Biomarkers of Rheumatoid Arthritis–Associated Interstitial Lung Disease

Abstract

Objective Interstitial lung disease (ILD) is a relatively common extraarticular manifestation of rheumatoid arthritis (RA) that contributes significantly to disease burden and excess mortality. The purpose of this study was to identify peripheral blood markers of RA-associated ILD that can facilitate earlier diagnosis and provide insight regarding the pathogenesis of this potentially devastating disease complication. Methods Patients with RA who were enrolled in a well-characterized Chinese identification cohort or a US replication cohort were subclassified as having RA–no ILD, RA–mild ILD, or RA–advanced ILD, based on high-resolution computed tomography scans of the chest. Multiplex enzyme-linked immunosorbent assays (ELISAs) and Luminex xMAP technology were used to assess 36 cytokines/chemokines, matrix metalloproteinases (MMPs), and acute-phase proteins in the identification cohort. Unadjusted and adjusted logistic regression models were used to quantify the strength of association between RA-ILD and biomarkers of interest. Results MMP-7 and interferon-γ–inducible protein 10 (IP-10)/CXCL10 were identified by multiplex ELISA as potential biomarkers for RA-ILD in 133 RA patients comprising the Chinese identification cohort (50 RA–no ILD, 41 RA-ILD, 42 RA–indeterminate ILD). The findings were confirmed by standard solid-phase sandwich ELISA in the Chinese identification cohort as well as an independent cohort of US patients with RA and different stages of ILD (22 RA–no ILD, 49 RA-ILD, 15 RA–indeterminate ILD), with statistically significant associations in both unadjusted and adjusted logistic regression analyses. Conclusion Levels of MMP-7 and IP-10/CXCL10 are elevated in the serum of RA patients with ILD, whether mild or advanced, supporting their value as pathogenically relevant biomarkers that can contribute to noninvasive detection of this extraarticular disease complication.

Detection of Rheumatoid Arthritis–Interstitial Lung Disease Is Enhanced by Serum Biomarkers

“…Baseline demographics and smoking history were obtained from the medical records. We have previously reported subject characteristics of the BRASS and ACR cohorts (18,25). More details including timing of the serum samples, autoantibodies, and PFTs are found in the online supplement.…”

“…For instance, risk factors for RA-ILD and most idiopathic interstitial pneumonias include older age, male sex, and smoking (16)(17)(18)(19)(20)(21). Moreover, our group has recently shown that peripheral blood levels of matrix metalloproteinase-7 (MMP7), a biomarker associated with survival in IPF (22)(23)(24), are significantly elevated in patients with RA with both clinically established and subclinical ILD (25). Based on these findings we hypothesize that validated IPF biomarkers associated with clinical outcomes, such as MMP7, pulmonary and activation-regulated chemokine (PARC)/CCchemokine ligand-18 (26,27), and surfactant protein D (SP-D) (28)(29)(30)(31), could identify RA-ILD (6).…”

Lung Disease in Rheumatoid Arthritis

“…Oka et al [5] suggested HLA-DQB1*03:01 as risk alleles of bronchiectasis or emphysema in RA. For biomarkers, matrix metalloproteinases-7, CXCL10, pulmonary and activation-regulated chemokine, and surfactant protein D were increased in RA with ILD patients compared to RA without ILD [15,16]. Tumor markers such as CA15-3, CA125, and CA19-9 were specifically increased in the sera of RA-ILD patients [3].…”

Practical Approach to the Evaluation and Management of Rheumatoid Arthritis-Interstitial Lung Disease based on its Proven and Hypothetical Mechanisms

“…Biomarkers were first studied in IPF, where higher levels of MMP-7 and SP-D are associated with reduced survival 31,32 . In RA ILD, a combinatorial signature including MMP-7 and IP-10 (a chemokine related to Th1 lymphocyte trafficking) significantly increased the detection of the disease, while MMP-7 and SP-D have also been shown to enhance our ability to risk-stratify clinically evident and subclinical disease 33,34 . However, the role of these or other biomarkers in clinical practice needs to be clarified.…”