Tofacitinib as a possible treatment for skin thickening in diffuse cutaneous systemic sclerosis

You, Hanxiao; Xu, Dong; Hou, Yong; Zhou, Jiaxin; Wang, Qian; Li, Mengtao; Zeng, Xiaofeng

doi:10.1093/rheumatology/keaa613

Cited by 28 publications

(31 citation statements)

References 19 publications

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“…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 . In another study conducted with a small number of patients, it was found that the modified Rodnan skin score (mRSS) decreased more than cyclophosphamide and mycophenolate mofetil in the 1st and 6th months after TOFA treatment in patients with diffuse SSc 31 . However, no significant improvement was observed in mRSS with TOFA treatment in patients with diffuse SSc in phase I/II placebo-controlled study (NCT0327407).…”

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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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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“…Whether they affect the esophageal smooth muscle in patients with SSc with esophageal dyskinesia should be investigated. Regarding internal fibrosis deposition, Janus kinase (JAK) inhibitors (e.g., torvatinib) that target the pro-fibrosis and pro-inflammatory pathways in macrophages have been proven to prevent the upregulation of some pro-inflammatory markers and pro-fibrotic markers at the molecular level [ 78 ]. Applications can reduce the occurrence of fibrosis and change the related symptoms [ 79 ].…”

Section: Existing Treatment Methods and 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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“…A prospective case series compared 10 patients with dcSSc treated with tofacitinib 5 mg twice daily to 12 dcSSc patients with similarly matched disease severity and features on various conventional therapies 28 . The authors found that 9/10 patients on tofacitinib had improvement with reduction of skin thickness, with 8/10 achieving the goal of a reduction in mRSS by >5 points and a greater than 25% improvement from baseline.…”

Section: Preclinical Studies Of Jak Inhibitors In Morphea and Sscmentioning

confidence: 99%

Janus kinase inhibitors for treatment of morphea and systemic sclerosis: A literature review

Kallis

Benedetto

Thomas

2022

Dermatologic Therapy

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Morphea and systemic sclerosis (SSc) are rare disorders of connective tissue characterized by increased skin thickness and fibrosis, with current treatment options having variable efficacies, many with limited therapeutic benefit. Janus kinase (JAK) inhibitors have been shown in preclinical studies to inhibit the fibrotic pathway in murine models of systemic sclerosis, by blocking TGF-beta mediated pathway of STAT protein activation. Additionally, case reports of the treatment of morphea and SSc with tofacitinib, a JAK 1/3 inhibitor, have shown improvement in skin sclerosis. Several JAK inhibitors have been developed and utilized in dermatologic and rheumatologic diseases. To date, tofacitinib has been by far the most commonly trialed JAK inhibitor in patients with SSc and morphea. Herein we review the preclinical studies reported in the literature supporting the use and efficacy of JAK inhibitors for the treatment of morphea and the cutaneous manifestations of SSc, as well as discuss the clinical cases published to date illustrating the benefits of JAK inhibitors in disease management. The pathogenesis and mechanism of action will be reviewed as it relates to the process of skin fibrosis in morphea and SSc, along with the murine models illustrating efficacy of JAK inhibitors in fibrotic disease. Based on available preclinical and clinical data as well as consideration of the mechanism of action of JAK inhibitors on the pathway for cutaneous fibrosis, there is promising evidence to support the use and further study of JAK inhibitors in the management of morphea and cutaneous fibrosis in SSc.

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Tofacitinib as a possible treatment for skin thickening in diffuse cutaneous systemic sclerosis

Cited by 28 publications

References 19 publications

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

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

Esophageal Dysfunction in Systemic Sclerosis: An Update

Janus kinase inhibitors for treatment of morphea and systemic sclerosis: A literature review

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