Higher protein levels may help predict who will develop finger, toe sores by Margarida Maia, PhD | September 3, 2024

Higher circulating levels of a protein called thymic stromal lymphopoietin, or TSLP, may be linked to a greater risk of digital ulcers — sores in the fingers and toes — in people with systemic sclerosis (SSc), also known as scleroderma, a study revealed.

These findings suggest that assessments of TSLP levels could be used to predict which patients may develop these painful sores.

“TSLP is higher in SSc [patients] with recurrent new DUs [digital ulcers],” the team wrote, noting their results showed “a high predictive value.”
​
The study, “Thymic stromal lymphopoietin and digital microvascular damage in systemic sclerosis patients: A pilot study,” was published in the journal Microvascular Research by a team of scientists in Italy.

Early treatment could benefit at-risk patients, researchers say by Margarida Maia, PhD | August 20, 2024

Long-term treatment with Volibris (ambrisentan), marketed as Letairis in the U.S., may help prevent mild pulmonary vascular disease from developing into pulmonary arterial hypertension (PAH) in people with scleroderma, a study suggested.

“Early treatment and close follow-up could be beneficial in this high-risk group,” wrote the researchers from Germany and the U.K., who collaborated on the EDITA Phase 2 study (NCT02290613) and its long-term follow-up, EDITA-ON.

The study, “Effect of ambrisentan in patients with systemic sclerosis and mild pulmonary arterial hypertension: long-term follow-up data from EDITA study,” was published in Arthritis Research & Therapy.
​
Scleroderma, or systemic sclerosis, occurs when the immune system attacks the body’s own healthy tissues, and potentially affects the lungs. This can cause complications such as pulmonary vascular disease, a term for any disease that affects the blood vessels leading to or branching from the lungs.
Patients with pulmonary vascular disease are at risk of developing PAH, which causes high blood pressure in the blood vessels taking blood from the heart to the lungs, making physical activity more difficult.

Therapy particularly effective as add-on treatment by Patricia Inácio, PhD | August 13, 2024

Intravenous immunoglobulin (IVIG) eases skin, muscle and digestive symptoms in people with scleroderma (SSc), particularly when used as an add-on therapy, according to a recent review study.

While no improvements were seen in respiratory function, IVIG still led to stabilization of these symptoms.

The findings “suggest that IVIG may be effective in treating a range of organ-specific manifestations with minimal side effects, thus making it a potentially attractive therapeutic option for SSc,” the researchers wrote.

The review, “Role of intravenous immunoglobulins in systemic sclerosis (SSc): A systematic literature review,” was published in Seminars in Arthritis and Rheumatism.
​
Scleroderma, also called systemic sclerosis, is an autoimmune disease that causes the hardening and fibrosis — thickening or scarring — of the skin. Often, scleroderma also affects internal organs, posing a risk of more severe outcomes.

25% of patients saw side effects months after treatment by Patricia Inácio, PhD | August 6, 2024

Scleroderma patients who have cancer may be treated with radiotherapy without a notable risk of skin and pulmonary worsening, a review study suggests, but around 25% of patients saw severe acute and late toxicities, that is, side effects months after radiation therapy.

As such, “individualized assessment, close collaboration between radiation oncologists and rheumatologists, use of high precision radiotherapy techniques to minimize dose to organs at risk, and vigilant monitoring are key to optimizing the risk-benefit balance,” scientists wrote in the review, “Effects of Radiotherapy for Malignancy in Systemic Sclerosis. A Systematic Review,” in The Journal of Rheumatology.

Studies have shown that having scleroderma increases the risk for developing cancer, especially lung, blood and head and neck cancers.

While radiotherapy is a cornerstone of cancer treatment, its use in scleroderma patients has raised concerns about causing severe skin thickening and localized scleroderma in people without prior disease. In fact, the American College of Radiology considers scleroderma and related disorders as contraindications for treatment to remove an area of cancer from the breast.
​
Evidence in scleroderma is scarce, however, leading researchers from Canada and Saudi Arabia to review 26 studies published across four databases to better understand safety and outcomes of radiotherapy in scleroderma. Half the studies analyzed were case reports and most were from the U.S. The studies were published between 1987 and 2021, and taken together they reported on 121 scleroderma patients treated with radiotherapy. The patients’ mean age was 56.4 and 83.3% were female.

Designation grants developer 7 years market exclusivity if therapy is approved
by Patricia Inácio, PhD | July 23, 2024

The European Medicines Agency (EMA) has granted orphan drug status to FT011, an oral therapy candidate that Certa Therapeutics is developing for systemic sclerosis (SSc).

The U.S. Food and Drug Administration (FDA) awarded the therapy a similar status last year, followed by fast track designation this year.

Orphan drug status is given by both agencies to medicines designed for the treatment of serious or life-threatening rare diseases — those affecting fewer than five in 10,000 people in the European Union or fewer than 200,000 individuals in the U.S. Among its benefits is a period of marketing exclusivity should the therapy be approved; that period is seven years in the U.S. and 10 years in Europe.

“With limited treatment options available for patients with SSc, the EMA orphan drug designation and FDA orphan drug and fast track designations reflect the potential for FT011 to address a critical need for people living with this debilitating and life-threatening condition,” Darren Kelly, PhD, founder and CEO of Certa, said in a company press release.
​
“These are significant validations for the company and highlight the unmet need for novel medicines to reduce inflammation and scarring in chronic fibrotic diseases, which are often progressive and can have a poor prognosis,” Kelly added.

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.
​
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.
​
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.
​
“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.
​
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.

Study finds subclinical issues in 25% of patients using 'more sensitive' tool by Steve Bryson, PhD | June 11, 2024

Problems with the heart’s left ventricle at a subclinical — not yet symptomatic and overt — level were evident in 1 in every 4 people with systemic sclerosis (SSc) taking part in an Australian study when a potentially more sensitive measure than left ventricle ejection fraction was used.

Both symptomatic or asymptomatic left ventricle dysfunction also associated with poorer physical function and survival, data showed.

These findings suggest “an under-appreciated burden of subtle LV [left ventricle] systolic dysfunction in SSc that has a significant impact on patient symptomatology,” the researchers wrote.

The study, “Prognostic and functional importance of both overt and subclinical left ventricular systolic dysfunction in systemic sclerosis,” was published in the journal Seminars in Arthritis and Rheumatism.

Left ventricle ejection fraction measures were normal in most study patients
SSc, also known as scleroderma, is marked by the abnormal buildup of scar tissue (fibrosis) in the skin and, potentially, other organs like the lungs, kidneys, heart, and those of the digestive system.

Heart involvement can be life-threatening in SSc, and advanced imaging techniques have shown scar tissue formation in heart muscle in up to 90% of patients without symptoms, the researchers noted. Asymptomatic myocarditis, or inflammation of the heart muscle, may also occur.

Despite these abnormalities, little is known about scleroderma-related dysfunction of the left ventricle, the side of the heart that pumps oxygenated blood throughout the body.

To address this gap, scientists across Australia collaborated to investigate the frequency of reduced left ventricle function in SSc.

A total of 1,141 patients were recruited from the Australian Scleroderma Cohort Study, a multicenter and observational disease study. All had at least one measure taken of left ventricle ejection fraction (LVEF), the percentage of blood pumped from the left ventricle with each heartbeat. Patients with a history of secondary or non-SSc causes of left ventricle dysfunction were excluded.

Nearly all participants (97.6 %) had a consistently normal LVEF of at least 50%, while 27 (2.4 %) had an LVEF of less than 50% at least once. Seven of them (0.6 %) had an LVEF of less than 40%.

Those with an LVEF of less than 50% were more likely to be male, to have diffuse cutaneous SSc, a larger left atria (the top left heart chamber), higher peak blood pressure in the right ventricle, and more frequent right ventricular dysfunction.
​
These 27 patients also were more likely to have higher levels of inflammatory markers and to more often use medicines for heart-related issues and immunosuppression. Diseases that affected skeletal muscle, those attached to bones, also were more frequent in patients with an LVEF of less than 50%.