Tocilizumab in Extracranial Giant-Cell Arteritis and Takayasu Arteritis: A Multicentric Observational Comparative Study

Abstract

Tocilizumab (TCZ) has demonstrated potential efficacy in managing large-vessel (LV) vasculitis such as giant-cell arteritis (GCA) and Takayasu arteritis (TAK). Despite the shared characteristics between the LV-GCA phenotype and TAK, there are differences between both entities that may affect therapeutic responses to TCZ. We aim to assess and compare the effectiveness and safety of TCZ in patients with LV-GCA and TAK. Multicenter, observational study on 70 LV-GCA patients and 57 TAK patients treated with TCZ. Outcomes were assessed at baseline and at 1, 3, 6 and 12 months post-treatment initiation. The variables analyzed included the following: (a) the achievement of clinical remission and improvement in laboratory markers; (b) imaging-based disease activity; (c) a glucocorticoid (GC)-sparing effect; and (d) side events and a safety profile. At the treatment initiation, TAK patients were younger, exhibited longer disease duration, had received more prior biologics, and were on higher doses of prednisone compared to LV-GCA patients. While TAK patients showed a slower initial clinical response, remission rates at 12 months were comparable between groups (74.5% for LV-GCA vs. 76.9% for TAK). Both groups experienced rapid laboratory marker improvement and a significant GC-sparing effect. However, complete imaging resolution was observed in only 18.9% of LV-GCA patients and 21.1% of TAK patients. The safety profile was similar in both groups, with severe infections leading to TCZ discontinuation in four LV-GCA and three TAK patients. In clinical practice, TCZ demonstrates similar efficacy in promoting remission and reducing GC dependency in both LV-GCA and TAK patients. Nonetheless, discrepancies between clinical outcomes and imaging improvement highlight the need for further investigation into disease monitoring and management strategies.

• Key Messages

What is already known on this topic:

The efficacy of TCZ in GCA has been demonstrated in a clinical trial and several clinical observational studies while efficacy of TCZ in TAK comes from two clinical trials and several/some retrospective observational studies. However, to date, no comparative studies on the effectiveness and safety of TCZ in GCA and TAK in a have been performed real-world setting.

What this study adds:

This is an observational, multicenter open-label study that compares the effectiveness and safety of TCZ in clinical practice conditions between a group of 70 patients diagnosed with LV-GCA (extracranial GCA phenotype) and 57 patients with TAK.

1. Introduction

Giant-cell arteritis (GCA) and Takayasu arteritis (TAK) are two granulomatous vasculitis classified under the umbrella of the large-vessel vasculitis (LVV) group [1]. While these conditions exhibit overlapping pathogenic, histopathological, and imaging characteristics, as well as certain therapeutic approaches, they present distinct epidemiological profiles and clinical manifestations [2,3].

GCA commonly occurs in individuals over 50 years old (mainly women), especially above 70 years old, with a higher prevalence in Northern Europe and North America [4,5]. By contrast, TAK is more prevalent in women aged 10–40 years, and is predominantly seen in East Asia, Africa, and South America [6].

Cranial GCA represents a well-established clinical phenotype, typically presenting with temporal headache, jaw claudication, and/or visual disturbances. However, GCA is not confined to the cranial arteries and can involve other vessels. In this sense, the extracranial or large-vessel GCA phenotype (LV-GCA) usually affects the aorta and/or its mayor blanches [7,8]. A mixed phenotype is defined by both cranial and extracranial involvement. Notably, isolated extracranial LV-GCA shares many clinical features with TAK.

In both TAK and LV-GCA, the aorta and its major branches are commonly affected, potentially resulting in severe vascular complications like stenosis, aneurysms, or even aortic dissection.

Different treatment options may be useful in both TAK and GCA. Typically, high-dose glucocorticoids (GCs) are the mainstay of therapy [9,10]. However, frequent relapses during dose reduction and adverse effects may occur. Consequently, other therapeutic alternatives can be used [11]. Immunosuppressive agents like methotrexate (MTX), azathioprine (AZA), mycophenolate mofetil (MMF), or cyclophosphamide (CYP) have been used in both conditions. However, their effectiveness is often inadequate and accompanied by multiple side effects [12].

Several inflammatory mediators, such as TNF-α, IL-1, IL-6, IL-18, and interferon-γ, play a role in the pathogenesis of GCA and TAK [3]. While these cytokines have been studied in both conditions, anti-TNF-α drugs have shown discouraging results in GCA despite the increased TNF-α presence in GCA lesions [12,13]. In contrast, retrospective observational studies, rather than randomized controlled studies, have shown the efficacy of anti-TNF-α inhibitors, particularly infliximab, in TAK [13,14,15].

Tocilizumab (TCZ), an IL-6 receptor monoclonal antibody, was approved in 2017 by the EMA and FDA for treating GCA, supported by randomized clinical trials [16,17]. Additionally, multiple clinical studies have confirmed the efficacy of TCZ in GCA treatment [4,5,18]. TCZ shows potential as a therapeutic option for TAK, as supported by small clinical trials and retrospective observational studies [6,19,20,21]. The efficacy of TCZ might be attributed to the role of IL-6 in the differentiation of Th0-lymphocytes to the Th17 subset, which plays a significant role in the pathogenesis of LVV.

Although both GCA and TAK share some pathogenic, clinical, and histological features, as previously mentioned, there are also considerable differences. LV-GCA (extracranial phenotype) is more similar to TAK. TCZ appears to be an effective treatment for both conditions [22]. However, to the best of our knowledge, no studies have yet been conducted to compare the effectiveness and safety of TCZ in LV-GCA and TAK.

Considering these factors, the objective of the present study was to evaluate and compare the the effectiveness and safety of TCZ in patients with extracranial LV-GCA and TAK in a clinical setting.

2. Patients and Methods

2.1. Patients and Study Protocol

We conducted an observational, national, open-label retrospective, and multicenter study in patients from clinical practice who had received TCZ therapy after being diagnosed with extracranial LV-GCA and TAK.

Patients were diagnosed at the Rheumatology or Autoimmune Units of 53 Spanish hospitals. The classification of GCA was performed based on the 2022 classification criteria of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) [23], and/or a positive temporal artery biopsy, and/or the presence of LV vasculitis as detected by any of the following imaging techniques: ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT), magnetic resonance imaging angiography (MRI-A), and/or computed tomography angiography (CT-A). Only patients with the extracranial LV-GCA phenotype were included, as this is the phenotype most similar to TAK. Patients with cranial or mixed GCA phenotypes were excluded.

TAK classification was performed according to the 2022 ACR/EULAR classification criteria [24] and/or the modified Ishikawa criteria by Sharma et al. [25]. Most patients were followed for at least 1 year after the initiation of TCZ, with follow-up visits scheduled at 1, 3, 6, and 12 months.

The treatment of LV-GCA and TAK was conducted based on the classic pharmacological scheme, starting with high doses of oral GC (between 40–60 mg of prednisone-equivalent per day) with a gradually decreasing dosage. We did not use <40 mg/day of prednisone as an initial therapy in any patients with a recent diagnosis of LV-vasculitis. The duration of corticosteroid therapy was variable. Prednisone was generally reduced by 5 mg every 2 weeks down to 25 mg. Then, prednisone was reduced by 2.5 mg every 2 weeks, until the dose reached 10 mg/day. In patients at high risk of developing glucocorticoid toxicity, we added a GC-sparing agent. cDMARDs and/or bDMARDs were used as GC-sparing agents, mainly in patients with a relapsing disease or in those with GC-induced side effects.

In accordance with the Spanish National Guidelines for the administration of biologic therapy in patients with rheumatic diseases, the presence of infectious diseases, including tuberculosis and hepatitis B or C, was ruled out prior to the initiation of biological treatment. To detect latent tuberculosis, tuberculin skin test (PPD) and/or an interferon assay (quantiFERON) were performed, together with chest radiography. In cases of positive results, prophylactic treatment with isoniazid was started at least 4 weeks before beginning biological therapy and then continued for 9 months. The presence of malignancies was also excluded in all patients [4,6].

TCZ was administered at its standard dose for both diseases, either at 8 mg/kg every 4 weeks intravenously (IV) or at 162 mg weekly subcutaneously (SC). TCZ was used off-label in all TAK cases and in the initial cases of GCA, as it was administered prior to its approval by the EMA and FDA for GCA treatment. Written informed consent was obtained from all patients in these cases.

This study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [26].

2.2. Clinical Definitions and Laboratory Data

According to clinical definitions, we considered constitutional syndrome as the presence of asthenia and anorexia and the loss of more than 5% of weight in the six months prior to TCZ initiation. Fever was considered to be a state when the temperature was ≥38 °C.

Polymyalgia rheumatica (PMR) was defined according to the provisional classification criteria proposed by the EULAR/ACR 2012 [27].

Remission was regarded, according to 2021 ACR definitions, as the absence of clinical signs or symptoms attributed to active GCA or TAK and on or off immunosuppressive therapy [9]. Imaging remission was defined as the resolution of vessel wall inflammation during the follow-up imaging technique. PET-CT scan, MRI-A and CT-A were used, depending on the hospitals, for the diagnosis and follow-up of the disease. All identified PET-CT scans were reviewed by a single nuclear medicine physician with expertise in LVV [28,29]. Active vasculitis was categorized using a visual 0–3 vascular-to-liver FDG uptake grading scale. Scans showing grade 1 and 0 FDG uptake (liver) were classified as ‘inactive’. MRI remission was defined as the absence of the gadolinium enhancement of the vascular wall and an absence of new lesions [30,31].

Complete remission was defined as when the patient had clinical remission plus imaging remission. Active disease was defined as a state with new, persistent, or worsening clinical signs and/or symptoms, which were attributed to GCA/TAK and unrelated to prior damage [9]. Relapse was defined as the recurrence of active disease following a period of remission [9].

Routine laboratory markers, including complete blood count, erythrocyte sedimentation rate (ESR), and serum C-reactive protein (CRP) levels, were assessed at the time of TCZ initiation, and at each subsequent visit. ESR was considered elevated if it exceeded 20 mm/1st hour in men or 25 mm/1st hour in women. A serum CRP value greater than 0.5 mg/dL was considered abnormal. Anemia was defined by a hemoglobin value <11 mg/dL.

2.3. Data Collection and Ethics

Patient data were reviewed to obtain clinical, laboratory, and imaging information, as well as details about the medications used, including GC doses during and after TCZ therapy, the response to TCZ, and adverse events. Each investigator extracted the data from clinical records and stored it in a database following a predefined protocol approved by all researchers. To reduce entry errors, all data were double-checked. Adverse events related to biological treatment were monitored and recorded during follow-up. The study was approved by the Ethics Committee for Clinical Research in Cantabria, Spain (approval number: 2018.080, approval date: 19 September 2018).

2.4. FDG-PET CT Scan Acquisition and Image Analysis

Patients fasted for at least 6 h before the ¹⁸F-FDG PET/CT scan, with serum glucose levels maintained below 160 mg/dL. The body uptake of ¹⁸F-FDG was evaluated 180 min after injecting 7 MBq/kg of the tracer. A low-dose CT scan was first performed to attenuate correction and anatomical localization. Remission on ¹⁸F-FDG PET/CT was defined as a vascular FDG uptake lower than the liver uptake or the absence of vascular uptake, based on the scoring system proposed by several authors [28,29].

2.5. Statistical Analysis

The results are presented as mean ± SD or as median and interquartile range (IQR), as appropriate. The Student’s t-test and Mann–Whitney U-test were used to compare of continuous variables, and the chi-squared test was used for categorical variables. The Wilcoxon signed-rank test was used to compare continuous variables across time periods. A p-value < 0.05 was considered statistically significant. Mixed-effects regression models were applied to study the differences in ESR, CRP, and prednisone doses between the TAK and GCA groups during follow-up. Statistical analyses were performed using the SPSS software package (IBM SPSS Statistics 29.0.1.0).

3. Results

3.1. Demographic and Clinical Features at TCZ Initiation

We included 70 patients (51 women/19 men) with an extracranial LV-GCA phenotype and 57 patients (49 women/8 men) with TAK who had received TCZ therapy. Table 1 summarizes the main baseline features of both groups. As expected, more patients were women in both groups and extracranial LV-GCA patients were older (67.2 ± 10.5 vs. 40.5 ± 16.3; p < 0.01) at TCZ initiation. Cardiovascular risk factors were also predominant in extracranial LV-GCA. Asthenia was the most frequent symptom, and was observed similarly in both groups. By contrast, constitutional syndrome (41.4% vs. 1.8%; p < 0.01), and PMR (72.9 vs. 3.5; p < 0.01) were more common in extracranial LV-GCA (Table 1).

The median [IQR] of ESR and CRP values at TCZ initiation was similar in both groups. A higher proportion of extracranial LV-GCA patients had involved different segments of the aorta and its main branches. However, TAK patients required a higher median prednisone dose, 30 (15–20) vs. 15 (10–20) mg/day (p < 0.01), and required a higher quantity of previous cDMARDs (77.2% vs. 64.3%) and bDMARDs (26.3% vs. 0%; p = 0.32), although these differences were not significant. Within the TAK cohort, the cDMARDs administered encompassed MTX (n = 33, 57.9%), AZA (n = 7, 12.3%), cyclosporine A (CsA) (n = 4, 7.1%), and MMF (n = 18, 31.6%). Among the used bDMARDs, infliximab (n = 10, 17.5%) was mostly employed. Patients diagnosed with LV-GCA received the following cDMARDs: MTX (n = 40, 57.1%), sulfasalazine (SSZ) (n = 2, 2.9%), and hydroxychloroquine (HCQ) (n = 1, 1.4%). The median [IQR] time from underlying vasculitis diagnosis to TCZ initiation was longer in TAK patients than in LVV-GCA patients (12 [3–37] vs. 5 [2–15] months; p < 0.01) (Table 1). TCZ was administered IV more frequently in TAK patients (80.7% vs. 48.6%; p < 0.01). Combined TCZ therapy was used more frequently in extracranial LV-GCA patients (48.6% vs. 42.1%; p < 0.01). In extracranial LV-GCA patients, the most common cDMARDs were MTX, SSZ, and HCQ. In TAK patients, the cDMARDs used were MTX, AZA, CsA and MMF.

3.2. Outcomes

After 6 and 12 months, respectively, 42/53 (79.2%) and 35/47 (74.5%) extracranial LV-GCA patients achieved remission. In the TAK group, remission was observed in 24/48 (50%) and 30/39 (76.9%) patients at 6 and 12 months, respectively (Figure 1A). In this regard, although the therapeutic response seemed to be slower in TAK patients, similar rates of clinical remission, around 75%, were observed at 12 months in both TAK and LV-GCA patients.

Similarly, the ESR and CRP significantly decreased during follow-up (Figure 1B,C). This reduction was found to be similar in both LV-GCA and TAK groups. In this line, no differences were found in ESR and CRP between both groups in every visit and at the end of the follow-up. Moreover, in the mixed-models analysis, ESR (p = 0.54) and CRP (p = 0.64) decrements during follow-up did not yield significant differences between either entity.

Regarding the GC-sparing effect, a rapid and sustained reduction in the GC dose was observed in both LV-GCA and TAK patients (Figure 1D). In this way, the mean prednisone dosage was 5.9 mg/day, 3.6 mg/day, 2.1 mg/day, and 1.1 mg/day, respectively, at 1, 3, 6 and 12 months following TCZ initiation in patients with extracranial LV-GCA. In TAK patients, these values were 14.3 mg/day, 12 mg/day, 8.3 mg/day, and 8.7 mg/day at the same intermediate times (Figure 1D). The prednisone dose was found to differ between each visit. TAK patients received higher doses of glucocorticoids during each visit and at the end of the follow-up (Figure 1D). Furthermore, the mixed-models analysis revealed a significant difference in the prednisone dose between the two conditions during the follow-up (p < 0.001).

In the study period, we utilized different imaging techniques. At the moment of TCZ initiation, the proportion of patients who had a PET/CT scan was 38/57 (66.7%) in the TAK group vs. 57/70 (81.4%) in the LV-GCA group. MRI-A was obtained in 16/57 (28.1%) vs. 4/70 (5.7%) and CT-A in 16/57 (28.1%) vs. 3/70 (4.3%) in the TAK and LV-GCA groups, respectively. There were patients who underwent more than one test at the time of treatment onset. In the follow-up, PET/CT was used in the TAK group in 20/38 (52.6%) patients, whereas in the GCA group it was used in 35/57 (61.4%) cases.

There was a mean follow-up period of 12 ± 6.4 months (TAK patients) vs. 13.3 ± 2.12 months (LV-GCA patients) from the initial examination to the first follow-up image examination.

All told, 24 (42.1%) of the TAK patients and 32 (45.7%) of the LV-GCA patients who were receiving TCZ underwent a 12-month follow-up imaging test. Remarkably, the percentage of patients with complete imaging normalization was low. In fact, it was only observed in (18.9%, 7/37) extracranial LV-GCA patients vs. (21.2%, 32/70) members of the TAK group at the 12-month follow-up (Figure 2). Conversely, the values of imaging improvement in LV-GCA and TAK were slightly higher, standing at 59.4% vs. 52.6%, respectively.

Figure 3 and Figure 4 show two representative cases for both groups of patients at 24 months of follow-up.

3.3. Follow-Up and Adverse Events

At the end of the follow-up (12 months), TCZ was maintained in 49 (70%) extracranial LV-GCA patients and in 41 (71.9%) TAK patients. A total of 35 patients with LV-GCA (75.5%) and 30 patients with TAK (76.9%) achieved remission. However, complete remission was observed in only 5 patients (14.3%) with LV-GCA and 6 patients (15.8%) with TAK. Relapses were observed in 2 (7.7%) and 3 (10.7%) patients (p = NS) with extracranial LV-GCA and TAK, correspondingly.

Relevant adverse events were observed in only 9 (12.8%) and 6 (11.1%) (p = NS) extracranial LV-GCA and TAK patients. The adverse events in extracranial LV-GCA were severe infections (n = 3 bacteriemia, upper tract infection, recurrent dental infection) and skin manifestations (n = 3) (rash and palpable purpura). Other side effects included moderate cytopenias (neutropenia and thrombocytopenia) and asymptomatic hypertransaminasemia. TCZ was discontinued in four of these patients due to (severe infections and moderate cytopenias). In the TAK group, a total of 6 (11.1%) patients experienced relevant adverse events during TCZ therapy. These were predominantly infections, including severe pneumonia (n = 2), mild upper respiratory tract infection (n = 1), and herpes zoster (n = 1). TCZ was discontinued in 3 of these cases due to severe infections. No deaths occurred during the study period in any of the groups.

TCZ was discontinued due to ineffectiveness in 1/70 (1.43%) of LV-GCA patients and 7/57 (12.3%) patients of the TAK group (p NS). Other reasons for discontinuation included a patient’s decision due to the pandemic era (2/70, 2.9%) in the LV-GCA group, as well as pregnancy (n = 1; 1.7%) in TAK group and (n = 1; 1.4%) in LV-GCA group.

4. Discussion

This multicenter observational study indicates that TCZ leads to both rapid and long-lasting clinical and laboratory improvements in patients with LV-GCA and TAK. This study offers valuable insights into the clinical characteristics, outcomes, and safety profile of TCZ therapy in both groups of patients. Indeed, GC treatment remains the cornerstone therapy for both conditions, but it is often associated with serious side effects, and relapses are common when GCs are tapered or discontinued [32,33].

GCA and TAK are the two more common examples of LVV in our environment. While both diseases exhibit similarities in their clinical, radiological, and histological features, certain pathogenic mechanisms are activated differently in LV-GCA and TAK patients [34,35]. Moreover, GCA can be differentiated from TAK by several epidemiological and clinical features [36].

When biological therapy started, the most common clinical manifestations in our series were constitutional symptoms (asthenia and weight loss), mainly fever and asthenia. Constitutional syndrome was found in a higher proportion of LV-GCA patients compared to TAK patients. This discrepancy may reflect the distinct clinical presentation and disease course of both conditions.

This study shows that the proportion of patients with an ESR/CRP increase at the beginning of TCZ was similar in both groups and no differences were found in the remission percentages at 3, 6, and 12 months of follow-up. It is known that CRP and ESR are of little value in patients treated with TCZ due to IL-6 signaling inhibition. This limitation is inherent to the use of these markers in patients receiving IL-6 inhibitors. However, ESR and CRP remain widely used as indicators of inflammation in clinical practice, and we interpreted them in conjunction with clinical findings and imaging results.

We also observed that at least half of the patients presented complete clinical improvement.

Our study reports that the segments of the aorta most frequently affected in LV-GCA patients were the thoracic aortic branches, whereas in TAK patients they were the supra-aortic vessels. The involvement of the abdominal aorta was higher in GCA (42.8%) patients than in the TAK group (33.3%). These findings underscore the different patterns of vascular involvement in these two diseases, which is essential for an accurate diagnosis and treatment strategy.

TCZ therapy demonstrated promising results in both LV-GCA and TAK patients, leading to rapid and sustained improvements in clinical manifestations and laboratory markers. The achievement of remission was notable, with a substantial proportion of patients in both groups experiencing complete remission within the first year after TCZ initiation. TAK patients received higher doses of glucocorticoids during each visit and at the end of the follow-up. It might confound the interpretation of TCZ’s effectiveness in this subgroup. Moreover, the absence of a control group receiving alternative treatments limits the ability to directly compare TCZ’s efficacy and safety against other therapies. Moreover, the GC-sparing effect of TCZ was patent, as evidenced by the significant decrease in the prednisone dosage during the follow-up. Consistent with our findings, Ferfar et al. reported that 79.1% of TAK patients achieved a reduction in prednisone the dosage following TCZ treatment [19,20]. Likewise, Pazzola et al. collected a table of 3 studies describing the reduction in prednisone dose after initiation of TCZ [37].

They described the reduction in the prednisone dose after treatment with tocilizumab.

These findings highlight TCZ as an effective therapeutic option in both LV-GCA and TAK treatment, particularly in terms of achieving disease remission and reducing the GC dependence.

This study compared the effectiveness of TCZ between LV-GCA and TAK patients. Although both conditions showed significant improvement, the proportion of patients achieving complete remission was higher in the LV-GCA group compared to the TAK group at 6 months of TCZ therapy. However, we did not find differences in complete CRP and ESR normalization between both groups. The safety profile of TCZ therapy was also evaluated, and adverse events were observed at similar rates in both LV-GCA and TAK patients. Infections were the most common adverse events, leading to TCZ discontinuation in some cases. Thus, it is important to note that, despite the overall effectiveness of TCZ, clinicians need to be vigilant in monitoring patients for potential adverse events during therapy.

The main limitations of this study are its retrospective nature, which could have introduced bias due to missing data, and its multicentre design. Therefore, the analysis could have been heterogeneous. Moreover, not all patients underwent the same imaging techniques, and follow-up imaging was inconsistent between groups. This heterogeneity could introduce bias in assessing imaging normalization or improvement evaluation.

This retrospective multicenter study provides valuable real-world evidence on the effectiveness and safety of TCZ in LV-GCA and TAK patients. TCZ therapy demonstrated significant clinical and laboratory improvements in both diseases, leading to remission and GC-sparing effects. However, some differences in response rates and adverse events were observed between LV-GCA and TAK patients. These findings underscore the importance of individualized treatment approaches based on specific disease characteristics and the patient’s profile. Nonetheless, further prospective studies and large cohorts are warranted to validate these findings and optimize the use of TCZ in the LV-GCA and TAK management.

Author Contributions

Conceptualization, C.L.-T., J.L., D.P.-P., F.L.-G., P.B., M.M.F.-G., B.G.-A., R.S.-L., M.M., S.C., R.B. and Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group; methodology, C.L.-T., J.L., D.P.-P., I.F.-A. and Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group; software, C.L.-T. and I.F.-A.; validation, I.F.-A., S.C., R.B. and Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group; formal analysis, C.L.-T.; investigation, C.L.-T., J.L., D.P.-P., F.L.-G., P.B., M.M.F.-G., B.G.-A., R.S.-L., M.M., I.F.-A., S.C., R.B. and Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group; resources, C.L.-T., J.L., D.P.-P., I.F.-A., R.B. and Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group; data curation, C.L.-T., J.L., D.P.-P., F.L.-G., P.B., M.M.F.-G., B.G.-A., R.S.-L., M.M. and Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group; writing—original draft preparation, C.L.-T.; writing—review and editing, C.L.-T., J.L., D.P.-P., S.C., R.B. and Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group; visualization, C.L.-T., J.L., D.P.-P. and Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group; supervision, S.C., R.B. and Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group; project administration, C.L.-T., J.L., D.P.-P. and Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group; funding acquisition, R.B. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was approved by Ethics Committee for Clinical Research of Santander, Cantabria, Spain (approval number: 2018.080) on 19 September 2018.

Data Availability Statement

Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article. Patient consent was waived due to its retrospective nature.

Acknowledgments

We thank all the members of the different Medical Services and patients included in this study. This study was partially presented at the ACR/ARHP Convergence Meeting of Rheumatology in Philadelphia, PA, US, in November 2022. Tocilizumab in Large-Vessel Vasculitis Spanish Collaborative Group: C. Moriano (Hospital Universitario de León, Rheumatology, León, Spain); P. Vela-Casasempere (Hospital General de Alicante, Rheumatology, Alicante, Spain); J. Narváez (Hospital de Bellvitge, Rheumatology, Barcelona, Spain); V. Aldasoro (Complejo Hospitalario de Navarra, Rheumatology, Pamplona, Spain); O. Maíz (Hospital Universitario de Donosti, Rheumatology, San Sebastián, Spain); R. Melero (Complejo H. De Vigo, Rheumatology, Vigo, Spain); I. Villa-Blanco (Hospital Sierrallana, Rheumatology, Torrelavega, Spain); J.L. Callejas-Rubio (Hospital San Cecilio, Internal Medicine, Granada, Spain); E. De Miguel (Hospital Universitario La Paz, Rheumatology, Madrid, Spain); S. Romero-Yuste (Complejo H. Universitario de Pontevedra, Rheumatology, Pontevedra, Spain); E. Galíndez-Agirregoikoa (Hospital de Basurto, Rheumatology, Bilbao, Spain); C. Galisteo (Hospital Parc Tauli, Rheumatology, Sabadell, Spain); J. Sánchez-Martin (Hospital Universitario 12 de Octubre, Rheumatology, Madrid, Spain); B. Bravo (Hospital Virgen de las Nieves, Rheumatology, Granada, Spain); C. Hidalgo (Complejo Universitario de Salamanca, Rheumatology, Salamanca, Spain); C. Romero-Gómez (Hospital Regional de Málaga, Rheumatology, Málaga, Spain).

Conflicts of Interest

Disclosures that might be interpreted as constituting possible conflict(s) of interest for the study: Dr. Javier Loricera had consultation fees/participation in company-sponsored speaker’s bureau from Roche, Novartis, UCB Pharma, MSD, Janssen, Galápagos, Celgene, Astra Zeneca and Grünenthal and received support for attending meetings and/or travel from Janssen, Abbvie, Roche, Novartis, MSD, UCB Pharma, Celgene, Lilly, Pfizer, Galápagos. Dr. Diana Prieto-Peña has received research support from UCB Pharma, Roche, Sanofi, Pfizer, Janssen, Amgen, AbbVie, Novartis and Lilly. Dr. Fernando López Gutiérrez has received support for attending meetings and/or travel from Janssen, Abbvie, Roche, Novartis, MSD, UCB Pharma, Celgene, Lilly, Pfizer, Galápagos. Dr. Mauricio Mínguez has received research support from Abbvie, Janssen, GSK, Faes Farma and Novartis. Dr. Santos Castañeda has received research support from MSD and Pfizer and had consultation fees/participation in company-sponsored speaker’s bureau from BMS, Eli-Lilly, MSD, Roche, and UCB. Dr. Ricardo Blanco received grants/research support from AbbVie, MSD, and Roche, and had consultation fees/participation in a company-sponsored speaker’s bureau from AbbVie, Pfizer, Roche, Bristol-Myers, Lilly, Galapagos, Novartis, Janssen, GSK, and MSD. The following authors did not declare financial disclosures: Carmen Lasa-Teja, Pilar Bernabéu, María Freire González, Beatriz González-Alvarez, Roser Solans-Laqué and Iván Ferraz-Amaro.

Footnotes

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Figures and Table

Figure 1. The evolution of the main outcomes in patients with extracranial LV-GCA and TAK at 1, 3, 6, and 12 months after tocilizumab initiation. (A) Remission (absence of symptoms and signs); (B) erythrocyte sedimentation rate (ESR) (mm/h); (C) serum C-reactive protein (CRP) (mg/L); (D) prednisone dose (mg/day). * p [less than] 0.001 vs. baseline values. Significant differences between both groups were expressed as +.

Figure 1. The evolution of the main outcomes in patients with extracranial LV-GCA and TAK at 1, 3, 6, and 12 months after tocilizumab initiation. (A) Remission (absence of symptoms and signs); (B) erythrocyte sedimentation rate (ESR) (mm/h); (C) serum C-reactive protein (CRP) (mg/L); (D) prednisone dose (mg/day). * p [less than] 0.001 vs. baseline values. Significant differences between both groups were expressed as +.

Figure 2. Improvement and remission as assessed by imaging techniques at 12 months of follow-up. All data are expressed as a %.

Figure 3. FDG-PET/CT scans of a 71-year-old woman with a diagnosis of giant-cell arteritis. FDG-PET/CT scans were performed initially (A,E–G) PET and (C) PET/CT images and after 24 months of TCZ therapy (B,H–J) PET and (D) PET/C images. Follow-up PET/CT images showed the disappearance of the baseline intense FDG uptake at the brachiocephalic trunk, subclavian, and axillary arteries (long arrows) and at the thoracic and abdominal aorta (short arrows).

Figure 4. An initial PET scan (A) axial, (C) coronal, (E) sagittal slices in a 47-year-old woman with Takayasu arteritis. Images showed FDG uptake along the thoracic aorta (arrows). After 24 months of TCZ therapy, the patient presented a good clinical and biochemical response and the follow-up PET (B) axial, (D) coronal, (F) sagittal slices showed the normalization of FDG uptake at the thoracic aorta wall (arrows).

Table 1

Main clinical features of patients with refractory extracranial LV-GCA and TAK at TCZ initiation.

	Extracranial LV-GCA (n = 70)	TAK(n = 57)	p
General features
Age (years), mean ± SD	67.2 ± 10.5	40.5 ± 16.3	<0.01
Sex (female), n (%)	51 (72.9)	49 (86)	0.07
Time from vasculitis diagnosis to TCZ initiation (months), median [IQR]	5 [2–15]	12 [3–37]	<0.01
Cardiovascular risk factors
High blood pressure, n (%)	37 (52.9)	2 (3.5)	<0.01
Dyslipidemia, n (%)	38 (54.3)	0	<0.01
Diabetes, n (%)	5 (7.1)	0	0.040
Clinical features
Asthenia, n (%)	44 (62.9)	34 (59.6)	0.712
Constitutional syndrome, n (%)	29 (41.4)	1 (1.8)	<0.01
Fever, n (%)	11 (15.7)	7 (12.2)	0.741
PMR, n (%)	51 (72.9)	2 (3.5)	<0.01
Involved segments of aorta and main branches
Thoracic aortic, n (%)	60 (85.7)	27 (47.4)	<0.01
Abdominal aortic, n (%)	30 (42.8)	19 (33.3)	<0.01
Supra-aortic vessels (aortic arch, carotids, brachiocephalic trunks, subclavian arteries), n (%)	52 (74.3)	43 (75.4)	<0.01
Iliac arteries, n (%)	13 (18.6)	6 (10.5)	<0.01
Baseline Laboratory parameters
ESR (mm/1st hour), median [IQR]	32 [12.5–55]	31 [10–52]	0.820
CRP (mg/dL), median [IQR]	1.4 [0.5–2.4]	1.4 [0.5–3.5]	0.410
Hb (g/dL), median [IQR]	12.7 [9.5–15.8]	12.32 [9.5–15.3]	0.057
Baseline prednisone dose (mg/day), median [IQR]	15 [10–20]	30 [15–50]	<0.01
Previous therapy
cDMARDs, n (%)	45 (64.3)	44 (77.2)	0.510
bDMARDs, n (%)	0 (0)	15 (26.3)	0.32
TCZ therapy
Intravenous/subcutaneous, n/n (% intravenous)	34/70 (48.6)	46/57 (80.7)	<0.01
TCZ mono/TCZ combo, n/n (% TCZ mono)	36/34 (51.4)	33/24 (57.9)	<0.01
Follow-up time after TCZ onset, median [IQR]	20 [10–36]	18 [7–41]	0.73

Abbreviations: CRP—C-reactive protein; DMARD—disease-modifying anti-rheumatic drug; ESR—erythrocyte sedimentation rate; GCA—giant-cell arteritis; IQR—interquartile range; LV—large vessel; n—number of patients; TCZ—tocilizumab; TAK—Takayasu’s arteritis.

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