Mortality Risk Greater for Men With SSc, Analysis Reveals

That is irrespective of the type of autoantibody a man carries

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Being male is linked with a higher risk of mortality among patients with scleroderma, irrespective of the type of autoantibody they carry, according to an analysis from two large databases.

The study, “Sex-specific risk of anti-topoisomerase antibodies on mortality and disease severity in systemic sclerosis: 10-year analysis of the Leiden CCISS and EUSTAR cohorts,” was published in the journal The Lancet Rheumatology.

In systemic sclerosis, also known as scleroderma, the immune system produces self-reacting antibodies (called autoantibodies) that attack the body’s own tissues and organs. Such abnormal immune attacks lead to tissue scarring that typically affects the skin, but other organs can also be affected, including the lungs and the heart.

Specific autoantibodies, which include anti-centromere antibodies (ACAs) and anti-topoisomerase antibodies (ATAs), have been associated with more severe disease distinct scleroderma types.

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While SSc is more common in females, the risk of severe outcomes is higher in males. Since ATAs have a higher prevalence in males compared to females, the researchers hypothesized “that the differences in outcomes observed between males and females with systemic sclerosis are partly explained by autoantibody expression”.

To test their hypothesis, the team led by researchers from the University Medical Center in Leiden, Netherlands, conducted an analysis of 10-year data from two independent patient groups called Leiden Combined Care in Systemic Sclerosis (CCISS) and European Scleroderma Trials and Research (EUSTAR).

They analysed data from patients diagnosed with SSc, and who hadh available data on their autoantibodies, at least one available radiographic assessment of interstitial lung disease — a group of conditions characterized by inflammation and fibrosis (scarring) of lung tissue — and a known date of disease onset.

Patients were categorized according to sex and autoantibody status, either positive or negative for ACAs or ATAs.

In total, 445 participants from CCISS and 4,263 from EUSTAR were eligible for the analysis. In both groups, eligible patients had diffuse cutaneous SSc more often than those who were excluded.

In the CCISS group, the majority of patients were female (344, 77%). In this group, the presence of ATA autoantibodies was significantly more common in males (39%) compared to females (19%). In contrast, ACA-positive patients were significantly more often female than male, 48% vs. 15%.

Significant differences

Survival was significantly worse overall in males than in females. Further analysis after adjusting for confounding factors (including age, race, autoantibodies status) still showed an all-cause mortality significantly higher for SSc males — 2.9 times higher than in women. No significant link was found between ATA status (positive or negative) and sex on all-cause mortality.

The EUSTAR group included 783 males (18%) and 3,480 (82%) females. Again, the presence of ATA autoantibodies was significantly more common in males than in females, 49% vs 38%. The opposite was seen for ACAs, 17% in males vs. 40% in females, “confirming the findings from the CCISS cohort,” the researchers wrote.

According to estimated survival rates of the CCISS group, 30% of males positive for ATAs died within 10 years compared to 12% of females during the same period. In the EUSTAR group, the percentages were 33% in males vs. 15% in females.

Data from EUSTAR showed that mortality risk was 2.6 times higher in males than in women, independently of age, race and autoantibody status.

“We show that increased mortality among males cannot be explained by a different autoantibody distribution,” the researchers wrote.

According to the EUSTAR group, being positive for ATAs was linked with a 1.3 times higher risk of death, whereas having ACA autoantibodies was significantly associated with greater survival rate.

Also, males had a higher risk to develop diffuse cutaneous SSc and pulmonary hypertension, a leading cause of death in scleroderma. Both conditions remained significantly associated with ATA status after adjustment for age, sex, and race.

Overall, “male sex is a strong risk factor for mortality in systemic sclerosis,” the researchers wrote. “Clinicians need to consider that mortality in males with systemic sclerosis is higher than in females, independent of ATA positivity.”

However, further studies are needed to assess the “effect of sex-specific characteristics on people with systemic sclerosis,” the study concluded.