According to an analysis of two large databases, being a man is linked to a higher risk of death in patients with scleroderma, regardless of the type of autoantibodies they carry.

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-reactive antibodies (called autoantibodies) that attack the body’s own tissues and organs. Such abnormal immune attacks lead to tissue scarring which usually affects the skin, but other organs can also be affected including the lungs and heart.

Specific autoantibodies, which include anti-centromere antibodies (ACA) and anti-topoisomerase antibodies (ATA), have been associated with more serious distinct types of scleroderma.

recommended reading

While SSc is more common in women, the risk of serious outcomes is higher in men. Because ATA has a higher prevalence in men than in women, the researchers hypothesized “that the observed differences in outcomes between men and women with systemic sclerosis are partly explained by the expression of autoantibodies”.

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

They analyzed data from patients diagnosed with SSc, and who had available data on their autoantibodies, at least available X-ray evaluation of interstitial lung disease – a group of conditions characterized by inflammation and fibrosis (scarring) of the lung tissue – and a known date of disease onset.

Patients were categorized by gender and autoantibody status, whether positive or negative for ACA or ATA.

A total of 445 participants from CCISS and 4263 from EUSTAR were eligible for analysis. In both groups, eligible patients more often had diffuse cutaneous SSc than those excluded.

In the CCISS group, the majority of patients were female (344.77%). In this group, the presence of anti-ATA autoantibodies was significantly more frequent in men (39%) than in women (19%). In contrast, ACA-positive patients were significantly more often female than male, 48% versus 15%.

Significant differences

Survival was significantly worse overall in men than in women. Further analysis after adjusting for confounding factors (including age, race, autoantibody status) again showed significantly higher all-cause mortality in SSc men – 2.9 times higher than in women. No significant association was found between ATA status (positive or negative) and sex on all-cause mortality.

The EUSTAR group included 783 men (18%) and 3480 (82%) women. Again, the presence of anti-ATA autoantibodies was significantly more common in men than in women, 49% versus 38%. The opposite was observed for ACAs, 17% in men versus 40% in women, “confirming the results of the CCISS cohort”, the researchers wrote.

According to CCISS group estimated survival rates, 30% of ATA-positive men died within 10 years compared to 12% of women during the same period. In the EUSTAR group, the percentages were 33% for men versus 15% for women.

EUSTAR data showed that the risk of death was 2.6 times higher in men than in women, regardless of age, race and autoantibody status.

“We show that the increased mortality in men cannot be explained by a different distribution of autoantibodies,” the researchers wrote.

According to the EUSTAR group, being positive for ATA was linked to a 1.3 times higher risk of death, while having anti-ACA autoantibodies was significantly associated with a higher survival rate.

Additionally, men had a higher risk of developing diffuse cutaneous SSc and pulmonary hypertension, a leading cause of death in scleroderma. Both conditions remained significantly associated with ATA status after adjusting for age, gender, and race.

Overall, “male gender is an important risk factor for mortality in systemic sclerosis,” the researchers wrote. “Clinicians should consider that mortality in men with systemic sclerosis is higher than in women, regardless of ATA positivity.”

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