Self-reactive antibody levels linked to scleroderma progression: Study
Changes in protein signatures a potential therapeutic target
Increasing levels of self-reactive antibodies in the bloodstream after the start of treatment are associated with the progression of systemic sclerosis (SSc), according to recent research.
“We hypothesize that rising antibody [levels] during treatment may reflect ongoing immune activation, insufficient therapeutic response, or impending flare, whereas decreasing [levels] may signal immune modulation and treatment efficacy,” researchers wrote.
Moreover, changes in protein signatures related to the metabolism of fat-like lipids and oxidative stress, a type of cellular damage, may drive SSc progression, “highlighting novel biomarkers and therapeutic targets for personalized SSc management,” they added.
The biomarker study, “Longitudinal Autoantibody and Proteomic Profiles Uncover Biomarkers and Mechanisms of Disease Progression in Systemic Sclerosis,” was published in Arthritis & Rheumatology.
Additional biomarkers to improve disease classification needed, researchers say
In SSc, or scleroderma, self-reactive antibodies, called autoantibodies, target the body’s connective tissues, stimulating an overproduction of collagen protein. This leads to the buildup of excess scar tissue in the skin and internal organs — including the heart, lungs, and kidneys — that causes damage.
Blood tests to detect the presence of autoantibodies, particularly antinuclear antibodies (ANAs), can help diagnose SSc. ANAs are detectable in most SSc patients.
However, about 10% of SSc patients test negative for ANAs, and as many as one-sixth lack detectable levels of established SSc-specific autoantibodies. ANAs are also associated with other immune disorders such as lupus, “underscoring the need for additional biomarkers to improve disease classification and prognosis,” the researchers wrote.
In this study, the team measured changes in autoantibody and protein signatures over time in SSc patients to identify biomarkers and mechanisms associated with disease progression.
Fasting blood samples were collected from 30 untreated SSc patients at the time of diagnosis (baseline) and 38 age- and sex-matched healthy individuals who served as controls. Follow-up samples were collected after treatment initiation at six, 12, 18, and 24 months.
These findings suggest that patients with high baseline antibody levels were more likely to experience a decline over time, whereas those with low baseline levels were more prone to an increase.
Baseline analysis revealed two distinct subgroups in samples from SSc patients: high- and low-level autoantibody groups. However, the researchers found no differences in demographics or clinical characteristics at diagnosis between these two groups. Additionally, anti-Scl-70 autoantibodies, which have been associated with lung involvement in SSc, were detected in most patients, but absent in controls.
Most patients (83%) with high levels of autoantibodies at baseline saw a decline in their autoantibody levels over time. In comparison, about half (47%) of those with low autoantibodies at baseline experienced an increase in autoantibody levels, while about one-third (29.4%) showed a decrease.
“These findings suggest that patients with high baseline antibody levels were more likely to experience a decline over time, whereas those with low baseline levels were more prone to an increase,” the team wrote.
Among patients whose autoantibody levels decreased over time, more than half (60%) showed clinical improvement, while about one-fourth (26.7%) experienced disease progression. Nearly all (88.9%) of those with increasing autoantibody levels over time showed disease progression, with no cases of improvement seen in either the increase or unchanged groups.
Looking more closely, an increase in the levels of 26 autoantibodies during treatment was significantly associated with disease progression, with anti-CENP-B antibodies showing the highest risk.
Changes observed in protein signatures over time
Regarding changes in protein signatures over time, the team identified 112 proteins that showed significant changes (54 increased, 58 decreased) in patients with reduced levels and improved clinical conditions. These proteins remained unchanged in those with elevated autoantibody levels and disease progression.
In patients with increased autoantibody levels and disease progression, results showed 46 distinct protein changes (16 increased, 30 decreased) that were absent in the improved group. These proteins were associated with the metabolism of fat-like lipids and oxidative stress, a type of tissue damage caused by an imbalance between oxidants generated by metabolic processes and antioxidants that neutralize them.
“These findings suggest that persistent dysregulation of lipid metabolism and oxidative stress may drive disease progression,” the team noted. “Targeting these pathways — such as correcting lipid metabolism abnormalities — could offer therapeutic benefits.”
Of the proteins identified, SERPINA10 emerged as the most substantial risk factor for disease progression, while ENTPD5 was most protective against progression.
“Our findings establish a connection between increasing autoantibody titers, [protein] changes, and the progression of SSc,” the researchers wrote. “Future research should focus on validating these biomarkers in diverse populations, clarifying the roles of the identified proteins, and creating tools for real-time clinical monitoring.”
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