Blood protein may help predict lung decline in scleroderma-related ILD
KL-6 above 1,000 U/mL linked to more than twice the rate of FVC decline
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Blood levels of a protein called KL-6 may help identify people with systemic sclerosis-associated interstitial lung disease (SSc-ILD) who are at greater risk of short-term lung function decline, according to a new analysis of data from a Phase 3 clinical trial.
Among participants who received a placebo in the SENSCIS trial (NCT02597933), those with KL-6 levels above 1,000 units per milliliter (U/mL) had more than twice the rate of lung function decline over one year as those whose levels were at or below that threshold.
Blood biomarkers may reflect different aspects of SSc
The analysis also identified several blood biomarkers associated with less improvement in skin disease over time, suggesting that different biomarkers may provide information about disease progression in different organs.
The study, “Circulating biomarkers in patients with systemic sclerosis-associated interstitial lung disease in the SENSCIS trial,” was published in Annals of the Rheumatic Diseases.
SSc, also called scleroderma, is an autoimmune disease marked by blood vessel abnormalities, immune system dysfunction, and excessive tissue scarring, or fibrosis. ILD is a common complication of SSc in which inflammation and scarring damage lung tissue and can make breathing increasingly difficult.
The course of SSc-ILD varies widely, making it difficult to predict whose disease will progress more rapidly. Blood biomarkers that signal a greater risk of progression could help doctors identify patients who may benefit from changes in their care.
To look for biomarkers that might help predict disease progression, an international team of researchers examined blood samples collected during SENSCIS. The trial evaluated Ofev (nintedanib) against a placebo in 576 adults with SSc-ILD and found that Ofev slowed the rate of lung function decline over 52 weeks by 44%.
Higher KL-6 linked to faster lung function decline
The researchers analyzed blood samples collected at the beginning of the trial from participants assigned to the placebo group. SENSCIS investigators, including researchers employed by Boehringer Ingelheim, which funded the trial and markets Ofev, conducted the analysis.
Results showed that higher starting levels of KL-6 and VICM were associated with faster declines in forced vital capacity (FVC), a measure of how much air a person can forcibly exhale after taking a deep breath. However, neither association remained statistically significant after the researchers corrected for multiple comparisons.
When the researchers assessed KL-6 levels using specific thresholds, however, they found a clearer association with lung function decline. In particular, participants with KL-6 levels above 1,000 units per milliliter (U/mL) had an estimated FVC decline of 132.5 mL per year, compared with 56.4 mL per year among those at or below that threshold. This difference was statistically significant.
The researchers also identified biomarkers associated with less improvement in skin disease. Higher levels of CRP and CCL2, two markers of inflammation, and pro-C3, a marker of changes in the extracellular matrix, or the network of proteins that helps support tissues, were associated with less improvement in skin thickening over one year.
Taken together, the findings suggest that different biomarkers may identify different patterns of disease progression in SSc-ILD. Elevated KL-6 may help identify people at greater risk of lung function decline, while higher CRP, CCL2, and pro-C3 levels were associated with less improvement in skin thickening over one year.
Ofev changes levels of some blood biomarkers
The researchers also investigated whether Ofev affected levels of the biomarkers measured in the study. Compared with the placebo, treatment with Ofev reduced levels of CA-125 and pro-C6 over one year. CA-125 is a marker of dysfunction or injury in cells that line the lungs, while pro-C6 is a marker of processes involved in tissue scarring. The differences were detectable as early as week four.
A mediation analysis suggested that the reduction in CA-125 at six months accounted for 48% of Ofev’s effect on FVC at one year. However, the researchers cautioned that this statistical association does not prove that the reduction in CA-125 caused the slower decline in lung function.
The changes in these biomarkers suggest that Ofev may affect biological processes related to lung injury and tissue scarring in people with SSc-ILD.
The researchers noted several limitations to the biomarker analysis. Because SSc can affect multiple organs, blood biomarkers may reflect disease activity outside the lungs or skin. In addition, limitations in the trial’s extension data prevented the researchers from reliably determining whether changes in KL-6 after one year could predict subsequent changes in lung function.
Despite these limitations, the researchers concluded that using specific KL-6 thresholds “represents a practical approach to aid in identifying patients with SSc-ILD who are more likely to experience a progressive ILD course in clinical practice and research settings. Likewise, [setting thresholds for] circulating biomarkers such as CRP may help identify patients at risk for a less favourable trajectory of skin involvement.”
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