Anti-inflammatory medicine eases fibrosis in cell, animal disease models
Iguratimod approved to treat rheumatoid arthritis in China and Japan
Treatment with iguratimod, an anti-inflammatory medication, reduced fibrosis (scarring) in cell and mouse models of scleroderma, a study from China reports.
An approved therapy in that country, “iguratimod is a promising disease-modifying drug with an anti-fibrotic effect,” the researchers wrote.
“It is reasonable to further investigate the efficacy of iguratimod for [systemic sclerosis] in the context of clinical practice, as well as other autoimmune diseases with fibrotic complications,” they added.
The study, “Iguratimod attenuated fibrosis in systemic sclerosis via targeting early growth response 1 expression,” was published in Arthritis Research & Therapy.Â
Early scleroderma research into possibly repurposing an approved treatment
Scleroderma is characterized by uncontrolled fibrosis or scarring that usually affects the skin, and it also can affect organs throughout the body.
Iguratimod is an anti-rheumatic disease-modifying drug that is approved in China and Japan to treat rheumatoid arthritis, a form of arthritis mainly characterized by inflammation in the joints. This therapy works by blocking the activity of a protein called EGR1 (early growth response 1).
EGR1 is a transcription factor — a protein that modulates the activity of genes inside cells. EGR1 is known to be important for pathways related to inflammation and fibrosis.
Scientists in Shanghai, alongside a collaborator in the U.S., evaluated fibroblasts (a type of skin cell involved in fibrosis) from people with or without scleroderma. They found that cells from patients with diffuse cutaneous scleroderma express high levels of EGR1. Specifically, EGR1 was preferentially found in cells not implicated in the immune response.
The team also showed that when fibroblasts are treated with TGF-beta — a signaling molecule known to promote fibrosis — EGR1 activity changes, which altered the activity of 327 other genes inside the cells.
These findings implied that treatment with an EGR1 inhibitor like iguratimod might help to reduce fibrotic activity in these cells. Indeed, the researchers found that iguratimod’s use led to a decrease in EGR1 activity and neutralized the effects of TGF-beta on 232 out of the 327 genes, ultimate reducing markers of fibrosis in the cells.
“Our study shows that iguratimod is an agent with the dual effect of anti-fibrotic and immune regulation,” the researchers wrote.
Skin thickness eases in mice treated for three weeks orally or topically
Iguratimod’s effects then were tested in a mouse model of scleroderma where fibrosis was induced by treating the mice with bleomycin, a chemical that triggers scarring. Three weeks of treatment with oral or topical iguratimod was seen to reduce skin thickness in mice with fibrosis, with no observed side effects. The proportions of fibroblasts containing EGR1 and TGF-beta fell with treatment.
Less skin thickening with iguratimod also was found in a different mouse model, in which scleroderma develops spontaneously.
The scientists next used a model where skin grafts from patients with early-stage scleroderma were implanted onto mice. None of these patients had been treated with immunosuppressants, anti-fibrotic medications, or steroids.
Consistent with the other cell and mouse experiments, findings in this model indicated that iguratimod reduced fibrosis in scleroderma skin. As in mice, researchers found a decrease in fibroblasts containing EGR1 and TGF-beta.
Collectively these data support iguratimod — and targeting EGR1 more broadly — as a potential way of treating scleroderma, the scientists said.
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