The Effect of Alpha-1 Proteinase Inhibitor on Biomarkers of Elastin Degradation in Alpha-1 Antitrypsin Deficiency: An Analysis of the RAPID/RAPID Extension Trials

Chronic Obstr Pulm Dis. 2016 Nov 18;4(1):34-44. doi: 10.15326/jcopdf.4.1.2016.0156.

Abstract

The RAPID (NCT00261833; N=180) and RAPID Extension (NCT00670007; N=140) trials demonstrated significantly reduced lung density decline in patients with alpha-1 antitrypsin deficiency (AATD) receiving alpha-1 proteinase inhibitor (A1PI) versus placebo. Desmosine and isodesmosine (DES/IDES) are unique crosslinkers of mature elastin fibers and are utilized as measures of elastin degradation. The aim of this post-hoc study was to determine the effect of A1PI therapy on DES/IDES levels in patients from RAPID/RAPID Extension. Plasma levels of DES/IDES were measured using high-performance liquid chromatography and tandem mass spectrometry. Correlation between changes in DES/IDES levels and computed tomography (CT) lung density decline was assessed. Analysis showed that DES/IDES levels were significantly reduced versus baseline in patients receiving A1PI at all time points, from month 3 through month 48. A significant increase from baseline in DES/IDES was observed with placebo at month 24 (n=54; 0.016; p=0.018). DES/IDES change from baseline was significantly different with A1PI versus placebo at months 3 (-0.021; 95% confidence interval [CI] -0.037, 0.004; p=0.026), 12 (-0.040; 95% CI -0.055, 0.025; p<0.001), and 24 (-0.052; 95% CI -0.070, 0.034; p<0.001). Placebo patients started A1PI therapy at month 24 and showed significant reductions in plasma DES/IDES at months 36 (p<0.001) and 48 (p<0.001). Reduced elastin degradation was associated with slower lung density decline (p=0.005), correlating a chemical index of therapy with an anatomical index by CT. In conclusion, A1PI therapy reduced elastin degradation, including pulmonary elastin, in patients with AATD. These data support using DES/IDES levels as biomarkers to monitor emphysema progression and treatment response.

Keywords: alpha-1 antitrypsin deficiency; desmosine; elastin biomarkers; isodesmosine; lung density.

Grant support

CSL Behring, the James P. Mara Center for Lung Disease, the Flight Attendants Medical Research Institute, the Charles A. Mastronardi Foundation, the Ned Doyle Foundation, and the Alpha-1 Foundation all provided funding for this study.