HPE Alpha 1 Antitrypsin Deficiency - Page 4

to a clear understanding of one of COPD’s most important pathophysiologic mechanisms. This glycoprotein serves an important protective role in the lung. Neutrophil elastase can injure lung parenchyma if not neutralised by normal amounts of AAT glycoprotein. In those with a severe deficiency, normal amounts of neutrophil elastase are present unopposed with resulting injury to lung structures. This appears to be the predominant mechanism for the development of emphysema in affected individuals but this protease–anti-protease imbalance is probably not limited to AATD. We understand that elastase levels are increased by tobacco smoking and that an excess of neutrophil elastase is may play a role in non-alpha forms of COPD as well. There is one way in which AATD emphysema remains unique among the various forms of COPD. It is possible to remedy the deficiency to halt or at least slow the progression of emphysema by infusing supplemental amounts of purified AAT to achieve protective levels. This treatment strategy was developed more than a quarter of a century ago and such therapy has been approved by regulatory authorities in several countries for almost that long. Initial studies were based on the premise that it would be sufficient to maintain serum levels at or above a protective threshold typically regarded as 11µM. This was an estimate based upon the observation that individuals with mild or moderate deficiencies of AAT and serum levels generally above this mark seemed to have little or no 4 | 2019 | hospitalpharmacyeurope.com In the era of personalised medicine, we are well positioned to detect the disorder and to offer specific therapy predisposition to emphysema. Proof of concept studies by Wewers and colleagues showed that infusions of AAT at a dose of 60mg/kg/week could maintain serum levels above the protective threshold and also showed that the infused AAT protein was detectable in bronchoalveolar lavage. 5 This evidence of biochemical efficacy was sufficient for widespread adoption of this therapy in the United States and Germany but uptake in other countries was much slower. 6 Typical was the view of the Canadian Thoracic Society demanding that proof of efficacy required spirometric evidence that the progression of emphysema was slowed by such treatment. 7 Unfortunately, such studies have not been feasible. Spirometry changes slowly with the development of emphysema and spirometry is a relatively noisy and imprecise measure of disease progression. A clinical trial using spirometry as its endpoint would require that almost 1000 patients with AATD be randomised to active therapy or placebo and followed for up to five years. To date, the largest randomised and controlled trial of AATD has been of 180 patients receiving an intervention of two years’ duration. That study required the coordinated efforts of 24 international sites specialising in this comparatively rare form of emphysema. In the absence of a large randomised and controlled trial based on forced expiratory volume in 1 second (FEV1), a number of observational studies have examined the natural history of the disorder in registries. The largest of these demonstrated that