loss to follow-up whereas no improvement was observed in 10 (n = 1). (26.3%) patients. Among these 10 patients with persistent inflammatory activity: four patients A total of six (11.1%) patients developed relevant were in clinical remission, five patients experi- adverse events during TCZ therapy, most of them enced only partial clinical improvement and one infections: severe pneumonia (n = 2), mild upper patient did not respond to TCZ. respiratory tract infection (n = 1), and herpes zos- ter (n = 1). Hematological side effects were observed in two patients: pancytopenia (n = 1) Follow-up and adverse events and thrombocytopenia (n = 1). TCZ was discon- The median (IQR) follow-up after TCZ onset was tinued in the two patients with severe pneumonia 13.5 (6.0–41.0) months (range 1–108 months). At and in the patient with pancytopenia. No deaths 12 months, 29/36 (80.6%) were still receiving occurred during the study period. journals.sagepub.com/home/tab 5 6 Table 1. Baseline features of 54 Caucasian patients with refractory Takayasu’s arteritis who were treated with Tocilizumab. Overall patients with TAK TCZCOMBO (n = 31) TCZMONO (n = 23) Difference* (95%CI) diagnosis (n = 54) Age (years), median (IQR) 42.0 (32.5–50.5) 38.0 (27.0–46.0) 45.0 (38.0–57.0) −7.0 (−17.9, −0.56) Sex (female), n (%) 46 (85.2) 26 (83.9) 20 (87) −3.1 (−21.9, 15.8) Time from TAK diagnosis to TCZ onset (months), median (IQR) 12.0 (3.0–31.5) 21.0 (6.0–38.0) 6.0 (1.0–23.0) 15.0 (−8.9, 35.5) Clinical manifestations Constitutional symptoms, n (%) 32 (59.3) 17 (54.8) 15 (65.2) −10.4 (−36.6, 15.8) Fever, n (%) 12 (22.2) 4 (12.9) 8 (34.8) −21.9 (−44.6, 0.9) Limb claudication, n (%) 30 (55.6) 20 (64.5) 10 (43.5) 21.0 (−5.3, 47.4) Abdominal pain, n (%) 11 (20.4) 5 (16.1) 6 (26.1) −10.0 (−32.1, 12.2) Chest pain, n (%) 9 (16.7) 6 (19.4) 3 (13.0) 6.4 (−13.3, 25.9) Visual symptoms, n (%) 7 (13.0) 3 (9.7) 4 (17.4) −7.7 (−26.4, 10.9) Therapeutic Advances in Musculoskeletal Disease 13 Type of vessel involvement Supra-abdominal vessels (Type I, IIa and IIb), n (%) 33 (61.1) 19 (61.3) 14 (60.9) 0.4 (−25.9, 26.7) Infra-abdominal vessels (Type III, IV and V), n (%) 21 (38.9) 12 (38.7) 9 (39.1) −0.4 (−26.7, 25.9) Laboratory parameters ESR (mm/first hour), median (IQR) 30.5 (8.7–52.7) 38.0 (25.0–52.0) 22.5 (5.8–56.8) 15.5 (−7.1, 25.3) CRP (mg/dl), median (IQR) 1.5 (0.5–3.5) 2.4 (0.7–5.6) 1.3 (0.3–3.3) 1.1 (−0.26, 2.99) Hemoglobin (g/dl), median (IQR) 12.4 ± 1.5 12.3 ± 1.7 12.4 ± 1.3 −0.1 (−1.01, 0.68) Corticosteroids at TCZ onset Prednisone dose (mg/day), median (IQR) 30.0 (12.5–50.0) 30.0 (10.0–40.0) 40.0 (22.5–52.5) −10.0 (−21.2, 4.2) TCZ route Intravenous, n (%) 40 (74.1) 23 (74.2) 17 (73.9) 0.3 (−23.4, 23.9) Subcutaneous, n (%) 14 (25.9) 8 (25.8) 6 (26.1) −0.3 (−23.9, 23.4) *Differences between patients who received TCZ monotherapy (TCZ MONO) and TCZ combined with conventional disease modifying anti-rheumatic drugs (TCZCOMBO). CI, confidence interval; CRP, C-reactive protein (mg/dl); ESR, erythrocyte sedimentation rate (mm/first hour); IQR, interquartile range; n, number; TAK, Takayasu’s arteritis; TCZ, tocilizumab. journals.sagepub.com/home/tab D Prieto-Peña, P Bernabeu et al. Table 2. Main outcome variables of 54 Caucasian patients with refractory Takayasu’s arteritis treated with tocilizumab. Baseline n = 54 Month 1 Month 3 Month 6 Month 12 n = 54 n = 49 n = 44 n = 36 Clinical remission, n (%) 12 (22.2) 19 (38.8) 23 (52.3) 27 (75.0) Laboratory improvement CRP (mg/dl), median (IQR) 1.5 (0.5–3.5) 0.2 (0.1–0.7)* 0.2 (0.5–0.5)* 0.2 (0.1–0.5)* 0.1 (0.0–0.4)* ESR (mm/first hour), median (IQR) 30.5 (8.7–52.7) 7.0 (3.0–14.0)* 4.5 (2.0–8.0)* 5.0 (2.0–6.0)* 4.0 (2.0–9.5)* Hemoglobin (g/dl), mean ± SD 12.4 ± 1.5 13.0 ± 1.2* 13.0 ± 1.4* 13.2 ± 1.5* 12.9 ± 1.6* Prednisone dose, median (IQR) 30.0 (12.5–50.0) 20.0 (10.0–30.0)* 10.0 (5.0–20.0)* 5.0 (5.0–10.5)* 5.0 (0.0–5.6)* *p < 0.01 versus baseline (Wilcoxon test). CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IQR, interquartile range; n, number; SD, standard deviation. Figure 3. Spaghetti plot of changes in C-reactive protein and hemoglobin for individual patients from baseline to 12 months. Discussion patients with TAK diagnosis,3,5,7 our patients TAK is often a refractory disease despite conven- were older at diagnosis and showed more fre- tional treatment with glucocorticoids and quently supra-aortic and thoracic aorta vessel cDMARDs.10 It should be noted that different involvement than patients of Asian origin. clinical features and higher mortality rates have been observed in Caucasian patients with TAK Our results support the efficacy of TCZ for the diagnosis in comparison to other ethnic groups.8 management of TAK. Table 3 summarizes the TCZ has shown to be effective for the manage- most relevant studies conducted on patients with ment of TAK, but most studies predominantly TAK treated with TCZ. As previously mentioned, involve patients of Asian origin. We report here two small trials, the TAKT18 and the TOCITAKA19 the largest study focused on Caucasian patients studies, showed that TCZ was useful for the man- with refractory TAK treated with TCZ. Most agement of TAK. The TAKT study is a placebo- patients achieved remission and experienced radi- controlled randomized trial which involved 36 ological improvement in imaging techniques. In Japanese patients. Longer time to relapse was addition, TCZ led to a sparing glucocorticoid- observed in TCZ-treated patients, although no sig- dose effect and a good safety profile was observed. nificant differences were achieved.18 A steroid- sparing effect and an improvement in patient In keeping with the scarce available literature reported outcomes were observed in the open- addressing the distinctive features of Caucasian label extension of the TAKT study over 96 weeks journals.sagepub.com/home/tab 7 Therapeutic Advances in Musculoskeletal Disease 13 Figure 4. Kaplan–Meier plot showing remission results in patients who received Tocilizumab as monotherapy (TCZMONO) and combined with cDMARDs (TCZCOMBO). of TCZ treatment.24 The TOCITAKA trial is an prednisolone was 28%, 67%, and 79% at 3, 6, open-label prospective study that assessed the and 12 months, respectively. Similar clinical out- effect of TCZ to discontinue glucocorticoids after comes were observed in our study. 6 months of IV TCZ therapy. Thirteen patients were included in the study, of which seven were Mekinian et al.12 observed that 20% and 17% of Caucasians. Clinical remission and withdrawal of patients showed persistence of inflammatory steroid therapy was achieved in 54% patients after activity in the follow-up imaging tests at 6 and 6 months of TCZ onset.19 In our study, 52.3% of 12 months, respectively. Nakaoka et al.24 reported patients achieved remission at 6 months, but most that 4 out of 28 (14.3%) of patients showed wors- of them were still receiving prednisone at a median ening from baseline in the follow-up imaging (IQR) dose of 5.0 (5.0–10.0) mg/day. It is worth evaluations. Interestingly, only one of the four mentioning that we assessed patients with refrac- patients with worsened imaging data met the pro- tory TAK, whereas the TOCITAKA study only tocol-defined clinical criteria for TAK relapse. In included treatment-naïve patients. The early use of our study, 10 (26.3%) of the 38 patients in whom TCZ may be more effective to induce TAK remis- an imaging follow-up test was performed showed sion and rapid withdrawal of glucocorticoids, but no radiographic improvement. In an attempt to well-randomized studies are needed to confirm correlate imaging findings with clinical outcomes, this hypothesis. we found that 4 of these 10 patients were in clini- cal remission despite the persistence of inflamma- Mekinian et al.12 conducted a retrospective study tory imaging activity. These findings suggest that of 46 patients with TAK diagnosis, including 29 a discordance between clinical and imaging activ- individuals of Caucasian origin. Both treatment- ity assessment may exist, as it has been observed naïve and refractory patients were included in the in patients with large-vessel giant cell arteritis study. As in our series of patients, TCZ was treated with TCZ.25 The assessment of disease mainly prescribed as IV injections. The percent- activity in TAK remains a challenge, particularly age of patients who achieved clinical remission, in patients undergoing TCZ therapy in whom defined as National Institute of Health (NIH) acute phase reactants levels are not reliable indi- scale < 2 receiving less than 7.5 mg/day of cators of relapse. Vascular progression has been 8 journals.sagepub.com/home/tab Table 3. The main studies on patients with Takayasu’s arteritis treated with TCZ. Decker et al.11 Mekinian et al.12 Nakaoka et al.18 (TAKT study) Mekinian et al.19 Nakaoka et al.24 (open Present study (TOCITAKA study) label extension TAKT study) Type of study Systematic review Retrospective Randomized controlled phase Prospective open- Open label extension of Retrospective of 26 retrospective III study on refractory patients labeled trial on naïve randomized phase III studies patients study journals.sagepub.com/home/tab Number of patients 105 46 36 (18 TCZ/18 placebo) 13 28 54 Sex (women/men) 77/9 (NR 19) 35/11 31/5 12/1 24/4 46/8 Median age (years) 28 43 26.5 32 31 42 Ethnicity ND 29 Caucasians 36 Asian 7 Caucasians 28 Asian 54 Caucasians 9 North Africans 4 North Africans 8 other origin 2 other origin Median disease duration 31 NR 34.7 8 34.7 12 (months) TCZ administration route NR IV SC IV SC 40 IV/14 SC Median CRP (mg/dl)/ESR 3/50 2.3/NR 1.5/NR 1.6/NR 1.5/NR 1.5/30.5 (mm/h) at baseline Median prednisone dose 25 15 0.5 mg/kg/day 45 0.5 mg/kg/day 30 (mg/day) at baseline Efficacy outcomes 85.7% patients Treatment response* Time to relapse was longer Treatment response* Mean 36-Item Short Remission# was experienced initial was achieved in but not statistically different was achieved in 69%, Form Health Survey achieved in 22.2%, clinical improvement 28%, 67%, 79% and between the TCZ and placebo 54%, 50%, 90% and physical and mental 38.8%, 52.3% and within 3 months. 75% at 3, 6, 12 and group: HR 0.41 (95.41% CI 36% at 6, 9, 12, 15 scores improved and 75% patients at 1, 3, 18 months. 0.15–1.10; p = 0.0596) and 18 months. maintained for 96 weeks. 6 and 12 months. Steroid-sparing effect 90.4% steroid dose Median daily PD The study was not designed to 54% patients 46.4% patients reduce Median daily PD reduction dose decreased from assess this effect discontinued steroids dose to <0.1 mg/kg/day dose decreased from 15 mg to 5 mg at after 7 infusions of 30 mg to 5 mg at 6 months. TCZ 12 months. Relapses after TCZ 46% patients within NR NR 45% patients within NR None discontinuation 5 months. 12 months. Safety outcomes 18% severe events 11% severe events 5.5% severe events 0% TCZ 0% severe events 0% 25% severe events 0% 11.1% severe events 7% TCZ withdrawal 4% TCZ withdrawal withdrawal TCZ withdrawal TCZ withdrawal 5.5% TCZ withdrawal Imaging outcomes 65.2% improvement 20% and 17% NR NR 85.7% improvement or 73.7% improvement persistent stable 14.3% worsening 26.3% no radiological activity at improvement 6 and 12 months. *Treatment response was defined as NIH scale <2 and prednisone <7.5 mg/dL #remission was defined as the absence of new symptoms and disappearance of all previous symptoms of TAK along with the normalization of CRP and ESR. CI, confidence interval; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HR, hazard ratio; IV, intravenous; NIH, National Institute of Health; NR, non-reported; PD, prednisone; SC, subcutaneous; TCZ, tocilizumab. 9 D Prieto-Peña, P Bernabeu et al. Therapeutic Advances in Musculoskeletal Disease 13 reported on imaging techniques despite clinical TAK in a real-world setting. In addition, this is the remission and normal acute phase reactants.25–28 first study to focus on Caucasian patients. More research is needed to address the role of In conclusion, TCZ is effective and safe in imaging techniques in monitoring disease activity Caucasian patients with refractory TAK despite in patients with LVV. In this sense, the identifica- demographical and clinical differences with other tion of new biomarkers and the validation of dis- ethnic groups. ease activity scores, including clinical, laboratory, and imaging outcomes, will be crucial to improve Acknowledgements the treatment of patients with TAK.29 The authors thank Dr. Isabel Martínez-Rodríguez from the Nuclear Medicine Department of Hospital It remains unknown if the combination of TCZ Universitario Marqués de Valdecilla, Santander with cDMARDs may have an additional favorable (Spain) for the generous contribution of the image effect in the management of TAK. Mekinian to Figure 1. The authors also thank all the mem- et al.12 observed similar event-free survival in 38 bers and patients of the participating hospitals. patients who received TCZ in monotherapy and 18 patients treated with combined therapy with Abbreviations cDMARDs. In our cohort of patients, those who cDMARDS, conventional disease modifying received TCZ along with cDMARDs were anti-rheumatic drugs; CI, confidence intervals; younger, had longer TAK disease duration, and CT-A, computed tomography angiography; 18F- higher acute phase reactants levels at baseline. FDG PET/CT, 18F-fluorodexyglucose positron Despite these differences, we observed similar out- emission tomography/computed tomography; IL, comes in patients receiving TCZ with and without interleukin; IQR, interquartile range; LVV, large- cDMARDs. Further studies are needed to deter- vessel-vasculitis; MRI-A, magnetic resonance mine if combined therapy may be particularly use- imaging angiography; MTX, methotrexate; OR, ful in patients with more severe TAK disease. odds ratio; PPD, tuberculin skin test; quantiF- ERON, interferon assay (for excluding latent It should be noted, that, in our study, none of the tuberculosis); SD, standard deviation; TAK, six patients in whom TCZ was discontinued due Takayasu’s arteritis; TCZ, tocilizumab. to sustained remission experienced a relapse after TCZ withdrawal. These six patients received TCZ for a median (IQR) of 57.0 (52.0–76.5) months Conflict of interest statement before TCZ discontinuation and maintained Disclosures that might be interpreted as consti- remission until the end of the study period for at tuting of possible conflict(s) of interest for the least 37.5 (24.0–63.5) months. In contrast, in the study: DP-P is supported by a research contract TOCITAKA study,19 a relapse occurred in 45% of from the Carlos III Health Institute of Spain (Rio patients within 12 months of TCZ withdrawal Hortega program, ref. CM20/00006) and has when TCZ was discontinued after 6 months of received research support from UCB Pharma, treatment. A longer duration of TCZ therapy in Roche, Sanofi, Pfizer, AbbVie, and Lilly. MAG-G our patients may explain these differences. Longer received grants/research supports from Abbvie, maintenance therapy with TCZ may be needed to MSD, Jansen, and Roche and had consultation prevent relapses. Further investigation is needed to fees/participation in company sponsored speak- define the most adequate duration of treatment er’s bureau from Abbvie, Pfizer, Roche, Sanofi, with TCZ for TAK management. Lilly, Celgene, and MSD. RB received grants/ research supports from Abbvie, MSD, and Roche, TCZ has shown a good-safety profile in several and had consultation fees/participation in com- studies.22,30 Our results are consistent with previ- pany sponsored speaker’s bureau from Abbvie, ous studies on TAK.11,12,18,19,24 In our study, only Lilly, Pfizer, Roche, Bristol-Myers, Janssen, UCB three (5.5%) patients had to discontinue TCZ Pharma, and MSD. The remaining authors due to severe effects including pneumonia and declare they do not have conflict of interest. pancytopenia. Funding Despite the limitations derived from the retrospec- The authors disclosed receipt of the following tive nature of this study, our results support the financial support for the research, authorship, efficacy of TCZ in the management of refractory and/or publication of this article: This work was 10 journals.sagepub.com/home/tab D Prieto-Peña, P Bernabeu et al. partially supported by RETICS Programs, Takayasu’s arteritis: a multicenter study of 318 RD08/0075 (RIER), RD12/0009/0013 and patients. J Autoimmun 2019; 96: 35–39. RD16/0012 from “Instituto de Salud Carlos III” 9. Hellmich B, Agueda A, Monti S, et al. 2018 (ISCIII) (Spain). update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum However, this research did not receive any spe- Dis 2020; 79: 19–30. cific grant from funding agencies in the commer- cial or not-for-profit sectors. 10. Comarmond C, Biard L, Lambert M, et al. Long-term outcomes and prognostic factors of complications in Takayasu arteritis: a multicenter ORCID iDs study of 318 patients. Circulation 2017; 136: Javier Narváez https://orcid.org/0000-0002- 1114–1122. 1614-8064 11. Decker P, Olivier P, Risse J, et al. Tocilizumab Patricia Moya https://orcid.org/0000-0001- and refractory Takayasu disease: four case reports 8339-5420 and systematic review. Autoimmun Rev 2018; 17: 353–360. José L. Alonso-Valdivielso https://orcid.org/ 0000-0002-1862-6883 12. Mekinian A, Resche-Rigon M, Comarmond C, et al. Efficacy of tocilizumab in Takayasu arteritis: Miguel A. González-Gay https://orcid.org/ multicenter retrospective study of 46 patients. 0000-0002-7924-7406 J Autoimmun 2018; 91: 55–60. Ricardo Blanco https://orcid.org/0000-0003- 13. Loricera J, Blanco R, Hernández JL, et al. 2344-2285 Tocilizumab in patients with Takayasu arteritis: a retrospective study and literature review. Clin Exp Rheumatol 2016; 34: S44–S53. 14. 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