Biomarker offers new prognostic tool in diffuse cutaneous systemic sclerosis

Dark, shiny skin on distal phalanges of both hands in systemic sclerosis. Photo by Maria Sieglinda von Nudeldorf via Wikimedia Commons

A study published in The Lancet Rheumatology has identified a blood-based signature of type 1 interferons (IFN) as a potential biomarker for predicting disease severity in patients with diffuse cutaneous systemic sclerosis, an autoimmune disorder.

Systemic sclerosis, also referred to as scleroderma, is characterized by the hardening of skin and connective tissues and frequently involves internal organs, including the heart, kidneys, lungs, and gastrointestinal tract. Among those affected, patients with diffuse cutaneous systemic sclerosis have a notably poorer prognosis compared to those with limited cutaneous involvement.

“It has the highest case fatality rate of all the autoimmune rheumatic diseases—worse than rheumatoid arthritis and lupus,” said Dr. Monique Hinchcliff, associate professor of medicine at Yale School of Medicine and co-lead author of the study, in a press release.

Early identification of high-risk patients remains a clinical challenge, as no validated biomarkers have been available to guide prognosis or therapeutic intensity. In this multicentre investigation, Dr. Hinchcliff and colleagues, in collaboration with  Francesco Del Galdo, MD, PhD, of Chapel Allerton Hospital in the United Kingdom, analyzed cohorts from the U.S. Prospective Registry of Early Systemic Sclerosis (PRESS) and the U.K.-based Stratification for Risk of Progression in Scleroderma (STRIKE) study. The PRESS registry consists of patients with early diffuse cutaneous systemic sclerosis who fulfill specific criteria. The new study included 110 PRESS patients. A group of scientists in the U.K. led by Dr. Del Galdo recruited 32 healthy individuals and 72 patients diagnosed with diffuse cutaneous systemic sclerosis to their STRIKE study.

The researchers measured serum concentrations of IFN-stimulated molecules, which serve as indirect indicators of type 1 IFN activity. High IFN serum scores were consistently associated with worse pulmonary function, greater disability—including chronic joint pain—and increased mortality, both at baseline and during follow-up. The findings were replicated across both the PRESS and STRIKE cohorts.

Given that scleroderma-related lung disease is the leading cause of mortality in this patient population, the identification of a blood biomarker for risk stratification is clinically significant. Notably, patients with elevated IFN signatures experienced poor outcomes despite receiving standard immunosuppressive therapy.

“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,” Dr. Hinchcliff said. She added, “Our results suggest that measuring type I IFN activity is akin to assessing the fuel driving autoimmune processes in systemic sclerosis patients.”

If validated in further studies, a standardized blood test for IFN activity could enable earlier and more tailored interventions for patients with diffuse cutaneous systemic sclerosis, marking a substantial advance in the management of this autoimmune disease. 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,” Dr. Hinchcliff said.