Systemic sclerosis, also called scleroderma, is an autoimmune
disease that causes scar-like thickening of the skin and internal organs,
such as the kidneys and lungs. It affects about 100,000 people in the United States.
Researchers at the Stanford University School of Medicine and six
other institutions have designed a new diagnostic tool for this rare and
deadly autoimmune disease.
‘By measuring the activity of genes in tiny skin samples, researchers were able to predict scleroderma progression in patients as much as a year earlier than clinicians who used standard methods.’
By measuring the activity of genes in tiny skin samples, the
researchers were able to predict disease progression in patients as much
as a year earlier than clinicians who used standard methods for
The study will be published in JCI Insight
. The lead
authors are Shane Lofgren, a research associate at Stanford, and Monique
Hinchcliff, MD, associate professor of medicine at Northwestern
University. The senior author is Purvesh Khatri, assistant
professor of medicine at Stanford.
A better test
The cause of systemic sclerosis is unknown, and there are no drugs
approved by the Food and Drug Administration for treating it. Many
patients are given drugs that are approved for use in other diseases,
but each drug is clinically effective in only a fraction of patients.
To find out if a patient is responding to treatment, clinicians use a
test called the modified Rodnan skin score, in which a doctor pinches
the skin to see how thick it is. For the test, the physician squeezes
the patient's skin in 17 places, rating the thickness of each pinch of
skin on a scale of zero to three and adding the scores together for a maximum
score of 51.
"It's a very crude measure," Khatri said. He noted that despite
careful training, doctors may give the same patient different scores.
Different physicians evaluating the same patients may agree only 60
to 70 percent of the time, Hinchcliff said. "It has always embarrassed
me to pinch a patient's skin in 17 areas to try and accurately assess
the degree of skin fibrosis. In this day and age, it would seem we
should be more precise," she said.
Because the measures of disease progression are imprecise, said
Khatri, it can take two years for physicians to be sure if a given
treatment is having any effect. A more precise measure of disease
progression has long been needed.
The team used publicly available patient data shared by hospitals
across the United States to search for a set of genes whose activity
would mark the progression of systemic sclerosis, or SSc.
Gene expression is the process by which cells extract information
from genes and render it as molecules of protein or RNA. Cells have the
capacity to express more or less of each molecule, creating a pattern of
expression that changes according to the presence of infections or of
autoimmune diseases such as SSc. Khatri and his team identified 415
genes whose expression changed in a pattern that indicated how serious a
person's SSc had become.
The researchers were able to use these
gene-expression patterns as the basis for a test, which they called the
SSc Skin Severity Score, or 4S. They used SSc patient data from two
clinical centers to identify the 415 genes, and data sets from patients
from five additional centers to validate the new test. They also
included data from healthy participants who served as controls.
It was easy to distinguish the gene-expression data related to
healthy skin samples from the data for diseased skin samples, said
Khatri. "The data for all the healthy skin fell within one bubble," he
said, "while all the data for the scleroderma patients fell within
Getting results a year earlier
The team looked at data from a cohort of Northwestern University
patients who had been tested repeatedly with the skin pinch test while
being treated with a drug. The 4S test -- applied to this preexisting
set of patient data -- could distinguish patients who were improving
from those who were not 12 months after their treatment began. In
contrast, the doctors' skin pinch test from the same set of data took 24
months to identify which patients were improving.
"In the data from Northwestern, all the patients were getting
exactly the same treatment, the same drug," said Shane. "Yet we were
able to predict a year before the clinician which patients were getting
better and which were getting worse."
Clinical trials, as opposed to retrospective studies looking at
pre-existing data, are needed to validate the 4S test, the researchers
said. But if it works as well as Khatri and his collaborators hope,
clinicians may be able to evaluate patients' response to treatments much
more quickly, so they can be switched to some other treatment that may
work. The test could also help advance the search for better therapies.
"And what was really cool was that we could predict on an individual
level which patients would get better or worse," Khatri said.
The 4S test is an example of Stanford Medicine's focus on precision
health, the goal of which is to anticipate and prevent disease in the
healthy and precisely diagnose and treat disease in the ill.
A possible treatment?
The study also uncovered a gene-activity signal suggesting the
involvement of epidermal growth factor receptors in the disease, a fact
that was previously unknown, said Khatri. EGFR is important in cell
division and plays a role in cancer and other diseases. In SSc, "we
showed that EGFR is consistently upregulated," Khatri said. And, he
added, drugs that have been approved by the FDA for treating
EGFR-related conditions may turn out to be useful in treating patients
with systemic sclerosis.
Soon, he said, his team will begin giving EGFR-inhibiting drugs to mice with a sclerodermalike condition to see if it helps.
"It's very exciting," said Khatri. "This is a disease that has stumped people for more than 25 years."