HPE Alpha 1 Antitrypsin Deficiency - Page 5

patients receiving AAT therapy had lower rates of FEV1 loss than those who did not receive therapy and, amongst those with the lowest FEV1, mortality was reduced. 8,9 These observations have encouraged the more widespread use of AAT therapy but have not slowed calls for a randomised controlled trial of efficacy for AAT therapy. A feasible clinical trial demonstrating the efficacy of AAT therapy required the development of a new specific and sensitive endpoint for the emphysema associated with AATD. In 1999, Asger Dirksen and colleagues explored the endpoints used to monitor emphysema using both serial spirometry and computerised tomographic estimates of lung density. 10 In a small population studied over three years, repeated spirometry remained insensitive to differences between treated and placebo- treated patients while lung density estimates traced a difference that was close to statistically significant. That is, individuals randomised to receive AAT therapy showed a slower loss of lung density than individuals who received placebo infusions. A subsequent pilot study further refined the technology (and showed similarly suggestive results). 11 In 2015, results of the RAPID trial were reported and showed that CT scan lung density measured at full inflation (total lung capacity) was better preserved in treated patients compared with those who received placebo. 12 This was the two-year trial noted above and was followed in the majority of subjects by a two-year open label extension in which all subjects received therapy. This extension provided further evidence of benefit; the rate of lung density loss remained low and constant in those who had been treated in the first two years and who continued to be treated in the second two years while the more rapid loss of lung density in those who received placebo in the first two years slowed to the rate of loss seen in the treated group when the therapy was started belatedly. The RAPID trial has been a rich source of observations. Elastin breakdown products measured through the trial showed a decrease in the treated subjects but not in those who received placebo suggesting a possible role for this endpoint in the monitoring of therapy. 13 Moreover, the protective effect of therapy was independent of age and initial FEV1. Although definitive changes in lung density were statistically significant in two years, spirometry and other conventional measures of lung function were insensitive to these differences although after four years of treatment, changes in FEV1 showed a statistical association with changes in lung density. 14 The availability of a specific therapy remains unique to emphysema caused by AATD. This References 1 American Thoracic Society/ European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency. Am J Respir Crit Care Med 2003;168(7):818–900. 2 Laurell CB, Eriksson S. The electrophoretic alpha1-globulin pattern of serum in alpha1- antitrypsin deficiency. Scand J Clin Lab Invest 1963;115:132–40. 3 Marciniuk DD et al. Alpha1 antitrypsin deficiency targeted testing and augmentation therapy: A Canadian Thoracic Society clincal practice guideline. Can Respir J 2012;19(2):109–16. 4 Boueiz A et al. Integrative genomics analysis identifies ACVR1B as a candidate causal gene of emphysema distribution. Am J Respir Cell Mol Biol 2019;60(4):388–98. 5 Wewers MD et al. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med 1987;316:1055–62. 6 Bradi AC et al. Alpha-1 antitrypsin deficiency in Canada: regional disparities in diagnosis and management. COPD 2015;12 Suppl 1:15–21. 7 Ad Hoc Committee on Alpha-1- Antitrypsin Replacement Therapy of the Standards Committee, CTS. Current status of alpha- 1-antitrypsin replacement therapy: recommendations for the management of patients with severe hereditary deficiency. Can Med Assoc J 1992;146:841–4. 8 Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha- 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 1998;158(1):49–59. 9 Chapman KR et al. Augmentation therapy for alpha1 antitrypsin deficiency: a meta- analysis. COPD 2009;6(3):177–84. 10 Dirksen A et al. A randomized clinical trial of alpha(1)- antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999;160(5 Pt 1):1468–72. 11 Dirksen A et al. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1- antitrypsin deficiency. Eur Respir J 2009;33(6):1345–53. therapeutic avenue may be replaced in future by interventions to correct the genetic abnormality. Using viral vectors, it has been possible to stimulate the production of normal AAT protein in deficient individuals although such success has been short- lived. Newer techniques may lead to sustained genetic correction. 15 If so, such intervention is likely to be limited to this special form of COPD given its single gene abnormality. More typical forms of COPD are likely associated with polygenic abnormalities either obviating genetic correction or requiring multiple corrections. Phenotyping In the 21st century, there is increasing use of the term personalised medicine. We are hopeful that a better understanding of each individual’s genetic background may lead to more precise use of medications and other interventions. This is happening in a rudimentary way with respiratory diseases. Patients with asthma are being challenged to ask their physicians “which asthma do I have?” 16 This simple phenotyping has immediate and practical consequences. Highly effective biological therapies are available for subtypes of asthma: severe allergic asthma (omalizumab); severe eosinophilic asthma (mepolizumab, reslizumab and benralizumab); and severe Type 2 asthma (dupilumab). Practical phenotyping and its consequences have been slower in the setting of COPD. However, we now recognise that patients with COPD of the common variety may differ in their clinical characteristics. We seldom use the terms chronic bronchitis or emphysema but we do recognise that some patients exacerbate frequently while others seldom exacerbate. This leads to practical consequences with respect to prescribing. Although all patients with significant COPD are likely to benefit from bronchodilator therapy, only those who exacerbate seem to benefit from inhaled corticosteroids. 17 Thus, exacerbation history and blood eosinophil counts have led to differential prescribing and COPD. In this context, identifying the small subset of individuals with deficient serum levels of AAT must become a routine part of our phenotyping. Conclusions We have expanded our understanding of COPD genetics and pathophysiology during the 50 years following the description of AATD and its pulmonary consequences. Nonetheless, emphysema related to severe AATD remains the most distinctive endotype of COPD. In the era of personalised medicine, we are well-positioned to detect the disorder and to offer specific therapy. 12 Chapman KR et al. Intravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet 2015;386(9991):360–8. 13 Ma S et al. 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;4(1):34–44. 14 McElvaney NG et al. Long- term efficacy and safety of alpha1 proteinase inhibitor treatment for emphysema caused by severe alpha1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). Lancet Respir Med 2017;5(1):51–60. 15 Chiuchiolo MJ, Crystal RG. Gene therapy for Alpha-1 Antitrypsin Deficiency Lung Disease. Ann Am Thorac Soc 2016;13 Suppl 4:S352–69. 16 Kleinert S, Horton R. After asthma: airways diseases need a new name and a revolution. Lancet 2018;391(10118):292–4. 17 Chapman KR et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): A randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med 2018;198(3):329–39. hospitalpharmacyeurope.com | 2019 | 5