Narrative ReviewBiological treatments in giant cell arteritis & Takayasu arteritis
Introduction
Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are the two main large vessel vasculitides [1]. It has been suggested that TAK and GCA may be different phenotypes of a single disease [2], [3], [4] since they share some similarities regarding their clinical, radiological and histological presentations, both being granulomatous vasculitides involving the aorta and its major branches [1]. However, some pathogenic processes in GCA and in TAK are activated differently [5], [6], [7]. Furthermore, GCA can be distinguished from TAK by several epidemiological, clinical, arterial distribution and therapeutic features [2]. GCA occurs in people over 50 years and its incidence increases progressively after 50 years with a peak occurring between 70 and 80 years [8], [9]. Women are affected two to three times more frequently than men. GCA is very rare in African, Arabic and Asian countries [10], [11], [12], [13], [14], whereas the highest prevalence is observed in Caucasian people, especially in Scandinavian countries and in Olmsted County, Minnesota, where the population has a similar ethnic background [15]. Assessment of GCA activity usually relies on clinical symptoms, erythrocyte sedimentation rate (ESR) and acute-phase reaction proteins – mainly C-reactive protein (CRP) and fibrinogen – which are increased in > 95% of cases and closely related to disease activity [16]. By contrast, TAK occurs in patients < 40 year old and is much rarer than GCA, accounting for 1–3 cases per million per year. In 90% of cases, patients affected by TAK are women. TAK has been described in all ethnic groups around the world but is more frequent in Asian countries and in northwest Turkey [17]. It is more challenging to assess disease activity in TAK than in GCA since TAK seems to be a more chronic and insidious disease. Particularly, a substantial number of patients with active disease have normal levels of acute phase reaction proteins and ESR. This situation has led to the proposal of scores to assess TAK activity: the National Institute of Health (NIH) criteria (or Kerr criteria) [18] and more recently the Indian Takayasu Clinical Activity Score (ITAS2010) [19].
In both diseases, glucocorticoids (GC) remain the cornerstone of treatment. They are very effective in inducing remission but relapses are common when doses are tapered. Immunosuppressive drugs, especially methotrexate, are therefore used to spare GC and/or prevent further relapse(s), but have not shown a major benefit [20]. Therefore, biologics are often used in GCA or TAK after failure of GC tapering despite the use of conventional immunosuppressive drugs. This review focuses on recent data available about the use of biologics in large-vessel vasculitis, and highlights the differences between GCA and TAK with regard to these treatments.
Section snippets
Anti-TNF-α drugs (Fig. 1)
- a.
GCA
By comparing the mRNA levels of interleukin-1beta (IL-1β), tumour necrosis factor-alpha (TNF-α) and IL-6 in temporal artery samples from 36 patients with biopsy-proven GCA and 11 controls, Hernández-Rodríguez et al. demonstrated that the tissue expressions of these three pro-inflammatory cytokines were high in GCA patients, and notably that a high production of TNF-α was associated with longer GC requirements [21]. These data, together with results of several case series reporting the
Blockade of the IL-6 pathway: tocilizumab and sirukumab (Fig. 1)
IL-6 is a pro-inflammatory cytokine produced by many cell types, especially monocytes and macrophages. IL-6 signalling depends on the membrane protein gp130, whose activation leads to the phosphorylation of STAT3. Gp130 is activated after its linkage to a complex composed of IL-6 and its receptor, which is either a transmembrane protein (mIL-6R, expressed by hepatocytes, monocytes, macrophages, some B and T cells, megakaryocytes and endothelial cells) or a soluble protein (sIL-6R). Signalling
Abatacept (Fig. 1)
Before being polarized into Th1, Th2 or Th17 cells, CD4+ T cells are activated by antigen presenting cells (APC), which are mainly dendritic cells. T cell activation relies on the addition of several signals. The first signal is the result of the interaction of the T cell receptor (TCR) and the major histocompatibility complex (MHC)-II/peptide complex which is presented by APC. Then, the second signal depends on other molecular interactions between APC and T cells, in particular through
Other biologics (Fig. 1)
- a.
Ustekinumab
Recent advances in our understanding of the pathophysiology of GCA showed that after dendritic cell activation in the adventitia, CD4+ T cells are recruited in the arterial wall and are critical for vasculitis induction [69]. T cells are polarized into Th1 and Th17 cells, which produce IFN-γ and IL-17, respectively [35], [70], [71]. IFN-γ triggers the recruitment and activation of macrophages and CD8+ T cells [72], [73], and could be implicated in the occurrence of relapses when GC
Other therapeutic targets (Fig. 1)
- a.
Baricitinib
Baricitinib is an orally administered inhibitor of Janus kinase (JAK)1 and JAK2 [88], which are tyrosine kinases involved in the signalling of many cytokines [89]. Baricitinib is thus a potential inhibitor of the Th17 (IL-6, IL23) and Th1 (IL-12, IFN-γ) pathways, which could be of particular interest for the treatment of GCA. A phase-II open-label pilot study is currently recruiting relapsing GCA patients (NCT030226504).
- b.
Inhibition of vascular remodelling
In contrast to inflammation,
Conclusion (Fig. 2)
GC remain the cornerstone of the treatment of GCA and TAK. Conventional immunosuppressive drugs (methotrexate in GCA; methotrexate, azathioprine, mycophenolate mofetil or leflunomide in TAK) are still used as second-line therapies if severe GC-related side-effects are expected or in cases of corticodependence or relapse(s). Therefore, biologics often remain as second- or third-line therapies. In GCA, tocilizumab and abatacept are effective, but more data are required for ustekinumab and
Disclosures
Maxime SAMSON received lecturing fees from Chugaï (total < €1000) and traveling fees from Abbvie, Roche, Chugaï, Novartis and Actelion. GEF, SPG, JHR and MCC participated in the GiACTA trial sponsored by Roche and MCC received traveling fees from Roche. MCC received consulting fees from Roche and GSK.
Fundings
MS is funded by the French Vasculitis Study Group (FVSG) and the Foundation for the Development of Internal Medicine in Europe (FDIME). NTG, SPG, MCB, RAR, JHR and MCC are supported by Ministerio de Economía, Industria y Competitividad (SAF 17/88275-R), Marató TV3 (201507). GEF is supported by Instituto de Salud Carlos III (PI15/00092) and Fondo Europeo de Desarrollo Regional (FEDER, una manera de hacer Europa). GEF was funded by Plà Estrategic de Recerca i Innovació en Salut (PERIS)
Acknowledgments
We thank Philip Bastable for his help in writing the manuscript.
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2022, Translational Autoimmunity: Treatment of Autoimmune DiseasesEffectiveness and safety of tocilizumab in patients with refractory or severe Takayasu's arteritis: A prospective cohort study in a Chinese population
2021, Joint Bone SpineCitation Excerpt :However, it has been reported that traditional ISs lack efficacy in treating severe or refractory TAK [8–10]. Biologic agents have been recommended as second or third-line therapy for TAK, especially for severe and/or refractory cases [11]. In recent years, tocilizumab (TCZ) has shown promising effectiveness for TAK treatment [12–15].
Myocardial infarction during giant cell arteritis: A cohort study
2021, European Journal of Internal MedicineCitation Excerpt :However, relapses are frequent when the doses are tapered. This leads to GC-related side effects, which are the primary cause of morbidity in GCA patients [10] and sometimes requires to use GC-sparing drugs such as methotrexate or tocilizumab [11–14]. Acute myocardial infarction (MI) is currently defined as the association of a rise and/or a fall in cardiac troponin (cTn) values with at least one value above the 99th percentile of the upper reference limit and clinical evidence of myocardial ischemia (chest pain or electrocardiography) [15].
Association between the antineutrophil cytoplasmic antibody and late coronary arterial occlusive disease in patients with Takayasu arteritis
2020, Journal of CardiologyCitation Excerpt :Methotrexate, azathioprine, mycophenolate mofetil, and leflunomide may be added to a glucocorticoid as second-line drugs. When these oral drugs are not efficient, biological agents including tumor necrosis factor inhibitors, tocilizumab, and rituximab, can be recommended [26]. In terms of AAV, since most patients exhibit major organ involvement, such as renal vasculitis or mononeuritis multiplex, either cyclophosphamide or rituximab along with a glucocorticoid is generally recommended as induction therapy.
Usefulness of serum amyloid a protein dosage for monitoring patients receiving tocilizumab
2020, European Journal of Internal Medicine