Autoantibodies tied to mortality, organ involvement in scleroderma

Classifying disease by skin symptoms was not associated with either by Katherine Poinsatte | January 14, 2025

Organ involvement and outcomes among people with systemic sclerosis (SSc) are strongly associated with seven specific self-reactive antibodies, a French study has found.

Among their findings, researchers identified antibodies that targets RNA polymerase III as strongly associated with scleroderma renal crisis, a rare and severe manifestation of SSc marked by high blood pressure, and kidney and heart failure.   Classification by skin symptoms wasn’t associated with survival or organ involvement.

“The systematic and accurate determination of [specific self-reactive antibodies] at diagnosis could help clinicians to better stratify the individual risk of developing SSc complications and personalize monitoring,” the researchers wrote. The study, “Impact of autoantibody status on stratifying the risk of organ involvement and mortality in SSc: experience from a multicentre French cohort of 1605 patients,” was published in RMD Open. 

SSc, also called systemic sclerosis, features excessive scarring in the skin and may also occur in the heart, kidney, lungs, and gastrointestinal tract. Patients are divided into two main subtypes, limited and diffuse, based on the extent of their skin symptoms. Limited SSc patients may have skin symptoms on the face, arms, hands, and fingers, while people with diffuse SSc have widespread skin fibrosis, or scarring, and a higher risk of internal organ involvement.

The skin-based subtypes have traditionally predicted organ involvement and mortality. However, given that not all SSc patients exhibit skin fibrosis and that serious lung involvement may occur in both subtypes, the researchers believe better ways of predicting organ involvement and disease outcomes are needed.

“The skin phenotype is not a sufficient and reliable factor to formally predict organ damage and disease complications for clinicians,” the researchers wrote.
​
The immune system of people with SSc makes self-reactive antibodies that mistakenly attack healthy tissue. While several specific autoantibodies have been linked to the disease and particular organ involvement, the exact biological consequences of self-reactive antibodies are poorly understood.

Link between self-reactive antibodies, disease characteristics
In this French multicenter study, scientists followed 1,605 SSc patients for a mean of 10 years to explore the associations between the clinical and biological characteristics of their disease with nine self-reactive antibodies in their blood. These were antinuclear antibodies, meaning they target proteins in the cell nucleus.

At least one of the antibodies was detected in 89.2% of the patients. Only a small percentage (1.9%) had multiple self-reactive antibodies.

During follow-up, 34.5% of patients developed interstitial lung disease, a group of lung conditions marked by lung inflammation or fibrosis and the leading cause of death in people with SSc. Patients with interstitial lung disease were significantly more likely to have anti-topoisomerase I antibodies and less likely to have anti-centromere antibodies.

Scleroderma renal crisis occurred in 60 (3.7%) participants and was associated with anti-RNA polymerase III antibodies. Anti-centromere antibodies weren’t as common with scleroderma renal crisis.

Sores on the fingers or toes caused by poor blood flow, called digital ulcers, developed in 35.8% of patients. This complication was associated with anti-topoisomerase I antibodies, having diffuse cutaneous SSc, and a younger age at diagnosis.

Arthritis, a chronic condition that causes joint inflammation and pain, occurred in 21.7% of patients and was associated with multiple self-reactive antibodies. While SSc patients with arthritis were less likely to have anti-centromere antibodies, they were, as a group, more likely to have antibodies that target anti-topoisomerase I, RNA polymerase III, U1RNP, and U3RNP.

Myositis, an inflammatory muscle disease causing muscle weakness, developed in 129 (8%) SSc patients, and was significantly associated with anti-Pm/Scl and anti-Ku antibodies. Myositis patients were also more likely to have anti-U3RNP and anti-U1RNP antibodies and less likely to have anti-centromere antibodies.

The researchers also looked at the relationship between self-reactive antibodies and survival.

Overall, 110 (6.9%) of the patients died during follow-up. Those with anti-centromere antibodies or anti-U1RNP antibodies were more likely to survive, while anti-topoisomerase I, anti-RNA polymerase III, or anti-U3RNP antibodies augured worse outcomes.

The age at diagnosis, presence of pulmonary arterial hypertension, or occurrence of scleroderma renal crisis were independently associated with increased mortality. No association was found between mortality and either skin subtype.
​
“Our study highlighted strong independent associations between each [self-reactive antibody] and internal organ involvement in this disease,” the researchers wrote. “By contrast, the skin phenotype was not an independent factor associated with organ involvement and mortality in SSc.”