Composite serum biomarker may improve identification of interstitial lung disease in SSc
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A composite biomarker index could improve the risk stratification and diagnosis of interstitial lung disease in patients with systemic sclerosis, according to data published in Arthritis & Rheumatology.
“ILD is detectable in up to 80% of patients with systemic sclerosis (SSc), and a leading cause of morbidity and mortality,” Adelle S. Jee, PhD, of the department of respiratory medicine at Prince Alfred Hospital, in Sydney, Australia, and colleagues wrote. “However, a definitive diagnosis of SSc-ILD may remain elusive until after irreversible lung injury has occurred.
“Timely, accurate identification of SSc-ILD to guide early management decisions is increasingly important, with effective therapies to stabilize and slow disease progression,” they added. “To reduce diagnostic delays, screening SSc patients with high resolution computed tomography (HRCT) and regular pulmonary function testing has been advocated.”
To examine possible composite serum biomarker panels for the identification and risk-stratification of SSc-ILD, Jee and colleagues assessed 28 prespecified blood biomarkers, using development and validation cohorts from the Australian Scleroderma Cohort Study (ASCS) and the Australian IPF registry (AIPFR). Patients were evaluated and measured at baseline and every 12 months thereafter. Recorded metrics included clinical determinations, immunomodulatory therapy, health-related quality of life scores and outcomes. The researchers included all patients who had sufficient data, including ILD diagnoses and lung function information.
Meanwhile, patients with SSc without ILD were additionally included and followed every 6 months, as well as healthy control individuals with no history of smoking or other lung disease. Biomarkers were selected following a systematic literature review and included 28 different potential markers.
The analysis included 259 patients with SSC-ILD, 179 patients with SSc but no ILD, 172 patients with idiopathic pulmonary fibrosis, and 30 healthy control individuals. Overall, a composite index comprised of SP-D, Ca15-3 and ICAM-1 was “strongly associated” with SSc-ILD, regardless of age, smoking status, sex or lung infection (OR = 12.72; 95% CI, 4.59-35.21), according to the researchers. In patients with SSc, a higher index score was also linked to more intense disease severity at baseline.
“We identified a simple composite biomarker index, comprised of SP-D, Ca15-3 and ICAM-1, which strengthened the performance of individual biomarkers to robustly discriminate ILD in SSc and was associated with disease severity, independent of clinical variables,” Jee and colleagues wrote. “Our data supports further investigation of composite biomarker indices as objective, minimally-invasive, point-of-care tests to complement current diagnostic modalities to enhance diagnostic precision and risk-stratification of ILD in SSc.”
Perspective
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Systemic sclerosis-associated interstitial lung disease (SSC-ILD) is a serious and difficult-to-diagnose consequence of SSc. Found in up to 80% of patients with SSc, ILD is a leading cause of morbidity and mortality, and earlier detection imparts an appreciable impact on quality and length of life. Unfortunately, diagnosis and risk stratification remain very challenging in clinical practice. Newer therapies, such as antifibrotics, have opened opportunities for outcome improvements in progressive fibrosing ILDs.
However, current ILD diagnosis is dependent on regular screening with high-resolution CT and complete pulmonary function testing. These bring significant cumulative radiation exposure risk and the risk for being compromised by common extra-parenchymal co-morbidities, respectively. Serum biomarkers hold promise as a minimally invasive tool to help identify SSc-ILD in a timely manner.
Jee and colleagues’ findings are consistent with prior research identifying three biomarkers — SP-D, Ca15-3, ICAM-1 — as responsive to endothelial and epithelial cell injury, known as a common trigger of fibrogenesis in SSc-ILD. Combining these biomarkers into a simple composite index strengthened their performance in identifying ILD from non-ILD. Furthermore, the authors suggest that this composite index is more reflective of the complex clinical and molecular heterogeneity of SSc-ILD, and therefore may be less susceptible to genetic or environmental confounders than an individual biomarker.
High-resolution CT and complete pulmonary function testing will remain necessary for diagnosis, but the authors suggest that the biomarker index will add additional point-of-care testing to guide assessment when standard work-up is indeterminant. This research establishes accurate prediction of SSc-ILD diagnosis at baseline. Further work needs to be done to assess the utility of serial biomarker index measurements to monitor disease severity over time. However, this research brings to bear welcome, valuable objective data to a difficult to diagnose condition.
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