Successful remission with tofacitinib in a patient with refractory Takayasu arteritis complicated by ulcerative colitis

Kuwabara, Saki; Tanimura, Shun; Matsumoto, Shogo; Nakamura, Hiroyuki; Horita, Tetsuya

doi:10.1136/annrheumdis-2019-216606

Cited by 44 publications

(28 citation statements)

References 5 publications

(5 reference statements)

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“…Treatment of two TAK patients with a JAK-STAT inhibitor resulted in a measurable decreased of Th1 and Th17 cell frequencies (17), supporting the premise that T cells activation in TAK is ultimately controlled by cytokines and growths factors utilizing the JAK-STAT pathway. This conclusion is supported by a series of case reports showing the efficacy of JAK inhibitors in refractory TAK patients (146,147). These studies suggest a potential role of JAK-STAT pathway blockade as a promising approach to dampen disease activity in TAK (148).…”

Section: Cd4 + Effector T Cellmentioning

confidence: 71%

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis

et al. 2020

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Autoimmune and autoinflammatory diseases of the medium and large arteries, including the aorta, cause life-threatening complications due to vessel wall destruction but also by wall remodeling, such as the formation of wall-penetrating microvessels and lumenstenosing neointima. The two most frequent large vessel vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are HLA-associated diseases, strongly suggestive for a critical role of T cells and antigen recognition in disease pathogenesis. Recent studies have revealed a growing spectrum of effector functions through which T cells participate in the immunopathology of GCA and TAK; causing the disease-specific patterning of pathology and clinical outcome. Core pathogenic features of disease-relevant T cells rely on the interaction with endothelial cells, dendritic cells and macrophages and lead to vessel wall invasion, formation of tissue-damaging granulomatous infiltrates and induction of the name-giving multinucleated giant cells. Besides antigen, pathogenic T cells encounter danger signals in their immediate microenvironment that they translate into disease-relevant effector functions. Decisive signaling pathways, such as the AKT pathway, the NOTCH pathway, and the JAK/STAT pathway modify antigen-induced T cell activation and emerge as promising therapeutic targets to halt disease progression and, eventually, reset the immune system to reestablish the immune privilege of the arterial wall.

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Section: Cd4 + Effector T Cellmentioning

confidence: 71%

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis

et al. 2020

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“…Interestingly, tofacitinib appears to be particularly effective in TKA complicated by UC. This may be related to a different underlying genetic background of these subjects (Terao et al, 2015;Abdolahi et al, 2020;Kuwabara et al, 2020;Palermo et al, 2020;Régnier et al, 2020;Sato et al, 2020;Watanabe, 2020;Yamamura et al, 2020).…”

Section: Clinical Evidencementioning

confidence: 99%

“…However, a poor response on gastrointestinal involvement has been observed. Although a clear explanation of this phenomenon is still lacking, it may be important to consider the similarity of BD gastrointestinal involvement with Crohn's disease, in which JAK inhibition is likely not effective (Abdi et al, 2018;Kuwabara et al, 2020;Liu et al, 2020;Sato et al, 2020).…”

Section: Clinical Evidencementioning

confidence: 99%

Contribution of Janus-Kinase/Signal Transduction Activator of Transcription Pathway in the Pathogenesis of Vasculitis: A Possible Treatment Target in the Upcoming Future

et al. 2021

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Janus-kinase (JAK) and signal transduction activator of transcription (STAT) signal transduction pathway is involved in a wide range of physiological and pathological processes, including in the pathogenesis of several autoimmune diseases. Data supporting the role of JAK/STAT in the development of vasculitis are limited and mostly focused on large vessel vasculitis and Behçet’s disease. In this review, we provide a thorough picture of currently available evidence on the topic, gathered from in vitro experiments, animal models and human real-life data, analyzing the rationale for the use of JAK inhibitors for the management of vasculitis. Overall, despite a very strong biological and pathogenic basis, data are too few to recommend this therapeutic approach, beyond very severe and refractory forms of vasculitis. However, for the same reasons, a strong scientific effort in this direction is indeed worthwhile.

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“…Unexpectedly, interfering with JAK-STAT signaling was highly successful in interrupting both intimal hyperplasia and wall capillarization in the human artery -SCID chimera model ( 77 ). Recently reports suggest that tofacitinib may have a place in managing patients with refractory Takayasu arteritis ( 108 ). These data support the concept that autoimmunity in the wall of large arteries relies disproportionally on JAK-STAT signaling and that therapeutic opportunities lie in dampening excessive activity in these fundamental signaling pathways.…”

Section: From Bench To Bedside: Potential Therapeutic Targets In Gcamentioning

confidence: 99%

Innate and Adaptive Immunity in Giant Cell Arteritis

et al. 2021

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Autoimmune diseases can afflict every organ system, including blood vessels that are critically important for host survival. The most frequent autoimmune vasculitis is giant cell arteritis (GCA), which causes aggressive wall inflammation in medium and large arteries and results in vaso-occlusive wall remodeling. GCA shares with other autoimmune diseases that it occurs in genetically predisposed individuals, that females are at higher risk, and that environmental triggers are suspected to beget the loss of immunological tolerance. GCA has features that distinguish it from other autoimmune diseases and predict the need for tailored diagnostic and therapeutic approaches. At the core of GCA pathology are CD4+ T cells that gain access to the protected tissue niche of the vessel wall, differentiate into cytokine producers, attain tissue residency, and enforce macrophages differentiation into tissue-destructive effector cells. Several signaling pathways have been implicated in initiating and sustaining pathogenic CD4+ T cell function, including the NOTCH1-Jagged1 pathway, the CD28 co-stimulatory pathway, the PD-1/PD-L1 co-inhibitory pathway, and the JAK/STAT signaling pathway. Inadequacy of mechanisms that normally dampen immune responses, such as defective expression of the PD-L1 ligand and malfunction of immunosuppressive CD8+ T regulatory cells are a common theme in GCA immunopathology. Recent studies are providing a string of novel mechanisms that will permit more precise pathogenic modeling and therapeutic targeting in GCA and will fundamentally inform how abnormal immune responses in blood vessels lead to disease.

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Successful remission with tofacitinib in a patient with refractory Takayasu arteritis complicated by ulcerative colitis

Cited by 44 publications

References 5 publications

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis

Contribution of Janus-Kinase/Signal Transduction Activator of Transcription Pathway in the Pathogenesis of Vasculitis: A Possible Treatment Target in the Upcoming Future

Innate and Adaptive Immunity in Giant Cell Arteritis

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