A composite serum biomarker index, comprised of surfactant protein D (SP-D), cancer antigen 15-3 (Ca15-3), and intercellular adhesion molecule-1 (ICAM-1), may identify interstitial lung disease (ILD) in patients with systemic sclerosis (SSc), according to a study in Arthritis & Rheumatology.
Currently, definitive diagnosis of SSc-ILD may not be possible until patients have experienced irreversible lung injury. Researchers in Australia therefore sought to identify a panel of serum biomarkers that could distinguish SSc-ILD from SSc without ILD.
The current analysis included 28 biomarkers, selected based on a literature review. The biomarkers were then used to analyze blood serum samples from 640 participants from the Australian Scleroderma Cohort Study — 259 with SSc-ILD and 179 with SSc but without ILD (control group); 172 participants from the Australian Idiopathic Pulmonary Fibrosis (IPF) Registry with IPF (control group); and 30 additional healthy individuals (control group).
The participants had an overall mean age of 60 years, 32.7% were male, and 55.9% were had never smoked but had mild-to-moderate lung function impairment (mean forced vital capacity [FVC] 87.9% and diffusing capacity for carbon monoxide [DLCO] 59.2% predicted).
Participants were divided into a derivation cohort of 292 patients and a validation cohort included 348 patients; the 2 cohorts were similar with respect to baseline characteristics or lung function. Notably, only the derivation cohort included the control group with healthy individuals.
Using univariable analysis, adjusted multivariable logistic analyses, and generalized linear models, researchers identified a group of biomarkers significantly associated with ILD. A biomarker index score (of 0 to 3, with a higher score more strongly associated with more severe lung function impairment) was calculated for combinations of biomarkers above the empirical threshold that were then subjected to validation.
Researchers ultimately found that 3 biomarkers — SP-D, Ca15-3, and ICAM-1 — constituted a composite index that collectively could “robustly discriminate SSc-ILD from SSc controls at baseline, independent of age, sex, smoking and FVC%,” thus providing “a baseline marker of ILD and disease severity, independent of clinical variables.”
In a sensitivity analysis involving only patients with SSc, the biomarker index remained robust to effectively discriminate individuals with SSc-ILD from those with SSc only. An index of 3 was strongly associated with SSc-ILD in the derivation, validation, and pooled analyses (aOR 12.72 in pooled analysis; 95% CI, 4.59-35.21; P <.001). In addition, an index of 2 was strongly associated with SSc-ILD in the derivation cohort and pooled data (aOR 3.24; 95% CI, 1.67-6.30; P =.001).
Study limitations include the use of observational registry data, in which diagnostic procedures were performed when clinically indicated rather than uniformly. Also, radiologic subtypes of SSc-ILD could not be accounted for, and the precise effect of immunomodulation on biomarker levels could not be determined.
“Our data support 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,” stated the investigators. “Ca15-3 may be a lower-cost, more accessible surrogate for KL-6 in future biomarker assessment.”
Disclosure: Research grants for this study were received from Arthritis Australia and Roche Pharmaceuticals. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Jee AS, Stewart I, Youssef P, et al. A composite serum biomarker index for the diagnosis of systemic sclerosis interstitial lung disease: a multicentre, observational, cohort study. Arthritis Rheumatol. Published online March 12, 2023. doi:10.1002/art.42491