Advances in the Treatment of Alpha1-antitrypsin Deficiency


and AAT regulates immunologic responses. For example, AAT modulates endotoxin-induced inflammation,20 necrosis factor (TNF)-induced lung injury in rabbits,21 production by neutrophils22 to pro-inflammatory stimuli.23,24


caspases17–19 reduces tumor inhibits superoxide


and regulates the response of macrophages In addition, AAT may have a role in


regulating airway epithelial lining fluid balance by associating with important regulators such as matryptase.25


AATD may further contribute to the development of disease.


The most important pathophysiologic mechanisms associated with AATD relate to the loss of NE inhibition and to the accumulation of Z-AAT polymers, both intra- and extracellularly. The Z mutation causes an important conformational change in the AAT protein that enables a loop-sheet polymerization process, causing its accumulation in the endoplasmic reticulum (ER) and loss of secretion.26


The AAT Z-polymers


are degraded by ER-associated degradation (ERAD) pathways via proteasomes and by autophagy as part of the ER overload response (EOR).27,28


However, if these cellular mechanisms fail, gain-of-toxic function and ER stress occurs that can lead to inflammation via NFkB activation29


and cell death by apoptosis.30 Although Z-AAT has reduced NE inhibitory capacity,31 most of the loss of


NE inhibition can be accounted for by defective secretion of AAT. The excess of protease activity in the lungs, particularly in periods of inflammation, leads to progressive degradation of the lung parenchyma (emphysema) and accelerated decline in lung function over time.32


The


development of airflow obstruction is most strongly associated with exposure to tobacco smoke, although other risk factors include male sex, asthma, and chronic bronchitis.33


AAT Z-polymers, which can be detected in the circulation,34 may contribute


to other clinical manifestations of the disease due to their property to act as neutrophil chemoattractants. When instilled in the trachea of mice, Z-polymers produce a significant, concentration-dependent influx of neutrophils that is not mediated by chemokines.35,36


Whether or not


polymers elicit this effect by trapping lypopolysaccharide or other chemoattractants,36


and have been proposed to be the mechanism for the association of vasculitis in subjects that carry the Z mutation.38–40 Z-polymers can be detected in bronchoalveolar lavages (BAL) of patients with AATD, which may further induce inflammation by their direct effect on epithelial cells.41,42


they have been associated clinically with inflammatory disorders. Z-polymers have been found in the skin biopsies of subjects with panniculitis37


Treatment of Alpha1-antitrypsin Deficiency Non-specific Therapies


Although the pharmacologic and non-pharmacologic treatment of COPD related to AATD follows the same guidelines and recommendations for COPD in general,43


their specific effectiveness


for this particular population has rarely been studied. For example, only two small trials have explored the benefits of inhaled corticosteroids on lung function in patients with AATD and COPD, noting significant improvement in airway obstruction and decreased hyperinflation.44,45


Specific Therapies for Alpha1-antitrypsin Deficiency Revisiting Intravenous Augmentation Therapy


To date, intravenous augmentation therapy with donor-derived purified AAT is the only specific US Food and Drug Administration (FDA)- approved treatment for lung disease associated with AATD. The studies supporting this therapy have been reviewed elsewhere.52


The loss of these effects in


Disease management programs have a potent impact in improving health-related quality of life and decreasing healthcare resource utilization in subjects with AATD and COPD.46


Lung volume reduction


surgery in subjects with AATD leads to improvements in six-minute walking test and dyspnea scores, but not in overall mortality compared with subjects receiving augmentation therapy alone.47,48 Overall survival rates post-lung transplantation appear to be better for patients with AATD compared with patients with ‘regular’ COPD, although the differences disappear when patients are stratified by age.49,50


Since the implementation of the 2005 lung allocation system, the number of transplants in AATD patients has decreased, from 8 % in 2002 to 3 % in 2008.51


These observations highlight the


importance of evaluating the impact of standard COPD interventions in the AATD population.


Unfortunately,


the suboptimal design of these studies (most are observational) has placed augmentation therapy in a controversial position. A recent meta-analysis of the only two randomised placebo-controlled trials published to date concluded that there was not sufficient evidence to recommend this treatment.53


However, concerns exists regarding the


power of these studies as well as the optimal dosage, therapeutic goals, treatment duration, and sub-populations that may benefit the most with augmentation therapy.


Current treatment recommendations are for individuals with AATD who develop lung disease and have a baseline serum AAT level below 11 µM.13 The recommended dose (60 mg/kg once per week) aims at keeping trough AAT levels above this value. However, several observations suggest that ‘standard’ dosing recommendations may not be applicable to all and may even be inadequate for a sub-group of individuals.


First, there is significant variability in the pulmonary manifestations of AATD as outlined above. Analyzing the rate of decline in forced


expiratory volume in one second (FEV1), Wencker et al. classified subjects as ‘rapid’ or ‘slow’ decliners.54


Rapid decliners were the ones


who experienced the most dramatic improvement when receiving augmentation therapy; however, the decline rate after treatment was initiated was still higher than that described in non-deficient individuals.


Second, some subjects continue to experience poor outcomes despite receiving standard augmentation therapy. In a large cohort of AATD individuals receiving augmentation therapy, we described that 90.1 % of individuals suffered from at least one acute COPD exacerbation per year (median 2 times).55


Patients with frequent


It is possible that some of these interventions have a unique effect in this population given their younger age and accelerated decline of lung function.


US RESPIRATORY DISEASE


exacerbations (three or more per year) were younger (<50 years of age) and more likely to have severe chronic bronchitis symptoms and poor health-related quality of life. Although no changes in lung function decline were measured, these younger individuals with frequent exacerbations, despite receiving augmentation therapy, are likely to be ‘rapid decliners’.


15


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