Background/Purpose: Based on the overlap in peripheral blood biomarkers associated with rheumatoid arthritis interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF), a composite biomarker score based on IPF-molecular profiles was previously derived that correlated with RA-ILD disease stage (Kass et al. Arth Rheum, 2022; 74(suppl 9)). In this study, we aimed to externally validate the predictive value of a modified version of this biomarker score with prevalent and incident ILD in a large, multicenter RA cohort.

Methods: We performed cross-sectional and longitudinal analyses of participants in the Veterans Affairs Rheumatoid Arthritis registry, a prospective cohort of U.S. veterans with RA. RA-ILD diagnoses were validated by medical record review, with prevalent and incident ILD defined pre- and post-enrollment, respectively. Concentrations of 7 of 8 previously proposed IPF mediators (matrix metalloproteinase [MMP]-7, MMP-9, eotaxin, macrophage-derived chemokine [MDC], monocyte chemoattractant protein-1 [MCP-1], Fms-like tyrosine kinase 3 ligand [Flt3L] and interleukin-8 [IL-8]; MMP-2 unavailable and not included) were measured from serum/plasma at enrollment (MesoScale Discovery platform). Log-transformed and standardized values (per cohort mean and standard deviation for each analyte) were summed to compute a composite biomarker score. Associations of the biomarker score (continuous and quartile) with prevalent and incident RA-ILD were assessed in multivariable regression models (logistic and Cox), adjusted for age, sex, race, smoking status, anti-CCP positivity, and RA disease activity. Discrimination of prevalent RA-ILD was evaluated with receiver operating characteristic (ROC) curves, initially using the aforementioned clinical predictors alone and subsequently with the addition of the biomarker score.

Results: Among 2,092 participants (89% male, mean age 64 years), prevalent RA-ILD was identified in 86 and incident RA-ILD developed in 116 participants during a mean follow-up of 7.7 years. Mean composite biomarker scores were significantly lower in participants without RA-ILD than in those with prevalent ILD or incident RA-ILD (-0.35 vs. 0.89 and 0.54, respectively, both p < 0.02). Higher biomarker scores were significantly associated with prevalent (aOR 1.08 [1.01, 1.15]) and incident (aHR 1.06 [1.01, 1.12] per 1 point increase) RA-ILD. Participants with biomarker scores in the highest quartile had over 2-fold higher odds of prevalent RA-ILD (Figure 1) and risk of incident RA-ILD (Figure 2). The addition of the biomarker score to clinical predictors did not significantly improve prevalent RA-ILD discrimination (AUC 0.653 [0.595, 0.711] clinical vs. 0.669 [0.613, 0.725] clinical and biomarker score, p = 0.30).

Conclusion: A modified composite biomarker score based on IPF molecular profiles was associated with prevalent and incident ILD in a large, multicenter RA cohort. While externally validating prior findings by Kass et al. and implicating IPF mediators in RA-ILD pathogenesis, the IPF-derived composite biomarker score had modest discriminative performance. Further work is needed to evaluate the clinical utility of this, and other, RA-ILD risk scores.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-modified-idiopathic-pulmonary-fibrosis-derived-composite-biomarker-score-is-associated-with-interstitial-lung-disease-among-u-s-veterans-with-rheumatoid-arthritis/