Elevated circulating MMP-9 is linked to increased COPD exacerbation risk in SPIROMICS and COPDGene

Abstract

Background: Matrix metalloprotease 9 (MMP-9) is associated with inflammation and lung remodeling in chronic obstructive pulmonary disease (COPD). We hypothesized that elevated circulating MMP-9 represents a potentially novel biomarker that identifies a subset of individuals with COPD with an inflammatory phenotype who are at increased risk for acute exacerbation (AECOPD).

Methods: We analyzed Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene) cohorts for which baseline and prospective data were available. Elevated MMP-9 was defined based on >95th percentile plasma values from control (non-COPD) sample in SPIROMICS. COPD subjects were classified as having elevated or nonelevated MMP-9. Logistic, Poisson, and Kaplan-Meier analyses were used to identify associations with prospective AECOPD in both cohorts.

Results: Elevated MMP-9 was present in 95/1,053 (9%) of SPIROMICS and 41/140 (29%) of COPDGene participants with COPD. COPD subjects with elevated MMP-9 had a 13%-16% increased absolute risk for AECOPD and a higher median (interquartile range; IQR) annual AECOPD rate (0.33 [0-0.74] versus 0 [0-0.80] events/year and 0.9 [0.5-2] versus 0.5 [0-1.4] events/year for SPIROMICS and COPDGene, respectively). In adjusted models within each cohort, elevated MMP-9 was associated with increased odds (odds ratio [OR], 1.71; 95%CI, 1.00-2.90; and OR, 3.03; 95%CI, 1.02-9.01), frequency (incidence rate ratio [IRR], 1.45; 95%CI, 1.23-1.7; and IRR, 1.24; 95%CI, 1.03-1.49), and shorter time-to-first AECOPD (21.7 versus 31.7 months and 14 versus 21 months) in SPIROMICS and COPDGene, respectively.

Conclusions: Elevated MMP-9 was independently associated with AECOPD risk in 2 well-characterized COPD cohorts. These findings provide evidence for MMP-9 as a prognostic biomarker and potential therapeutic target in COPD.

Trial registration: ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene).

Funding: This work was funded by K08 HL123940 to JMW; R01HL124233 to PJC; Merit Review I01 CX000911 to JLC; R01 (R01HL102371, R01HL126596) and VA Merit (I01BX001756) to AG. SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) is funded by contracts from the NHLBI (HHSN268200900013C, HHSN268200900014C,HHSN268200900015C HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C) and a grant from the NIH/NHLBI (U01 HL137880), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals Inc.; Chiesi Farmaceutici; Forest Research Institute Inc.; GlaxoSmithKline; Grifols Therapeutics Inc.; Ikaria Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. COPDGene is funded by the NHLBI (R01 HL089897 and R01 HL089856) and by the COPD Foundation through contributions made to an Industry Advisory Board composed of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

Keywords: COPD; Proteases; Pulmonology.

Conflict of interest statement

Conflict of interest: JMW has received grant support and consulting fees from GSK, AZ, Gilead, Bayer, Quintiles, Mylan, and Mereo BioPharma. MTD has received grants from; Consulting fees from AstraZeneca, BI, GSK, PneummRx/BTG, and Quark; and contracted clinical trial support from AstraZeneca, BI, Boston Scientific, GSK, Novartis PneumRx/BTG, Pulmonx, and Yungjin. JLC has received grants from MedImmune Corp. Ltd. IB has received grant support and consulting fees from AZ, Grifols, CSL Behring, and Amgen. EKS has received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GSK. PJC has received grant support and consulting fees from GSK. AG has received grant support from the and consulting fees from Gilead Sciences, Grifols Inc., and Celtaxsys Inc.

Figures

Figure 1. Flow diagrams for the participants in the study.

(A) SPIROMICS and (B) COPDGene. All allocated subjects in both cohorts were included in analysis. COPD, chronic obstructive pulmonary disease; MMP, matrix metalloprotease.

Figure 2. Plasma MMP-9 distribution in the 2 cohorts.

(A) The distribution of log-transformed MMP-9 values in 1,053 individuals with COPD in SPIROMICS. (B) The distribution of log-transformed MMP-9 values in 140 individuals with COPD in COPDGene. The red line corresponds to elevated MMP-9 (MMP-9 >2.67 ng/ml, log transformed; defined as the 95th percentile value in the non-COPD cohort). COPD, chronic obstructive pulmonary disease; MMP, matrix metalloprotease.

Figure 3. MMP-9 values across GOLD stages.

MMP-9 (ng/ml log transformed) values were different across GOLD stage in (A) SPIROMICS (P = 0.023) but not in (B) COPDGene (P = 0.48) by 1-way ANOVA. In COPDGene, GOLD stages 1 and 2 were combined due to the presence of a single GOLD stage 1 participant. The values included within the box(es) represent the interquartile range, the horizontal line the median, and the whiskers the 95% CI; outliers are represented by circles. GOLD, Global initiative for Obstructive Lung Disease; MMP, matrix metalloproteinase.

Figure 4. Associations between elevated MMP-9 prospective exacerbations.

Models were adjusted for age, race, sex, FEV1 percent predicted, smoking status, chronic bronchitis, leukocyte count, and history of previous exacerbations. (A) Logistic regression was used to measure associations with ≥1 AECOPD, and (B) Poisson regression was used for exacerbation frequency. Boxes represent the point estimates (OR or IRR), and the horizontal bars represent the 95% CI. AECOPD, acute exacerbation of chronic obstructive pulmonary disease; MMP, matrix metalloprotease; OR, odds ratio; IRR, incidence rate ratio.

Figure 5. Kaplan-Meier plots for the probability of remaining free of AECOPD.

(A) In SPIROMICS, the median time-to-first event was 10 months shorter in individuals with elevated MMP-9 compared with those without MMP-9 elevation (21.7 months [95% CI, 17.5–25.9] versus 31.7 months [95% CI, 27.2–36.2], P = 0.015). (B) In COPDGene, the median time-to-first AECOPD was also shorter among the elevated MMP-9 group (14 months [95% CI, 9.4–18.6] versus 21 months [95% CI, 15–27], P = 0.065). AECOPD, acute exacerbation of chronic obstructive pulmonary disease; MMP, matrix metalloprotease.