A systematic review of clinical and preclinical evidences for Janus kinase inhibitors in large vessel vasculitis

Rathore, Upendra; Thakare, D.; Patro, Pallavi; Agarwal, Vikas; Sharma, Aman; Misra, Durga Prasanna

doi:10.1007/s10067-021-05973-4

Cited by 26 publications

(15 citation statements)

References 50 publications

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“…Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibition with tofacitinib (JAK1/Janus kinase 3 (JAK3) inhibitor) in patients with refractory Takayasu arteritis have shown promise in several case reports and small series 20–25. A preclinical vascular inflammation model has demonstrated that JAK inhibition with tofacitinib suppressed innate and adaptive immunity in the arterial wall, particularly through suppression of tissue-resident memory T cells, and additionally further reduced inflammation by inhibition of vasculogenic effector pathways 26.…”

Section: Introductionmentioning

confidence: 99%

Baricitinib for relapsing giant cell arteritis: a prospective open-label 52-week pilot study

et al. 2022

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Background/purposePreclinical vascular inflammation models have demonstrated effective suppression of arterial wall lesional T cells through inhibition of Janus kinase 3 and JAK1. However, JAK inhibition in patients with giant cell arteritis (GCA) has not been prospectively investigated.MethodsWe performed a prospective, open-label, pilot study of baricitinib (4 mg/day) with a tiered glucocorticoid (GC) entry and accelerated taper in patients with relapsing GCA.Results15 patients were enrolled (11, 73% female) with a mean age at entry of 72.4 (SD 7.2) years, median duration of GCA of 9 (IQR 7–21) months and median of 1 (1–2) prior relapse. Four (27%) patients entered the study on prednisone 30 mg/day, 6 (40%) at 20 mg/day and 5 (33%) at 10 mg/day. Fourteen patients completed 52 weeks of baricitinib. At week 52, 14/15 (93%) patients had ≥1 adverse event (AE) with the most frequent events, including infection not requiring antibiotics (n=8), infection requiring antibiotics (n=5), nausea (n=6), leg swelling (n=2), fatigue (n=2) and diarrhoea (n=1). One subject required baricitinib discontinuation due to AE. One serious adverse event was recorded. Only 1 of 14 (7%) patients relapsed during the study. The remaining 13 patients achieved steroid discontinuation and remained in disease remission during the 52-week study duration.ConclusionIn this proof-of-concept study, baricitinib at 4 mg/day was well tolerated and discontinuation of GC was allowed in most patients with relapsing GCA. Larger randomised clinical trials are needed to determine the utility of JAK inhibition in GCA.Trial registration numberNCT03026504.

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Section: Introductionmentioning

confidence: 99%

Baricitinib for relapsing giant cell arteritis: a prospective open-label 52-week pilot study

et al. 2022

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“…The third one is selective blockade of SASP ( Ovadya and Krizhanovsky, 2018 ). Among those therapies, inhibitors of JAK-STAT pathway are not only expected to be effective against cellular senescence by suppressing excessive cytokine signaling, but also expected for treating GCA ( Zhang et al, 2018 ; Rathore et al, 2022 ; Vieira et al, 2022 ). In addition, recent research has shown that the complement C3a receptor, expressed on ECs, promotes dysfunction of blood brain barrier as well as vascular inflammation during aging, leading to neurodegenerative disease ( Propson et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Aging-Related Vascular Inflammation: Giant Cell Arteritis and Neurological Disorders

Watanabe¹,

Hashimoto²

2022

Front. Aging Neurosci.

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Aging is characterized by the functional decline of the immune system and constitutes the primary risk factor for infectious diseases, cardiovascular disorders, cancer, and neurodegenerative disorders. Blood vessels are immune-privileged sites and consist of endothelial cells, vascular smooth muscle cells, macrophages, dendritic cells, fibroblasts, and pericytes, among others. Aging also termed senescence inevitably affects blood vessels, making them vulnerable to inflammation. Atherosclerosis causes low-grade inflammation from the endothelial side; whereas giant cell arteritis (GCA) causes intense inflammation from the adventitial side. GCA is the most common autoimmune vasculitis in the elderly characterized by the formation of granulomas composed of T cells and macrophages in medium- and large-sized vessels. Recent studies explored the pathophysiology of GCA at unprecedented resolutions, and shed new light on cellular signaling pathways and metabolic fitness in wall-destructive T cells and macrophages. Moreover, recent reports have revealed that not only can cerebrovascular disorders, such as stroke and ischemic optic neuropathy, be initial or coexistent manifestations of GCA, but the same is true for dementia and neurodegenerative disorders. In this review, we first outline how aging affects vascular homeostasis. Subsequently, we review the updated pathophysiology of GCA and explain the similarities and differences between vascular aging and GCA. Then, we introduce the possible link between T cell aging, neurological aging, and GCA. Finally, we discuss therapeutic strategies targeting both senescence and vascular inflammation.

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“…This observation indicates IL-17 as a promising target for precision medicine in LVV therapy, as it is potentially suppressed by JAK inhibitors. A systematic review reported that current evidence regarding the use of JAK inhibitors in LVV is derived mostly from case reports of moderate quality (38). However, a recent transcriptomic study demonstrates a clear type I interferon signature upregulation in aortas of 43 patients with active large-vessel GCA (LV-GCA).…”

Section: Therapy Of Lvvmentioning

confidence: 99%

Systemic vasculitis: one year in review 2023

Moretti

Treppo

Monti

et al. 2023

Clinical and Experimental Rheumatology

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Systemic vasculitides are heterogeneous disabling diseases characterised by chronic inflammation of the blood vessels potentially leading to tissue destruction and organ failure. The recent COVID-19 pandemic has had a significant impact on the epidemiology and management of patients with systemic vasculitis. In parallel, new insights have been provided on systemic vasculitis pathogenetic mechanisms, possible new therapeutic targets, and newer glucocorticoid-sparing treatments with better safety profiles. As in the previous annual reviews of this series, in this review we will provide a critical digest of the most recent literature regarding pathophysiology, clinical manifestations, diagnostic tools and treatment options in smalland large-vessel vasculitis focusing on precision medicine in vasculitis.

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A systematic review of clinical and preclinical evidences for Janus kinase inhibitors in large vessel vasculitis

Cited by 26 publications

References 50 publications

Baricitinib for relapsing giant cell arteritis: a prospective open-label 52-week pilot study

Baricitinib for relapsing giant cell arteritis: a prospective open-label 52-week pilot study

Aging-Related Vascular Inflammation: Giant Cell Arteritis and Neurological Disorders

Systemic vasculitis: one year in review 2023

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