Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients

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Abstract

Objective

To assess the efficacy of tocilizumab (TCZ) in giant cell arteritis (GCA) patients with refractory disease and/or with unacceptable side effects due to corticosteroids.

Methods

A retrospective multicenter open-label study on 22 GCA patients treated with TCZ at standard dose of 8 mg/kg/month. The main outcomes were achievement of disease remission and reduction of corticosteroid dose.

Results

The mean age ± standard deviation of patients was 69 ± 8 years. The main clinical features at TCZ onset were polymyalgia rheumatica (n = 16), asthenia (n = 7), headache (n =5), constitutional symptoms (n = 4), jaw claudication (n = 2), and visual loss (n = 2). Besides corticosteroids and before TCZ onset, 19 of 22 patients had also received several conventional immunosuppressive and/or biologic drugs. Of 22 patients, 19 achieved rapid and maintained clinical improvement following TCZ therapy. Also, after a median follow-up of 9 (interquartile range: 6–19) months, the C-reactive protein level had fallen from 1.9 (1.2–5.4) to 0.2 (0.1–0.9) mg/dL (p < 0.0001) and the erythrocyte sedimentation rate decreased from 44 (20–81) to 12 (2–20) mm/1st hour (p = 0.001). The median dose of prednisone was also tapered from 18.75 (10–45) to 5 (2.5–10) mg/day (p < 0.0001). However, TCZ had to be discontinued in 3 patients due to severe neutropenia, recurrent pneumonia, and cytomegalovirus infection. Moreover, 1 patient died after the second infusion of TCZ due to a stroke in the setting of an infectious endocarditis.

Conclusion

TCZ therapy leads to rapid and maintained improvement in patients with refractory GCA and/or with unacceptable side effects related to corticosteroids. However, the risk of infection should be kept in mind when using this drug in patients with GCA.

Introduction

Giant cell arteritis (GCA) is a vasculitis of large- and medium-sized arteries affecting people older than 50 years. This vasculitis is common in Europe and North America. The disease is characterized by the granulomatous involvement of the aorta with predilection for the involvement of the extracranial branches of the carotid artery [1], [2]. The most common serious consequence of GCA is the development of irreversible visual loss [3], but aortitis and its related complications, such as aneurysms, dissection, and rupture of the aortic wall, are also potential life-threatening manifestations of the disease [4], [5], [6], [7].

The pathogenesis of GCA remains unknown. Nevertheless, a number of studies have shown abnormal production of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-18, tumor necrosis factor-α (TNF-α), or interferon-γ by T lymphocytes and macrophages in inflamed arterial walls [8], [9], [10].

High-dose corticosteroids are the mainstay of treatment in GCA [1], [11]. Regrettably, relapses are common when the corticosteroid dose is tapered, leading to prolonged duration of this therapy that is often associated with important adverse events [12]. In these cases, synthetic immunosuppressive drugs such as methotrexate (MTX), azathioprine (AZA), and cyclophosphamide may be used as corticosteroid-sparing agents or second-line therapy. Nevertheless, the efficacy of these drugs is variable, and in some cases they have also been associated with severe side effects [13], [14], [15], [16], [17], [18].

Currently, there are no drugs capable of achieving or maintaining disease remission after the discontinuation of corticosteroids therapy. Therefore, new targeted therapies for GCA are needed to improve the management of this vasculitis. In this scenario and based on the pathogenesis of this vasculitis, biologic drugs have also been used. Thus, anti-TNF-α agents have been the biologic drugs more commonly studied. However, 2 prospective randomized double-blind studies of GCA patients treated with the TNF-α inhibitors infliximab and adalimumab did not show good results [19], [20].

Because of that, the search for alternative drugs that may be used in patients with GCA is of potential interest. In this context, a potential therapeutic target is the pivotal proinflammatory cytokine IL-6, whose serum concentration is elevated in GCA patients, and it is up-regulated within the inflamed arteries [8], [9], [10], [21], [22], [23], [24], [25]. In this context, a humanized monoclonal antibody against the IL-6 receptor tocilizumab (TCZ) has been approved for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. However, information related to TCZ use in GCA is limited to reports on single cases or small series [26], [27], [28], [29], [30], [31], [32], [33].

Taking these considerations into account, we performed a multicenter study to assess the efficacy and adverse events of TCZ in GCA patients with refractory disease and/or with severe side effects of corticosteroid therapy. A literature review of the cases of GCA treated with TCZ was also conducted.

Section snippets

Patients and study protocol

We performed a retrospective, open-label, multicenter study on 22 patients diagnosed with GCA who were treated with TCZ. Before the onset of this biologic therapy, all the patients had received high-dose corticosteroids, and 19 of them standard synthetic and/or biologic immunosuppressive drugs. Treatment with TCZ was given due to lack of efficacy and/or unacceptable adverse events related to previous therapy. Patients were diagnosed with GCA between January 1999 and December 2012 at the

Results

A total of 22 patients (17 women and 5 men) with GCA who received treatment with TCZ were assessed. The mean ± SD age at the onset of this biologic therapy was 69 ± 8 years. The median (IQR) time from GCA diagnosis to TCZ onset was 14.5 months (5–38 months). Of the patients, 16 (73%) had a positive temporal artery biopsy. Large-vessel involvement, considered to be present if the patient had aortitis with or without involvement of the extracranial arteries, was disclosed by imaging techniques [18

Discussion

The results from this multicenter observational study indicate that TCZ yields a rapid and maintained clinical and laboratory improvement in patients with GCA, refractory to corticosteroids or other immunosuppressive agents.

Treatment with corticosteroids remains as the cornerstone of the therapy in GCA. However, they are frequently associated with serious side effects and, besides, relapses of the disease are not uncommon when corticosteroids are tapered or withdrawn [11], [12].

In the last

Conclusion

In view of the results obtained so far, we can conclude that TCZ treatment yields a rapid and maintained clinical improvement in patients with refractory GCA and/or with unacceptable side effects related to corticosteroids. A rapid reduction of laboratory markers of inflammation after the onset of TCZ therapy is also observed. However, it is important to keep in mind the risk of infection when using this drug in patients with GCA.

Acknowledgments

We would like to thank the members of the participating hospitals.

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    This study was presented at the 2014 American College of Rheumatology held in Boston in November 2014.

    This study was supported by a grant from “Fondo de Investigaciones Sanitarias”, Spain PI12/00193. This work was also partially supported by RETICS Programs, RD08/0075 (RIER) and RD12/0009/0013 from “Instituto de Salud Carlos III” (ISCIII), Spain.

    1

    J. Loricera and R. Blanco share first authorship.

    2

    J.L. Hernández and M.A. González-Gay share senior authorship.

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