Biomarkers of rheumatoid arthritis-associated interstitial lung disease.

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. 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. 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. 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.

Chen J ，Doyle TJ ，Liu Y ，Aggarwal R ，Wang X ，Shi Y ，Ge SX ，Huang H ，Lin Q ，Liu W ，Cai Y ，Koontz D ，Fuhrman CR ，Golzarri MF ，Liu Y ，Hatabu H ，Nishino M ，Araki T ，Dellaripa PF ，Oddis CV ，Rosas IO ，Ascherman DP ... -  《-》

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

Doyle TJ ，Patel AS ，Hatabu H ，Nishino M ，Wu G ，Osorio JC ，Golzarri MF ，Traslosheros A ，Chu SG ，Frits ML ，Iannaccone CK ，Koontz D ，Fuhrman C ，Weinblatt ME ，El-Chemaly SY ，Washko GR ，Hunninghake GM ，Choi AM ，Dellaripa PF ，Oddis CV ，Shadick NA ，Ascherman DP ，Rosas IO ... -  《-》

Comparative Profiling of Serum Protein Biomarkers in Rheumatoid Arthritis-Associated Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis.

Interstitial lung disease (ILD) is a frequent complication of rheumatoid arthritis (RA), occurring in up to 40% of patients during the course of their disease. Early diagnosis is critical, particularly given the shared clinicoepidemiologic features between advanced rheumatoid arthritis-associated ILD (RA-ILD) and idiopathic pulmonary fibrosis (IPF). This study was undertaken to define the molecular basis of this overlap through comparative profiling of serum proteins in RA-ILD and IPF. Multiplex enzyme-linked immunosorbent assays (ELISAs) were used to profile 45 protein biomarkers encompassing cytokines/chemokines, growth factors, and matrix metalloproteinases (MMPs) in sera obtained from RA patients with ILD and those without, individuals with IPF, and healthy controls. Levels of selected serum proteins were compared between patient subgroups using adjusted linear regression, principal component analysis (PCA), and least absolute shrinkage and selection operator (LASSO) modeling. Multiplex ELISA-based assessment of sera from 2 independent cohorts (Veterans Affairs [VA] and Non-VA) revealed a number of non-overlapping biomarkers distinguishing RA-ILD from RA without ILD (RA-no ILD) in adjusted regression models. Parallel analysis of sera from IPF patients also yielded a discriminatory panel of protein markers in models adjusted for age/sex/smoking, which showed differential overlap with profiles linked to RA-ILD in the VA cohort versus the Non-VA cohort. PCA revealed several distinct functional groups of RA-ILD-associated markers that, in the VA cohort, encompassed proinflammatory cytokines/chemokines as well as 2 different subsets of MMPs. Finally, LASSO regression modeling in the Non-VA and VA cohorts revealed distinct biomarker combinations capable of discriminating RA-ILD from RA-no ILD. Comparative serum protein biomarker profiling represents a viable method for distinguishing RA-ILD from RA-no ILD and identifying population-specific mediators shared with IPF.

Kass DJ ，Nouraie M ，Glassberg MK ，Ramreddy N ，Fernandez K ，Harlow L ，Zhang Y ，Chen J ，Kerr GS ，Reimold AM ，England BR ，Mikuls TR ，Gibson KF ，Dellaripa PF ，Rosas IO ，Oddis CV ，Ascherman DP ... -  《-》

Plasma Matrix Metalloproteinase Concentrations and Risk of Interstitial Lung Disease in a Prospective Rheumatoid Arthritis Cohort.

To evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA). Within a multicenter, prospective cohort of US veterans with RA, we performed a cross-sectional study of prevalent ILD and cohort study of incident ILD. ILD diagnoses were validated by medical record review of provider diagnoses and chest imaging and/or pathology reports. MMP-1, 3, 7, and 9 concentrations were measured in plasma samples, then standardized and categorized into quartiles. The associations of MMPs with prevalent and incident ILD were assessed with logistic (prevalent) and Cox (incident) regression models adjusted for RA-ILD risk factors. Among 2,312 participants (88.9% male; mean age 63.8 years), 96 had prevalent ILD. Incident ILD developed in 130 participants over 17,378 person-years of follow-up (crude incidence rate 7.5/1,000 person-years). Participants with the highest quartile of MMP-7 concentrations had a nearly four-fold increased odds of prevalent ILD (adjusted odds ratio 3.78 [95% confidence interval (95% CI) 1.86-7.65]) and over two-fold increased risk of incident ILD (adjusted hazard ratio 2.33 [95% CI 1.35-4.02]). Higher MMP-9 concentrations were also associated with prevalent and incident ILD, as well as negatively correlated with forced vital capacity among those with prevalent ILD (r = -0.30, P = 0.005). MMP-7 and MMP-9 were strongly associated with both prevalent and incident ILD in this large, multicenter RA cohort after adjustment for other RA-ILD risk factors. These population-level findings further support a potential pathogenic role for MMPs in RA-ILD and suggest that their measurement could facilitate RA-ILD risk stratification.

Luedders BA ，Wheeler AM ，Ascherman DP ，Baker JF ，Duryee MJ ，Yang Y ，Roul P ，Wysham KD ，Monach P ，Reimold A ，Kerr GS ，Kunkel G ，Cannon GW ，Poole JA ，Thiele GM ，Mikuls TR ，England BR ... -  《-》

Improving risk-stratification of rheumatoid arthritis patients for interstitial lung disease.

Avouac J ，Cauvet A ，Steelandt A ，Shirai Y ，Elhai M ，Kuwana M ，Distler O ，Allanore Y ... -  《PLoS One》