Plasma Matrix Metalloproteinase Concentrations and Risk of Interstitial Lung Disease in a Prospective Rheumatoid Arthritis Cohort

Abstract

Objective: To evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA).

Methods: Within a multicenter, prospective cohort of US veterans with RA, we performed a cross-sectional study of prevalent ILD and cohort study of incident ILD. ILD diagnoses were validated by medical record review of provider diagnoses and chest imaging and/or pathology reports. MMP-1, 3, 7, and 9 concentrations were measured in plasma samples, then standardized and categorized into quartiles. The associations of MMPs with prevalent and incident ILD were assessed with logistic (prevalent) and Cox (incident) regression models adjusted for RA-ILD risk factors.

Results: Among 2,312 participants (88.9% male; mean age 63.8 years), 96 had prevalent ILD. Incident ILD developed in 130 participants over 17,378 person-years of follow-up (crude incidence rate 7.5/1,000 person-years). Participants with the highest quartile of MMP-7 concentrations had a nearly four-fold increased odds of prevalent ILD (adjusted odds ratio 3.78 [95% confidence interval (95% CI) 1.86-7.65]) and over two-fold increased risk of incident ILD (adjusted hazard ratio 2.33 [95% CI 1.35-4.02]). Higher MMP-9 concentrations were also associated with prevalent and incident ILD, as well as negatively correlated with forced vital capacity among those with prevalent ILD (r = -0.30, P = 0.005).

Conclusion: MMP-7 and MMP-9 were strongly associated with both prevalent and incident ILD in this large, multicenter RA cohort after adjustment for other RA-ILD risk factors. These population-level findings further support a potential pathogenic role for MMPs in RA-ILD and suggest that their measurement could facilitate RA-ILD risk stratification.

Figure 1.. Forest plot illustrating the associations of plasma MMP concentrations in quartiles with prevalent ILD in patients with RA.

Matrix metalloproteinases (MMPs) assessed in separate logistic regression models adjusted for age, sex, race, smoking, anti-citrullinated peptide antibody positivity, RA disease activity, and period of enrollment. Quartile 1 (referent) represents the lowest values. Abbreviations: MMP = matrix metalloproteinase, ILD = interstitial lung disease, RA = rheumatoid arthritis, aOR = adjusted odds ratio, ref. = referent.

Figure 2.. Mean plasma MMP-7 concentrations (per 1 SD) by ILD pattern and MUC5B rs35705950 promoter variant.

Standardized values of log-transformed matrix metalloproteinase (MMP)-7 concentrations were calculated by subtracting the mean value from the sample value and dividing by the standard deviation. Comparisons of MMP-7 concentrations across interstitial lung disease (ILD) patterns and presence of MUC5B rs35705950 promoter variant are shown. Error bars indicate standard error of the mean. *across entire sample by Kruskal-Wallis test ^xpairwise comparison by post hoc Dunn test with Bonferroni correction Abbreviations: MMP = matrix metalloproteinase, ILD = interstitial lung disease, UIP = usual interstitial pneumonia

Figure 3.. Forest plot illustrating the associations of plasma MMP concentrations in quartiles with incident ILD in patients with RA.

Matrix metalloproteinases (MMPs) assessed in separate Cox models adjusted for age, sex, race, smoking, anti-citrullinated peptide antibody positivity, RA disease activity, and period of enrollment. Quartile 1 (referent) represents the lowest values. Abbreviations: MMP = matrix metalloproteinase, ILD = interstitial lung disease, RA = rheumatoid arthritis, aHR = adjusted hazard ratio, Q = quartile, CI = confidence interval.

Figure 4.. Cumulative hazard plots of incident ILD by MMP quartile.

Cumulative hazard plots constructed using Cox models adjusted for age, sex, race, smoking, anti-citrullinated peptide antibody positivity, RA disease activity, and period of enrollment. X-axes indicate follow-up time (years) and y-axes indicate the cumulative hazard of incident RA-ILD in adjusted models. Abbreviations: ILD = interstitial lung disease, MMP = matrix metalloproteinase, RA = rheumatoid arthritis.