Tocilizumab in giant cell arteritis. Observational, open-label multicenter study of 134 patients in clinical practice

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Abstract

Objective: Tocilizumab (TCZ) has shown efficacy in clinical trials on giant cell arteritis (GCA). Real-world data are scarce. Our objective was to assess efficacy and safety of TCZ in unselected patients with GCA in clinical practice

Methods: Observational, open-label multicenter study from 40 national referral centers of GCA patients treated with TCZ due to inefficacy or adverse events of previous therapy. Outcomes variables were improvement of clinical features, acute phase reactants, glucocorticoid-sparing effect, prolonged remission and relapses. A comparative study was performed: (a) TCZ route (SC vs. IV); (b) GCA duration (≤6 vs. >6 months); (c) serious infections (with or without); (d) ≤15 vs. >15 mg/day at TCZ onset.

Results: 134 patients; mean age, 73.0 ± 8.8 years. TCZ was started after a median [IQR] time from GCA diagnosis of 13.5 [5.0–33.5] months. Ninety-eight (73.1%) patients had received immunosuppressive agents. After 1 month of TCZ 93.9% experienced clinical improvement. Reduction of CRP from 1.7 [0.4–3.2] to 0.11 [0.05–0.5] mg/dL (p < 0.0001), ESR from 33 [14.5–61] to 6 [2–12] mm/1st hour (p < 0.0001) and decrease in patients with anemia from 16.4% to 3.8% (p < 0.0001) were observed. Regardless of administration route or disease duration, clinical improvement leading to remission at 6, 12, 18, 24 months was observed in 55.5%, 70.4%, 69.2% and 90% of patients. Most relevant adverse side-effect was serious infections (10.6/100 patients-year), associated with higher doses of prednisone during the first three months of therapy.

Conclusion: In clinical practice, TCZ yields a rapid and maintained improvement of refractory GCA. Serious infections appear to be higher than in clinical trials.

Introduction

Giant cell arteritis (GCA) is a large-vessel vasculitis (LVV) which affects medium and large sized arteries. It is common in European people older than 50 years as well as in North American of European ancestry [1], [2], [3]. Although blindness is the most feared complication, other severe manifestations such as stroke and aneurysms can also occur [4], [5], [6], [7].

The mainstay treatment of GCA are glucocorticoids [8], [9]. However, adverse events related to these drugs are common [9], [10], [11]. Besides, relapses are relative frequent in GCA patients [12], [13]. Therefore, other medications such as leflunomide (LFN), azathioprine (AZA) or cyclophosphamide (CYC) have been used with no efficacy [14], [15], [16]. For methotrexate, results are controversial but a metaanalysis confirmed its efficacy [17].

Although the etiology of GCA remains unknown, different proinflammatory cytokines including TNFα and IL-6 act as soluble pathogenic factors [18]. However, prospective, double-blind studies with monoclonal TNFα inhibitors led to poor results [19].

In contrast, several case series suggested that tocilizumab (TCZ), a humanized monoclonal antibody against the IL-6 receptor, may be a good therapeutic option in GCA [20], [21], [22], [23], [24], [25], [26], [27]. In this regard, two recent randomized clinical double-blinded Phases II and III studies showed efficacy of TCZ in patients with GCA [28], [29]. Consequently, TCZ has been approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for the treatment of patients with GCA. However, it is not uncommon to see that patients are often excluded from clinical trials due to comorbidities. Also, many of the individuals included in these two trials were patients with a recent diagnosis of GCA and some others had a relative short period of follow-up with TCZ therapy [29]. In this regard, 23 of 30 (77%) patients in a Phase II study, and 119 of 251 (47%) in a Phase III study were patients with GCA of recent onset [28], [29]. In the GiACTA trial, newly diagnosed GCA was defined if diagnosis was done ≤6 weeks before baseline, with a mean ± SD time between diagnosis and TCZ onset of 0.5 ± 0.5 months [29]. However, in a real-world scenario, TCZ will probably be more frequently used in patients with GCA refractory to conventional treatment or in those who experience side effects, including also GCA patients with one or several comorbidities. Therefore, in real life, patients with GCA undergoing TCZ therapy have longer disease duration, being often relapsing patients who are refractory to conventional immunosuppressive drugs. In addition, in the phase II study TCZ was prescribed intravenously (IV) whereas in the phase III GiACTA trial TCZ was given subcutaneously (SC) [28], [29]. Moreover, the recommended dose of prednisone at the onset of TCZ therapy has not clearly established.

Taking all these considerations into account, the aim of the present study was to assess the usefulness and safety of TCZ in GCA patients from a real clinical setting with refractory disease and/or with unacceptable side effects due to conventional treatment.

Section snippets

Patients, enrollment criteria and study protocol

We set up an observational, retrospective open-label multicenter study that included 134 GCA patients treated with TCZ in real clinical practice and followed-up, in some cases, up to 48 months. Before TCZ onset, all of them had received high-dose glucocorticoids, and 98 (73.1%) conventional synthetic and/or other biologic immunosuppressive drugs. To reduce selection bias, in the present study we included all the patients who had received at least one TCZ dose, regardless of the outcome.

Baseline main clinical features prior to TCZ onset

We studied 134 patients (101 women/33 men); mean age 73.0 ± 8.8 years, diagnosed with GCA and treated with TCZ. Of them, 119 (88%) fulfilled the 1990 ACR classification criteria for GCA [30]. The remaining patients were diagnosed by a positive temporal artery for GCA in 9 cases. Six patients did not fulfill the ACR classification criteria for GCA and had a negative TAB. All of them were older than 50 years but had an ESR at the time of diagnosis lower than 50 mm/1st hour. Nevertheless, they

Discussion

We present the largest multicenter series of real-life GCA patients in whom short and long-term efficacy of TCZ was assessed. All of them were refractory and/or had unacceptable side effects due to conventional therapy. Our results show that TCZ yields a rapid and maintained clinical and laboratory improvement, regardless of GCA time course (≤6 months or >6 months), TCZ administration route (IV vs. SC) or prednisone dose at TCZ onset (≤15 mg/day or >15 mg/day). However, the frequency of serious

Conclusion

Taken together our findings and the results of the randomized control trials, TCZ seems to be an excellent therapeutic option in GCA, regardless of the administration route and GCA duration, helping to minimize the glucocorticoid exposure over time. The most relevant side effects are serious infections that seem to be higher than in the GiACTA trial.

In conclusion, TCZ improves clinical manifestations, acute-phase reactants and imaging findings. However, GCA patients treated with TCZ may have

Acknowledgments

To all the members and patients of the participating hospitals.

Competing interests

Disclosures that might be interpreted as constituting of possible conflict(s) of interest for the study: Dr. MA Gonzalez-Gay received grants/research supports from Abbvie, MSD and Roche, and had consultation fees/participation in company sponsored speaker´s bureau from Pfizer, Lilly, Roche and Sanofi. Dr. R Blanco received grants/research supports from Abbvie, MSD and Roche, and had consultation fees/participation in company sponsored speaker´s bureau from Abbvie, Pfizer, Roche, Bristol-Myers,

Financial disclosures

No financial disclosures declared.

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      The 2018 EULAR guidelines recommend this agent for relapsing patients or for patients with new-onset disease only if there is occurrence or increased risk of glucocorticoid-related adverse events. Since the review of the evidence for the development of the 2018 EULAR guidelines in 2017, the use of tocilizumab for giant cell arteritis has been widespread, and several real-world studies61,62 have substantiated and expanded the findings of the landmark phase 2 and 3 randomised controlled trials.8,27 In addition, further evidence has shown that tocilizumab not only improves remission maintenance and glucocorticoid-sparing outcomes,8 but it also reduces the impact that giant cell arteritis and glucocorticoid treatment have on health-related quality of life.29,63,64

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    This study was presented in part at the 2017 American College of Rheumatology Meeting held in San Diego, CA, USA.

    1

    Mónica Calderón-Goercke and Javier Loricera shared first authorship.

    2

    Prof. MA González-Gay, R Blanco and J.L. Hernández shared senior authorship.

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