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Research identifies sex differences in SSc-ILD outcomes

By Claire Barnard, medwireNews Reporter

Men with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) may have a more severe disease course than women, whereas women with the condition could be more likely to experience certain adverse events (AEs) when treated with immunosuppressive therapy, suggest findings from two studies.

The first study was carried out by Elizabeth Volkmann (University of California, Los Angeles, USA) and team and the second by Anna-Maria Hoffmann-Vold (Oslo University Hospital, Norway) and colleagues; both studies are published in The Lancet Rheumatology.

Volkmann et al conducted a post-hoc analysis of two randomized controlled trials – the Scleroderma Lung Study (SLS) I and SLS II – to evaluate whether clinical outcomes differ by sex in people with SSc-ILD. SLS I involved 158 participants (70% women) who were treated with cyclophosphamide or placebo, while SLS II involved 142 participants (74% women) who were given cyclophosphamide or mycophenolate mofetil 1500 mg twice daily. The maximum dose of cyclophosphamide in both studies was 2 mg/kg per day.

Overall, men with SSc-ILD from these two trials “had a less favourable course of ILD” than women, in both the active treatment and placebo groups, say the researchers.

For instance, in the cyclophosphamide arm of SLS II, men experienced a decline in lung function, with the percentage predicted forced vital capacity (FVC) decreasing from approximately 66% at the 3-month follow-up to 64% at 1 year. By comparison, women experienced an improvement from approximately 67% to 72%, which was significantly different from the change in men.

Both men and women treated with mycophenolate mofetil achieved an improvement in lung function during the study period, but the rate of improvement was significantly lower in men. Conversely, both male and female participants given placebo in SLS I experienced a decline in percentage predicted FVC, with a greater decline, albeit not significantly, among men.

When the active treatment arms of the SLS I and II trials were pooled, men were more likely than women to experience a decline in percentage predicted FVC of at least 10%, particularly during the first year of treatment. The proportions of participants experiencing this outcome were 10% versus 5% at 1 year and 12% versus 10% at 2 years.

“This finding highlights the importance of monitoring lung function within the first year of treatment”, write Volkmann et al.

The team then analysed levels of 68 biomarkers in bronchoalveolar lavage samples from 103 participants of SLS I to explore the biological mechanisms behind their findings. They found that men were more likely to have detectable levels of proteins involved in matrix remodelling and fibrosis, whereas women were more likely to have detectable levels of proteins involved in inflammation.

The researchers note that these biomarker findings “should be considered exploratory in nature”, but suggest that they “could signify a more advanced fibrotic ILD present in men at baseline, or could suggest a difference in the pathobiology of ILD between men and women”.

Volkmann and colleagues also looked at the safety profiles of the immunosuppressive therapies, finding that men had a lower frequency of anaemia than women (2.1 vs 5.4% in SLS I and 5.4 vs 18.1% in SLS II) but a higher dropout rate (38 vs 23%) in SLS I. However, they note that there were “no appreciable sex differences” in dropout, treatment failure or death rates in SLS II.

The second study, from Hoffmann-Vold and team, took a closer look at the impact of sex on AEs with ILD therapy, with a specific focus on nintedanib.

The authors carried out a post-hoc pooled analysis of data from the SENSCIS trial (patients with fibrosing SSc-ILD), the two INPULSIS trials (patients with idiopathic pulmonary fibrosis [IPF]) and the INBUILD trial (patients with non-IPF progressive fibrosing ILDs). A total of 746 participants (70% women) had autoimmune disease-related ILD, primarily SSc-ILD (82%), while 1554 (28% women) had non-autoimmune disease-related ILD. Participants were treated with nintedanib 150 mg twice daily or placebo.

The team reports that “[t]he adverse event profile of nintedanib was generally similar between male and female patients”. However, nausea, vomiting and liver enzyme elevations were more common among women, whereas serious AEs were more common among men.

Discussing the results of both studies in an accompanying comment, Amanda Grant-Orser and Kerri Johannson, both from the University of Calgary in Alberta, Canada, say that sex has the potential to be considered “a variable to inform disease management in patients with interstitial lung disease.”

They believe, however, that more research is needed to provide evidence for the observed sex differences, and to show “that these differences are biologically relevant.”

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