Serum Metabolomic Profiling in Rheumatoid Arthritis Patients With Interstitial Lung Disease: A Case–Control Study

Abstract

Objectives: Interstitial lung disease (ILD) is an extra-articular manifestation in rheumatoid arthritis (RA), detected in 10.7% of patients, and causing a poor prognosis. Hence, biomarkers for ILD are urgently required in RA. Low molecular weight metabolites can be assessed by metabolomic analyses, and although these have been conducted in RA and in idiopathic pulmonary fibrosis, few have been carried out for ILD in the context of RA. Therefore, we analyzed serum metabolomic profiles of ILD in RA to identify novel biomarkers.Methods: Serum samples from 100 RA patients with ILD and 100 matched RA patients without chronic lung disease (CLD) were collected. These samples were subjected to metabolomic analyses using capillary electrophoresis time-of-flight mass spectrometry.Results: A total of 299 metabolites were detected in the metabolomic analysis. By univariate analysis, 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 CLD. Serum levels of these metabolites in RA with usual interstitial pneumonia or RA with non-specific interstitial pneumonia were also altered. The partial least squares-discriminant analysis model generated from these three metabolites could successfully discriminate ILD in RA (area under the curve: 0.919, 95% confidence interval: 0.867–0.968, sensitivity 0.880, specificity 0.780).Conclusions: Serum levels of some metabolites were significantly different in RA with ILD compared with RA without CLD. It is concluded that metabolomic profiling will be useful for discovering candidate screening biomarkers for ILD in RA.

Serum rheumatoid factor IgA, anti-citrullinated peptide antibodies with secretory components, and anti-carbamylated protein antibodies associate with interstitial lung disease in rheumatoid arthritis

“…Based on the 98th percentile among 52 healthy controls, the cut-off value for positivity was set to 0. The presence of RF and ACPA IgG autoantibodies in patients with RA has been reported in previous studies [ 19 , 20 ]. Krebs von den lungen-6 (KL-6) was detected using a Picolumi KL-6 Electrochemiluminescence immunoassay system (EIDIA Co., Ltd., Tokyo, Japan) and the cut-off value set by manufacturer was 500 U/ml.…”

Biomarkers for interstitial lung disease and acute-onset diffuse interstitial lung disease in rheumatoid arthritis

“…Serum metabolomic profiles of ILD in RA have been systematically analyzed. 118 Serum levels of decanoic acid and morpholine were decreased in RA with ILD, and glycerol was increased. Serum levels of these metabolites in RA with UIP or RA with NSIP were similarly changed.…”

“…Oka et al 13 Other biomarkers Amino acid Furukawa et al 26 Decanoic acid, morpholine, and glycerol Furukawa et al 118 Mannosamine, alliin, kynurenine, and 2-hydroxybutyric acid Furukawa et al 27 Platelet/lymphocyte ratio Chen et al 119 AoDILD, acute-onset diffuse interstitial lung disease; HLA, human leukocyte antigen; IPF, idiopathic pulmonary fibrosis; RA, rheumatoid arthritis; RA-ILD, rheumatoid arthritis-associated interstitial lung disease. gene was found.…”

“…Chen et al 106 Interleukin-18 Matsuo et al 107 Interleukin-13 Hussein et al 109 Soluble programmed death-ligand 1 Wu et al 108 Matrix metalloproteinase-1, tissue inhibitors of metalloproteinases-1, osteopontin, soluble interleukin-2 receptor α, and interleukin-1 receptor antagonist Oka et al 13 Other biomarkers Amino acid Furukawa et al 26 Decanoic acid, morpholine, and glycerol Furukawa et al 118 Mannosamine, alliin, kynurenine, and 2-hydroxybutyric acid Furukawa et al 27 Platelet/lymphocyte ratio Chen et al 119 AoDILD, acute-onset diffuse interstitial lung disease; HLA, human leukocyte antigen; IPF, idiopathic pulmonary fibrosis; RA, rheumatoid arthritis; RA-ILD, rheumatoid arthritis-associated interstitial lung disease.…”

Multi-omics analysis of biomarkers and molecular mechanism of rheumatoid arthritis with bone destruction

“…Metabolism is a general term for a series of ordered chemical reactions that take place in living organisms to maintain life [4] and is indispensable for the maintenance of life [5]. At present, metabolomics is an effective tool to identify biomarkers of RA and other diseases, Hiroshi Furukawa et al have proved that metabolomic pro ling will be useful for discovering candidate screening biomarkers for interstitial lung disease in RA [6], Lun Zhang et al successfully identi ed and validated a simple, highperforming, metabolite-based test for detecting early stage (I/II) non-small cell lung cancer patients in plasma [7].…”