Background/Purpose:

Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA) and a significant cause of morbidity and mortality.  Asymptomatic, subclinical RA-associated ILD (RA-ILD) may represent a more treatable precursor to end stage fibrotic lung disease.  The objective of this study was therefore to define peripheral blood protein signatures capable of identifying subclinical RA-ILD.

Methods:

We analyzed the serum concentration of 37 cytokines, chemokines, and remodeling proteins in 55 RA patients and 24 healthy controls recruited through the First Hospital of Xiamen University.  RA patients were independently classified as RA-ILD or RA-no ILD based on the presence/absence of high resolution chest CT (HRCT) abnormalities consisting of ground glass opacification, septal thickening, traction bronchiectasis, and/or honeycombing.  Levels of specific serum proteins were then correlated with disease subset as well as pulmonary function tests (percent predicted forced vital capacity (%FVC), total lung capacity (%TLC), and carbon monoxide diffusion capacity (%DLCO)) using non-parametric rank sum analysis and Spearman’s correlation coefficients, respectively.

Results:

Among the 55 RA patients who generally lacked symptoms of dyspnea or cough (2/55 patients presented with these pulmonary manifestations) at the time of serum assessment, 38 (69%)had HRCT evidence of ILD (RA-ILD), while 17 (31%) had no clinical or radiographic evidence of ILD (RA-no ILD).  Within the RA-ILD subgroup, the predominant HRCT abnormality was ground glass opacification (55%) suggestive of nonspecific interstitial pneumonia (NSIP).  

Multiplex ELISA demonstrated that concentrations of MMP7, IFNg, IP-10, and IL-2Ra were statistically higher in the sera of RA-ILD relative to RA-no ILD patients (respective means ± SEM:  1739 ± 292.3 vs. 761.5 ± 83.85 pg/ml (p=0.0317); 9.084 ± 1.502 vs. 4.419 ± 0.6553 pg/ml (p=0.0474); 204.6 ± 34.83 vs. 95.49 ± 13.75 pg/ml (p=0.0449); and 157.0 ± 25.16 vs. 71.55 ± 11.04 pg/ml (p=0.0307)).  By ROC analysis, levels of MMP7, IFNg, and IL-2Ra distinguished RA-ILD from RA-no ILD with optimal sensitivities and specificities of 0.87/0.71/0.95 and 0.71/0.65/0.47, respectively.  A composite index based on levels of MMP7, IFNg, IL-2Ra, IP-10, and TNFa further discriminated these subgroups with a sensitivity of 0.76 and a specificity of 0.94. Individual concentrations of MMP7, IFNg, IL-2Ra, and IP-10 correlated significantly with overall disease activity, effectively distinguishing individuals with RA-ILD and RA-no ILD.  At the same time, MMP7, IFNg, IL-2Ra, and IP-10 concentrations were negatively correlated with %FVC, %TLC, and %DLCO.

Conclusion:

In a cohort of RA patients lacking overt clinical features of pulmonary involvement, MMP7, IFNg, IL-2Ra, and IP10 emerged as serum biomarkers of radiographically defined ILD.  Supporting a relationship to underlying pulmonary disease activity, serum levels of these proteins were inversely correlated with various measures of pulmonary function.  However, future longitudinal studies will be required to fully assess the capacity of these serum biomarkers to predict disease progression.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/peripheral-blood-biomarkers-of-rheumatoid-arthritis-associated-interstitial-lung-disease/