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

Abstract

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.

Targeting cytokines and potentiality of JAK–STAT inhibition in systemic sclerosis

“…Tofacitinib diminishes skin and lung fibrosis in BLM‐induced SSc by inhibiting proinflammatory cytokine production from T and B cells and promoting regulatory balance 21 . In a murine BLM‐induced SSc model, tofacitinib reportedly reduces dermal fibrosis by reducing TGF‐β and IL‐17 levels 72 . Hence, a phase I/II study of tofacitinib in patients with diffuse cutaneous SSc is currently ongoing.…”

Local and Sustained Baricitinib Delivery to the Skin through Injectable Hydrogels Containing Reversible Thioimidate Adducts

“…[ 1 ] To date, several small molecule inhibitors of JAK‐STAT signaling have been FDA approved and are highly effective in dermatology, including in atopic dermatitis (e.g., ruxolitinib, abrocitinib, upadacitinib), vitiligo (ruxolitinib), alopecia areata (e.g., ritlecitinib, baricitinib), and psoriasis/psoriatic arthritis (e.g., deucravacitinib, tofacitinib), while many others are currently under investigation for other dermatologic diseases. [ 2–5 ] Despite their broad clinical efficacy in dermatology, systemic use of JAK inhibitors is associated with serious risks of infections, major adverse cardiovascular events, thromboses, malignancy, and death leading to a black box warning for all FDA approved JAK inhibitors. [ 6,7 ] Due to the risks, medical professionals and patients must exercise caution in their use while patients at high risk for cardiovascular events and malignancy are excluded altogether.…”