MMP-7 as Biomarker for Scleroderma-Associated Interstitial Lung Disease

An association between baseline matrix metalloproteinase-7 (MMP7) levels and baseline lung function/survival was observed in a single cohort of patients with systemic sclerosis (SSc)-linked interstitial lung disease (ILD).  This was among the findings of a retrospective study published in the European Respiratory Journal.

In this study, researchers sought to evaluate whether the use of disease-relevant biomarkers could refine our comprehension of the prognosis of patients with SSc-ILD.  The biomarkers that were assessed included MMP7, chemokine (C-C motif), ligand 18 (CCL18), and chemokine (CX-X-C motif) ligand 13 (CXCL13). They explored the association of these biomarkers with baseline lung function and prognosis among patients with SSc-ILD.

The study was conducted among patients who were identified from the University of California San Diego Interstitial Lung disease biorepository. All patients enrolled in the study needed a rheumatologist-confirmed diagnosis of scleroderma and evidence of ILD on high-resolution computed tomography (HRCT) scan or lung biopsy. Clinical data, including demographics, comorbidities, pulmonary function, and smoking history, as well as serum samples, were obtained prospectively as part of a longitudinal registry. Sections of lung tissue were immunostained for MMP7 with the use of polyclonal goat antibody against human MMP7. RNA that was isolated from homogenized lung tissue underwent quantitative polymerase chain reaction to test for MMP7. Commercially available enzyme-linked immunosorbent assays for MMP7, CCL18, and CXCL13 were utilized.

A total of 115 participants with SSc-ILD were included in the study cohort. Overall, 83.2% of the participants were female. The mean patient age was 57.5 years, and 46.5% of the participants reported a history of smoking. The median follow-up time for all participants was 4.34 years. Among the study cohort, the average baseline lung function was 77.1% predicted forced vital capacity (FVC) and 57.0% predicted diffusion capacity of the lung for carbon monoxide (DLCO). Pulmonary hypertension (PH) was detected in 24.3% of the participants. The mean extent of fibrosis on HRCT scans was 14.9%.

In patients with SSc-ILD, higher serum MMP7 levels were associated with lower FVC% predicted and lower DLCO% predicted (P <.001 for both). These associations retained significance after adjustments for such potential confounders as age, sex, PH, and smoking status were made. For every doubling of the MMP7 value, a 6.64-unit reduction in FVC% predicted (95% CI, –9.17 to –4.11) and a 7.00-unit reduction in DLCO% predicted (95% CI, –10.09 to –3.92) were observed. No association was observed between CCL18 or CXCL13 level and baseline predicted FVC% or DLCO% in the participants.

MMP7 levels were also predictive of mortality in this cohort. During follow-up, 20 patients with SSc-ILD either died or underwent lung transplantation. MMP7 level was associated with mortality or lung transplantation in 20 patients with SSc-ILD (hazard ratio [HR], 2.05; 95% CI, 1.23-3.42 per doubling; P =.009). MMP7 was categorized into 3 groups— low, medium, and high: MMP7 <2000 pg/mL, MMP7=2000 to 4000 pg/mL, and MMP7 >4000 pg/mL, respectively, which corresponded significantly with disease severity (P <.001). The association between MMP7 and transplant-free survival remained significant following adjustment for smoking history, age, and diffusion capacity of the lung (SADL) score (HR, 1.62; 95% CI, 1.05-2.66; P =.03) and gender, age, and lung physiology (GAP) score (HR, 1.66; 95% CI, 1.05-2.83; P =.03). No relationship was reported between CCL18 or CXCL13 level and transplant-free survival.

The researchers concluded that although MMP7 levels have demonstrated the ability to be prognostic in patients with idiopathic pulmonary fibrosis (IPF), the use of MMP7 has not yet gained widespread clinical use in this population. Compared with IPF, mortality from SSc-ILD is more heterogeneous in nature, disease progression is not as predictable, and decisions about timing and initiation of pharmacotherapy are not as straightforward. Additional studies are warranted to investigate the benefits of such biomarkers as MMP7 in patients with SSc-ILD, along with validation of the current study findings in another patient cohort.

Reference  

Matson SM, Lee SJ, Peterson RA, et al.  The prognostic role of matrix metalloproteinase-7 in scleroderma-associated interstitial lung disease. Eur Respir J. Published online December 9, 2021. doi:10.1183/13993003.01560-2021