SCOT trial studied potential benefits over high-dose Cytoxan by Andrea Lobo, PhD | July 16, 2024

Patients with systemic sclerosis (SSc) who have a stem cell transplant see normalized gene activity related to immune function up to 4.5 years after the procedure.

That’s according to recent data from samples in the Phase 2/3 SCOT trial (NCT00114530), wherein the potential benefits of a stem cell transplant were compared with those of high-dose Cytoxan (cyclophosphamide) in severe SSc.
“The normalization of the SSc [molecular] signature … parallels the clinical benefits of [stem cell transplant] at this time point and provides support for these disease-related pathways as therapeutic targets,” the researchers wrote in “Myeloablation Followed by Hematopoietic Stem Cell Transplantation and Long-Term Normalization of Systemic Sclerosis Molecular Signatures,” which was published in Arthritis & Rheumatology.

SSc, or scleroderma, is an autoimmune disease where scar tissue (fibrosis) accumulates in the skin and possibly in the organs, such as the lungs, heart, or kidneys.
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Transplanting hematopoietic stem cells (HSC), which are precursors to all types of blood cells, has been investigated as a way to reset the immune system in people with SSc.

Ferroptosis, natural block on uncontrolled cell growth, seen to be suppressed by Lindsey Shapiro, PhD | July 9, 2024

Ferroptosis, a cell death process that can help to regulate uncontrolled cell growth, was suppressed in skin cells from people with systemic sclerosis (SSc), according to recent research.

Such suppression appears to be mediated by increased activity of an antioxidant protein called GPX4.

Researchers believe that targeting GPX4 to increase ferroptosis could offer a way of preventing the uncontrolled cell growth that drives scar tissue buildup, or fibrosis, in the skin of SSc patients.

The study, “Upregulation of GPX4 drives ferroptosis resistance in scleroderma skin fibroblasts,” was published in Free Radical Biology and Medicine.

Skin fibrosis in SSc tied to excess of fibroblasts and collagen
SSc, also known as scleroderma, is an autoimmune disease wherein scar tissue accumulates in the skin and, in another disease type, in internal organs as well. Skin fibrosis is caused by the rapid and uncontrolled growth, or proliferation, of cells called fibroblasts and excessive production of collagen, a connective tissue protein.

However, it is not clear what initially drives these processes, and current disease treatments aim to manage symptoms associated with scleroderma. No available therapies are specifically designed to target fibrosis in SSc, the study’s researchers stated.

Programmed cell death refers to types of cell death that occur naturally and serve important biological functions. Ferroptosis is one form of programmed cell death that’s believed to help prevent the excessive cell growth that characterizes cancer.

In ferroptosis, iron triggers the overproduction of toxic reactive oxygen species (ROS) molecules. This leads to a state of oxidative stress, an imbalance between ROS and the antioxidant molecules that counterbalance them, which ultimately drives cell death. As such, antioxidants can regulate ferroptosis.
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This form of programmed cell death has been identified as a possible therapeutic target in SSc, but the exact relationship remains to be thoroughly investigated.

Updates shared at 2024 EULAR Congress may help 'better manage' SSc care by Marisa Wexler, MS | June 25, 2024

Treatment with Letairis (ambrisentan) — approved to treat pulmonary arterial hypertension (PAH), a common complication of systemic sclerosis (SSc) — may help prevent the development of PAH, or high blood pressure in the arteries of the lungs, in people with SSc.

That’s according to new data from SSc patients who completed the Phase 2 EDITA clinical trial (NCT02290613), which tested Letairis against a placebo, and who then continued their assigned regimen over a longer period.

These results, along with positive data from the Phase 2 AST-MOMA trial (NCT01895244) — which evaluated a reduced-toxicity regimen of stem cell transplant in SSc patients — were presented at the 2024 European Alliance of Associations for Rheumatology (EULAR) Congress, held earlier this month in Vienna.
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“Taken together, these new findings could have an important bearing on the current standard of care for patients with SSc,” the alliance stated in a press release. Overall, EULAR stated that “new, strong evidence is now available to help better manage patients with this life-threatening condition,” noting, however, that “gaps remain.”

Therapy is designed to block PAI-1, a mediator of inflammation, fibrosis by Patricia Inácio, PhD | June 18, 2024

The first healthy volunteers have been dosed in a Phase 1 clinical study that’s evaluating MDI-2517, a small molecule candidate to treat scleroderma and interstitial lung disease (ILD), which occurs when the lungs become scarred.

According to developers MDI Therapeutics, MDI-2517 is a potent blocker of plasminogen activator inhibitor-1 (PAI-1), a protein and key mediator of inflammation and fibrosis, or tissue scarring and thickening.
“Based on comprehensive preclinical studies, this first in-human study of MDI-2517 will inform continued development of our novel, proprietary compound for the potential treatment of systemic sclerosis and interstitial lung disease, conditions where disability is significant and survival rates are poor,” Mark Weinberg, MD, chief medical officer at MDI Therapeutics, said in a company press release.
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In scleroderma, a self-reactive immune system causes fibrosis in the skin and possibly in internal organs, including the heart, kidney, lungs, and digestive tract. The disease is thought to develop due to a combination of genetic and environmental factors, resulting in the attack of body tissues by so-called autoantibodies.