Identification of Subclinical Lung Involvement in ACPA-Positive Subjects through Functional Assessment and Serum Biomarkers

Int J Mol Sci. 2020 Jul 21;21(14):5162. doi: 10.3390/ijms21145162.


Lung involvement is related to the natural history of anti-citrullinated proteins antibodies (ACPA)-positive rheumatoid arthritis (RA), both during the pathogenesis of the disease and as a site of disease-related injury. Increasing evidence suggests that there is a subclinical, early lung involvement during the course of the disease, even before the onset of articular manifestations, which can potentially progress to a symptomatic interstitial lung disease. To date, reliable, non-invasive markers of subclinical lung involvement are still lacking in clinical practice. The aim of this study is to evaluate the diagnostic potential of functional assessment and serum biomarkers in the identification of subclinical lung involvement in ACPA-positive subjects. Fifty ACPA-positive subjects with or without confirmed diagnosis of RA (2010 ARC-EULAR criteria) were consecutively enrolled. Each subject underwent clinical evaluation, pulmonary function testing (PFT) with assessment of diffusion lung capacity for carbon monoxide (DLCO), cardiopulmonary exercise testing (CPET), surfactant protein D (SPD) serum levels dosage and high-resolution computed tomography (HRCT) of the chest. The cohort was composed of 21 ACPA-positive subjects without arthritis (ND), 10 early (disease duration < 6 months, treatment-naïve) RA (ERA) and 17 long-standing (disease duration < 36 months, on treatment) RA (LSRA). LSRA patients had a significantly higher frequency of overall HRCT abnormalities compared to the other groups (p = 0.001). SPD serum levels were significantly higher in ACPA-positive subjects compared with healthy controls (158.5 ± 132.3 ng/mL vs 61.27 ± 34.11 ng/mL; p < 0.0001) and showed an increasing trend from ND subjects to LSRD patients (p = 0.004). Patients with HRCT abnormalities showed significantly lower values of DLCO (74.19 ± 13.2% pred. vs 131.7 ± 93% pred.; p = 0.009), evidence of ventilatory inefficiency at CPET and significantly higher SPD serum levels compared with subjects with no HRCT abnormalities (213.5 ± 157.2 ng/mL vs 117.7 ± 157.3 ng/mL; p = 0.018). Abnormal CPET responses and higher SPD levels were also associated with specific radiological findings. Impaired DLCO and increased SPD serum levels were independently associated with the presence of HRCT abnormalities. Subclinical lung abnormalities occur early in RA-associated autoimmunity. The presence of subclinical HRCT abnormalities is associated with several functional abnormalities and increased SPD serum levels of SPD. Functional evaluation through PFT and CPET, together with SPD assessment, may have a diagnostic potential in ACPA-positive subjects, contributing to the identification of those patients to be referred to HRCT scan.

Keywords: ACPA; CPET; DLCO; HRCT; interstitial lung disease; pulmonary function testing; rheumatoid arthritis; subclinical involvement; surfactant protein D.

MeSH terms

  • Adult
  • Anti-Citrullinated Protein Antibodies / blood*
  • Anti-Citrullinated Protein Antibodies / immunology
  • Arthritis, Rheumatoid / blood*
  • Arthritis, Rheumatoid / diagnosis
  • Arthritis, Rheumatoid / diagnostic imaging
  • Arthritis, Rheumatoid / immunology
  • Autoimmunity
  • Biomarkers / blood
  • Cohort Studies
  • Exercise Test / methods*
  • Female
  • Humans
  • Lung / diagnostic imaging
  • Lung / physiopathology*
  • Lung Diseases, Interstitial / blood*
  • Lung Diseases, Interstitial / diagnosis
  • Lung Diseases, Interstitial / immunology
  • Male
  • Middle Aged
  • Pulmonary Surfactant-Associated Protein D / blood
  • Respiratory Function Tests
  • Rheumatoid Factor / blood
  • Tomography, X-Ray Computed


  • Anti-Citrullinated Protein Antibodies
  • Biomarkers
  • Pulmonary Surfactant-Associated Protein D
  • Rheumatoid Factor