Stem cell transplant normalizes scleroderma gene activity: Study

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.

​Comparing stem cell transplant, CytoxanIn
SCOT, 75 adults, ages 18-69, with severe SSc and extensive skin and internal organ involvement, were randomly assigned to an autologous stem cell transplant or to one year of monthly Cytoxan infusions. An autologous transplant involves collecting healthy bone marrow stem cells from a patient, who is then treated with a conditioning regimen to wipe out the rest of their stem cells before the collected ones are reintroduced surgically.

Data from SCOT previously showed stem cell transplants significantly increased patient survival over Cytoxan. After 11 years, the estimated survival was 80% for those who had the transplant and 52% for those on Cytoxan.
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Before treatment, that is, the baseline, patients had a higher activity of interferon and neutrophil-related genes, and decreased activity of cytotoxic/natural killer (NK)-related genes, compared with healthy people. Interferons are proteins that form part of the body’s natural defenses, while neutrophils are immune cells involved in scarring that release certain molecules to control the immune response. NK cells detect and eliminate infected cells and cancer cells. 

After 26 months, or slightly more than two years, the gene activity changes normalized for those who had the transplant.

Here, two later time points are reported — at 38 months, or more than three years, with data from 19 transplanted and 11 Cytoxan-treated patients, and at 54 months, or 4.5 years, with data from 16 transplanted and 11 Cytoxan-treated participants.

Compared with the baseline, there was lower activity in interferon genes and higher activity of NK-related genes at both time points in the transplant patients, “indicating a long-term normalization of baseline SSc gene expression signature,” the investigators wrote. No such effects were seen with Cytoxan.

After 38 months, the transplant group had more activity of genes related to B-cells, which are immune cells that produce antibodies, and a downregulation of genes related to myeloid cells, which are white blood cells, and inflammation, over healthy participants.

After 54 months, there were no difference in gene activity between the stem cell transplant group and healthy people, suggesting a complete “reconstitution” of the immune system. Those treated with Cytoxan had stable gene activity and continued to have the SSc gene expression signature.
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“We show [stem cell transplant] can normalize the SSc immune dysregulation on a long-term basis. These findings parallel the observed long-term clinical benefits of this treatment modality,” wrote the researchers, who said the data contribute to evidence that hematopoietic stem cell transplant may be an effective disease-modifying option for severe SSc.