Autoantibodies Better Predictors of Scleroderma Prognosis Than Disease Overlap, Study Finds

The types of autoantibodies a person has are a better predictor of scleroderma prognosis than whether the person has other connective tissue diseases, a study reports.

The study, “Clinical characteristics and survival in systemic sclerosis-mixed connective tissue disease and systemic sclerosis-overlap syndrome,” was published in the journal Arthritis Care & Research.

Mixed connective tissue disease (MCTD) is characterized by features of multiple connective tissue disorders, which can include scleroderma, rheumatoid arthritis, and lupus. The blood biomarker of MCTD is the presence of autoantibodies (self-targeting antibodies) against U1 ribonucleoprotein complex (RNP), an RNA-protein complex.

People with scleroderma may show signs of another other disease, such as lupus or Sjogren’s syndrome. This is known as scleroderma overlap syndrome (SSc overlap).

Researchers in Australia compared the clinical manifestations and outcomes among people with scleroderma only, SSc overlap, and scleroderma as part of MCTD (SSc MCTD) using data from the Australian Scleroderma Cohort Study.

They analyzed data from 1,728 people. Most of them (74%) had limited scleroderma, and 26% had diffuse scleroderma. Ninety-seven (5.6%) had SSc-MCTD and 126 (7.3%) had SSc overlap. The remaining patients had scleroderma only.

People with SSc-MCTD were significantly younger at disease onset (38.4, compared with 46.5 with SSc overlap, and 46.8 with SSc only). The proportion of people who were ethnically Asian was higher among those with SSc-MCTD (18.3%, compared with 3.6% with SSc only and 10.1% with SSc overlap).

In general, rates of clinical manifestations in the kidney, heart, and lungs were comparable among all three groups. Pulmonary arterial hypertension was less common in the SSc overlap group than in the other two groups (6.4%, compared with 11.1% for SSc only, and 12.4% for SSc-MCTD).

The frequency of several gastrointestinal, musculoskeletal and skin symptoms also differed across the three groups. Rates of swallowing difficulties were 60.3% in SSc-overlap, 45.4% in SSc-MCTD, and 45.5% in SSc only. Rates of dry eyes were also higher in SSc overlap (79.4%) than in SSc-MCTD (66.0%) or SSc only (62.5%).

Muscle inflammation (myositis) was more common in SSc-MCTD (18.6%) and SSc overlap (22.2%) than in SSc only (4.3%).

The most frequently used disease-modifying anti-rheumatic drugs (DMARDs) were hydroxychloroquine and methotrexate. People with SSc overlap or SSc-MCTD were generally more likely to have been given DMARDs than those with SSc only.

“This increased frequency of immunomodulatory and immunosuppressive therapies likely reflects a greater frequency of ‘inflammatory’ manifestations [such as myositis] in [the] SSc-MCTD and SSc-overlap groups than SSc-only,” the researchers wrote.

As for autoantibody profiles, the team found several differences across the three groups. By definition, 100% of the SSc-MCTD group was positive for anti-RNP autoantibodies; these autoantibodies were also detected in 2.4% of SSc overlap and 0.3% of SSc only patients.

Anti-Scl-70 autoantibodies were more common among those with SSc only (15%) or SSc overlap (20.2%) than those with SSc-MCTD (7.5%), while anti-RNA polymerase 3 autoantibodies were more common in SSc only (14.6%) compared with the other two groups (8% for SSc overlap and 2.1% for SSc-MCTD).

Both anti-scl-70 and anti-RNA polymerase 3 autoantibodies target the cell nucleus and are specific for scleroderma.

No significant differences in survival across the three groups were found after accounting for sex and age at disease onset. Yet differences were found if based on autoantibody profiles.

In particular, those with anti-Scl-70 or anti-RNA polymerase 3 autoantibodies had shorter survival rates than patients with anti-RNP or ant-centromere antibodies (also a hallmark of scleroderma). Relative to anti-centromere autoantibodies, anti-Scl-70 autoantibodies conferred a 2.75 times higher risk of mortality.

“In terms of survival, scleroderma-specific antibodies were a more reliable indicator of survival than disease groups,” the researchers wrote. “These data suggest that testing for antibody to RNP is a valuable prognostic tool in patients with SSc.”

Being male and older at disease onset were also significant predictors of mortality, independent of disease groups.

The study had limitations. “We did not have scope within our study to investigate patients with MCTD who do not fulfill criteria for SSc,” the researchers wrote, and “on average patients in our study were recruited more than 10 years after diagnosis of their disease, which may mean there is a degree of ‘survivor bias.'”