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

Abstract

ObjectiveTo evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA).MethodsWithin a multicenter, prospective cohort of U.S. 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.ResultsAmong 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 (aOR 3.78 [95% CI: 1.86‐7.65]) and over two‐fold increased risk of incident ILD (aHR 2.33 [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).ConclusionMMP‐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.

Pulmonary Damage Biomarkers for Risk of Rheumatoid Arthritis–Associated Interstitial Lung Disease: Enabling Early Detection and Risk Stratification

“…After adjustment for traditional RA-ILD risk factors, the highest quartiles of MMP-7 and MMP-9 were each associated with both prevalent and incident RA-ILD. 15 The associations were stronger for MMP-7 than MMP-9, consistent with previous studies. 11,13,14 Among participants with prevalent RA-ILD, higher plasma concentrations of MMP-9, but not MMP-7, were correlated with lower forced vital capacity as a surrogate for ILD severity.…”

“…11,13,14 Among participants with prevalent RA-ILD, higher plasma concentrations of MMP-9, but not MMP-7, were correlated with lower forced vital capacity as a surrogate for ILD severity. 15 However, MMP-7 was significantly higher among patients with the UIP pattern of RA-ILD compared with those with a non-UIP pattern on chest HRCT. The MUC5B promoter variant did not seem to impact the levels of MMPs.…”

“…In this issue of Arthritis & Rheumatology, Luedders et al investigated the association of MMPs with both prevalent and incident RA-ILD. 15 Using the prospective Veterans Affairs Rheumatoid Arthritis (VARA) registry, they investigated 2,312 participants with RA, systematically identifying both prevalent and incident RA-ILD during a mean follow-up of 7.4 years. 3,15 MMP-1, 3, 7, and 9 were measured using banked plasma samples collected at registry enrollment.…”

“…15 Using the prospective Veterans Affairs Rheumatoid Arthritis (VARA) registry, they investigated 2,312 participants with RA, systematically identifying both prevalent and incident RA-ILD during a mean follow-up of 7.4 years. 3,15 MMP-1, 3, 7, and 9 were measured using banked plasma samples collected at registry enrollment. After adjustment for traditional RA-ILD risk factors, the highest quartiles of MMP-7 and MMP-9 were each associated with both prevalent and incident RA-ILD.…”

Genetic evidence reveals a causal relationship between rheumatoid arthritis and interstitial lung disease

“…Among them, MMP-7 was identified as a potential biomarker for RA–ILD and was significantly elevated in the serum of RA patients with clinical and subclinical ILD ( Chen et al, 2015 ). A prospective cohort study evaluated the association of plasma matrix metalloproteinases (MMPs) with the incidence of interstitial lung disease in patients with rheumatoid arthritis in a large multicenter RA cohort, further supporting the potential pathogenic role of MMP-7 and MMP-9 for RA–ILD ( Luedders et al, 2024 ). The association of RA-induced pulmonary fibrosis also involves MHC gene loci on chromosome 6, such as HLA-B54 , HLA-DQ1B*0601 , HLA-B40 , and sites encoding a-1 protease inhibitors, which are associated with increased ILD risk in patients with RA ( Spagnolo et al, 2014 ).…”