medwireNews: Men with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) may experience worse outcomes than women, which could be explained by sex differences in biomarker profiles, suggests a post-hoc analysis of the SLS I and SLS II trials.
The study, published in The Lancet Rheumatology, included 158 participants treated with cyclophosphamide or placebo in SLS I and 142 participants who were given cyclophosphamide or mycophenolate mofetil in SLS II. Approximately three-quarters of participants were women.
Elizabeth Volkmann (University of California, Los Angeles, USA) and colleagues report that in the placebo arm of the SLS I trial, men experienced a decline in lung function, as measured by percent predicted forced vital capacity (FVC), from approximately 67% after 3 months of treatment to 63% after 12 months. This was greater than the decline seen among women, from approximately 68% to 65%, albeit without reaching statistical significance. Men and women treated with cyclophosphamide in SLS I experienced a comparable improvement in FVC during the same period.
On the other hand, there was a significant difference in the FVC response to cyclophosphamide by sex in the SLS II trial. Men experienced a decline from approximately 66% at 3 months to 64% at 12 months, whereas women experienced an improvement from approximately 67% to 72%. In the mycophenolate arm, both men and women had an improvement in FVC, with a significantly greater benefit seen in women.
Therefore, men with SSc-ILD “appear to have a more severe phenotype of ILD than women, even when treated with immunosuppression,” summarize the researchers.
They say that this could be explained by “sex differences in biological mediators of disease pathogenesis.” Specifically, an analysis of 68 biomarkers in bronchoalveolar lavage samples from 103 participants of the SLS I trial showed that men had increased levels of proteins involved in fibrosis – such as matrix metalloproteinase-13 and tissue inhibitor of metallopeptidase 1 – while women had increased levels of proteins involved in inflammation, including interleukin (IL)-12 and IL-7.
The authors of an accompanying commentary, Amanda Grant-Orser and Kerri Johannson (both from University of Calgary, Alberta, Canada) believe that these results “indicate differential states of disease activity between male and female patients, despite a shared clinical diagnosis of systemic sclerosis-associated interstitial lung disease.”
Volkmann et al also compared the safety profiles of the immunosuppressive drugs in men and women, finding that men in SLS I had a lower frequency of anemia than women (2.1 vs 5.4%), but a higher dropout rate (38.3 vs 23.4%). There were “no appreciable sex differences” in dropout, treatment failure. or death rates in SLS II, however.
A second study, which was also published in The Lancet Rheumatology and additionally presented at The Lancet Summit: Sex and gender in rheumatology, took a closer look at the association between sex and adverse events with ILD therapy, focusing specifically on the tyrosine kinase inhibitor nintedanib.
Anna-Maria Hoffmann-Vold (Oslo University Hospital, Norway) and team carried out a post-hoc analysis of four trials involving people with either autoimmune-related ILD (n=746; 70% women) or other forms of ILD (n=1554; 28% women) who were treated with nintedanib 150 mg twice daily or placebo.
They found that the safety profile of nintedanib was “generally similar” among men and women, but nausea, vomiting, and liver enzyme elevations were more common in women.
Discussing the findings from both teams in their commentary, Grant-Orser and Johannson say that the studies “are the first to report differential efficacy of immunomodulatory therapy in patients with systemic sclerosis-associated interstitial lung disease, and differential safety and tolerability of an antifibrotic drug across different subtypes of interstitial lung disease.”
They ask: “Should sex be considered a variable to inform disease management in patients with interstitial lung disease?
“Possibly, particularly if more evidence accumulates that sex differences exist, and that these differences are biologically relevant.”
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Lancet Rheumatol 2022; 4: e668–678
Lancet Rheumatol 2022; 4: e679–687
Lancet Rheumatol 2022; 4: e648–649
The Lancet Summit: Sex and gender in rheumatology; September 22–23, 2022