Clinical utility of alpha-1 proteinase inhibitor in the management of adult patients with severe alpha-1 antitrypsin deficiency: a review of the current literature

Abstract

Alpha-1 antitrypsin (AAT) functions primarily to inhibit neutrophil elastase, and its deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD). The putative protective serum concentration is generally considered to be above a threshold of 11 μM/L, and therapeutic augmentation of AAT above this value is believed to retard the progression of emphysema. Several AAT preparations, all derived from human donor plasma, have been commercialized since approval by the US Food and Drug Administration (FDA) in 1987. Biochemical efficacy has been demonstrated by augmentation of pulmonary antiprotease activity, but demonstration of clinical efficacy in randomized, placebo-controlled trials has been hampered by the practical difficulties of performing conventional studies in a rare disease with a relatively long natural history. Computed tomography has been applied to measure lung density as a more specific and sensitive surrogate outcome measure of emphysema than physiologic indices, such as forced expiratory volume in 1 second, and studies consistently show a therapeutic reduction in the rate of lung density decline. However, convincing evidence of benefit using traditional clinical measures remains elusive. Intravenous administration of AAT at a dose of 60 mg/kg/week is the commonest regime in use and has well-documented safety and tolerability. International and national guidelines on the management of AAT deficiency recommend intravenous augmentation therapy to supplement optimized usual COPD treatment in patients with severe deficiency and evidence of lung function impairment.

Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling

“…Neutrophil elastase is one of the main targets of α1-antitrypsin, an acute-phase reactant protein that functions primarily as a serine protease inhibitor. 229 The recent R andomized, placebo-controlled trial of augmentation therapy in A lpha 1- P roteinase I nhibitor D eficiency (RAPID) and the RAPID Extension trials confirmed the benefits of α1-antitrypsin therapy in slowing disease progression in patients with α1-antitrypsin deficiency. 230…”

Opinions and Attitudes of Pulmonologists About Augmentation Therapy in Patients with Alpha-1 Antitrypsin Deficiency. A Survey of the EARCO Group

“…[12][13][14] In this context, it would be of great help to identify responders to AT, patients that share some characteristics that either increase the concentrations or activity of proteases or make them more susceptible to the effects of proteases; however, the largest placebocontrolled, randomized clinical trial of AT to date included only 90 patients per arm, which makes subgroup analysis of responders unfeasible. 6 Some authors have proposed a personalized approach to AT considering variables such as age, rate of decline of lung function and CT imaging of the lungs; 11,14,32 our results indicate that most experts consider these variables for the prescription of AT despite the lack of definitive evidence.…”

Neutrophil elastase inhibitor purification strategy from cowpea seeds

“…As mentioned before, it is believed that A1AT augmentation can retard the progression of emphysema. Intravenous A1AT augmentation therapy has been in use for more than 20 years already and the results show that it is a safe procedure with positive consequences for treated patients [91].…”