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Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients
Journal of Autoimmunity xxx (2018) 1e6
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Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients Comarmond b, d, e, f, Arsene Mekinian a, b, *, Mathieu Resche-Rigon c, Cloe Alessandra Soriano g, Joel Constans h, Laurent Alric i, Patrick Jego j, Florian Busato k, Matthieu Cabon l, Robin Dhote m, Lazaro Estibaliz n, Isabelle Kone Pault o, p, dric Landron q, Christian Lavigne r, Bertrand Lioger s, Martin Michaud t, Ce Marc Ruivard u, v, Karim Sacre w, Jacques Eric Gottenberg l, Francis Gaches u, v, Tiphaine Goulenok w, Carlo Salvarani g, Patrice Cacoub b, d, e, f, Olivier Fain a, b, David Saadoun b, d, e, f, **, for the French Takayasu network a ^pital Saint Antoine, service de m AP-HP, Ho edecine interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Facult e de M edecine Sorbonne Universit e, F-75012, Paris, France b Sorbonne Universit es, UPMC Universit e Paris 06, UMR 7211, D epartement Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (DHU i2B), F-75005, Paris, France c ^pital Saint Louis, Paris, France Unit e Epid emiologie et Biostatistiques, INSERM, Ho d INSERM, UMR_S 959, F-75013, Paris, France e CNRS, FRE3632, F-75005, Paris, France f AP-HP, Groupe Hospitalier Piti e-Salp^ etri ere, D epartement de M edecine Interne et Immunologie Clinique, National center for Autoimmune and Systemic rare disease, National center for Autoinflammatory diseases and amyloidosis, F-75013, Paris, France g di Modena e Reggio Emilia, Reggio Emilia Italy Division of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, Universita h ^pital st Andre, 1 rue Jean burguet, 33075 Bordeaux, France Service de m edecine Vasculaire, ho i Department of Internal Medicine, CHU Purpan, UMR 152 Pharma Dev, IRD Toulouse 3 University, France j Service de M edecine Interne, CHU Rennes, Rennes, France k Service de M edecine interne Centre Hospitalier de Bigorre Boulevard de Lattre de Tassigny 65013 TARBES Cedex 9, France l ^pitaux Universitaires de Strasbourg, Inserm UMR_1109, F ed eration de M edecine Translationnelle, Universit e de Strasbourg, Service de rhumatologie, Ho Strasbourg, France m ^pital Avicenne, service de m AP-HP, Ho edecine interne, Universit e Paris 13, 93000, Bobigny, France n ^pital Haut-L Service de m edecine interne, ho ev^ eque, 33600 Pessac, France o Pediatric rheumatology, APHP, CHU Bic^ etre, 78, Rue Gal. Leclerc, 94275, Le Kremlin-Bic^ etre, France p CeR eMAIA- French reference center for auto-inflammatory diseases and inflammatory amyloidosis, 94270, Le Kremlin Bic^ etre, France q ^pital Poitiers, CHU Poitiers, France Service de m edecine interne, Ho r ^pital Angers, CHU Angers, France Service de m edecine interne, Ho s ^pital Saint Louis, service de m AP-HP, Ho edecine interne, Universit e Paris 7, Paris, France t ^pital Joseph Ducuing, 15, rue de Varsovie BP 53160, 31027 Toulouse Cedex 3, France Service de m edecine interne, Ho u CHU Clermont-Ferrand, Service M edecine Interne, CHU Estaing, F-63003 Clermont-Ferrand, France v Universit e Clermont Auvergne, CNRS-UMR 6602, Institut Pascal, Axe TGI (gpe. PEPRADE), F-63000 Clermont-Ferrand, France w ^pital Bichat, APHP, Paris, France Service de M edecine Interne Ho
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Article history: Received 3 March 2018 Received in revised form 31 March 2018 Accepted 5 April 2018 Available online xxx
Objectives: To assess the efficacy of tocilizumab in patients with Takayasu arteritis (TA). Methods: We conducted a retrospective multicenter study in 46 TA patients treated with tocilizumab. We analyzed factors associated with response to tocilizumab (assessed using NIH score). Results: Forty-six patients with TA were included, with a median age of 43 years [29e54], and 35 (76%) females. We observed a decrease in the median NIH scale (from 3 [2e3] at baseline to 0 [0e1] and 0 at 3 and 6 months, respectively; p < 0.0001). The daily prednisone dose also decreased from 15 mg [8e19] at
decine, Ho ^pital Saint Antoine, service de medicine interne and Inflammation-Immunopathology-Biotherapy Department * Corresponding author. AP-HP, Sorbonne Me (DHU i2B), F-75012, Paris, France. ** Corresponding author. Department of Internal Medicine and clinical immunology, DHU I2B, inflammation, immunopathology, biotherapy, UPMC, Paris VI, Centre national fe rence des maladies autoimmunes et syste miques rares, Ho ^pital Pitie -Salpe trie re, 47-83 boulevard de l’Ho ^ pital, 75013 Paris, France. de re E-mail addresses: [email protected] (A. Mekinian), [email protected] (D. Saadoun). https://doi.org/10.1016/j.jaut.2018.04.002 0896-8411/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
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A. Mekinian et al. / Journal of Autoimmunity xxx (2018) 1e6
Keywords: Takayasu arteritis Tocilizumab Vasculitis treatment
baseline to 4 mg [5e21] and 5 mg [4.5e9] at 3 and 6 months, respectively (p < 0.0001) under tocilizumab. The overall tocilizumab failure free survival was 81% [CI 95%; 0.7e0.95], 72% [CI 95%; 0.55e0.95] and 48% [CI 95%; 0.2e0.1] at 12, 24 and 48 months, respectively. The presence of constitutional symptoms (HR 5.6 [CI 95%; 1.08e29], p ¼ 0.041), and C-reactive protein level (HR 1.16 [CI 95%; 1.01e1.31], P ¼ 0.003) at the time of tocilizumab initiation were significantly associated with tocilizumab event-free survival. The event-free survival was significantly better under tocilizumab therapy in comparison to DMARDs (p ¼ 0.02). Conclusion: This large multicenter study shows that tocilizumab is efficient and may reduce the incidence of relapses in TA. © 2018 Elsevier Ltd. All rights reserved.
1. Introduction Takayasu arteritis (TA) is a chronic inflammatory vasculitis that affect the large vessels, in particular the aorta and its main branches [1]. The main complications are consequence of vascular inflammation, with arterial stenosis, aneurisms and thrombosis. The better treatment strategy in TA remains to be determined. Steroids remain the cornerstone of therapeutic management. However, only 60% of patients achieve a sustained remission with less than prednisone 10 mg/day [2]. The use of steroid-sparing agents like azathioprine, methotrexate, or mycophenolate mofetil have been described mostly in little case-series, and the growing data about the benefit of biological-targeting agents have been recently reported. We recently reported the French multicenter experience showing the benefit of biological-targeted treatments in refractory TA with substantial benefit in comparison to DMARDs for relapsefree and vascular-events free survivals [3]. Increasing evidence supports arguments for a role of IL-6 in the pathogenesis of TA. Data from immuno-histochemical analyses from aortic wall samples in patients with TA showed the presence of IL-6 producing T cells in vascular inflammatory infiltrates [4]. Previous data, mainly case-reports and small series reported rapid and sustained remission with tocilizumab, mostly in refractory TA [5,6]. However, some cases reported vascular progression under tocilizumab [5,7e10]. A recent randomized trial did not show the benefit of tocilizumab for relapse-free survival in comparison to placebo [11]. In this multicenter study, we assessed the long term outcome and the predictive factors of response in 46 TA patients treated with tocilizumab. We also analyzed the efficacy of tocilizumab a) use alone or associated without DMARDs, b) use as first-line therapy or in treatment-experienced patients and c) the event free survival and cumulative incidence of relapses of tocilizumab compared to a control group of TA patients treated by DMARDs therapy. 2. Patients We conducted a retrospective multicenter study between January 2009 and January 2016. All patients fulfilled TA ACR and/or Ishikawa criteria modified by Sharma et al. The patients' clinical, laboratory and imaging data, treatments were analyzed at baseline, at the initiation of each treatment regimen, at 3, 6, 12, 18 months, 3 years after each line and at the last available visit. Steroids amounts were analyzed at the initiation and the end of each treatment regimen. Disease-specific vascular complications were defined as any ischemic vascular event and/or the need for vascular intervention during the follow-up. The different lines of immunosuppressive agents (conventional DMARDs, biological-targeting treatments and among then the tocilizumab), were analyzed separately for each patient. Five patients in the current case-series have been previously reported [3]. Adverse events were recorded
and severe infection was defined as any infection requiring intravenous antibiotic use, hospitalization or infection-related death. A control group of TA patients treated by DMARDs and which have never been treated with any biological-therapy was extracted from the “French Takayasu network” registry and matched to tocilizumab treated TA according to age, sex and the number of lines of treatment.
3. Disease activity and treatment response definitions Disease activity was defined according to the NIH criteria as previously defined [12]. Briefly, disease was considered active if NIH score was 2 or more, and inactive otherwise. Steroid dependence was defined as prednisone 20 mg/day before each new therapeutic. Treatment response was considered if NIH scale <2, and nonresponse in other situations [3]. Because of usual decrease of Creactive protein under tocilizumab, the prednisone decrease and sparing effect was considered in the response definition and combined scale with NIH scale <2 and prednisone <7.5 mg/day was also evaluated at 6 months. Tocilizumab failure was considered in the case of non-response, treatment changes, ischemic vascular event and/or the need for vascular intervention during the tocilizumab treatment time. Relapse was defined as active disease after a remission period and with change of the treatment regimen.
4. Statistical analysis Data are presented as medians with ranges for continuous variables and frequencies with percentages for qualitative variables. Fisher's exact test was used to compare qualitative variables and the Wilcoxon rank sum test were used to compare continuous variables as appropriate. Treatment and patient’s characteristics at the initiation of each treatment regimen were considered as potential time dependent variables. Event-free and relapse-free survivals under treatments were estimated using Kaplan Meier estimator. Relapse was defined as the fact that disease becomes active after a remission period requiring change of the treatment regimen. Differences between survivals curves were tested using Logrank tests. Hazard Ratios (HR with their 95% CI) of the cause specific hazard of relapse were obtained using Cox proportional hazard model and were tested using Wald tests. Cumulative incidences of relapse were estimated using Gray estimator, with relapse without complicqation considered a competing event of complication. Differences between cumulative incidences were performed using Fine and Gray models and Wald tests. All tests were two-sided and a p. value < 0.05 was considered statistically significant. Statistical analyses were carried out using R (version 3.1.0).
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
A. Mekinian et al. / Journal of Autoimmunity xxx (2018) 1e6
5. Results 5.1. Patients baseline characteristics Forty-six patients with TA were included, with a median age of 43 years [29e54], and 35 (76%) females. Geographic origin included 29 (63%) caucasians, 9 (20%) north-africans and 8 (17%) from other origin. Baseline risk factors for cardiovascular diseases were arterial hypertension in 10 (22%) cases, hyperlipidemia in 5 (11%), tobacco use in 8 (17%) cases and type 2 diabetes in 1 (2%) case. The median body mass index was 25 kg/m2 [19e29]. Autoimmune or inflammatory associated diseases were present in 8 patients: Sjogren's syndrome (n ¼ 3), Crohn's disease (n ¼ 2), sarcoidosis (n ¼ 2), and juvenile idiopathic arthritis (n ¼ 1). 5.2. Treatment and efficacy of tocilizumab Among the 46 TA patients, 126 lines of treatments were used during the follow-up, with a median number of DMARDS of 1 [1e3]. Among the 126 lines, 46 lines of tocilizumab have been used and among them tocilizumab was used as first-line treatment in 7 cases without associated DMARDs. Tocilizumab was prescribed in 39 remaining lines because of inadequately controlled TA or intolerance to DMARDs or steroids (n ¼ 27 lines) or relapse (n ¼ 12) (Fig. 1). Tocilizumab was mainly used intravenously at 8 mg/kg monthly. Patients characteristics before tocilizumab and during the follow-up are summarized in Table 1. At the initiation of tocilizumab, the vascular symptoms were present in 29/43 (67%) cases and
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constitutional symptoms in 16/43 (37%). The main vascular signs included vascular bruit (n ¼ 32; 70%), limb claudications (upper n ¼ 11; 24% and lower n ¼ 3; 6.5%), carotidodynia (n ¼ 11; 24%), vascular cerebral attack (n ¼ 3; 6.5%), and acute coronary syndrome (n ¼ 1; 2%). During the follow-up, the median NIH scale (from 3 [2e3] at baseline to 0 [0e1] 0 at 3 and 6 months, respectively; p < 0.0001), C-reactive protein levels (from 23 mg/l [16e40] at baseline to 1 [0e2] at 3 and 6 months, respectively; p < 0.0001) and daily prednisone amounts (from 15 mg/day [8e19] to 4 mg/day [5e21] and 5 mg/day [4.5e9] at 3 and 6 months, respectively; p < 0.0001) significantly decreased under tocilizumab (Table 1). There was a significant decrease of patients with persistent radiological activity under tocilizumab (from 83% at baseline to 20% and 17% at 6 and 12 months, respectively; p < 0.001). Treatment response (NIH scale < 2) was noted in 89% of TA patients at 6 months. Because of usual decrease of C-reactive protein under tocilizumab, the difficulty to consider the radiological response at 6 months, we analyzed the number of TA with NIH scale <2 and prednisone <10 mg/day and <7.5 mg/day at 6 months. The number of TA under tocilizumab were 7/36 (80%) and 12/36 (67%) with NIH scale < 2 and prednisone <10 mg/day and <7.5 mg/day at 6 months, respectively. In responders relative to non-responders, no significant factors have been shown, in particular considering C-reactive protein level, NIH scale, prednisone doses or associated DMARDs at the tocilizumab initiation. The overall survival without tocilizumab failure was 0.81 [CI 95%; 0.7e0.95] at 12 months, 0.72 [CI 95%; 0.55e0.95] at 24 months and 0.48 [CI 95%; 0.2e0.1] at 48 months (Fig. 2). The presence of constitutional symptoms at the time of tocilizumab initiation
Fig. 1. Flow chart of long term use of biological-targeted treatment in 46 TA patients.
Table 1 Patients characteristics at the initiation and during tocilizumab treatment.
Vascular symptoms Constitutional symptoms Radiological activity/progression NIH activity score C-reactive protein level (mg/l) Prednisone use (n; %) Prednisone dose (mg/day) DMARDs use (n; %) Tocilizumab continuation NIH<2 þ prednisone <7.5 mg/day
Initiation of tocilizumab N ¼ 46
At 3 months N ¼ 29
At 6 months N ¼ 36
At 12 months N ¼ 19
At 18 months N ¼ 12
29/43 (67%) 16/43 (37%) 35/42 (83%)* 3 [2e3]* 23 [16e40]* 39 (85%) 20 [10e45]* 18 (39%) e e
5/29 (17%) 1/29 (3%) e 0 [0e1] 1 [0e2] 24 (83%) 15 [8e19] 7/28 (25%) 28 (97%) 8 (28%)
7/36 (19%) 0 3/15 (20%) 0 [0] 1 [0e2] 26 (81%) 7 [5e11] 11 (31%) 34 (94%) 24 (67%)
2/19 (11%) 0 2/12 (17%) 0 [0] 0 [0e1] 19 (100%) 5 [4.5e9] 6 (30%) 16 (80%) 15 (79%)
5/12 (42%) 1/12 (8%) 3/6 (50%) 0 [0] 0 [0e2] 12 (100%) 5 [5e7] 3 (25%) 11 (92%) 9 (75%)
Values are medians [ranges] and numbers (frequencies). *p < 0.0001 between baseline and all visits during the follow-up (Kruskall Wallis tests or Fisher test).
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
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A. Mekinian et al. / Journal of Autoimmunity xxx (2018) 1e6
Fig. 2. Event-free survival in 46 TA patients after tocilizumab initiation.
(hazard ratio 5.6 [CI 95%; 1.08e29], p ¼ 0.041), C-reactive protein level (hazard ratio 1.16 [CI 95%; 1.01e1.31] for every 10 mg/l, P ¼ 0.003) was significantly associated with tocilizumab-event-free survival. Seven patients received tocilizumab as first-line treatment combined to steroids alone and 39 patients received tocilizumab after a median of 2 [2e3] lines of other regimen (Table 2) (Fig. 3). There was no differences in the median NIH scale, C-reactive protein levels at tocilizumab initiation, but prednisone daily amounts were higher in first-line TA patients without any associated DMARDs (p < 0.05). At 3 and 6 months, the NIH scale, C-reactive protein levels, and prednisone decrease were similar in 2 groups (Table 2). Tocilizumab event-free survival was similar in patients receiving tocilizumab as first-line treatment in comparison to those which have received other regimen before tocilizumab (log rank p ¼ 0.98) (Fig. 3). Among patients receiving tocilizumab at first line (n ¼ 7), 6 (86%) were still under treatment at the end of the followup (Fig. 1). Among patients receiving tocilizumab after a median of 2 [2e3] lines of other treatments (mainly DMARDs in 24 cases and other biologics in 9 cases), tocilizumab induced remission in 29 (74%) TA patients without DMARDs in 17 cases, and tocilizumab was switched to other biologics in 6 cases. DMARDs were used in combination with tocilizumab in 18 patients (39%) (all after other lines of regimen) (Fig. 1). Tocilizumab event-free survival was similar in patients under tocilizumab associated with and without DMARDs (log rank p ¼ 0.25) (Fig. 4).
Fig. 3. Event-free survival in 46 TA patients according to first-line tocilizumab (n ¼ 7) and other lines (n ¼ 39).
Fig. 4. Event-free survival in 46 TA patients according to tocilizumab used in monotherapy (n ¼ 38) and combined with DMARDs (n ¼ 18).
Table 2 Outcome of 46 TA patients treated with tocilizumab.
Vascular symptoms Constitutional symptoms NIH activity score C-reactive protein level (mg/L) Prednisone use Prednisone dose (mg/day) NIH<2 þ prednisone <7.5 mg/day
Initiation of tocilizumab
At 3 months
First line N¼7
Other lines N ¼ 38
First line N¼6
Other lines N ¼ 22
First line N¼7
Other lines N ¼ 29
5 (71%) 3 (43%) 3 [3] 28 [20e40] 5 (71%) 60 [48e68] e
25/36 (69%) 13/36 (36%) 3 [2e3] 23 [15e41] 34 (94%) 18 [10e38] e
2 0 0 0 5 7 2
3 (14%) 1 (5%) 0 [0e1] 1 [0e5] 19 (86%) 15 [8e18] 7 (32%)
2 0 0 0 5 7 6
5 (17%) 0 0 [0] 1 [0e3] 21 (72%) 8 [5e15] 17 (59%)
(33%) [0] [0e1] (83%) [4e9] (33%)
At 6 months
(29%) [0] [0e1] (71%) [4e9] (86%)
Values are medians [ranges] and numbers (frequencies).
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
A. Mekinian et al. / Journal of Autoimmunity xxx (2018) 1e6
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At the last available visit after a median follow-up of 0.9 years [0.5e2], for the 42 evaluable patients, the median NIH scale was at 0 (0) with C-reactive protein levels at 0 mg/l [0e1], and 25/42 patients were still under steroids with 9.5 mg/day [5e14] amounts. Thirty-four patients were still under biological-targeted treatments: tocilizumab (n ¼ 28 associated with methotrexate in 5 cases), infliximab and adalimumab (n ¼ 5; with methotrexate in 2 cases) and rituximab (n ¼ 1), 4 under methotrexate and 3 under prednisone alone. 5.3. Events-free survival under tocilizumab and DMARDs Tocilizumab treated TA patients (n ¼ 46) were compared to 46 age- and sex-matched TA patients which have been treated by DMARDs. At the treatment initiation, vascular symptoms, C-reactive protein levels, prednisone daily amounts and NIH scale were similar in 2 groups. The proportion of vascular complications and vascular interventions was similar under tocilizumab in comparison to DMARDs [p > 0.05], respectively. The 3-year vascular eventsfree survival under tocilizumab was at 80% and significantly better compared to DMARDs therapy (80% vs 50%; p ¼ 0.02, respectively) (Fig. 5). The cumulative incidence of relapse was significantly higher under DMARDs therapy compared to tocilizumab (34.6% vs 6.3%; p ¼ 0.049, respectively) (Fig. 6). 5.4. Safety During the follow-up, 5 (11%) adverse effects occurred: 2 asymptomatic neutropenia (<500/mm3), infusion reaction (n ¼ 1), dental abscess (n ¼ 1), and neoplasm (n ¼ 1) [1 breast cancer]. Two (4%) cases required treatment discontinuation, including the neoplasm and one severe asymptomatic neutropenia. The breast neoplasm occurred in a patient with familial history of neoplasm (breast neoplasm in sister). 6. Discussion The conclusions drawn by this study are that tocilizumab can lead patients with DMARDS-refractory TA to remission in 80% of cases at 6 months, have significant steroid sparing effect and a relatively good safety profile. Tocilizumab event-free survivals were
Fig. 5. Event-free survival under tocilizumab in comparison to DMARDs therapy.
Fig. 6. Cumulative incidence of relapse under tocilizumab in comparison to DMARDs therapy.
81% and 72% at 12 and 24 months, respectively considering clinical improvement, relapse and steroid sparing effect. Although the number of analyzed patients is low, tocilizumab seem to have similar efficacy when considered in monotherapy and with associated DMARDs. We report the largest original study assessing the long-term outcome of tocilizumab in TA and the vascular events under treatment. In steroid-resistant or -dependant TA patients, the adjunction of DMARDS (methotrexate, azathioprine, mycophenolate mofetil) to the ongoing steroid therapy often allows a better disease control and tapering steroids [12,13]. Nonetheless, clinical relapses and progression of vascular involvement remain frequent and represent one of the major therapeutic goals in TA [1]. The uncontrolled TA vascular disease is one of major factor of vascular progression and risk of stenosis, thrombosis or aneurysm. Patients with uncontrolled disease with immunosuppressive agents can benefit from biological-targeted treatments. Recent randomized trial compared 36 patients which received subcutaneous tocilizumab or placebo [11]. Although time to relapse was not significantly different under tocilizumab and placebo, longer time to relapse was showed in the tocilizumab group. Several retrospective studies reported the efficacy of tocilizumab, mostly in refractory TA patients [14e17]. In a recent literature review, 105 TA patients have been treated by tocilizumab with an overall clinical and radiological response rate of 85.7%and 65.2%, respectively [15]. We recently reported data from the French nationwide study about the use of infliximab and tocilizumab in TA. We have shown similar risk of vascular complications under these biological targeted drugs [3]. In TA the overall incidence of vascular complications reach more than 50% at 5 years with DMARDs [18] and was significantly reduced under tocilizumab in the present study. In TA the event-free survival was significantly improved under tocilizumab, in comparison to DMARDs [13]. Strikingly, the efficacy of tocilizumab was analyzed according to its use as first line or in treatment experienced patients. No significant difference was noted in tocilizumab event-free survival, underscoring the efficacy of tocilizumab in difficult to treat refractory and/or steroid-dependent TA patients. The early use of tocilizumab could be argued to better control the TA disease activity, and open-labeled trial is ongoing in France to show the
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
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A. Mekinian et al. / Journal of Autoimmunity xxx (2018) 1e6
benefit of first-line tocilizumab for the control of TA activity and relapse-free survival. Safety of tocilizumab is actually well established in several autoimmune conditions, as rheumatoid arthritis. In our study, sideeffects occurred in 11% of cases and are consistent with previous reported data [15]. Along this line, the literature review of TA treated by tocilizumab reported a low rate of severe adverse effects, with mainly infections, few cases of hyperlipidemia and neutropenia. Our study had several limitations, such as its retrospective design which can lead to the lack of uniformity in tocilizumab prescription and associated drugs. Treatment decisions were left at the physician's discretion. Radiological vascular improvement assessment is a major concern in TA patients, but there is currently no consensual recommendations for imaging methods to monitored these patients. Although only tertiary centers with expertise in TA have been considered for this multicenter study, the absence of centralized imaging lecture to detect the vascular progression constituted an important limitation of our study. In conclusion, this multicenter study is the largest study assessing the long-term efficacy of tocilizumab in TA. We observed a good efficacy of tocilizumab and with reasonable safety profile. We showed a better event-free survival under tocilizumab therapy compared to DMARDs. Tocilizumab might be use as first-line therapy and lead to good overall response in TA patients. Conflicts of interest and funding None. Funding sources None. Conflicts of interest None. Author contributions ne MekiAll authors were involved in drafting the article. Arse nian had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of data analysis. Acknowledgements We thank the Club Rhumatismes et Inflammation (CRI), and the French National Society of Internal Medicine (SNFMI) for their help in the organization of this study.
G.S. Hoffman, Takayasu arteritis, Ann. Intern. Med. 120 (1994) 919e929. [2] J. Schmidt, T.A. Kermani, A.K. Bacani, C.S. Crowson, L.T. Cooper, E.L. Matteson, K.J. Warrington, Diagnostic features, treatment, and outcomes of Takayasu arteritis in a US cohort of 126 patients, Mayo Clin. Proc. 88 (2013) 822e830. [3] A. Mekinian, C. Comarmond, M. Resche-Rigon, T. Mirault, J.E. Kahn, M. Lambert, J. Sibilia, A. Neel, P. Cohen, M. Hie, S. Berthier, I. Marie, C. Lavigne, M. Anne Vandenhende, G. Muller, Z. Amoura, H. Devilliers, S. Abad, M. Hamidou, L. Guillevin, R. Dhote, B. Godeau, E. Messas, P. Cacoub, O. Fain, D. Saadoun, Efficacy of biological-targeted treatments in Takayasu arteritis: multicenter, retrospective study of 49 patients, Circulation 132 (2015) 1693e1700. [4] D. Saadoun, M. Garrido, C. Comarmond, A.C. Desbois, F. Domont, L. Savey, B. Terrier, G. Geri, M. Rosenzwajg, D. Klatzmann, P. Fourret, P. Cluzel, L. Chiche, J. Gaudric, F. Koskas, P. Cacoub, Th1 and Th17 cytokines drive inflammation in Takayasu arteritis, Arthritis Rheumatol(Hoboken, N.J.) 67 (2015) 1353e1360. [5] N. Abisror, A. Mekinian, C. Lavigne, M.A. Vandenhende, M. Soussan, O. Fain, Tocilizumab in refractory Takayasu arteritis: a case series and updated literature review, Autoimmun. Rev. 12 (2013) 1143e1149. [6] M. Samson, G. Espigol-Frigole, N. Terrades-Garcia, S. Prieto-Gonzalez, M. Corbera-Bellalta, R. Alba-Rovira, J. Hernandez-Rodriguez, S. Audia, B. Bonnotte, M.C. Cid, Biological treatments in giant cell arteritis & Takayasu arteritis, Eur. J. Intern. Med. 50 (2018) 12e19. [7] C.A. Canas, F. Canas, J.H. Izquierdo, A.F. Echeverri, M. Mejia, F. Bonilla-Abadia, G.J. Tobon, Efficacy and safety of anti-interleukin 6 receptor monoclonal antibody (tocilizumab) in Colombian patients with Takayasu arteritis, J. Clin. Rheumatol. Practical Reports on Rheumatic & Musculoskeletal Diseases 20 (2014) 125e129. [8] J. Loricera, R. Blanco, J.L. Hernandez, S. Castaneda, A. Humbria, N. Ortego, B. Bravo, M. Freire, S. Melchor, M. Minguez, J. Salvatierra, C. Gonzalez-Vela, V. Calvo-Rio, M. Santos-Gomez, T. Pina, M.A. Gonzalez-Gay, Tocilizumab in patients with Takayasu arteritis: a retrospective study and literature review, Clin. Exp. Rheumatol. 34 (2016) S44eS53. [9] M. Bredemeier, C.M. Rocha, M.V. Barbosa, E.H. Pitrez, One-year clinical and radiological evolution of a patient with refractory Takayasu's arteritis under treatment with tocilizumab, Clin. Exp. Rheumatol. 30 (2012) S98eS100. [10] T. Xenitidis, M. Horger, G. Zeh, L. Kanz, J.C. Henes, Sustained inflammation of the aortic wall despite tocilizumab treatment in two cases of Takayasu arteritis, Rheumatology 52 (2013) 1729e1731. [11] Y. Nakaoka, M. Isobe, S. Takei, Y. Tanaka, T. Ishii, S. Yokota, A. Nomura, S. Yoshida, N. Nishimoto, Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study), Ann. Rheum. Dis. 77 (3) (2018) 348e354. [12] G.S. Hoffman, R.Y. Leavitt, G.S. Kerr, M. Rottem, M.C. Sneller, A.S. Fauci, Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate, Arthritis Rheum. 37 (1994) 578e582. [13] K. Maksimowicz-McKinnon, T.M. Clark, G.S. Hoffman, Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients, Arthritis Rheum. 56 (2007) 1000e1009. [14] E.D. Batu, H.E. Sonmez, T. Hazirolan, F. Ozaltin, Y. Bilginer, S. Ozen, Tocilizumab treatment in childhood Takayasu arteritis: case series of four patients and systematic review of the literature, Semin. Arthritis Rheum. 46 (2017) 529e535. [15] P. Decker, P. Olivier, J. Risse, S. Zuily, D. Wahl, Tocilizumab and refractory Takayasu disease: four case reports and systematic review, Autoimmun. Rev. 17 (4) (2018) 353e360. [16] Y.H. Lee, G.G. Song, Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis, Ann. Rheum. Dis. (2017). Epub ahead of print. [17] J. Zhou, Z. Chen, J. Li, Y. Yang, J. Zhao, H. Chen, M. Liu, F. Sun, M. Li, X. Tian, X. Zeng, The efficacy of tocilizumab for the treatment of Chinese Takayasu's arteritis, Clin. Exp. Rheumatol. 35 (Suppl 103) (2017) 171e175. [18] C. Comarmond, L. Biard, M. Lambert, A. Mekinian, Y. Ferfar, J.E. Kahn, Y. Benhamou, L. Chiche, F. Koskas, P. Cluzel, E. Hachulla, E. Messas, M. RescheRigon, P. Cacoub, T. Mirault, D. Saadoun, Long-term outcomes and prognostic factors of complications in Takayasu arteritis: a multicenter study of 318 patients, Circulation 136 (2017) 1114e1122.
References [1] G.S. Kerr, C.W. Hallahan, J. Giordano, R.Y. Leavitt, A.S. Fauci, M. Rottem,
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
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Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients Comarmond b, d, e, f, Arsene Mekinian a, b, *, Mathieu Resche-Rigon c, Cloe Alessandra Soriano g, Joel Constans h, Laurent Alric i, Patrick Jego j, Florian Busato k, Matthieu Cabon l, Robin Dhote m, Lazaro Estibaliz n, Isabelle Kone Pault o, p, dric Landron q, Christian Lavigne r, Bertrand Lioger s, Martin Michaud t, Ce Marc Ruivard u, v, Karim Sacre w, Jacques Eric Gottenberg l, Francis Gaches u, v, Tiphaine Goulenok w, Carlo Salvarani g, Patrice Cacoub b, d, e, f, Olivier Fain a, b, David Saadoun b, d, e, f, **, for the French Takayasu network a ^pital Saint Antoine, service de m AP-HP, Ho edecine interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Facult e de M edecine Sorbonne Universit e, F-75012, Paris, France b Sorbonne Universit es, UPMC Universit e Paris 06, UMR 7211, D epartement Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (DHU i2B), F-75005, Paris, France c ^pital Saint Louis, Paris, France Unit e Epid emiologie et Biostatistiques, INSERM, Ho d INSERM, UMR_S 959, F-75013, Paris, France e CNRS, FRE3632, F-75005, Paris, France f AP-HP, Groupe Hospitalier Piti e-Salp^ etri ere, D epartement de M edecine Interne et Immunologie Clinique, National center for Autoimmune and Systemic rare disease, National center for Autoinflammatory diseases and amyloidosis, F-75013, Paris, France g di Modena e Reggio Emilia, Reggio Emilia Italy Division of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, Universita h ^pital st Andre, 1 rue Jean burguet, 33075 Bordeaux, France Service de m edecine Vasculaire, ho i Department of Internal Medicine, CHU Purpan, UMR 152 Pharma Dev, IRD Toulouse 3 University, France j Service de M edecine Interne, CHU Rennes, Rennes, France k Service de M edecine interne Centre Hospitalier de Bigorre Boulevard de Lattre de Tassigny 65013 TARBES Cedex 9, France l ^pitaux Universitaires de Strasbourg, Inserm UMR_1109, F ed eration de M edecine Translationnelle, Universit e de Strasbourg, Service de rhumatologie, Ho Strasbourg, France m ^pital Avicenne, service de m AP-HP, Ho edecine interne, Universit e Paris 13, 93000, Bobigny, France n ^pital Haut-L Service de m edecine interne, ho ev^ eque, 33600 Pessac, France o Pediatric rheumatology, APHP, CHU Bic^ etre, 78, Rue Gal. Leclerc, 94275, Le Kremlin-Bic^ etre, France p CeR eMAIA- French reference center for auto-inflammatory diseases and inflammatory amyloidosis, 94270, Le Kremlin Bic^ etre, France q ^pital Poitiers, CHU Poitiers, France Service de m edecine interne, Ho r ^pital Angers, CHU Angers, France Service de m edecine interne, Ho s ^pital Saint Louis, service de m AP-HP, Ho edecine interne, Universit e Paris 7, Paris, France t ^pital Joseph Ducuing, 15, rue de Varsovie BP 53160, 31027 Toulouse Cedex 3, France Service de m edecine interne, Ho u CHU Clermont-Ferrand, Service M edecine Interne, CHU Estaing, F-63003 Clermont-Ferrand, France v Universit e Clermont Auvergne, CNRS-UMR 6602, Institut Pascal, Axe TGI (gpe. PEPRADE), F-63000 Clermont-Ferrand, France w ^pital Bichat, APHP, Paris, France Service de M edecine Interne Ho
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 March 2018 Received in revised form 31 March 2018 Accepted 5 April 2018 Available online xxx
Objectives: To assess the efficacy of tocilizumab in patients with Takayasu arteritis (TA). Methods: We conducted a retrospective multicenter study in 46 TA patients treated with tocilizumab. We analyzed factors associated with response to tocilizumab (assessed using NIH score). Results: Forty-six patients with TA were included, with a median age of 43 years [29e54], and 35 (76%) females. We observed a decrease in the median NIH scale (from 3 [2e3] at baseline to 0 [0e1] and 0 at 3 and 6 months, respectively; p < 0.0001). The daily prednisone dose also decreased from 15 mg [8e19] at
decine, Ho ^pital Saint Antoine, service de medicine interne and Inflammation-Immunopathology-Biotherapy Department * Corresponding author. AP-HP, Sorbonne Me (DHU i2B), F-75012, Paris, France. ** Corresponding author. Department of Internal Medicine and clinical immunology, DHU I2B, inflammation, immunopathology, biotherapy, UPMC, Paris VI, Centre national fe rence des maladies autoimmunes et syste miques rares, Ho ^pital Pitie -Salpe trie re, 47-83 boulevard de l’Ho ^ pital, 75013 Paris, France. de re E-mail addresses: [email protected] (A. Mekinian), [email protected] (D. Saadoun). https://doi.org/10.1016/j.jaut.2018.04.002 0896-8411/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
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A. Mekinian et al. / Journal of Autoimmunity xxx (2018) 1e6
Keywords: Takayasu arteritis Tocilizumab Vasculitis treatment
baseline to 4 mg [5e21] and 5 mg [4.5e9] at 3 and 6 months, respectively (p < 0.0001) under tocilizumab. The overall tocilizumab failure free survival was 81% [CI 95%; 0.7e0.95], 72% [CI 95%; 0.55e0.95] and 48% [CI 95%; 0.2e0.1] at 12, 24 and 48 months, respectively. The presence of constitutional symptoms (HR 5.6 [CI 95%; 1.08e29], p ¼ 0.041), and C-reactive protein level (HR 1.16 [CI 95%; 1.01e1.31], P ¼ 0.003) at the time of tocilizumab initiation were significantly associated with tocilizumab event-free survival. The event-free survival was significantly better under tocilizumab therapy in comparison to DMARDs (p ¼ 0.02). Conclusion: This large multicenter study shows that tocilizumab is efficient and may reduce the incidence of relapses in TA. © 2018 Elsevier Ltd. All rights reserved.
1. Introduction Takayasu arteritis (TA) is a chronic inflammatory vasculitis that affect the large vessels, in particular the aorta and its main branches [1]. The main complications are consequence of vascular inflammation, with arterial stenosis, aneurisms and thrombosis. The better treatment strategy in TA remains to be determined. Steroids remain the cornerstone of therapeutic management. However, only 60% of patients achieve a sustained remission with less than prednisone 10 mg/day [2]. The use of steroid-sparing agents like azathioprine, methotrexate, or mycophenolate mofetil have been described mostly in little case-series, and the growing data about the benefit of biological-targeting agents have been recently reported. We recently reported the French multicenter experience showing the benefit of biological-targeted treatments in refractory TA with substantial benefit in comparison to DMARDs for relapsefree and vascular-events free survivals [3]. Increasing evidence supports arguments for a role of IL-6 in the pathogenesis of TA. Data from immuno-histochemical analyses from aortic wall samples in patients with TA showed the presence of IL-6 producing T cells in vascular inflammatory infiltrates [4]. Previous data, mainly case-reports and small series reported rapid and sustained remission with tocilizumab, mostly in refractory TA [5,6]. However, some cases reported vascular progression under tocilizumab [5,7e10]. A recent randomized trial did not show the benefit of tocilizumab for relapse-free survival in comparison to placebo [11]. In this multicenter study, we assessed the long term outcome and the predictive factors of response in 46 TA patients treated with tocilizumab. We also analyzed the efficacy of tocilizumab a) use alone or associated without DMARDs, b) use as first-line therapy or in treatment-experienced patients and c) the event free survival and cumulative incidence of relapses of tocilizumab compared to a control group of TA patients treated by DMARDs therapy. 2. Patients We conducted a retrospective multicenter study between January 2009 and January 2016. All patients fulfilled TA ACR and/or Ishikawa criteria modified by Sharma et al. The patients' clinical, laboratory and imaging data, treatments were analyzed at baseline, at the initiation of each treatment regimen, at 3, 6, 12, 18 months, 3 years after each line and at the last available visit. Steroids amounts were analyzed at the initiation and the end of each treatment regimen. Disease-specific vascular complications were defined as any ischemic vascular event and/or the need for vascular intervention during the follow-up. The different lines of immunosuppressive agents (conventional DMARDs, biological-targeting treatments and among then the tocilizumab), were analyzed separately for each patient. Five patients in the current case-series have been previously reported [3]. Adverse events were recorded
and severe infection was defined as any infection requiring intravenous antibiotic use, hospitalization or infection-related death. A control group of TA patients treated by DMARDs and which have never been treated with any biological-therapy was extracted from the “French Takayasu network” registry and matched to tocilizumab treated TA according to age, sex and the number of lines of treatment.
3. Disease activity and treatment response definitions Disease activity was defined according to the NIH criteria as previously defined [12]. Briefly, disease was considered active if NIH score was 2 or more, and inactive otherwise. Steroid dependence was defined as prednisone 20 mg/day before each new therapeutic. Treatment response was considered if NIH scale <2, and nonresponse in other situations [3]. Because of usual decrease of Creactive protein under tocilizumab, the prednisone decrease and sparing effect was considered in the response definition and combined scale with NIH scale <2 and prednisone <7.5 mg/day was also evaluated at 6 months. Tocilizumab failure was considered in the case of non-response, treatment changes, ischemic vascular event and/or the need for vascular intervention during the tocilizumab treatment time. Relapse was defined as active disease after a remission period and with change of the treatment regimen.
4. Statistical analysis Data are presented as medians with ranges for continuous variables and frequencies with percentages for qualitative variables. Fisher's exact test was used to compare qualitative variables and the Wilcoxon rank sum test were used to compare continuous variables as appropriate. Treatment and patient’s characteristics at the initiation of each treatment regimen were considered as potential time dependent variables. Event-free and relapse-free survivals under treatments were estimated using Kaplan Meier estimator. Relapse was defined as the fact that disease becomes active after a remission period requiring change of the treatment regimen. Differences between survivals curves were tested using Logrank tests. Hazard Ratios (HR with their 95% CI) of the cause specific hazard of relapse were obtained using Cox proportional hazard model and were tested using Wald tests. Cumulative incidences of relapse were estimated using Gray estimator, with relapse without complicqation considered a competing event of complication. Differences between cumulative incidences were performed using Fine and Gray models and Wald tests. All tests were two-sided and a p. value < 0.05 was considered statistically significant. Statistical analyses were carried out using R (version 3.1.0).
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
A. Mekinian et al. / Journal of Autoimmunity xxx (2018) 1e6
5. Results 5.1. Patients baseline characteristics Forty-six patients with TA were included, with a median age of 43 years [29e54], and 35 (76%) females. Geographic origin included 29 (63%) caucasians, 9 (20%) north-africans and 8 (17%) from other origin. Baseline risk factors for cardiovascular diseases were arterial hypertension in 10 (22%) cases, hyperlipidemia in 5 (11%), tobacco use in 8 (17%) cases and type 2 diabetes in 1 (2%) case. The median body mass index was 25 kg/m2 [19e29]. Autoimmune or inflammatory associated diseases were present in 8 patients: Sjogren's syndrome (n ¼ 3), Crohn's disease (n ¼ 2), sarcoidosis (n ¼ 2), and juvenile idiopathic arthritis (n ¼ 1). 5.2. Treatment and efficacy of tocilizumab Among the 46 TA patients, 126 lines of treatments were used during the follow-up, with a median number of DMARDS of 1 [1e3]. Among the 126 lines, 46 lines of tocilizumab have been used and among them tocilizumab was used as first-line treatment in 7 cases without associated DMARDs. Tocilizumab was prescribed in 39 remaining lines because of inadequately controlled TA or intolerance to DMARDs or steroids (n ¼ 27 lines) or relapse (n ¼ 12) (Fig. 1). Tocilizumab was mainly used intravenously at 8 mg/kg monthly. Patients characteristics before tocilizumab and during the follow-up are summarized in Table 1. At the initiation of tocilizumab, the vascular symptoms were present in 29/43 (67%) cases and
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constitutional symptoms in 16/43 (37%). The main vascular signs included vascular bruit (n ¼ 32; 70%), limb claudications (upper n ¼ 11; 24% and lower n ¼ 3; 6.5%), carotidodynia (n ¼ 11; 24%), vascular cerebral attack (n ¼ 3; 6.5%), and acute coronary syndrome (n ¼ 1; 2%). During the follow-up, the median NIH scale (from 3 [2e3] at baseline to 0 [0e1] 0 at 3 and 6 months, respectively; p < 0.0001), C-reactive protein levels (from 23 mg/l [16e40] at baseline to 1 [0e2] at 3 and 6 months, respectively; p < 0.0001) and daily prednisone amounts (from 15 mg/day [8e19] to 4 mg/day [5e21] and 5 mg/day [4.5e9] at 3 and 6 months, respectively; p < 0.0001) significantly decreased under tocilizumab (Table 1). There was a significant decrease of patients with persistent radiological activity under tocilizumab (from 83% at baseline to 20% and 17% at 6 and 12 months, respectively; p < 0.001). Treatment response (NIH scale < 2) was noted in 89% of TA patients at 6 months. Because of usual decrease of C-reactive protein under tocilizumab, the difficulty to consider the radiological response at 6 months, we analyzed the number of TA with NIH scale <2 and prednisone <10 mg/day and <7.5 mg/day at 6 months. The number of TA under tocilizumab were 7/36 (80%) and 12/36 (67%) with NIH scale < 2 and prednisone <10 mg/day and <7.5 mg/day at 6 months, respectively. In responders relative to non-responders, no significant factors have been shown, in particular considering C-reactive protein level, NIH scale, prednisone doses or associated DMARDs at the tocilizumab initiation. The overall survival without tocilizumab failure was 0.81 [CI 95%; 0.7e0.95] at 12 months, 0.72 [CI 95%; 0.55e0.95] at 24 months and 0.48 [CI 95%; 0.2e0.1] at 48 months (Fig. 2). The presence of constitutional symptoms at the time of tocilizumab initiation
Fig. 1. Flow chart of long term use of biological-targeted treatment in 46 TA patients.
Table 1 Patients characteristics at the initiation and during tocilizumab treatment.
Vascular symptoms Constitutional symptoms Radiological activity/progression NIH activity score C-reactive protein level (mg/l) Prednisone use (n; %) Prednisone dose (mg/day) DMARDs use (n; %) Tocilizumab continuation NIH<2 þ prednisone <7.5 mg/day
Initiation of tocilizumab N ¼ 46
At 3 months N ¼ 29
At 6 months N ¼ 36
At 12 months N ¼ 19
At 18 months N ¼ 12
29/43 (67%) 16/43 (37%) 35/42 (83%)* 3 [2e3]* 23 [16e40]* 39 (85%) 20 [10e45]* 18 (39%) e e
5/29 (17%) 1/29 (3%) e 0 [0e1] 1 [0e2] 24 (83%) 15 [8e19] 7/28 (25%) 28 (97%) 8 (28%)
7/36 (19%) 0 3/15 (20%) 0 [0] 1 [0e2] 26 (81%) 7 [5e11] 11 (31%) 34 (94%) 24 (67%)
2/19 (11%) 0 2/12 (17%) 0 [0] 0 [0e1] 19 (100%) 5 [4.5e9] 6 (30%) 16 (80%) 15 (79%)
5/12 (42%) 1/12 (8%) 3/6 (50%) 0 [0] 0 [0e2] 12 (100%) 5 [5e7] 3 (25%) 11 (92%) 9 (75%)
Values are medians [ranges] and numbers (frequencies). *p < 0.0001 between baseline and all visits during the follow-up (Kruskall Wallis tests or Fisher test).
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
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Fig. 2. Event-free survival in 46 TA patients after tocilizumab initiation.
(hazard ratio 5.6 [CI 95%; 1.08e29], p ¼ 0.041), C-reactive protein level (hazard ratio 1.16 [CI 95%; 1.01e1.31] for every 10 mg/l, P ¼ 0.003) was significantly associated with tocilizumab-event-free survival. Seven patients received tocilizumab as first-line treatment combined to steroids alone and 39 patients received tocilizumab after a median of 2 [2e3] lines of other regimen (Table 2) (Fig. 3). There was no differences in the median NIH scale, C-reactive protein levels at tocilizumab initiation, but prednisone daily amounts were higher in first-line TA patients without any associated DMARDs (p < 0.05). At 3 and 6 months, the NIH scale, C-reactive protein levels, and prednisone decrease were similar in 2 groups (Table 2). Tocilizumab event-free survival was similar in patients receiving tocilizumab as first-line treatment in comparison to those which have received other regimen before tocilizumab (log rank p ¼ 0.98) (Fig. 3). Among patients receiving tocilizumab at first line (n ¼ 7), 6 (86%) were still under treatment at the end of the followup (Fig. 1). Among patients receiving tocilizumab after a median of 2 [2e3] lines of other treatments (mainly DMARDs in 24 cases and other biologics in 9 cases), tocilizumab induced remission in 29 (74%) TA patients without DMARDs in 17 cases, and tocilizumab was switched to other biologics in 6 cases. DMARDs were used in combination with tocilizumab in 18 patients (39%) (all after other lines of regimen) (Fig. 1). Tocilizumab event-free survival was similar in patients under tocilizumab associated with and without DMARDs (log rank p ¼ 0.25) (Fig. 4).
Fig. 3. Event-free survival in 46 TA patients according to first-line tocilizumab (n ¼ 7) and other lines (n ¼ 39).
Fig. 4. Event-free survival in 46 TA patients according to tocilizumab used in monotherapy (n ¼ 38) and combined with DMARDs (n ¼ 18).
Table 2 Outcome of 46 TA patients treated with tocilizumab.
Vascular symptoms Constitutional symptoms NIH activity score C-reactive protein level (mg/L) Prednisone use Prednisone dose (mg/day) NIH<2 þ prednisone <7.5 mg/day
Initiation of tocilizumab
At 3 months
First line N¼7
Other lines N ¼ 38
First line N¼6
Other lines N ¼ 22
First line N¼7
Other lines N ¼ 29
5 (71%) 3 (43%) 3 [3] 28 [20e40] 5 (71%) 60 [48e68] e
25/36 (69%) 13/36 (36%) 3 [2e3] 23 [15e41] 34 (94%) 18 [10e38] e
2 0 0 0 5 7 2
3 (14%) 1 (5%) 0 [0e1] 1 [0e5] 19 (86%) 15 [8e18] 7 (32%)
2 0 0 0 5 7 6
5 (17%) 0 0 [0] 1 [0e3] 21 (72%) 8 [5e15] 17 (59%)
(33%) [0] [0e1] (83%) [4e9] (33%)
At 6 months
(29%) [0] [0e1] (71%) [4e9] (86%)
Values are medians [ranges] and numbers (frequencies).
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
A. Mekinian et al. / Journal of Autoimmunity xxx (2018) 1e6
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At the last available visit after a median follow-up of 0.9 years [0.5e2], for the 42 evaluable patients, the median NIH scale was at 0 (0) with C-reactive protein levels at 0 mg/l [0e1], and 25/42 patients were still under steroids with 9.5 mg/day [5e14] amounts. Thirty-four patients were still under biological-targeted treatments: tocilizumab (n ¼ 28 associated with methotrexate in 5 cases), infliximab and adalimumab (n ¼ 5; with methotrexate in 2 cases) and rituximab (n ¼ 1), 4 under methotrexate and 3 under prednisone alone. 5.3. Events-free survival under tocilizumab and DMARDs Tocilizumab treated TA patients (n ¼ 46) were compared to 46 age- and sex-matched TA patients which have been treated by DMARDs. At the treatment initiation, vascular symptoms, C-reactive protein levels, prednisone daily amounts and NIH scale were similar in 2 groups. The proportion of vascular complications and vascular interventions was similar under tocilizumab in comparison to DMARDs [p > 0.05], respectively. The 3-year vascular eventsfree survival under tocilizumab was at 80% and significantly better compared to DMARDs therapy (80% vs 50%; p ¼ 0.02, respectively) (Fig. 5). The cumulative incidence of relapse was significantly higher under DMARDs therapy compared to tocilizumab (34.6% vs 6.3%; p ¼ 0.049, respectively) (Fig. 6). 5.4. Safety During the follow-up, 5 (11%) adverse effects occurred: 2 asymptomatic neutropenia (<500/mm3), infusion reaction (n ¼ 1), dental abscess (n ¼ 1), and neoplasm (n ¼ 1) [1 breast cancer]. Two (4%) cases required treatment discontinuation, including the neoplasm and one severe asymptomatic neutropenia. The breast neoplasm occurred in a patient with familial history of neoplasm (breast neoplasm in sister). 6. Discussion The conclusions drawn by this study are that tocilizumab can lead patients with DMARDS-refractory TA to remission in 80% of cases at 6 months, have significant steroid sparing effect and a relatively good safety profile. Tocilizumab event-free survivals were
Fig. 5. Event-free survival under tocilizumab in comparison to DMARDs therapy.
Fig. 6. Cumulative incidence of relapse under tocilizumab in comparison to DMARDs therapy.
81% and 72% at 12 and 24 months, respectively considering clinical improvement, relapse and steroid sparing effect. Although the number of analyzed patients is low, tocilizumab seem to have similar efficacy when considered in monotherapy and with associated DMARDs. We report the largest original study assessing the long-term outcome of tocilizumab in TA and the vascular events under treatment. In steroid-resistant or -dependant TA patients, the adjunction of DMARDS (methotrexate, azathioprine, mycophenolate mofetil) to the ongoing steroid therapy often allows a better disease control and tapering steroids [12,13]. Nonetheless, clinical relapses and progression of vascular involvement remain frequent and represent one of the major therapeutic goals in TA [1]. The uncontrolled TA vascular disease is one of major factor of vascular progression and risk of stenosis, thrombosis or aneurysm. Patients with uncontrolled disease with immunosuppressive agents can benefit from biological-targeted treatments. Recent randomized trial compared 36 patients which received subcutaneous tocilizumab or placebo [11]. Although time to relapse was not significantly different under tocilizumab and placebo, longer time to relapse was showed in the tocilizumab group. Several retrospective studies reported the efficacy of tocilizumab, mostly in refractory TA patients [14e17]. In a recent literature review, 105 TA patients have been treated by tocilizumab with an overall clinical and radiological response rate of 85.7%and 65.2%, respectively [15]. We recently reported data from the French nationwide study about the use of infliximab and tocilizumab in TA. We have shown similar risk of vascular complications under these biological targeted drugs [3]. In TA the overall incidence of vascular complications reach more than 50% at 5 years with DMARDs [18] and was significantly reduced under tocilizumab in the present study. In TA the event-free survival was significantly improved under tocilizumab, in comparison to DMARDs [13]. Strikingly, the efficacy of tocilizumab was analyzed according to its use as first line or in treatment experienced patients. No significant difference was noted in tocilizumab event-free survival, underscoring the efficacy of tocilizumab in difficult to treat refractory and/or steroid-dependent TA patients. The early use of tocilizumab could be argued to better control the TA disease activity, and open-labeled trial is ongoing in France to show the
Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002
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A. Mekinian et al. / Journal of Autoimmunity xxx (2018) 1e6
benefit of first-line tocilizumab for the control of TA activity and relapse-free survival. Safety of tocilizumab is actually well established in several autoimmune conditions, as rheumatoid arthritis. In our study, sideeffects occurred in 11% of cases and are consistent with previous reported data [15]. Along this line, the literature review of TA treated by tocilizumab reported a low rate of severe adverse effects, with mainly infections, few cases of hyperlipidemia and neutropenia. Our study had several limitations, such as its retrospective design which can lead to the lack of uniformity in tocilizumab prescription and associated drugs. Treatment decisions were left at the physician's discretion. Radiological vascular improvement assessment is a major concern in TA patients, but there is currently no consensual recommendations for imaging methods to monitored these patients. Although only tertiary centers with expertise in TA have been considered for this multicenter study, the absence of centralized imaging lecture to detect the vascular progression constituted an important limitation of our study. In conclusion, this multicenter study is the largest study assessing the long-term efficacy of tocilizumab in TA. We observed a good efficacy of tocilizumab and with reasonable safety profile. We showed a better event-free survival under tocilizumab therapy compared to DMARDs. Tocilizumab might be use as first-line therapy and lead to good overall response in TA patients. Conflicts of interest and funding None. Funding sources None. Conflicts of interest None. Author contributions ne MekiAll authors were involved in drafting the article. Arse nian had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of data analysis. Acknowledgements We thank the Club Rhumatismes et Inflammation (CRI), and the French National Society of Internal Medicine (SNFMI) for their help in the organization of this study.
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Please cite this article in press as: A. Mekinian, et al., Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients, Journal of Autoimmunity (2018), https://doi.org/10.1016/j.jaut.2018.04.002