Tocilizumab in giant cell arteritis. Observational, open-label multicenter study of 134 patients in clinical practice☆
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.
References (46)
- et al.
Polymyalgia rheumatica and giant-cell arteritis
Lancet Lond Engl
(2008) - et al.
New insights into the pathogenesis of giant cell arteritis
Autoimmun Rev
(2017) - et al.
Tocilizumab in giant cell arteritis: multicenter open-label study of 22 patients
Semin Arthritis Rheum
(2015) - et al.
Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial
Lancet
(2016) - et al.
Epidemiology of giant cell arteritis and polymyalgia rheumatica
Arthritis Rheum
(2009) Giant cell arteritis
Ann Intern Med
(2016)- et al.
Clinical features of polymyalgia rheumatica and giant cell arteritis
Nat Rev Rheumatol
(2012) - et al.
Visual loss and other cranial ischaemic complications in giant cell arteritis
Nat Rev Rheumatol
(2017) - et al.
Visual manifestations of giant cell arteritis. Trends and clinical spectrum in 161 patients
Medicine (Baltimore)
(2000) - et al.
Aortic aneurysm and dissection in patients with biopsy-proven giant cell arteritis from northwestern Spain: a population-based study
Medicine (Baltimore)
(2004)
Giant cell arteritis: epidemiology, diagnosis, and management
Curr Rheumatol Rep
Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes
Arthritis Rheum
Current and emerging diagnosis tools and therapeutics for giant cell arteritis
Exp Rev Clin Immunol
Incidence of giant cell arteritis and characteristics of patients: data-driven analysis of comorbidities
Arthritis Care Res
Relapses and recurrences in giant cell arteritis: a population-based study of patients with biopsy-proven disease from northwestern Spain
Medicine (Baltimore)
Disease relapses among patients with giant cell arteritis: a prospective, longitudinal cohort study
J Rheumatol
Prednisolone combined with adjunctive immunosuppression is not superior to prednisolone alone in terms of efficacy and safety in giant cell arteritis: meta-analysis
Clin Rheumatol
Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis
Arthritis Rheum
Leflunomide as a corticosteroid-sparing agent in giant cell arteritis and polymyalgia rheumatica: a case series
BioMed Res Int
Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis
Arthritis Rheum
Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial
Ann Intern Med
Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series
Swiss Med Wkly
Tocilizumab in refractory aortitis: study on 16 patients and literature review
Clin Exp Rheumatol
Cited by (70)
Secondary headaches - red and green flags and their significance for diagnostics
2023, eNeurologicalSciUnmet need in the treatment of polymyalgia rheumatica and giant cell arteritis
2022, Best Practice and Research: Clinical RheumatologyPan American League of Associations for Rheumatology guidelines for the treatment of giant cell arteritis
2022, The Lancet RheumatologyCitation Excerpt :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
- ☆
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.