11/27/18. Challenges in Pulmonary and Critical Care: Alpha-1 Antitrypsin Deficiency: New Hope for Diagnosis and Treatment. Faculty.

Transcription

1 Challenges in Pulmonary and Critical Care: 2018 Alpha-1 Antitrypsin Deficiency: New Hope for Diagnosis and Treatment 1 Faculty Adam Wanner, MD Joseph Weintraub Professor of Medicine Division of Pulmonary & Critical Care Medicine University of Miami Miller School of Medicine Scientific Director Alpha-1 Foundation Miami, FL 2 Disclosures Adam Wanner, MD - Dr. Wanner has no financial relationships to disclose. 3 1

2 Learning Objectives 1. Discuss the pathophysiology of AAT deficiency (AATD) and its impact on chronic obstructive pulmonary disease (COPD) risk. 2. Interpret the clinical significance of laboratory test results for AATD. 3. Discuss treatment options for AATD and latest GOLD guideline recommendations. 4. Discuss strategies to enhance detection and treatment of AATD in clinical practice. 4 PRE-TEST QUESTIONS 55 Pre-test ARS Question 1 Pre-AA1: Please rate your confidence in your ability to integrate the detection and treatment of AATD into your practice: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 6 2

3 Pre-test ARS Question 2 Pre-AA2: Two carriers of the alpha-antitrypsin gene have children. The statistical chance they will have a child with severe alpha-1 antitrypsin deficiency disease is: 1. 0% 2. 25% 3. 33% 4. 50% % 7 Pre-test ARS Question 3 Pre-AA3: What lung conditions are clearly associated with alpha-1 antitrypsin deficiency? 1. COPD 2. Interstitial Lung Disease 3. Bronchiectasis 4. COPD and Bronchiectasis 5. COPD and Interstitial Lung Disease 8 Pre-test ARS Question 4 Pre-AA4: What are chemical chaperones thought to do in alpha-1 antitrypsin deficiency? 1. Prevent sexual interaction between cells 2. Supervise cellular social activities 3. Promote the intracellular trafficking of misfolded proteins and their transport out of the cell 4. Block reverse transcriptase 5. Discard alcohols created during chemical reactions 9 3

4 Pre-test ARS Question 5 Pre-AA5: Are there other treatments for lung disease due to alpha-1 antitrypsin deficiency, in addition to augmentation therapy? 1. No 2. Yes, all the treatments one would offer to any patient with COPD 3. Yes, although alpha-1 antitrypsin patients should always avoid pulmonary rehabilitation 4. Yes, but their effectiveness is less than in common COPD 5. No, but some homeopathic remedies have been shown to be highly effective in the treatment of emphysema 10 Outline Alpha-1 antitrypsin deficiency: the condition Detection Treatment 11 Chromosome 14q 12.2 kb glycosylation 52 kda glycoprotein serpin family (NE) 394 AA 12 Wood A.M.,

5 Polymerization of Z-mutant AAT 13 Lomas, 2007 UPR Apoptosis Proteosomal proteolysis glycolization secretion normal protein folding + trafficking abnormal protein folding polymerization normal transcription + translation normal transcription + translation MM ZZ 14 Pathogenesis of lung and liver disease intrahepatic polymerization plasma deficiency protease/ antiprotease Z-AAT intrapulmonary polymerization inflammation apoptosis 15 5

6 The Condition Alpha-1 antitrypsin deficiency is a hereditary Autosomal co-dominant disorder Decreased circulating levels of alpha-1 antitrypsin Increased risk of serious lung disease in adults, and liver disease in infants, children and adults Over 100 abnormal alleles, 1/3 cause disease (Z,S) Lung disease is linked to cigarette smoking Lung disease: Liver disease: COPD Cirrhosis Bronchiectasis Hepatocellular CA Therapy-resistant asthma 16 AAT Co-dominant Inheritance Carrier of Z Carrier of Z 17 AAT Co-dominant Inheritance Carrier of Z Carrier of Z MM ZZ 18 6

7 AAT Co-dominant Inheritance Carrier of Z Carrier of Z MM ZZ Normal Carrier Carrier AATD 19 AATD in the World At least 116 million carriers of abnormal alleles* 3.4 million with severe deficiency allele combinations (SS, ZZ, SZ) AATD in the US *from studies of 373 cohorts in 58 countries Deficiency allele combinations 1:17 MS (MM = wild type) 1:36 1:1058 SS 1:1124 SZ ~100,000 individuals 1:4775 ZZ De Serres, 2002 and % 20 The Deficiency AAT serum level (μm) APR MM % % protection threshold 0 MM MS SS SZ ZZ 21 Sanford et al,

8 CLINICAL FEATURES of AATD in the US (N = 1,062 patients) IV I III II Genotypes ZZ 93.3% SZ 2.5% Znull 0.9% Other 3.1% FEV 1(% pred): FEV 1/FVC: On oxygen: 44% GOLD stage 22 Campos et al 2005 Awareness by physicians Age at diagnosis: 46 10yr Average number of physicians seen before Number of physicians correct needed diagnosis: to 2make -3 diagnosis: 2-3 Symptoms to diagnosis interval: 7.8 ± 9.2 Symptom-to-diagnosis years interval: 8 9yr Average age at diagnosis: 45.5 ± 9.5 years 23 Campos et al, 2005 Do carriers have a clinical phenotype? carrier smokers have a lower FEV1 than MM smokers Alcohol consumption has an effect on the incidence of chronic liver disease in carriers McElvany et al, 2016 Strand et al,

9 Outline Alpha-1 antitrypsin deficiency: the condition Detection Treatment 25 Why Diagnose Alpha-1 Antitrypsin Deficiency? Genetic counseling and screening of relatives Smoking cessation Avoidance of risk factors Specific therapy available for lung disease Disease management 26 How to Test for Alpha-1 Antitrypsin Deficiency? Serum alpha-1 antitrypsin level (quantity of gene product) Phenotyping (phenotype of gene product) Genotyping 27 9

10 2003 Clinical Practice Guidelines The Diagnosis and Management of Alpha-1 Antitrypsin Deficiency in the Adult Sandhaus et al J COPD F 2016 Testing recommendations Level A COPD Therapy resistant asthma Unexplained liver disease Necrotizing panniculitis Level B Bronchiectasis C-ANCA-positive (antiprotease-3 positive) vasculitis 28 Detection Strategies Newborn testing Targeted testing Large campaigns Medical-record-based Industry-promoted Provider education Direct-to-consumer genetic testing 29 Tested at US PFT labs by RTs or pulmonary function technicians Rahaghi FF, et al. COPD N= 24,550 Severely Deficient % Florida Targeted Detection Program

11 In-office Strategies to Rule Out Alpha-1 Establish a formal practice protocol or standard orders for ruling out alpha-1 in COPD patients ATS guidelines recommend testing all COPD patients Seek out protocols/guidance from the Alpha-1 Foundation s Clinical Resource Centers (alpha1.org/newly-diagnosed/living-with- Alpha-1/Find-an-Alpha-1-Specialist) or from published literature and choose what s right for your practice Identify 1 to 2 in-office champions Include alpha-1 testing in your practice EMR for current and newly diagnosed COPD patients 31 Outline Alpha-1 antitrypsin deficiency: the condition Detection Treatment 32 Types of treatment Non-specific COPD treatment Specific treatment for COPD associated with AATD (augmentation therapy) Non-specific treatment for liver disease (cirrhosis and hepatocellular carcinoma) 33 11

12 Non-specific Treatment Smoking cessation LABA/ICS/LAMA/RFL O2, rehabilitation LVR, lung transplant 34 Corda et al, 2008 Augmentation Therapy IV Administration of human plasmaderived AAT (Prolastin, Aralast, Zemaira, Glassia) Weekly dose of 60 mg/kg Biochemical efficacy Results of randomized clinical trials suggest efficacy Expensive Doesn t treat liver disease Stocks et al, Cost of Drugs in US in 2017 (NORD) 56% Non-orphan traditional drugs Total $451 Billion/yr 34.4% Non-orphan specialty drugs 9.6% Orphan drugs ($10,000/pt/yr) 36 12

13 Outcomes Lung function Lung structure Mortality 37 Meta-analysis of Augmentation Therapy FEV1 <30% n=454 FEV % n=308 26% slower decline in FEV1 FEV1 >65% n=43 Total n=924 23% slower decline in FEV1 Chapman et al, 2009 Favors control Difference in FEV1 slope (ml/yr) Favors augmentation 38 CT-densitometry in AAT-associated COPD (two pilot studies) Danish/Dutch Study (Dirksen et al, 1999) EXACTLE Study (Dirksen et al, 2009) Randomized, placebo controlled n = 56 BL FEV % 250 mg/kg AAT q 4 wk Duration: 3 yr p = 0.07 favoring AAT Randomized, placebo-controlled n = 77 BL FEV % 60 mg/kg AAT q wk Duration: yr p = 0.07 favoring AAT 39 13

14 Pivotal Study (CT-densitometry) Rapid study: 177 never/ex-smokers 52% AAT 60mg/kg/wk AAT Lung density at TLC p<0.007 Lancet 2015 Lancet Resp Med Mortality in Individuals with/without Augmentation Therapy (n = 1129) The Alpha-1-Antitrypsin Deficiency Registry Study Group, Cause of Death in Adults Non-smokers Liver failure and carcinoma (70%) Other causes including respiratory failure (30%) Smokers Respiratory failure and other causes (70%) Liver failure and hepatocellular carcinoma (30%) Eriksson et al, 2009 Tanash et al,

15 Emerging Therapies for Alpha-1 Antitrypsin Deficiency Aerosol AAT Daily administration Less expensive Efficacy unproven Broader indication New serine protease inhibitors Small molecules and chaperones to prevent mutant AAT polymerization and promote intracellular trafficking Gene therapy (M) and gene silencing (Z), cell therapy 43 Summary Alpha-1 antitrypsin deficiency is associated with lung disease in adults and liver disease in adults and children. Alpha-1 is under-diagnosed and underappreciated as a cause of COPD. Standard of care today is to test every patient with COPD. Detection is easy. Alpha-1 antitrypsin augmentation for lung disease therapy is effective and available in the US. 44 POST-TEST QUESTIONS 45 15

16 Post-test ARS Question 1 Post-AA1: After participating in this program, please rate your confidence now in your ability to integrate the evaluation and management of AATD into your practice: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 46 Post-test ARS Question 2 Post-AA2: Two carriers of the alpha-antitrypsin gene have children. The statistical chance they will have a child with severe alpha-1 antitrypsin deficiency disease is: 1. 0% 2. 25% 3. 33% 4. 50% % 47 Post-test ARS Question 3 Post-AA3: What lung conditions are clearly associated with alpha-1 antitrypsin deficiency? 1. COPD 2. Interstitial Lung Disease 3. Bronchiectasis 4. COPD and Bronchiectasis 5. COPD and Interstitial Lung Disease 48 16

17 Post-test ARS Question 4 Post-AA4: What are chemical chaperones thought to do in alpha-1 antitrypsin deficiency? 1. Prevent sexual interaction between cells 2. Supervise cellular social activities 3. Promote the intracellular trafficking of misfolded proteins and their transport out of the cell 4. Block reverse transcriptase 5. Discard alcohols created during chemical reactions 49 Post-test ARS Question 5 Post-AA5: Are there other treatments for lung disease due to alpha-1 antitrypsin deficiency, in addition to augmentation therapy? 1. No 2. Yes, all the treatments one would offer to any patient with COPD 3. Yes, although alpha-1 antitrypsin patients should always avoid pulmonary rehabilitation 4. Yes, but their effectiveness is less than in common COPD 5. No, but some homeopathic remedies have been shown to be highly effective in the treatment of emphysema 50 17