Study Identifies Potential New Biomarkers of ILD in Rheumatoid Arthritis

Study findings, published in Frontiers in Medicine, underscore the importance of metabolic profiling for discovering candidate screening biomarkers for interstitial lung disease (ILD) in rheumatoid arthritis.

Results of a case-control study found serum levels of some metabolites were significantly different in patients with both rheumatoid arthritis (RA) and interstitial lung disease (IDL) compared with patients who only have RA. The findings, published in Frontiers in Medicine, underscore the importance of metabolic profiling when it comes to discovering candidate screening biomarkers for ILD in RA.

ILD, an extra-articular manifestation in RA characterized by interstitial inflammation of the lung, is detected in almost 11% of patients with RA and contributes to an overall poor prognosis. Krebs von den lungen-6 and surfactant protein-D have been used in the past as biomarkers for ILD. However, researchers argue their sensitivity is insufficient and cutoff levels were higher for their application to RA-associated ILD (RA-ILD).

“Low molecular weight metabolites are commonly analyzed to elucidate altered metabolisms in pathological conditions,” the researchers explained. In an effort to uncover biomarkers for IDL in patients with RA, they collected serum samples form 200 patients with RA, 100 of whom also had IDL.

All patients underwent chest CT imaging and were recruited from 5 medical centers in Japan. Controls were matched for age group, sex, use of corticosteroids, conventional synthetic disease-modifying antirheumatic drugs, and other factors. The researchers analyzed the serum metabolic profiles of each participant using capillary electrophoresis time-of-flight mass spectrometry.

Overall, the metabolomic analysis detected 299 metabolites. Additional analyses revealed:

  • Serum levels of decanoic acid and morpholine were lower in RA with ILD (false discovery rate Q = 1.87 × 10−11 and 7.09 × 10−6, respectively), and glycerol was higher (Q = 1.20 × 10−6), relative to RA without chronic lung disease
  • Serum levels of these metabolites in RA with usual interstitial pneumonia or RA with nonspecific interstitial pneumonia were altered
  • The partial least squares-discriminant analysis (PLS-DA) model generated from these 3 metabolites could successfully discriminate ILD in RA (area under the curve, 0.919; 95% CI, 0.867-0.968; sensitivity 0.880, specificity 0.780)

Because diabetes is a risk factor for idiopathic pulmonary fibrosis, the researchers hypothesized their findings could be explained by an altered carbohydrate metabolism in the pathogenesis of ILD. However, “although altered levels of glycerol have been reported in metabolomic analyses in several diseases, few studies have noted altered morpholine levels.” Because no animal model for RA-ILD has been established, it is difficult for researchers to investigate causality.

Future independent larger-scale studies are warranted to replicate these results while comparisons with other potential controls, such as patients with idiopathic pulmonary fibrosis, or healthy controls should be performed to discriminate RA-ILD from other conditions.

“This is the first metabolomic analysis to discriminate RA-ILD from RA without lung disease,” authors concluded. “PLS-DA analyses provided candidate screening biomarkers for RA-ILD generated from these 3 metabolites and offer better sensitivity (0.880) than current biomarkers for ILD. Metabolomic profiling would be useful to generate better biomarkers for ILD in RA.”


Furukawa H, Oka S, Shimada K, et al. Serum metabolomic profiling in rheumatoid arthritis patients with interstitial lung disease: a case-control study. Front Med (Lausanne). Published online December 17, 2020. doi:10.3389/fmed.2020.599794