A Composite Serum Biomarker Index for the Diagnosis of Systemic Sclerosis-Associated Interstitial Lung Disease: A Multicenter, Observational Cohort Study

Arthritis Rheumatol. 2023 Aug;75(8):1424-1433. doi: 10.1002/art.42491. Epub 2023 May 15.


Objective: In patients with systemic sclerosis (SSc), we investigated composite serum biomarker panels for the diagnosis and risk stratification of SSc-associated interstitial lung disease (SSc-ILD).

Methods: We analyzed 28 biomarkers in 640 participants: 259 patients with SSc-ILD and 179 SSc patients without ILD (Australian Scleroderma Cohort Study), 172 patients with idiopathic pulmonary fibrosis (IPF-controls) (Australian IPF Registry), and 30 healthy controls. A composite index was developed from biomarkers associated with ILD in multivariable analysis derived at empirical thresholds. We evaluated the performance of the index to identify ILD, and specifically SSc-ILD, and its association with lung function, disease extent on radiography, and patient health-related quality of life in derivation and validation cohorts. Biomarkers to distinguish SSc-ILD from IPF-controls were identified.

Results: A composite biomarker index, comprising surfactant protein D (SP-D), Ca15-3, and intercellular adhesion molecule 1 (ICAM-1), was strongly associated with SSc-ILD diagnosis, independent of age, sex, smoking history, and lung function (for biomarker index score 3, pooled adjusted odds ratio was 12.72 (95% confidence interval 4.59-35.21) (P < 0.001). The composite index strengthened the performance of individual biomarkers for SSc-ILD identification. In SSc patients, a higher index was associated with worse baseline disease severity (for biomarker index score 3 relative to biomarker index score 0, the adjusted absolute change in forced vital capacity percent predicted was -17.84% and the diffusing capacity for carbon monoxide percent predicted was -20.16%; both P < 0.001).

Conclusion: A composite serum biomarker index, comprising SP-D, Ca15-3, and ICAM-1, may improve the identification and risk stratification of ILD in SSc patients at baseline.

Publication types

  • Observational Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Australia
  • Biomarkers
  • Cohort Studies
  • Humans
  • Idiopathic Pulmonary Fibrosis*
  • Intercellular Adhesion Molecule-1
  • Lung
  • Lung Diseases, Interstitial* / diagnosis
  • Lung Diseases, Interstitial* / etiology
  • Pulmonary Surfactant-Associated Protein D
  • Quality of Life
  • Scleroderma, Systemic*


  • Intercellular Adhesion Molecule-1
  • Pulmonary Surfactant-Associated Protein D
  • Biomarkers