Genetic Activity in Skin May Define Stages of Juvenile Localized Scleroderma

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Distinct profiles of gene activity in skin samples distinguish different disease stages in juvenile localized scleroderma, a study suggests.

These profiles did not necessarily match the patients’ clinical subtype or the disease’s location on the body, suggesting that they may better represent distinct and clinically relevant subgroups of patients, which may be key to predict treatment response and outcomes, its researchers noted.

They plan additional studies to assess these profiles’ clinical and predictive values.

The study, “Transcriptomic evaluation of pediatric localized scleroderma skin with histological and clinical correlation,” was published in the journal Arthritis & Rheumatology.

In localized scleroderma — the most common form in children — the immune system produces autoantibodies, such as antinuclear antibodies (ANAs), which mistakenly attack the body’s healthy tissue.

This causes the overproduction of collagen and the buildup of scar tissue (fibrosis) in the skin and underlying tissues, such as muscle, bones, and joints.

The disease is characterized by an initial inflammatory phase, with excessive infiltration of immune cells in the skin that precedes fibrosis. Previous studies have suggested an interaction between certain immune cells and collagen-producing cells, called fibroblasts.

However, the underlying mechanisms of localized scleroderma remain largely unclear.

A team of researchers in the U.S. investigated potential molecular players in juvenile localized scleroderma by analyzing gene activity in skin samples from 28 children with the condition and 10 age-matched, healthy peers.

Researchers also assessed whether these gene activity differences were associated with tissue and clinical features, and whether they could distinguish different subgroups of patients.

Patients’ median age was 13 (range, 10–16 years), and most were white (89%) and girls (61%).

Most (93%) patients were newly diagnosed, with no previous use of topical or systemic treatment prior to skin biopsy. Two had longstanding disease, which was in remission for more than six years and not being managed with treatment for two to three years prior to biopsy.

Results showed that the activity of 589 genes was significantly different between children with juvenile localized scleroderma and healthy children. Most of these genes (75%) were significantly less active among patients, while one-quarter were overly active.

Overly active genes in juvenile localized scleroderma included those involved in immune activation, inflammatory responses, and collagen regulation. Pathways important for maintenance of healthy skin layers and for cell-to-cell adhesion were suppressed in these patients.

These opposing trends may reflect the predominant infiltration of immune cells in the skin, leading to the destruction of its layers, the team noted.

Further analysis revealed three distinct genetic profiles, termed immunosubphenotypes, between patients and healthy children.

Group one, called an inflammatory group, was characterized by higher activity of inflammatory-associated pathways and of human leukocyte antigen (HLA) genes, which are involved in immune responses.

Notably, variants in HLA genes were previously shown to affect the risk of developing scleroderma, and their overactivation has also been described in the blood of localized scleroderma patients.

Group two, a fibroproliferative group, was characterized by overly active fibrosis- and collagen-related pathways.

Group three, termed healthy-like group, corresponded to healthy skin gene activity, and included both healthy children and the two patients with longstanding disease in remission.

The inflammatory group was associated with higher inflammatory cell infiltration, active disease, more severe skin disease — as assessed with the modified localized scleroderma severity index — and the presence of ANAs. Those in the fibroproliferative group associated with processes such as collagen formation.

However, neither of these groups matched with clinical subtypes or anatomic location of scleroderma, “which serve as the foundation of the classic clinical categorization of localized scleroderma (morphea), challenging the importance of clinical subtypes to shift the paradigm potentially to immunophenosubtypes,” the researchers wrote.

Interestingly, higher-than-normal activity of HLA and pro-inflammatory genes showed a strong association not only with greater inflammatory cell infiltration, but also with higher skin collagen thickness, indicative of more severe fibrosis.

These findings suggest that in localized scleroderma, potentially more so than in systemic disease, “inflammation is truly the catalyst promoting both the inflammatory infiltrative response but also the collagen thickness and deposition,” further defining it as an “inflammatory driven fibrotic disease,” the team added.

These profiles “will most likely prove most important for medication choices and prediction of treatment response compared to clinical phenotype [presentation],” the researchers wrote, adding that they are conducting further analyses to evaluate whether these profiles can accurately predict treatment response in this group of patients.

“Our goal for future studies includes incorporating these immunophenotypes … with longitudinal follow-up to determine predictive value of [gene activity profiles] regarding treatment response and clinical outcomes, augmenting the possibility of personalized medical treatments,” the team concluded.