Classifying Scleroderma by Genes in Skin Aids in Identifying Subtypes

Molecular barcode system likely to benefit SSc treatment, targeted therapies

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

Share this article:

Share article via email
types of scleroderma | Scleroderma News | SSc molecular barcodes | illustration of puzzle cube

A ranked list of genes in the skin may provide a molecular barcode, or signature, for subtypes of systemic sclerosis (SSc) that would otherwise be missed by the usual methods of diagnosing this disease, a study reported.

The finding breaks further ground toward the use of a new classification scheme for clinical care of SSc, also known as scleroderma, and the testing of experimental disease treatments, potentially moving efforts closer to “clinical trials for patients with similar molecular programs underlying skin disease who may respond to targeted treatment,” the researchers wrote.

“Recent clinical trial results for SSc skin disease have been disappointing,” they added. “One reason for negative trial results may be our inability to identify SSc patients with similar phenotypes in whom targeted treatments are more likely to be

The study, “Clinical phenotypes of patients with systemic sclerosis with distinct molecular signatures in skin,” was published in the journal Arthritis Care & Research.

Recommended Reading
scleroderma interstitial lung disease | Scleroderma News | illustration of doctor looking at patient charts

Interstitial Lung Disease Can Be Early Sign of SSc, Study Reports

Scleroderma occurs when the immune system makes autoantibodies that mistakenly attack the skin’s connective tissue, a type of tissue that provides a scaffolding for other tissues. When this happens, the connective tissue makes too much of collagen, a protein, causing the skin to harden and undergo scarring (fibrosis).

In scleroderma, the attack may stretch over to the blood vessels underneath the skin and involve internal organs, such as the heart, the lungs, and the kidneys. This can bring about a wide range of symptoms.

There is no single test to diagnose scleroderma, but doctors most likely start by doing a physical examination to check for changes in the skin. They also may take a skin biopsy or a blood sample to test for the presence of autoantibodies, and see if there may be damage to any organs.

People with SSc usually fall into either of two disease subtypes according to the extent to which skin fibrosis is present: limited scleroderma and diffuse scleroderma.

Advantages seen in classifying SSc by molecular barcodes

Limited scleroderma is milder and tends to worsen slowly over time, while diffuse scleroderma is more likely to affect internal organs and its symptoms can quickly worsen. However, neither type has a fixed pattern of progression, which makes it hard for doctors to give patients a timeline of what is likely to happen.

A team of researchers in the U.S. wanted to see whether a more comprehensive classification scheme could help tell subtypes apart. They used a classification scheme developed by other researchers and based on patterns of gene expression, an “on” and “off” switch that controls when, where, and how much of proteins are made in cells.

Their study included 165 SSc patients; 115 had diffuse scleroderma and 50 had limited scleroderma. Patients’ mean age was 50 and they had a median disease duration of 23 months. Their mean mRSS (short for modified Rodnan Skin Score, a measure of skin thickness) was 15.2 points, being higher for patients with diffuse scleroderma than for those with limited scleroderma (19.4 vs. 5.6 points). As controls, the researchers included 58 healthy adults with a mean age of 42.

To be able to tell which genes were turned “on” or “off” in a skin biopsy, the researchers looked at RNA, a molecule that carries a gene’s information from DNA in a cell’s nucleus to the cytoplasm where proteins are made.

They then ranked the “on” or “off” genes to obtain four different barcodes, one for each of the patterns identified previously: normal-like, limited, fibroproliferative, and inflammatory.

More than half (56%) of the diffuse scleroderma patients were classified into the inflammatory pattern; 23% were normal-like and 21% had a fibroproliferative pattern.

About two-thirds (64%) of the limited scleroderma patients were normal-like; 18% had a fibroproliferative, 14% had an inflammatory, and 4% had a limited pattern. Most of the healthy individuals (93%) were classified as normal-like and 7% were classified as fibroproliferative.

In general, patients with an inflammatory pattern had a higher mRSS than those with other patterns or the overall diffuse scleroderma group (22.1 vs. 19.4 points) despite a similar median disease duration (14.9 vs. 18.4 months).

Interstitial lung disease occurs when the lungs become inflamed and scarred, making it hard to breathe. It can occur in patients with limited or diffuse scleroderma.

The vast majority (91%) of these people had signs of interstitial lung disease on a chest scan, and they were 5.6 times more likely to have interstitial lung disease than those who a normal-like pattern. All limited scleroderma patients classified as fibroproliferative had signs of interstitial lung disease.

This indicates that molecular barcodes may help to identify people with limited scleroderma who may be at highest risk for interstitial lung disease so they can receive adequate care, the researchers noted.

The molecular barcodes shared “unique clinical characteristics and varying disease severity that may provide added value” to the usual classification into limited and diffuse subtypes.

In addition to these two subtypes, molecular barcodes may help in identifying patients with more skin fibrosis (inflammatory) and interstitial lung disease (fibroproliferative). Those with normal-like and limited may have “milder disease,” the researchers concluded.