You are here

Article Text

Article menu

This article has a correction. Please see:

Download PDFPDF

Vasculitis
Original research
Intravenous versus subcutaneous tocilizumab in Takayasu arteritis: multicentre retrospective study
  1. Arsène Mekinian1,
  2. Lucie Biard2,
  3. Dagna Lorenzo3,
  4. Pavel I Novikov4,
  5. Carlo Salvarani5,
  6. Olivier Espitia6,
  7. Savino Sciascia7,
  8. Martin Michaud8,
  9. Marc Lambert9,
  10. José Hernández-Rodríguez10,
  11. Nicolas Schleinitz11,
  12. Abid Awisat12,
  13. Xavier Puechal13,
  14. Achille Aouba14,
  15. Helene Munoz Pons15,
  16. Ilya Smitienko16,
  17. Jean Baptiste Gaultier17,
  18. Le Mouel Edwige18,
  19. Ygal Benhamou19,
  20. Antoinette Perlat18,
  21. Patrick Jego18,
  22. Tiphaine Goulenok20,
  23. Karim Sacre20,
  24. Bertrand Lioger21,
  25. Nolan Hassold22,
  26. Jonathan Broner23,
  27. Virginie Dufrost24,
  28. Thomas Sené25,
  29. Julie Seguier11,
  30. Francois Maurier26,
  31. Sabine Berthier27,
  32. Alexandre Belot28,
  33. Faten Frikha29,
  34. Guillaume Denis30,
  35. Alexandra Audemard-Verger31,
  36. Isabelle Koné-Paut22,
  37. Sebastien Humbert32,
  38. Pascal Woaye-Hune33,
  39. Alessandro Tomelleri3,
  40. Elena Marina Baldissera3,
  41. Masataka Kuwana34,
  42. Alberto Lo Gullo35,
  43. Vahan Mukuchyan36,
  44. Azeddine Dellal37,
  45. Francis Gaches8,
  46. Pierre Zeminsky24,
  47. Elena Galli3,
  48. Moya Alvarado5,
  49. Luigi Boiardi5,
  50. Francesco Muratore5,
  51. Mathieu Vautier2,
  52. Corrado Campochiaro3,
  53. Sergey Moiseev4,
  54. Matheus Vieira38,
  55. Patrice Cacoub38,
  56. Olivier Fain1 and
  57. David Saadoun38
  58. for the French Takayasu network
  1. 1Sorbonne Université, AP-HP, Hôpital Saint Antoine, Service de médecine interne et Inflammation-Immunopathology-Biotherapy Department (DMU i3), F-75012, Paris, France, French Armenian research center, Erevan, Armenia
  2. 2Université de Paris, AP-HP, Hôpital Saint Louis, Service de Biostatistique et Information Médicale (DMU PRISME), INSERM U1153 Team ECSTRRA, Paris, France
  3. 3Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
  4. 4Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russian Federation
  5. 5Azienda USL-IRCCS; Division of Rheumatology, Azienda USL-IRCCS di Reggio Emilia and Università di Modena e Reggio Emilia, Reggio Emilia, Italy
  6. 6Department of internal and vascular medicine, Nantes Université, CHU Nantes, F-44000 Nantes, France
  7. 7Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Aosta Valley Network for Rare Diseases, Nephrology and Dialysis, S. Giovanni Bosco Hospital, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
  8. 8Médecine Interne, Hôpital Joseph Ducuing, Toulouse, France
  9. 9Univ. Lille, CHU Lille, Département de Médecine Interne et d’Immunologie Clinique, Centre National de Référence Maladies Systémiques et Auto-immunes Rares Nord et Nord-Ouest de France (CeRAINO), European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNECT), INSERM, UMR 1167, RID-AGE, Lille, France
  10. 10Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
  11. 11Département de médecine interne, CHU de La Timone, Marseille, France
  12. 12Rheumatology Unit, Bnei Zion Hospital, Haifa, Israel
  13. 13Université Paris Descartes, Paris, France ; AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, Service de médecine interne, 27 rue du Faubourg Saint-Jacques, Paris, France
  14. 14Département de médecine interne, CHU Caen, Caen, France
  15. 15Département de médecine interne, CHU Saint Etienne, Saint-Etienne, France
  16. 16Rheumatology Department, Medical Center K-31, Moscow, Russian Federation
  17. 17Service de Médecine Interne, Hôpital Nord, Centre Hospitalier universitaire de St Etienne, Saint Etienne, France
  18. 18Internal Medicine and Clinical Immunology Department, CHU Rennes, Universitaire de Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
  19. 19Service de médecine interne, Université Rouen, CHU de Rouen, Rouen, France
  20. 20Département de Médecine Interne, Hôpital Bichat, Université de Paris, Assistance Publique Hôpitaux de Paris, INSERM U1149, Paris, France
  21. 21Service de médecine interne, CHU de Blois, Blois, France
  22. 22Service de Rhumatologie pédiatrique et centre de référence des maladies autoinflammatoires et de l'amylose inflammatoire, CEREMAIA, hôpital de Bicêtre, APHP, France, université de Paris Sud-Saclay, Paris, France
  23. 23Service de médecine interne, CHU de Nimes, Nimes, France
  24. 24Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, University of Lorraine, Inserm UMR_S 1116, CHRU de Nancy, Nancy, France
  25. 25Service de médecine interne, Rothschild, Paris, France
  26. 26Service de Médecine Interne et Immunologie Clinique Groupe Hospitalier UNEOS, Vantoux, France
  27. 27Service de médecine interne et immunologie clinique, Université Dijon, Hôpital Dijon, Dijon, France
  28. 28Service de pédiatrie et immunologie clinique, Université Lyon, Hôpital Lyon, Lyon, France
  29. 29Service de Médecine interne CHU Hédi Chaker, Route El Ain 3029 Sfax -Faculté de Médecine de Sfax, Sfax, Tunisia
  30. 30Service de médecine et d’hématologie, Hopital Rochefort, Rochefort, France
  31. 31Department of Internal Medicine and Clinical Immunology, CHRU Tours, University of Tours, Tours, France
  32. 32Service de médecine interne et immunologie clinique, Hôpital Besancon, Besancon, France
  33. 33Service de médecine interne, Hôpital de la Réunion, Réunion, France
  34. 34Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan
  35. 35Rheumatology Unit, Arnas Garibaldi Hospital, Catania, Italy
  36. 36Department of Internal Medicine and Rheumatology, Nairi hospital, Erevan, Armenia
  37. 37Service de rhumatologie, Hôpital Montfermeil, GHI Le Raincy Montfermeil, Montfermeil, France
  38. 38AP-HP, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology France, Centre national de référence maladies Autoimmunes Systémiques rares, Centre national de référence maladies Autoinflammatoires et Amylose, and Inflammation-Immunopathology-Biotherapy Department (DMU i3), Sorbonne Universités, Paris, France
  1. Correspondence to Dr Arsène Mekinian; arsene.mekinian{at}aphp.fr

Abstract

Objectives In this large multicentre study, we compared the effectiveness and safety of tocilizumab intravenous versus subcutaneous (SC) in 109 Takayasu arteritis (TAK) patients.

Methods We conducted a retrospective multicentre study in referral centres from France, Italy, Spain, Armenia, Israel, Japan, Tunisia and Russia regarding biological-targeted therapies in TAK, since January 2017 to September 2019.

Results A total of 109 TAK patients received at least 3 months tocilizumab therapy and were included in this study. Among them, 91 and 18 patients received intravenous and SC tocilizumab, respectively. A complete response (NIH <2 with less than 7.5 mg/day of prednisone) at 6 months was evidenced in 69% of TAK patients, of whom 57 (70%) and 11 (69%) patients were on intravenous and SC tocilizumab, respectively (p=0.95). The factors associated with complete response to tocilizumab at 6 months in multivariate analysis, only age <30 years (OR 2.85, 95% CI 1.14 to 7.12; p=0.027) and time between TAK diagnosis and tocilizumab initiation (OR 1.18, 95% CI 1.02 to 1.36; p=0.034). During the median follow-up of 30.1 months (0.4; 105.8) and 10.8 (0.1; 46.4) (p<0.0001) in patients who received tocilizumab in intravenous and SC forms, respectively, the risk of relapse was significantly higher in TAK patients on SC tocilizumab (HR=2.55, 95% CI 1.08 to 6.02; p=0.033). The overall cumulative incidence of relapse at 12 months in TAK patients was at 13.7% (95% CI 7.6% to 21.5%), with 10.3% (95% CI 4.8% to 18.4%) for those on intravenous tocilizumab vs 30.9% (95% CI 10.5% to 54.2%) for patients receiving SC tocilizumab. Adverse events occurred in 14 (15%) patients on intravenous route and in 2 (11%) on SC tocilizumab.

Conclusion In this study, we confirm that tocilizumab is effective in TAK, with complete remission being achieving by 70% of disease-modifying antirheumatic drugs-refractory TAK patients at 6 months.

  • Autoimmune Diseases
  • Systemic vasculitis
  • Inflammation

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2022-002830

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Summarise the state of scientific knowledge on this subject before you did your study and why this study needed to be done Few high-quality evidence is available to guide therapy in Takayasu arteritis (TAK).

    WHAT THIS STUDY ADDS

    • Summarise what we now know as a result of this study that we did not know before.

    • Tocilizumab therapy achieved 6 months complete remission in 70% of disease-modifying antirheumatic drug (DMARDs)-refractory TAK patients and compare subcutaneous and intravenous tocilizumab route.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Summarise the implications of this study.

    • This study confirms that tocilizumab is effective in DMARDs-refractory TAK patients and compares the subcutaneous and intravenous formulations of tocilizumab for the first time.

    Introduction

    Takayasu arteritis (TAK) is a chronic inflammatory large-vessel vasculitis, predominantly affecting the aorta and its major branches.1 Vessel inflammation leads to wall thickening, fibrosis, stenosis and thrombus formation. TAK mostly affects women and many ethnic groups worldwide. Morbidity from TAK itself is substantial: up to 50% of TAK patients will relapse and experience a vascular complication within 10 years of initial diagnosis.2 The mortality rate in TAK patients is 2.7 times higher as compared with age-matched and sex-matched healthy controls.3 In parallel, treatment strategies are not well recognised. The place of glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), and more recently biological targeted therapies, is still not determined.

    The first-line therapy consists of glucocorticoids which often results in substantial toxicity. In addition, approximately one-half of TAK patients have steroid-resistant or relapsing disease, and the addition of other immunosuppressive agents is frequently needed to achieve remission and to reduce the glucocorticoid dose. Methotrexate, azathioprine, leflunomide or mycophenolate mofetil are conventional synthetic DMARDs (csDMARDs) usually used in TAK initial management.4–7 However, in a setting where few high-quality evidence is available to guide pharmacotherapy in TAK4 increasing data have reported the benefit of biological-targeted therapies8–23.

    Recently, the effectiveness of biological therapies such as inhibitors of tumour necrosis factor-α (TNF-α) and IL-6 receptor (tocilizumab) in TAK patients who were refractory to other immunosuppressive therapies has been reported in several studies.8–26 We have recently reported a French nationwide registry that showed quite similar effectiveness of TNF-α antagonists and tocilizumab, with acceptable safety profile and significant steroid sparing effect27. A recent phase III, randomised, double blind, placebo-controlled trial of tocilizumab versus placebo in TAK failed to reach its primary intention-to-treat analysis, but tocilizumab was favoured in a secondary per-protocol analysis regarding TAK time to relapse.28 Besides its role on refractory patients, intravenous tocilizumab was also evaluated in treatment-naïve TAK patients in the French TOCITAKA prospective multicentre open-labelled trial, showing 6-month remission rates of 80%, of whom 54% were in glucocorticoid-free remission at 6 months.29 So far, data regarding the effectiveness and safety of intravenous versus subcutaneous (SC) use of tocilizumab in TAK are currently lacking.

    In this large multicentre study, we compared the effectiveness and safety of tocilizumab intravenous versus SC in 109 TAK patients. We assessed long-term outcomes and predictive factors for response, relapse and revascularisation in these patients.

    Methods

    Patients and data collection

    We conducted a retrospective multicentre study in referral centres from France, Italy, Spain, Armenia, Israel, Japan, Tunisia and Russia regarding biological-targeted therapies in TAK, with the data collection period corresponding to January 2017 to September 2019 . All physicians were asked to fulfil standardised anonymised excel form for all patients which were followed in their centre and which have been treated by any biological targeted therapy. From this registry, only patients with active TAK that were treated with tocilizumab (intravenous and/or SC forms) were extracted and analysed in this study. All patients fulfilled TAK ACR and/or Ishikawa criteria modified by Sharma.1 The patients’ age, sex, associated diseases, TAK duration and vascular extension (Numano scale), clinical, laboratory and imaging data, as well as treatments were analysed at baseline (ie, tocilizumab initiation), at 6 months, at each new treatment regimen initiation and at the last available visit. Glucocorticoids dosages were analysed at the initiation of each new treatment regimen and during the follow-up. Routine laboratory indicators of disease activity, including C reactive protein (CRP) levels, were collected. The different lines of tocilizumab therapies used in intravenous and SC forms were separately analysed and pooled for the statistical analysis.

    Disease activity and treatment response definitions

    Disease activity was defined according to the NIH criteria as previously defined.27 Briefly, disease is active if NIH score is of two or superior and in remission otherwise. Treatment response was initially considered using NIH scale <2; because of usual decrease of CRP on tocilizumab, the prednisone dose decrease and sparing effect were also considered in complete response definition, determined by the combination of NIH scale <2 and prednisone <7.5 mg/day by 6 months. Relapse was defined as active disease after a remission period and with the need for treatment regimen change. Tocilizumab failure was considered in the case of non-response (persistent NIH score equal or superior to 2,27 treatment changes, ischaemic vascular event and/or the need for vascular intervention during the tocilizumab course. Steroid dependence was defined as a prednisone dose ≥20 mg/day before each new therapeutic line.

    Statistical analysis

    For descriptive analyses, categorical variables are reported with counts (per cent) and quantitative variables with median (IQR) (ranges). Six-month response was analysed as a binary endpoint. Time to treatment failure was defined as the time between the date of tocilizumab initiation and the date of treatment discontinuation due adverse event, inefficacy, relapse, death, whichever occurred first. Treatment discontinuation due to remission was treated as informative censoring (competing risk); treatment discontinuation due to lost to follow-up or pregnancy was treated as non-informative censoring. Multiple imputation by chained equations was used to handle missing data on endpoint and covariates for 6-month response and covariates for relapse risk analysis. The multivariable models were selected using a majority approach combined with Wald testing (variable selection procedure using Akaike’s information criterion performed on each imputed data set, variables being selected on more than 50% of imputed datasets being considered for the final model then confirmed for inclusion in the final model using Wald testing). These results are presented either as OR or HR along with their 95% CI. Sensitivity analyses were performed on complete cases, with variable selection using Akaike’s information criterion, yielding consistent results for the different outcomes. All statistical tests were two sided at a 5%-significance level. Analyses were performed on R statistical platform, V.3.5.3.30

    Results

    Characteristics of Tak patients on tocilizumab

    A total of 109 TAK patients received tocilizumab therapy and were included in this study. Among them, 91 and 18 patients received intravenous and SC tocilizumab, respectively. Intravenous tocilizumab was used initially at 8 mg/kg/monthly and SC at 162 mg/week. Patients’ characteristics and TAK-specific features on the initiation of tocilizumab are summarised in tables 1 and 2. Overall, the demographic and comorbidity profile, TAK-specific features, and treatments used concurrently with tocilizumab were similar between groups. Tocilizumab was used as first-line therapy in 25 (27%) and 4 (22%) cases of intravenous and SC routes, respectively. In the remaining patients, the median number of csDMARDs before tocilizumab was similar between groups, but patients using SC route had significantly higher number of previous biological DMARDs than those on intravenous tocilizumab (p=0.039). Tocilizumab was prescribed along with a csDMARD in 51 (49.5%) patients.

    View this table:
    Table 1

    Overall patient characteristics and previous treatments at baseline

    View this table:
    Table 2

    Overall TAK features and concomitant treatments at baseline

    Effectiveness of tocilizumab

    A complete response (NIH <2 with less than 7.5 mg/day of prednisone) at 6 months was evidenced in 69% of TAK patients, of whom 57 (70%) and 11 (69%) patients were on intravenous and SC tocilizumab, respectively (p=0.95). The factors associated with complete response to tocilizumab at 6 months in univariate analysis were age <30 years, time between TAK diagnosis and tocilizumab initiation, absence of vascular signs and baseline prednisone dose <20 mg/day (table 3). In multivariate analysis, only age <30 years (OR 2.85, 95% CI 1.14 to 7.12; p=0.027) and time between TAK diagnosis and tocilizumab initiation (OR 1.18, 95% CI 1.02 to 1.36; p=0.034) were significantly associated with complete response at 6 months.

    View this table:
    Table 3

    Univariate analysis of factors associated with complete response at 6 months

    Relapses

    During the median follow-up of 30.1 months (0.4; 105.8) and 10.8 (0.1; 46.4) (p<0.0001) in patients who received tocilizumab in intravenous and SC forms, respectively, the risk of relapse was significantly higher in TAK patients on SC tocilizumab (HR 2.55, 95% CI 1.08 to 6.02; p=0.033) (figure 1A,B). In univariate analysis, only SC route was significantly associated with higher relapse rates as compared with intravenous one (table 4). The overall cumulative incidence of relapse at 6 months in TAK patients was at 6.8% (95% CI 3.0% to 12.7), with 3.4% (95% CI 0.9% to 8.9%) for patients on intravenous tocilizumab vs 24% (95% CI 7.0% to 46.4%) for those receiving SC tocilizumab, and, at 12 months 13.7% (95% CI 7.6% to 21.5) overall, 10.3% (95% CI 4.8% to 18.4%) for those on intravenous tocilizumab vs 30.9% (95% CI 10.5% to 54.2%) for patients receiving SC tocilizumab (table 5) (with 79% estimated with 12 months or more follow-up in the intravenous group and 44% in the SC group).

    Figure 1
    Figure 1

    (A) The cumulative incidence of relapse by route of administration. (B) HR of risk of relapse by route of administration. IV, intravenous; SC, subcutaneous. *=p<0.05.

    View this table:
    Table 4

    Univariate analysis of factors associated with relapse in TAK patients

    View this table:
    Table 5

    Overall cumulative incidences of relapse, treatment failure and revascularisation in TAK patients and according IV and SC route

    Time to treatment failure

    The cumulative incidence of treatment discontinuation by route of administration is displayed in figure 2, and was not significantly different between groups (HR 1.52, 95% CI 0.51 to 4.50; p=0.35). Although smoking was associated with treatment discontinuation in univariate analysis (p=0.009), no independent factor was found in multivariate analysis.

    Figure 2
    Figure 2

    The cumulative incidence of treatment doiscontinuation by route of administration. IV, intravenous; SC, subcutaneous.

    The revascularisation-free survival was not significantly different regarding intravenous and SC tocilizumab (table 5), and there was no factor significantly associated with the risk of revascularisation (data not shown).

    Safety

    Overall, adverse events occurred in 16 (15%) TAK patients during tocilizumab treatment. They included mainly viral infections, non-severe infections and mild hepatitis. Adverse events occurred in 14 (15%) patients on intravenous route (infusion reaction=5, bacterial infections=4, mild cytolysis=2, zoster and herpes reactivation=2 and neutropenia with infection=1) and in 2 (11%) on SC tocilizumab (mild hepatitis and zooster infection). Serious adverse events leading to treatment discontinuation occurred in one case on intravenous tocilizumab (ie, neutropenia with infection). There was no drug-related death.

    Discussion

    In this study, we confirm that tocilizumab is effective in TAK, with complete remission being achieving by 70% of DMARDs-refractory TAK patients at 6 months. Tocilizumab had a significant steroid-sparing effect and we did not evidence specific safety signal. We define high-risk patients for relapse according to a multivariate model.

    Monoclonal antibodies have been increasingly employed in the management of large-vessel vasculitis. In giant cell arteritis (GCA), the other prototype of large vessel vasculitis, tocilizumab has been shown to be effective and safe in both clinical trial24 and real-life settings.26 For TAK, a recent meta-analysis endorsed the benefits of both TNF inhibitors and tocilizumab, although a high degree of heterogeneity was noted among observational studies.4 Looking specifically at pooled data from tocilizumab, it was able to induce at least a partial response in 87% of patients, being also effective in angiographic stabilisation and daily corticosteroid doses reduction. Although the single randomised controlled trial to date (ie, TAKT study) was felt to be underpowered, SC tocilizumab was statistically superior to placebo in the per protocol analysis for time-to-relapse reduction in csDMARD-refractory TAK patients.28 Its use has proven promising in other settings as well, with a recent open-label trial that evaluated tocilizumab in TAK treatment-naïve patients revealing its efficacy in inducing remission and making these patients corticosteroid-free within 6 months.29 All together, these data have led to international guidelines consensus in recommending tocilizumab for patients with relapsing or refractory disease despite first-line DMARDs. In our study, we confirmed the effectiveness of tocilizumab in TAK, by demonstrating a 6-month 70% rate of complete response, regardless of the route of administration. About a half of our patients were on combined therapy with other csDMARD, which did not seem to affect tocilizumab therapeutic response. Although tocilizumab either in combination or monotherapy has been proven effective in refractory patients, studies evaluating the effect of concomitant csDMARD use on retention rates of biological agents in TAK have yielded conflicting results.11 27 Data regarding DMARDs combination in TAK remain very scarce and variably reported in studies,4 precluding formal recommendations to be formulated.

    Despite its overall clinical effectiveness in TAK, the direct effects of tocilizumab on vascular inflammation—and therefore its ability to prevent complications—are not yet fully known. This is well illustrated in studies designed to assess vascular inflammation by imaging techniques in GCA with large-vessel involvement, in which persistent aortic inflammation was documented in a non-negligible proportion of patients on tocilizumab.31 32 In TAK, case reports have been documenting disease progression and vascular complications (eg, aortic ulceration) in patients receiving tocilizumab.14–16 These patients’ management should rely on combined clinical assessments and serial imaging studies, given the expected suppression of serum inflammatory markers (eg, CRP) on tocilizumab, regardless of therapeutic response. In the post hoc analysis of TAKT trial, about 40% of TAK patients on tocilizumab experienced wall thickness progression in CT angiography within 96 weeks of treatment initiation.33 The occurrence of such vascular complications may require surgical treatment, which is extremely challenging in TAK. Despite largely based on retrospective series, current recommendations are consistent regarding optimal clinical control on surgical intervention, underlining the role of immunosuppressants in achieving favourable outcomes. Here, we describe the overall revascularisation rate in TAK patients on tocilizumab as roughly 15% at 36 months, with no significant role for route of administration in this outcome. Although we did not identify any factors associated with revascularisation, elevated erythrocyte sedimentation rate at diagnosis has been associated with the need for future intervention.2 The preventive immunosuppressive benefit seems similar across biological DMARDs, as no difference in surgery requirement for TAK patients on either TNF inhibitors or tocilizumab have been documented.11 27 This topic, however, lacks further prospective and specific investigation.

    Intravenous or SC formulations of tocilizumab are label approved for some immune-mediated diseases. Among these, rheumatoid arthritis (RA) is the one with the most available data, where both SC and intravenous are comparable in terms of long-term efficacy and safety. In GCA, each of the available randomised controlled trials evaluated different routes of tocilizumab, but no comparative data between these have been published so far. The data comparing intravenous versus SC use of tocilizumab are mainly available in RA, and among 3448 patients with 2414 with TCZ-IV and 1034 with TCZ-SC, clinical disease activity and low disease activity was lower in TCZ-IV patients: 41.0% in TCZ-IV vs 49.1% in TCZ-SC (difference: 8.0%; bootstrap 95% CI 2.4%–12.4%).34 Although tocilizumab route did not influence the 6 month complete response rate in our study, relapse risk in SC group was significantly higher than in the intravenous one. Possible explanations could lie in the different pharmacokinetic properties of tocilizumab routes of administration. Although these differences do not pose clinical implications in RA, the SC route has lower bioavailability (ie, 79%) and longer time to reach steady-state maximum serum concentration (ie, 12 weeks vs right after the first intravenous dose), which may have a distinct impact on TAK.35 36 Also, possible lower compliance with SC treatment, as opposed to supervised intravenous infusions, may have contributed to a higher relapse risk following an adequate primary response. Antitocilizumab antibodies could be another argument, as SC route is more immunogenic, but few data are available on this issue.

    As with immunosuppressive therapies in general, infectious adverse events are a common concern for tocilizumab. In line with our findings, infections have indeed been the most frequent adverse events in clinical trial settings for RA, GCA and TAK.8 12 16 26 35 However, in both the GiACTA (ie, SC tocilizumab in GCA) and TAKT trials, adverse event rates o n tocilizumab were not significantly different when compared with placebo arms, including infections.26 28 In TAKT longer-term open-label extension, serious adverse event rate was at 25% after a median follow-up of 108 weeks; however, all infections resolved without sequelae, there were no study withdrawals due to adverse events, and no deaths were documented, a long-term safety profile that is comparable to the one seen in RA.33 There were no new or unexpected safety issues in both TAKT and GiACTA open-label extensions.24 25 In our cohort, the overall adverse event rate of 15% lies within the range of pooled data from meta-analysed observational studies evaluating TAK patients on tocilizumab (ie, 95% CI 12% to 35%).4 Moreover, treatment discontinuation due to serious adverse event occurred in only one case on intravenous tocilizumab, and there was no drug-related death. Regarding the safety of different tocilizumab formulations, comparative data are available from a 97-week trial in RA, where adverse event rates were similar between SC and intravenous arms.35 The sole exception was site injection reactions, more frequent in those receiving SC route. Notably, the overall safety profile remained stable throughout the study period even for patients switching routes, whereas infection rates decreased over time. This is also consistent with the frequency and side effects profile that we found comparing tocilizumab routes, favouring the safe use of the SC formulation within the management of TAK patients.

    Our study has several limitations, such as its retrospective design and the fact that the choices of tocilizumab formulation and csDMARDs combination were at treating physicians’ discretion. Since there was no formal sample size calculation, the available number of patients in the SC arm may have been insufficient to identify more subtle differences between the groups, especially for multivariate analyses. Also, as patients’ compliance to SC tocilizumab could not be weighed, this bias should be recognised when analysing relapse rates.

    In this international multicentre cohort, the effectiveness and safety profile of SC and intravenous formulations of tocilizumab are reported for the first time. The 6-month complete response rates and safety profile were similar between groups, offering a promising posological possibility for TAK patients and their treating physicians. These data should be further validated in clinical trials, ideally with proper pharmacokinetic and compliance surveillance.

    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information.

    Ethics statements

    Patient consent for publication

    Acknowledgments

    We thank the Takayasu group for their participation in this paper.

    References

    1. ↵
      1. Kerr GS,
      2. Hallahan CW,
      3. Giordano J, et al
      . Takayasu arteritis. Ann Intern Med 1994;120:919–29. doi:10.7326/0003-4819-120-11-199406010-00004
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Comarmond C,
      2. Biard L,
      3. Lambert M, et al
      . Long-term outcomes and Prognostic factors of complications in Takayasu arteritis: A multicenter study of 318 patients. Circulation 2017;136:1114–22. doi:10.1161/CIRCULATIONAHA.116.027094
      OpenUrlAbstract/FREE Full Text
    3. ↵
      1. Mirouse A,
      2. Biard L,
      3. Comarmond C, et al
      . Overall survival and mortality risk factors in Takayasu's arteritis: A multicenter study of 318 patients. J Autoimmun 2019;96:35–9.:S0896-8411(18)30368-8. doi:10.1016/j.jaut.2018.08.001
      OpenUrlPubMed
    4. ↵
      1. Misra DP,
      2. Rathore U,
      3. Patro P, et al
      . Disease-Modifying anti-rheumatic drugs for the management of Takayasu arteritis-a systematic review and meta-analysis. Clin Rheumatol 2021;40:4391–416. doi:10.1007/s10067-021-05743-2
      OpenUrl
    5. ↵
      1. Hoffman GS,
      2. Leavitt RY,
      3. Kerr GS, et al
      . Treatment of glucocorticoid-resistant or Relapsing Takayasu arteritis with methotrexate. Arthritis Rheum 1994;37:578–82. doi:10.1002/art.1780370420
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Numano F,
      2. Okawara M,
      3. Inomata H, et al
      . Takayasu's arteritis. Lancet 2000;356:1023–5. doi:10.1016/S0140-6736(00)02701-X
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Ogino H,
      2. Matsuda H,
      3. Minatoya K, et al
      . Overview of late outcome of medical and surgical treatment for Takayasu arteritis. Circulation 2008;118:2738–47. doi:10.1161/CIRCULATIONAHA.107.759589
      OpenUrlFREE Full Text
    8. ↵
      1. Abisror N,
      2. Mekinian A,
      3. Lavigne C, et al
      . Tocilizumab in refractory Takayasu arteritis: A case series and updated literature review. Autoimmunity Reviews 2013;12:1143–9. doi:10.1016/j.autrev.2013.06.019
      OpenUrlCrossRefPubMed
    9. ↵
      1. Bravo Mancheño B,
      2. Perin F,
      3. Guez Vázquez Del Rey MDMR, et al
      . Successful Tocilizumab treatment in a child with refractory Takayasu arteritis. Pediatrics 2012;130:e1720–4. doi:10.1542/peds.2012-1384
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      1. Bredemeier M,
      2. Rocha CM,
      3. Barbosa MV, et al
      . One-year clinical and radiological evolution of a patient with refractory Takayasu's arteritis under treatment with Tocilizumab. Clin Exp Rheumatol 2012;30(1 Suppl 70):S98–100. doi:10.1016/j.semarthrit.2020.01.005
      OpenUrlPubMed
    11. ↵
      1. Comarmond C,
      2. Plaisier E,
      3. Dahan K, et al
      . Anti TNF-alpha in refractory Takayasu's arteritis: cases series and review of the literature. Autoimmun Rev 2012;11:678–84. doi:10.1016/j.autrev.2011.11.025
      OpenUrlCrossRefPubMed
    12. ↵
      1. de Kruif MD,
      2. van Gorp ECM,
      3. Bel EH, et al
      . Streptococcal lung abscesses from a dental focus following Tocilizumab: a case report. Clin Exp Rheumatol 2012;30:951–3. doi:10.1093/rheumatology/key015
      OpenUrlPubMed
    13. ↵
      1. Goel R,
      2. Danda D,
      3. Kumar S, et al
      . Rapid control of disease activity by Tocilizumab in 10 'difficult-to-treat' cases of Takayasu arteritis. Int J Rheum Dis 2013;16:754–61. doi:10.1111/1756-185X.12220
      OpenUrlCrossRefPubMed
    14. ↵
      1. Hoffman GS,
      2. Merkel PA,
      3. Brasington RD, et al
      . Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis. Arthritis Rheum 2004;50:2296–304. doi:10.1002/art.20300
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Maffei SF,
      2. Di Renzo M
      . Refractory Takayasu arteritis successfully treated with Infliximab. Eur Rev Med Pharmacol Sci 2009;13:63–5. doi:10.1136/annrheumdis-2019-215459
      OpenUrlPubMedWeb of Science
    16. ↵
      1. Mekinian A,
      2. Neel A,
      3. Sibilia J, et al
      . Efficacy and tolerance of Infliximab in refractory Takayasu arteritis: French Multicentre study. Rheumatology 2012;51:882–6. doi:10.1093/rheumatology/ker380
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      1. Molloy ES,
      2. Langford CA,
      3. Clark TM, et al
      . Anti-tumour necrosis factor therapy in patients with refractory Takayasu arteritis: long-term follow-up. 2008;67(11):1567-9. Ann Rheum Dis 2008;67:1567–9. doi:10.1136/ard.2008.093260
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. Nakaoka Y,
      2. Higuchi K,
      3. Arita Y, et al
      . Tocilizumab for the treatment of patients with refractory Takayasu arteritis. 2013;54(6):405-11. Int Heart J 2013;54:405–11. doi:10.1536/ihj.54.405
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Nishimoto N,
      2. Nakahara H,
      3. Yoshio-Hoshino N, et al
      . Successful treatment of a patient with Takayasu arteritis using a Humanized anti-Interleukin-6 receptor antibody. Arthritis Rheum 2008;58:1197–200. doi:10.1002/art.23373
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Nunes G,
      2. Neves FS,
      3. Melo FM, et al
      . Takayasu arteritis: anti-TNF therapy in a Brazilian setting. Rev Bras Reumatol 2010;50:291–8. doi:10.1161/CIRCULATIONAHA.114.014321
      OpenUrlCrossRefPubMed
    21. ↵
      1. Osman M,
      2. Aaron S,
      3. Noga M, et al
      . Takayasu's arteritis progression on anti-TNF Biologics: a case series. Clin Rheumatol 2011;30:703–6. doi:10.1007/s10067-010-1658-1
      OpenUrlCrossRefPubMed
    22. ↵
      1. Salvarani C,
      2. Magnani L,
      3. Catanoso MG
      . Rescue treatment with Tocilizumab for Takayasu arteritis resistant to TNF-alpha blockers. Clin Exp Rheumatol 2012;30:S90–3. doi:10.1080/17425247.2019.1618828
      OpenUrlPubMed
    23. ↵
      1. Schmidt J,
      2. Kermani TA,
      3. Kirstin Bacani A, et al
      . Tumor necrosis factor inhibitors in patients with Takayasu arteritis: experience from a referral center with long-term followup. Arthritis Care Res 2012;64:n. doi:10.1002/acr.21636
    24. ↵
      1. Seitz M,
      2. Reichenbach S,
      3. Bonel HM, et al
      . Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011;141:w13156. doi:10.4414/smw.2011.13156
    25. ↵
      1. Tombetti E,
      2. Franchini S,
      3. Papa M, et al
      . Treatment of refractory Takayasu arteritis with Tocilizumab: 7 Italian patients from a single referral center. J Rheumatol 2013;40:2047–51. doi:10.3899/jrheum.130536
      OpenUrlAbstract/FREE Full Text
    26. ↵
      1. Unizony S,
      2. Arias-Urdaneta L,
      3. Miloslavsky E, et al
      . Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and Polymyalgia Rheumatica. Arthritis Care Res (Hoboken) 2012;64:1720–9. doi:10.1002/acr.21750
      OpenUrl
    27. ↵
      1. Mekinian A,
      2. Comarmond C,
      3. Resche-Rigon M, et al
      . Efficacy of biological-targeted treatments in Takayasu arteritis: multicenter, retrospective study of 49 patients. Circulation 2015;132:1693–700. doi:10.1161/CIRCULATIONAHA.114.014321
      OpenUrlAbstract/FREE Full Text
    28. ↵
      1. Nakaoka Y,
      2. Isobe M,
      3. Takei S, et al
      . 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 2018;77:348–54. doi:10.1136/annrheumdis-2017-211878
      OpenUrlAbstract/FREE Full Text
    29. ↵
      1. Mekinian A,
      2. Saadoun D,
      3. Vicaut E, et al
      . Tocilizumab in treatment-Naïve patients with Takayasu arteritis: TOCITAKA French prospective multicenter open-labeled trial. Arthritis Res Ther 2020;22:218. doi:10.1186/s13075-020-02311-y
    30. ↵
      1. Therneau T GP
      . Modeling survival data: extending the Cox model statistics for biology and health. Springer, 2000: 189.
    31. ↵
      1. Reichenbach S,
      2. Adler S,
      3. Bonel H, et al
      . Magnetic resonance angiography in giant cell arteritis: results of a randomized controlled trial of Tocilizumab in giant cell arteritis. Rheumatology (Oxford) 2018;57:982–6. doi:10.1093/rheumatology/key015
      OpenUrlPubMed
    32. ↵
      1. Quinn KA,
      2. Dashora H,
      3. Novakovich E, et al
      . Use of 18F-Fluorodeoxyglucose positron emission tomography to monitor Tocilizumab effect on vascular inflammation in giant cell arteritis. Rheumatology (Oxford) 2021;60:4384–9. doi:10.1093/rheumatology/keaa894
      OpenUrlPubMed
    33. ↵
      1. Nakaoka Y,
      2. Yamashita K,
      3. Yamakido S
      . Long-term efficacy and safety of Tocilizumab in refractory Takayasu arteritis: final results of the randomized controlled phase 3 TAKT study. Rheumatology (Oxford) 2020;59:e48–9. doi:10.1093/rheumatology/keaa255
      OpenUrl
    34. ↵
      1. Lauper K,
      2. Mongin D,
      3. Iannone F, et al
      . Comparative effectiveness of TNF inhibitors and Tocilizumab with and without conventional synthetic disease-modifying Antirheumatic drugs in a pan-European observational cohort of bio-Naïve patients with rheumatoid arthritis. Semin Arthritis Rheum 2020;50:17–24. doi:10.1016/j.semarthrit.2019.06.020
      OpenUrl
    35. ↵
      1. Burmester GR,
      2. Rubbert-Roth A,
      3. Cantagrel A, et al
      . Efficacy and safety of subcutaneous Tocilizumab versus intravenous Tocilizumab in combination with traditional Dmards in patients with RA at week 97 (SUMMACTA). Ann Rheum Dis 2016;75:68–74. doi:10.1136/annrheumdis-2015-207281
      OpenUrlAbstract/FREE Full Text
    36. ↵
      1. Scott LJ
      . Tocilizumab: A review in rheumatoid arthritis. Drugs 2017;77:1865–79. doi:10.1007/s40265-017-0829-7
      OpenUrlCrossRefPubMed

    Footnotes

    • Correction notice This article has been corrected since it was first published online. The author Corrado Campochiaro was incorrectly listed as Corrado Campochiaro. The author Alberto Lo Gullo was incorrectly listed as Alberto Logullo and their affiliation was updated to Rheumatology Unit, Arnas Garibaldi Hospital, Catania, Italy. Lastly, the author Francesco Muratore was incorrectly listed as Muratore Francesco.

    • Contributors Am is the guarantor of this manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.