News — Systemic sclerosis, or , causes the hardening of skin and connective tissues. Often, the disease harms other organs, such as the heart, kidneys, lungs, and gastrointestinal tract, and it can lead to death.
Within the population of people who have systemic sclerosis, those who have diffuse cutaneous systemic sclerosis often have a worse prognosis and higher mortality rate compared to patients with limited cutaneous systemic sclerosis. Early diagnosis and treatment could slow disease progression, but, currently, there is no clinical biomarker to identify patients at risk for worse outcomes.
In a new study published recently in , a group of scientists led by , at Yale School of Medicine (YSM) and Francesco Del Galdo, MD, PhD, at Chapel Allerton Hospital in the United Kingdom, showed for the first time that a signature of type 1 interferons (IFN)—a group of proteins involved in cell signaling—can be used as a blood biomarker to predict outcomes of patients with diffuse cutaneous systemic sclerosis.
The findings are an important step toward early identification of this high-risk group of patients.
Early detection is key
While scleroderma is rare, affecting around 300,000 people in the United States, it can be very serious.
“It has the highest case fatality rate of all the autoimmune rheumatic diseases—worse than rheumatoid arthritis and lupus,” says Hinchcliff, associate professor of medicine (rheumatology, allergy, and immunology) at YSM.
Doctors usually classify patients with suspected systemic sclerosis based on their disease presentation: Those with skin fibrosis below the elbows and knees are considered to have limited cutaneous scleroderma. These patients usually have less severe outcomes than those with the diffuse subtype, where the skin fibrosis spreads above the knees and elbows, and to other parts of the body.
Some patients with the diffuse subtype can become disabled or can develop progressive and debilitating conditions.
“If we catch patients early and treat them more aggressively, we can often prevent bad outcomes,” says Hinchcliff.
IFN as a potential biomarker
To find a reliable marker that can help doctors predict poor outcomes in diffuse cutaneous scleroderma patients, Hinchcliff and clinician scientists from 11 academic centers in the United States partnered to recruit patients with early diffuse cutaneous systemic sclerosis. In 2012, the scientists teamed up to create the U.S. Prospective Registry of Early Systemic Sclerosis (PRESS). The registry consists of patients with early diffuse cutaneous systemic sclerosis who fulfill specific criteria. The new study included 110 PRESS patients.
Around the same time, a group of scientists in the U.K. led by Del Galdo began recruiting another cohort of 32 healthy individuals and 72 patients diagnosed with diffuse cutaneous systemic sclerosis. This cohort was called the Stratification for Risk of Progression in Scleroderma (STRIKE).
High levels of type 1 IFN are linked to worse outcomes in individuals with autoimmune diseases such as rheumatoid arthritis and lupus. But blood levels of type 1 IFN are difficult to measure. To overcome that challenge, the scientists measured the concentrations of several molecules that are stimulated by type 1 IFN, which are abundant enough to detect and can serve as an indirect measure of type 1 IFN.
They found that individuals in the PRESS cohort who had high IFN serum scores tended to have worse lung function and disability, such as chronic joint pain, at the beginning of the study and worse lung function during follow-up compared to patients with low IFN serum scores. In the STRIKE cohort, patients with high IFN serum scores had worse lung function than those with low scores, and the differences persisted during follow-up. Across both cohorts, those with high IFN scores also had higher mortality rates than those with lower scores.
Given that scleroderma-related lung disease is the leading cause of death in the scleroderma patient population, the identification of a blood biomarker that may be able to identify patients at heightened risk for lung disease is an important finding.
Further, patients with elevated IFN serum signatures suffered the worst outcomes despite receiving the standard of care, which includes immunosuppression treatment .
An noted the promise of these findings.
“These are people at high risk, and we really need to be focused on monitoring them closely and treating them aggressively before lung damage occurs,” Hinchcliff says. If the results are validated in additional studies, a standardized blood test can be developed for use in clinics for individual patients.
“Our results suggest that measuring type I IFN activity is akin to assessing the fuel driving autoimmune processes in systemic sclerosis patients,” Hinchcliff says. While additional validation and testing are necessary, “the ability to possibly discriminate between high-risk and low-risk patients with diffuse cutaneous systemic sclerosis using a blood test represents a large step forward for the community.”
The work reported in this story was supported by the National Institute of Arthritis Musculoskeletal and Skin Diseases (awards P30AR061271, R01AR073270, R01AR073208, K24AR080217, P30AR070254, R01AR073284, and R01AR081280) and the National Heart, Lung, and Blood Institute (award R01HL152677). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support came from the National Scleroderma Foundation, the National Institute of Health Research–Leeds Biomedical Research Centre, the Kennedy Trust for Rheumatology Research, and the U.S. Department of Defense.
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