TAB0010.1177/1759720X20971908Therapeutic Advances in Musculoskeletal DiseaseJ Liu, D Yan 971908research-article20202020 Therapeutic Advances in Musculoskeletal Disease Case Series Ther Adv Musculoskel Dis Tocilizumab in the treatment of severe and 2020, Vol. 12: 1–8 DOI:https://doi.org/10.1177/1759720X20971908 10.1177/ refractory parenchymal neuro-Behçet’s 1759720X20971908https://doi.org/10.1177/1759720X20971908 © The Author(s), 2020. Article reuse guidelines: syndrome: case series and literature review sagepub.com/journals- permissions Jinjing Liu* , Dong Yan*, Zhimian Wang, Yunjiao Yang, Shangzhu Zhang, Di Wu, Lingyi Peng, Zhichun Liu and Wenjie Zheng Abstract Correspondence to: Objectives: This study aimed to investigate the efficacy and safety of tocilizumab (TCZ) in Wenjie Zheng severe and refractory parenchymal neuro-Behçet’s syndrome (p-NBS). Department of Rheumatology and Clinical Methods: We retrospectively analyzed five patients with p-NBS treated with TCZ in our center Immunology, Peking Union between 2013 and 2020, and six cases from literature research with the index terms “neuro- Medical College Hospital, Chinese Academy of Behçet’s syndrome” and “tocilizumab” on PubMed NCBI. Medical Sciences & Peking Union Medical Results: A total of 11 patients with p-NBS were enrolled (5 males, 6 females), with a mean College, Key Laboratory of age of 34.5 ± 8.0 years at the onset. All the patients had parenchymal neurological lesions, Rheumatology and Clinical Rheumatology, Ministry six patients (54.5%) suffered from multiple lesions, and nine patients (81.8%) were disabled. of Education, National Clinical Research Center Before TCZ administration, all the patients had failed conventional therapy, eight patients for Dermatologic and (72.7%) received two or more immunosuppressants, and five patients showed insufficient Immunologic Diseases, No. 1 Shuafuyuan, response or intolerance to other biologics. TCZ was administrated at 8 mg/kg every 4 weeks, Dongcheng District, with background glucocorticoids (GCs) and immunosuppressants. After a median follow- Beijing, 100730, China [email protected] up of 13 (interquartile range, 3.5–23.5) months, all the patients achieved both clinical and Jinjing Liu radiological improvements, and the Behçet’s Disease Current Activity Form score improved Department of Rheumatology and Clinical significantly (3 versus 0, median, p = 0.004), the Rankin score also decreased (4 versus 2, Immunology, Peking Union Medical College Hospital, median, p = 0.005). Levels of interleukin-6 in the cerebrospinal fluid decreased significantly Chinese Academy of in five patients (533.4 ± 389.7 pg/ml versus 34.5 ± 27.1 pg/ml, p = 0.048), after a median of two Medical Sciences & Peking Union Medical (interquartile range, 1–4) times of TCZ infusions. Furthermore, the GC dosage (per os) reduced College, Key Laboratory of from 69.2 16.9 mg/d to 16.4 16.2 mg/d (p = 0.000), and immunosuppressants were tapered Rheumatology and Clinical ± ± Rheumatology, Ministry in number and dosage in seven (63.6%) and four (36.3%) patients, respectively. No serious of Education, National Clinical Research Center adverse events or deaths were observed during follow-up. for Dermatologic and Conclusions: TCZ is well tolerated and effective in severe and refractory p-NBS, with a Immunologic Diseases, Beijing, China favorable GC- and immunosuppressant-sparing effect. Cerebrospinal fluid interleukin-6 might Dong Yan be used to monitor the effects of TCZ in p-NBS. Department of Rheumatology and Immunology, The Second Affiliated Hospital of Keywords: Behçet’s syndrome, neurological involvement, tocilizumab Soochow University, Suzhou, China Received: 5 June 2020; revised manuscript accepted: 24 September 2020. Zhimian Wang Yunjiao Yang Shangzhu Zhang Di Wu Lingyi Peng Introduction of NBS among patients with BS is approximately Department of Rheumatology and Clinical 4 Behçet’s syndrome (BS) is a multifactorial poly- 9% (ranging 3–30%). Generally, there are two Immunology, Peking Union genic autoinflammatory disorder characterized by categories of NBS: parenchymal (p-NBS) and Medical College Hospital, Chinese Academy of 5–8 multi-organ involvement, presenting different nonparenchymal involvement. The former Medical Sciences & phenotypic clusters.1 Neurological involvement, involves meningoencephalitis, which can cause Peking Union Medical College, Key Laboratory of so-called neuro-Behçet’s syndrome (NBS), is one significant neurological consequences from cog- Rheumatology and Clinical of its life-threatening manifestations with high nitive changes to paralysis, with brain stem Rheumatology, Ministry of Education, National 2,3 mortality and severe disability. The frequency involvement as the most characteristic feature; Clinical Research Center 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 12 for Dermatologic and the latter refers to the vascular phenotype, involv- 6 months after TCZ treatment or by a decrease of Immunologic Diseases, ing intracranial arteries and venous sinuses. >50% of the GC dose as compared with baseline. Beijing, China Glucocorticoids (GCs) and immunosuppressants Other patients were considered nonresponders.17 Zhichun Liu Department of remain to be the cornerstones for NBS manage- We chose the modified Rankin score to assess the Rheumatology and ment. The international consensus recommenda- disability status of patients with NBS. Severe NBS Immunology, The Second 7 18 Affiliated Hospital of tions of p-NBS suggested that tumor necrosis was defined as Rankin score ⩾3. The BS disease Soochow University, factor (TNF)-α inhibitors could be alternatives as activity was assessed according to the BD Current Suzhou, China *These authors second-line therapies when conventional therapy Activity Form (BDCAF) 2006 (http://www. contributed equally to this is ineffective or intolerable. In addition, the 2018 behcet.ws/pdf/BehcetsDiseaseActivityForm.pdf). work. European League Against Rheumatism guidelines recommend that TNF-α inhibitors be considered This study was approved by the Institutional first-line therapy in severe and (or) refractory Review Board of Peking Union Medical College p-NBS.9 However, issues including inadequate Hospital. All participants signed written informed response, loss of the initial efficacy over time, intol- consent. erance, and relative contraindications limited the use of TNF-α inhibitors, which necessitated seek- ing alternative therapies to treat severe or refrac- Statistical analysis tory p-NBS. Although growing evidence supported Statistical analysis was performed with SPSS ver- the advantage of interleukin (IL)-6 receptor antag- sion 21.0 (IBM Inc., Armonk, USA). Categorical onist tocilizumab (TCZ) in treating refractory variables were presented with counts and propor- BS,10,11 only case studies reported the treatment of tions. Data with Gaussian distribution were TCZ in NBS. In this study, we aimed to elucidate described as mean ± SD and non-Gaussian dis- the efficacy and safety of TCZ in p-NBS. tributed data were described as median and range. The continuous variables were analyzed by the paired sample t-test. Non-Gaussian dis- Methods tributed data and Ranked ordinal data were ana- lyzed by the Wilcoxon signed-rank test, and the Patients correlation was performed with Spearman’s rank We retrospectively analyzed the clinical data of correlation test. A value of p < 0.05 was consid- refractory patients with NBS treated with TCZ in ered significant. our center from January 2013 to January 2020. All the patients fulfilled the International Criteria for BD (ICBD).12 The diagnosis of neurological Result involvement was made by two rheumatologists and two neurologists, based on neurological Epidemiology symptoms, physical examination, cerebrospinal A total of 11 patients with p-NBS were enrolled fluid (CSF) analysis, and neuroradiological (5 patients from our center and 6 patients from examinations, adhering to the classification crite- the literature), including 6 males and 5 females. ria of the 2014 International Consensus on NBS7 The mean age of onset of BS and NBS was and were categorized as p-NBS. Clinical data 24.8 ± 8.4 and 34.5 ± 8.0 years, respectively. including demographics, clinical features, labora- tory tests, imaging, treatment, and outcome measures were retrospectively collected. We also BS manifestations searched and summarized the papers with the In these patients, oral ulceration was presented in index terms “neuro-Behçet’s syndrome” and all, followed by skin lesions (8 of 11, 72.7%) “tocilizumab” on PubMed NCBI.13–16 (including pseudo folliculitis, nodular erythema or positive pathergy test), genital ulcers (7 of 11, The clinical response and safety of TCZ treat- 63.6%), uveitis (3 of 11, 27.3%), arthritis (2 of ment were evaluated. Complete response (CR) 11, 18.2%) and vascular involvement (2 of 11, was defined by the disappearance of all neurologi- 18.2%), presented as deep vein thrombosis. cal symptoms and by the improvement of radio- logical abnormalities related to NBS 6 months after TCZ treatment. Partial