Blood Biomarker Profiling May Distinguish RA-ILD From RA-No ILD

Interstitial pulmonary fibrosis (IPF). Computed tomography (CT) scan of lungs affected by IPF. The two dark structures are the lungs. The white space in the upper center is the heart. The left lung is the most severely affected, with diseased tissue appearing white. IPF is characterized by progressive thickening and stiffening of the lining of the air sacs in the lungs, causing breathlessness and pain. The cause is often unknown but in some cases the disease is thought to result from an autoimmune disorder. Without treatment IPF can lead to heart failure or bronchopneumonia. Treatment depends on the suspected underlying cause.
Researchers sought to identify the molecular basis of the overlap between rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary fibrosis by comparative profiling of serum proteins.

Peripheral blood biomarker profiling may be a viable way to distinguish rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) from RA without ILD (RA-no ILD), and to identify population-specific mediators that overlap with idiopathic pulmonary fibrosis (IPF), according to study results published in Arthritis & Rheumatology.1

Previous studies have shown that compared with the general population, patients with RA are nearly at a 9-fold higher risk of developing clinically significant ILD.2 Results from the research have shown associations between RA-ILD and a number of alternative biomarkers also found to be associated with IPF.

The objectives of this study were to define serum protein biomarker profiles in IPF and RA-ILD and to identify novel therapeutic targets.

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Researchers evaluated the data of patients meeting the 1987 American College of Rheumatology (ACR) classification criteria for RA. The primary cohort comprised patients from 3 Veterans Administration (VA) facilities and a group of United States Veterans enrolled in the Veterans Affairs RA registry; the comparator group included patients with RA recruited from the University of Pittsburgh and Brigham and Women’s Hospital in Boston. Serum samples were obtained from healthy controls (n=36) and from patients meeting the criteria for RA in both the VA and ACR cohorts, who were then stratified into subcategories of no ILD (n=17 for VA group, n=22 for ACR group), indeterminate ILD, subclinical ILD, or clinically evident ILD. The total cohort comprised 86 patients in the VA group with RA-ILD, 49 patients in the ACR group with RA-ILD, and 100 patients with IPF.

Multiplex enzyme-linked immunosorbent assay was used to measure serum levels of 45 proteins, including cytokines/chemokines, growth factors, and matrix metalloproteinases (MMPs). Researchers then compared serum protein levels between patient subgroups by using adjusted linear regression, principal component analysis, and least absolute shrinkage and selection operator modeling.

Results revealed that there were several biomarkers with statistically significant differences in RA-ILD vs RA-no ILD in the VA cohort after correction for multiple comparisons. In the ACR cohort, parallel assessment of serum samples revealed a different profile of RA-ILD-associated mediators when adjusting for models including age, sex, Disease Activity Score 28, and smoking. In the VA cohort, principal component analysis revealed distinct functional groups of RA-ILD-associated markers that encompassed 2 subsets of MMPs (MMP-2 and MMP-7 vs MMP-1, MMP-9, and MMP-10) and proinflammatory mediators, including MIP1β, MCP-3, and tumor necrosis factor α. Least absolute shrinkage and selection operator modeling in both the VA and ACR cohorts revealed 7 distinct biomarker combinations that effectively distinguished RA-ILD from RA-no ILD: MMP-1, MMP-2, MMP-7, MMP-9, IL-1RA, sCD40L, and CXCL9, with high sensitivity and specificity in the VA cohort.

Study limitations included prediction models that may have been less applicable to patients with subclinical RA-ILD, and the small comparative groups for RA-no ILD that may have resulted in additional bias. In addition, researchers lacked data surrounding pulmonary function for the VA cohort.

The study researchers concluded that serum protein biomarker profiling may be an effective way to distinguish RA-ILD from RA-no ILD and to identify mediators that overlap with IPF so new therapies can be developed that target RA-ILD.


1. Kass DJ, Nouraie M, Glassberg MK, et al. Comparative profiling of serum protein biomarkers in rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary fibrosis [published online September 18, 2019]. Arthritis Rheumatol. doi:10.1002/art.41123

2. Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010;62(6):1583-1591.