Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial

Cid, María C.; Unizony, Sebastian; Blockmans, Daniel Engelbert; Brouwer, Elisabeth; Dagna, Lorenzo; Dasgupta, Bhaskar; Hellmich, Bernhard; Molloy, Eamonn; Salvarani, Carlo; Trapnell, Bruce C.; Warrington, Kenneth J.; Wicks, Ian P.; Samant, Manoj; Zhou, Teresa; Pupim, Lara B.; Paolini, John F.

doi:10.1136/annrheumdis-2021-221865

Cited by 66 publications

(40 citation statements)

References 30 publications

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“…The most recent work also showed the involvement of processes leading to the amplification and/or maintenance of inflammation and vascular remodeling, such as regulatory T response defects (regulated by IL-6), GM-CSF and the roles of macrophages and NOTCH, along with probably a major role of arterial wall resident cells. These mechanisms identify targets for the development of new therapeutics such as tocilizumab [ 77 ], and more recently, mavrilimumab [ 162 ], secukinumab [ 167 ], JAK inhibitors [ 168 ], abatacept [ 137 ] and ustekinumab [ 169 , 170 , 171 ] ( Figure 3 ) [ 172 ].…”

Section: Discussionmentioning

confidence: 99%

“…Using a model of an ex vivo culture of temporal arteries treated with GM-CSF or anti-GM-CSF (mavrilimumab), researchers showed that GM-CSF increased the activation of macrophages (expression of IL-1β, IL-6, TNF-α, CD83 and HLA-DR), Th1 cell polarization, angiogenesis and tissue injury (MMP9/TIMP1 ratio) [ 160 ]. These results led a phase-2, randomized, placebo-controlled therapeutic trial to be conducted, the results of which strongly suggest the efficacy of mavrilimumab, a fully human IgG4 monoclonal antibody targeting GM-CSF, in the treatment of GCA [ 162 ].…”

Section: Mechanisms Involved In Maintaining Inflammationmentioning

confidence: 99%

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New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

Greigert

Genet

Bonnotte

et al. 2022

JCM

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The giant cell arteritis (GCA) pathophysiology is complex and multifactorial, involving a predisposing genetic background, the role of immune aging and the activation of vascular dendritic cells by an unknown trigger. Once activated, dendritic cells recruit CD4 T cells and induce their activation, proliferation and polarization into Th1 and Th17, which produce interferon-gamma (IFN-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ and GM-CSF induce the differentiation of macrophage subpopulations, which play a role in the destruction of the arterial wall, in neoangiogenesis or intimal hyperplasia. Under the influence of different mediators, mainly endothelin-1 and PDGF, vascular smooth muscle cells migrate to the intima, proliferate and change their phenotype to become myofibroblasts that further proliferate and produce extracellular matrix proteins, increasing the vascular stenosis. In addition, several defects in the immune regulatory mechanisms probably contribute to chronic vascular inflammation in GCA: a defect in the PD-1/PD-L1 pathway, a quantitative and qualitative Treg deficiency, the implication of resident cells, the role of GM-CSF and IL-6, the implication of the NOTCH pathway and the role of mucosal‑associated invariant T cells and tissue‑resident memory T cells.

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Section: Discussionmentioning

confidence: 99%

Section: Mechanisms Involved In Maintaining Inflammationmentioning

confidence: 99%

New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

Greigert

Genet

Bonnotte

et al. 2022

JCM

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“…Other therapeutic options include inhibition of released cytokines, including IL-17, GM-CSF, and IFN-γ. The efficacy and safety of anti-IL-17 and anti-GM-CSF receptor antibodies against GCA are being actively pursued in clinical trials, and the results obtained to date appear promising ( 100 , 101 ). Signaling downstream of GM-CSF and IFN-γ involves the JAK-STAT pathway, and the efficacy of JAK inhibitors is widely recognized in RA ( 102 ), which raises expectations for the treatment of LVV ( 103 ).…”

Section: Discussionmentioning

confidence: 99%

Vasculitogenic T Cells in Large Vessel Vasculitis

Watanabe¹,

Hashimoto²

2022

Front. Immunol.

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Vasculitis is an autoimmune disease of unknown etiology that causes inflammation of the blood vessels. Large vessel vasculitis is classified as either giant cell arteritis (GCA), which occurs exclusively in the elderly, or Takayasu arteritis (TAK), which mainly affects young women. Various cell types are involved in the pathogenesis of large vessel vasculitis. Among these, dendritic cells located between the adventitia and the media initiate the inflammatory cascade as antigen-presenting cells, followed by activation of macrophages and T cells contributing to vessel wall destruction. In both diseases, naive CD4+ T cells are polarized to differentiate into Th1 or Th17 cells, whereas differentiation into regulatory T cells, which suppress vascular inflammation, is inhibited. Skewed T cell differentiation is the result of aberrant intracellular signaling, such as the mechanistic target of rapamycin (mTOR) or the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathways. It has also become clear that tissue niches in the vasculature fuel activated T cells and maintain tissue-resident memory T cells. In this review, we outline the most recent understanding of the pathophysiology of large vessel vasculitis. Then, we provide a summary of skewed T cell differentiation in the vasculature and peripheral blood. Finally, new therapeutic strategies for correcting skewed T cell differentiation as well as aberrant intracellular signaling are discussed.

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“…Therefore, imaging the extent of CD206+ infiltration in the vessels may also predict the GC dependency of these patients. Recently, a phase II clinical trial with a GM-CSF receptor blocker (mavrlimumab) demonstrated GM-CSF receptor blockade to be efficacious in the treatment of GCA ( 390 ). Furthermore, ex vivo treatment of GCA-affected vessels with mavrilimumab documented a reduction of CD206 expression ( 40 ).…”

Section: Future Perspectives: Toward Disease Stratification and Bette...mentioning

confidence: 99%

Novel PET Imaging of Inflammatory Targets and Cells for the Diagnosis and Monitoring of Giant Cell Arteritis and Polymyalgia Rheumatica

et al. 2022

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Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are two interrelated inflammatory diseases affecting patients above 50 years of age. Patients with GCA suffer from granulomatous inflammation of medium- to large-sized arteries. This inflammation can lead to severe ischemic complications (e.g., irreversible vision loss and stroke) and aneurysm-related complications (such as aortic dissection). On the other hand, patients suffering from PMR present with proximal stiffness and pain due to inflammation of the shoulder and pelvic girdles. PMR is observed in 40–60% of patients with GCA, while up to 21% of patients suffering from PMR are also affected by GCA. Due to the risk of ischemic complications, GCA has to be promptly treated upon clinical suspicion. The treatment of both GCA and PMR still heavily relies on glucocorticoids (GCs), although novel targeted therapies are emerging. Imaging has a central position in the diagnosis of GCA and PMR. While [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) has proven to be a valuable tool for diagnosis of GCA and PMR, it possesses major drawbacks such as unspecific uptake in cells with high glucose metabolism, high background activity in several non-target organs and a decrease of diagnostic accuracy already after a short course of GC treatment. In recent years, our understanding of the immunopathogenesis of GCA and, to some extent, PMR has advanced. In this review, we summarize the current knowledge on the cellular heterogeneity in the immunopathology of GCA/PMR and discuss how recent advances in specific tissue infiltrating leukocyte and stromal cell profiles may be exploited as a source of novel targets for imaging. Finally, we discuss prospective novel PET radiotracers that may be useful for the diagnosis and treatment monitoring in GCA and PMR.

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Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial

Cited by 66 publications

References 30 publications

New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

New Insights into the Pathogenesis of Giant Cell Arteritis: Mechanisms Involved in Maintaining Vascular Inflammation

Vasculitogenic T Cells in Large Vessel Vasculitis

Novel PET Imaging of Inflammatory Targets and Cells for the Diagnosis and Monitoring of Giant Cell Arteritis and Polymyalgia Rheumatica

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