Researchers Uncover Frequency, Features of 2 Rare SSc Subtypes

Marta Figueiredo PhD avatar

by Marta Figueiredo PhD |

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Patients with two rare subtypes of systemic sclerosis (SSc) — based on the presence of specific antibodies and the extent of skin involvement — have mild disease courses and specific clinical features, symptoms, and outcomes, a study shows.

The data also confirmed that the presence of anti-topoisomerase-I autoantibodies (ATAs) is specifically associated with lung involvement, and that diffuse SSc, which more extensively affects the skin, is linked to poorer survival, even in these rare subtypes.

These findings highlight the importance of assessing antibody type in SSc patients to predict organ involvement, the researchers said. It’s also essential, they noted, to analyze the extent of skin involvement to predict survival.

The study, “Autoantibodies versus Skin Fibrosis Extent in Systemic Sclerosis: A Case-Control Study of Inverted Phenotypes,” was published in the journal Diagnostics.

In systemic sclerosis, also known as scleroderma, the immune system produces antibodies that wrongly recognize the body’s own proteins as foreign, and mount immune attacks against them. These abnormal antibodies are also known as autoantibodies.

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SSc-associated abnormal immune attacks lead to extensive blood vessel dysfunction and tissue scarring that most often affects the skin. However, multiple other organs, such as the lungs, also may be affected. Interstitial lung disease (ILD), characterized by inflammation and scarring in the lungs, affects about half of SSc patients and is the leading cause of death in people with scleroderma.

Limited SSc (lSSc) and diffuse SSc (dSSc) are the two main clinical subtypes of SSc. Overall, lSSc is associated with “less extensive skin involvement, less frequent organ involvement, and a better survival than dSSc,” the researchers wrote.

However, the type of SSc-associated autoantibodies — anti-centromere autoantibodies (ACAs), ATAs, or those against RNA polymerase III — also may determine the clinical features, symptoms, and outcomes of these subtypes.

Notably, ACAs are most often found in lSSc patients and are linked to better prognosis. Conversely, ATAs are commonly associated with dSSc, severe organ involvement, including ILD, and poorer survival.

Patients with inverted types — meaning those with either ACAs and dSSc (ACA dSSc) or ATAs and lSSc (ATA lSSc) — have been reported in some studies, but little is known about their frequency, clinical features, and survival.

To learn more, a team of researchers at Hôpital Cochin, Université de Paris, in France, retrospectively analyzed the data of 1,040 SSc patients. The information, from 2000 to 2019, was culled from a database of a French national referral center for SSc.

For each patient with ATA lSSc, one with ATA dSSc and another with ACA lSSc were randomly extracted from the same database; they also were used as controls for those with ACA dSSc. Patients were followed for a median of five years.

The results showed that 93 patients (8.9%) had the ATA lSSc subtype — accounting for 16% of total lSSc cases — while the ACA dSSc subtype was present in 12 patients (1.1%), representing 3.6% of total dSSc cases.

ATA lSSc patients had the second-highest rate of ILD of all groups (72%). That rate was surpassed only by that of the ATA dSSc patients (79.6%), who also showed more severe ILD. The presence of ACAs was associated with lower rates of ILD (41.7% in dSSc, and 33.3% in lSSc), and with less severe skin involvement among lSSc patients.

The rarer ACA dSSc subtype was significantly associated with higher rates of gastrointestinal tract involvement (91.7% vs. 58.1%), muscle involvement (33.3% vs. 7.5%), and heart involvement (25% vs. 4.3%) than ACA lSSc.

Compared with ATA dSSc patients, those with the rarer ATA lSSc subtype had significantly less frequent involvement of the joints (62.4% vs. 86%), gastrointestinal tract (60.2% vs. 80.6%), muscles (16.1% vs. 58.1%), and heart (6.5% vs. 20.4%).

ATA lSSc patients also were significantly older at diagnosis (51 vs. 43 years) and had less severe skin sclerosis.

None of the lSSc patients converted into dSSc over the five-year follow-up.

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A survival analysis, conducted among the 203 patients with at least one year of follow-up data, showed that the cumulative five-year survival rate was significantly different between the four groups.

Notably, there were no significant differences in survival in terms of type of antibody, but lSSc patients showed significantly better survival rates  relative to the dSSc group. The survival rates were 95% among ATA lSSc patients and 84% for those with ACA lSSc. Meanwhile, for ACA dSSc patients the survival rate was 71%, and 66% among ATA dSSc patients.

While the rates of heart and muscle involvement did not significantly differ between ATA dSSc and ACA dSSc patients, the latter showed better survival, which “may reflect the protective role of ACA,” the researchers wrote.

These findings suggest that ATA lSSc and ACA dSSc account for about 10% of all SSc patients, representing rare and unique subtypes with a mild disease course. They should be considered a separate group, the researchers noted.

The data also highlight that ATAs are “specifically associated with ILD,” and confirm that dSSc is associated with “a worse prognosis both in term[s] of organ involvement and mortality,” the team wrote.

As such, the type of SSc-associated autoantibodies “may predict organ involvement, whereas the extent of skin sclerosis may predict survival,” the researchers wrote, further supporting the assessment of both parameters to predict SSc patients’ clinical course.