Background/Purpose: Several peripheral biomarkers for RA-associated interstitial lung disease (RA-ILD) have been evaluated to enhance early RA-ILD identification. The MUC5B rs35705950 promoter variant, matrix metalloproteinase-7 (MMP-7), and anti-malondialdehyde-acetaldehyde (MAA) antibodies are among the most promising peripheral biomarkers for RA-ILD identification discovered to date. We investigated whether a score based on elevations in these three biomarkers would stratify prevalent and incident RA-ILD risk.

Methods: We performed cross-sectional and cohort studies within a multicenter, prospective cohort of U.S. veterans with RA. RA-ILD was systematically identified in the cohort, and all cases were validated based on standardized medical record review by a board-certified rheumatologist requiring a clinical diagnosis and supportive imaging or biopsy findings. MUC5B promoter variant was measured using the Infinium Global Screening Array, and autosomal dominant inheritance was assumed. MMP-7 was measured from plasma using the MesoScale Discovery platform. IgM anti-MAA-albumin antibodies were measured by ELISA in the serum. A combined three biomarker score (range 0-3) was calculated from the presence of the MUC5B variant and elevations (upper 25% vs. lower 75%) in MMP-7 and anti-MAA antibody concentrations. Multivariable logistic (prevalent RA-ILD) and Cox (incident RA-ILD) regression models evaluated score performance adjusting for age, sex, race, smoking status, BMI category, anti-CCP antibody positivity, DAS28, and Rheumatic Disease Comorbidity Index Score.

Results: We studied 2,231 RA participants (89% male, mean age 64 years), with 88 having prevalent RA-ILD and 148 developing incident RA-ILD over 16,905 patient-years of follow-up. Among those with prevalent RA-ILD, 76% had at least one elevated biomarker and 31% had at least two elevated biomarkers (i.e., sensitivity). Referent to those with no elevated biomarkers (2.2% RA-ILD prevalence), RA patients with 1 (4.8% RA-ILD prevalence, aOR 2.00), 2 (10.1% RA-ILD prevalence, aOR 4.62), or 3 (22.7% RA-ILD prevalence, aOR 13.57) elevated biomarkers had significantly higher odds of prevalent RA-ILD (Table 1). A score of ≥2 had 89% specificity for prevalent RA-ILD (Table 2). Negative predictive values were high and positive predictive values were low, reflecting the low prevalence of RA-ILD. Among those who developed incident RA-ILD, 67.6% had at least one elevated biomarker and 23.0% had at least two elevated biomarkers. In incident RA-ILD analyses (Figure 1), RA patients with combined biomarker scores of 1 (aHR 1.69), 2 (aHR 3.12), or 3 (aHR 5.10) had a significantly increased risk of developing incident RA-ILD during follow-up compared to those with no elevated biomarkers.

Conclusion: A combined biomarker score based on MUC5B, MMP-7, and anti-MAA antibody risk stratified RA patients for prevalent and incident RA-ILD. Because these biomarkers have been previously studied within this cohort, external validation of the biomarker score is needed to further evaluate if this score could be utilized to improve RA-ILD screening approaches.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/combining-three-peripheral-biomarkers-to-stratify-rheumatoid-arthritis-associated-interstitial-lung-disease-risk/