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.
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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.
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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.
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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.

Analysis IDs over 1,000 genes with different expression vs. controls 
by Patricia Inácio, PhD | July 30, 2024

Cells present along the walls of small blood vessels in the lungs, called pericytes, have distinct gene activity in people with systemic sclerosis (SSc)-associated pulmonary fibrosis (PF), according to a new study.

Pericytes from SSc patients showed an increased expression, or activity, of genes involved in lung fibrosis (scarring), blood vessel formation, and extracellular matrix organization. The extracellular matrix is a network of molecules that maintain cell structure.

The study, “Transcriptomic characterization of lung pericytes in systemic sclerosis-associated pulmonary fibrosis,” was published in the journal iScience.
Pulmonary fibrosis is a type of interstitial lung disease, a group of disorders marked by inflammation and fibrosis. SSc-associated PF is the leading cause of death in SSc patients.

Pericytes are key cells for the maintenance of blood vessels in the lungs. These cells establish communication routes with other cells types, via a direct interaction or the release of growth factors.
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However, the role of pericytes in SSc-PF is still far from understood. Studies have suggested that they may contribute to the transition of fibroblasts into myofibroblasts, a normal process in wound healing. However, the persistent presence of myofibroblasts is key in driving tissue fibrosis.

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.
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“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.
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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.

The self-reactive antibodies are an indicator of Sjögren’s syndrome by Patricia Inácio, PhD | May 21, 2024

Anti-SSA self-reactive antibodies, a hallmark of Sjögren’s syndrome, are associated with a higher risk of organ involvement in people with scleroderma, including the lungs and skin, a study in Japan shows.
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The findings suggest “anti-SSA may be a valuable biomarker of organ involvement and skin severity in patients with SSc [systemic sclerosis, also called scleroderma],” wrote the researchers, who said “periodic screening for these involvements should be recommended in patients with SSc” who are positive for such antibodies.

The study, “Clinical features of patients with systemic sclerosis positive for anti-SS-A antibody: a cohort study of 156 patients,” was published in Arthritis Research and Therapy.

Sjögren’s syndrome is a chronic inflammatory autoimmune disease wherein a misdirected immune attack affects the glands that produce tears and saliva. It’s called primary Sjögren’s syndrome when it appears as an isolated illness and secondary when it follows another autoimmune disease.

Anti-SSA antibodies are a diagnostic marker of Sjögren’s syndrome and are often detected in people with SSc. In fact, studies report that up to 24% of SSc patients have Sjögren’s syndrome.

While SSc patients may have anti-SSA antibodies, but not symptoms of Sjögren’s syndrome, “few studies have focused on patients with anti-SSA-positive SSc, and the clinical significance of this presentation is not fully understood,” wrote researchers in Japan who analyzed data from 156 patients with SSc who were followed at the Yokohama City University Hospital between 2018-2021.
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The patients were mostly (88.5%) women, were a median age of 69 and a mean disease duration of 13.3 years. As for SSc subtypes, most (75%) had limited cutaneous SSc and 25% had diffuse cutaneous SSc.