Tofacitinib rapidly ameliorated polyarthropathy in a patient with systemic sclerosis

In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.

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“…Other disorders of the skin in which jakinibs are being tried include: systemic sclerosis, vitiligo, and actinic dermatitis …”

Section: A Brief Survey Of Approved and Late Phase Jakinibsmentioning

confidence: 99%

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

129

100

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“…In another experimental study, the TOFA treatment was shown to improve fibrosis in skin and lung tissue by reducing T lymphocyte, CD4 + T lymphocyte levels that produce IL-13 and IL-17, B lymphocyte levels that produce IL-6, profibrotic macrophage levels and collagen synthesis 24 . Interestingly, Komai et al reported that the modified Rodnan skin score (mRSS) rapidly improved on the 4th day with TOFA treatment in patients with SSc 29 . In their study on patients with SSc, Karaliova et al found a 12.8% decrease in skin thickness with TOFA treatment compared to baseline at the 26th week 30 .…”

Section: Discussionmentioning

confidence: 99%

Tofacitinib and metformin reduce the dermal thickness and fibrosis in mouse model of systemic sclerosis

Karataş

Öz²,

Çelik

et al. 2022

Sci Rep

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Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is important in the process of inflammation and fibrosis. The adenosine 5′-monophosphate-activated protein kinase (AMPK) enzyme can affect JAK/STAT pathway. Tofacitinib is a pan-JAK inhibitör. Metformin activates AMPK enzyme. We aimed to investigate the therapeutic efficacy of tofacitinib and metformin on IL-17 and TGF-β cytokines, skin fibrosis and inflammation in mouse model of systemic sclerosis (SSc). 40 Balb/c female mice were divided into 4 groups: (control, sham (BLM), tofacitinib and metformin). The mice in the tofacitinib group received oral tofacitinib (20 mg/kg/daily) and mice in the metformin group received oral metformin (50 mg/kg/day) for 28 days. At the end of 4th week, all groups of mice were decapitated and tissue samples were taken for analysis. Histopathological analysis of skin tissue was performed, and mRNA expressions of collagen 3A, IL-17 and TGF-β were assessed by real-time PCR and ELISA. Repeated BLM injections had induced dermal fibrosis. Moreover, the tissue levels of collagen 3A, IL-17 and TGF-β were elevated in the BLM group. Tofacitinib and metformin mitigated dermal fibrosis. They reduced dermal thickness and tissue collagen 3A, IL-17 and TGF-β levels. Tofacitinib and metformin demonstrated anti-inflammatory and anti-fibrotic effects in the mouse model of SSc.

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“…Applications can reduce the occurrence of fibrosis and change the related symptoms [ 79 ]. At present, there are only a few related studies and these are limited to the external body and the skin and joint level [ 80 ].…”

Section: Existing Treatment Methods and Potential Therapeutic Targetsmentioning

confidence: 99%

“…Targeting vascular injury Statins have been used in patients with SSc because statins can significantly regulate the blood-vessel wall [66] and they reduce the levels of inflammatory cytokines and increase circulating endothelial precursors in a dose-dependent manner [66][67][68]. Statins have been shown to improve Raynaud's phenomenon in some clinical trials, leading us to speculate that they could improve Being studied in patients with skin and joint involvement [80] Tocritizumab Anti-IL-6 d receptor antibody Ability to affect fibroblasts early [81][82][83] Belimumab/ Rituximab Specific inhibitor of B lymphocyte stimulating factor Improvement of fibrosis and microcirculation [84][85][86] Abaproxil Prevent T lymphocyte activation Improvement of the skin thickness of patients [87] a The RhoA/Rho kinase pathway is an important pathway in many cell functions and is related to oxidative stress and vascular damage b PDGF (platelet-derived growth factor) promotes the chemotaxis of fibroblasts in tissue repair and is associated with pathological fibrosis c c-Abl (cellular Abelson) is ,a non-receptor tyrosine kinase d IL-6 (interleukin 6) is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine esophageal vascular damage [68,69]. a2-Adrenergic receptors and the RhoA/Rho kinase pathway are potential therapeutic targets.…”

Section: Potential Therapeutic Targetsmentioning

confidence: 99%

Esophageal Dysfunction in Systemic Sclerosis: An Update

Yan

et al. 2021

Rheumatol Ther

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Esophageal motility disorders are prevalent in 90% of patients with systemic sclerosis [scleroderma (SSc)], with an increased mortality rate in patients with severe esophageal involvement. Esophageal smooth muscle damage caused by ischemia, nerve damage, and inflammatory factors may be responsible for discomfort and various complications in these patients. The clinical manifestations are diverse. Most hospitals still use traditional esophageal manometry and 24-h pH monitoring to diagnose esophageal function in patients with SSc. The aim of this review article is to provide an overview of SSc-related esophageal motility disorders and related research progress, including the pathogenesis and clinical features of these disorders and the progress made in endoscopic diagnosis. We also discuss the possible pathogenesis and potential therapeutic targets.

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Tofacitinib rapidly ameliorated polyarthropathy in a patient with systemic sclerosis

Cited by 20 publications

References 7 publications

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Tofacitinib and metformin reduce the dermal thickness and fibrosis in mouse model of systemic sclerosis

Esophageal Dysfunction in Systemic Sclerosis: An Update

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