New skin markers help doctors refine dcSSc treatment prognosis

Analysis: Protein markers and disease duration strongly predict MMF response
by Margarida Maia, PhD | October 14, 2025

In people with diffuse cutaneous systemic sclerosis (dcSSc), certain skin features, including levels of specific molecules and cells, depend on disease duration, a study finds.

These features, combined with disease duration, allowed researchers to predict patients’ response to mycophenolate mofetil (MMF), an immunosuppressive therapy commonly used for dcSSc.

These findings suggest “skin biopsies may be useful for refining prognosis and guiding patient management decisions,” the researchers wrote.

​The study, “Skin biopsies enhance prediction of clinical trajectory in diffuse cutaneous systemic sclerosis,” was published in Arthritis & Rheumatology.

Defining scleroderma and the problem
In scleroderma, the immune system mistakenly attacks skin and connective tissue, causing excessive inflammation and scarring (fibrosis). As scar tissue builds up, the skin thickens and hardens, resulting in symptoms that can vary widely in severity.

People with the diffuse form of scleroderma (dcSSc) are more likely to develop extensive fibrosis on the arms, legs, and trunk. They are also more likely to have damage to the body’s internal organs, and symptoms may worsen rapidly.

“Estimating individual disease trajectories in dcSSc remains a major unmet need with direct implications for patient care decisions and clinical trial design,” the researchers wrote. “Previous observational studies have shown that disease duration and [initial] modified Rodnan skin score (mRSS) are associated with disease progression.”

The mRSS is a measure of how thick the skin is in 17 areas of the body, with higher scores indicating thicker skin and more severe skin involvement.

Here, a team of U.S. researchers investigated whether changes in the skin are associated with disease duration and whether some of these skin features can help predict treatment responses.

They analyzed skin biopsies — small samples of skin examined under a microscope — from 105 adults with dcSSc. All had participated in previous clinical trials of experimental therapies for dcSSc: 79 in the Phase 3 RESOLVE-1 trial (NCT03398837) of lenabasum, 18 in a Phase 2 study (NCT01670565) of belimumab, and eight in a Phase 2 trial (NCT01166139) of nilotinib.

A total of 49 people had early-stage disease (duration of less than 1.5 years) and 56 had late-stage disease (lasting 1.5 years or more).

Skin biopsies reveal cell markers and scores
The researchers focused on fibroblasts — the cells that produce collagen, the main component of scar tissue — by looking at the levels of two proteins: alpha-SMA and CD34. Alpha-SMA is a marker of activated fibroblasts, called myofibroblast, that are more active in producing collagen. Higher levels of alpha-SMA are linked to worse mRSS. In contrast, CD34 is produced by fibroblasts in healthy skin, but found at reduced levels in scleroderma.

They also counted immune cells, including B-cells and T-cells, in skin samples.
Results showed people with early-stage dcSSc had significantly fewer fibroblasts producing high levels of CD34, significantly higher levels of alpha-SMA in fibroblasts, and significantly more B-cells in the skin compared with the late-stage disease group.

This suggests early dcSSc is more active, with more scar-forming fibroblasts and immune cells.

To measure treatment response, the researchers analyzed mRSS data from 68 people treated with MMF, which “was the most common medication used” in this group, and has had a “prominent role in dcSSc skin treatment in recently published guidelines,” the team wrote.

A decrease of more than 5 points in the mRSS after one year was considered a meaningful improvement.

Statistical analyses showed the strongest predictors of treatment response were sex and disease duration, as well as CD34 and alpha-SMA levels in skin fibroblasts at treatment start. Notably, “the effect of fibroblast scores on clinical outcomes varied by disease duration at the time of biopsy,” the researchers wrote.

Among people with early-stage disease, high levels of both CD34 and alpha-SMA predicted better chances of clinical improvement. High alpha-SMA levels, in contrast, predicted worse outcomes in the late-stage disease group.

The lowest response rates occurred in early disease patients with low levels of both CD34 and alpha-SMA (14%), and in late-disease patients with high alpha-SMA, regardless of CD34 levels (40%-50%).

While immune cells did not differ by alpha-SMA status in early-stage disease, B-cells were much more frequent in late disease patients with high SMA levels.

“These findings demonstrate that mRSS alone does not capture key differences in [fibroblast-related profile] between early and later stages of SSc that were shown to influence disease trajectory,” the researchers wrote. “Skin fibroblast and immune profiles may offer more precise insights into disease subsets, beyond clinical measures, and may be used to inform patient management decisions.”
​
“Skin biopsies have a role, along with disease duration, in identifying periods of time during which patients may be more or less likely to improve with MMF,” the team concluded.