Kass DJ, Nouraie M, Glassberg MK, et al. - Multiplex ELISA was utilized to profile 45 protein biomarkers encompassing cytokines/chemokines, growth factors, and matrix metalloproteinases in sera derived from RA patients with/without interstitial lung disease (ILD), individuals with idiopathic pulmonary fibrosis (IPF), and healthy controls to explain the molecular basis of this overlap through comparative profiling of serum proteins in RA-ILD and IPF. Levels of selected serum proteins were contrasted between patient subgroups. Multiplex ELISA-based evaluation of sera from two independent cohorts (VA, ACR) of RA patients exhibited a number of non-overlapping biomarkers differentiating RA-ILD from RA-no ILD. Parallel analysis of sera from IPF patients also gave a differentiating panel of protein markers in age/gender/smoking adjusted models that exhibited differential overlap with profiles associated with RA-ILD in the VA vs ACR cohorts. PCA exhibited several different functional groups of RA-ILD-associated markers that, in the VA cohort, incorporated pro-inflammatory cytokines/chemokines as well as two distinctive subsets of MMPs. Lastly, LASSO regression modeling in the ACR and VA cohorts exposed different biomarker combinations competent in distinguishing RA-ILD from RA-no ILD. Hence, comparative serum protein biomarker profiling exemplified a viable method for discriminating RA-ILD from RA-no ILD and recognizing population-specific mediators shared with IPF.