Alpha 1 Antitrypsin

Deficiency Vasculitis
BY BARBARA MCMULLAN
Mr. R 65 year old
HPI Rheumatology consulted twice
Recent diagnosis of AAT deficiency (PI*SZ)
1st Nephrology concern for possible ANCA
Presented with AMS and acute respiratory vasculitis mediated renal failure
failure, intubated for a couple of days
+ ANA titer 1:320
Developed septic shock and acute renal failure
requiring dialysis + ANCA speckled, - PR3 and - MPO

PMH 2st On readmission thought to have

CAD, stroke x3, unilateral renal agenesis, and
petechial rash
AAT deficiency Complements low, platelets 40
Derm biopsy proven ischemia
Social History
Smoking Active 40+ years
Alpha 1 Antitrypsin Deficiency
AAT is a protease inhibitor of the proteolytic enzyme elastase and also trypsin, chymotrypsin, and
thrombin
Inherited by autosomal co-dominant transmission
Genetics:
M normal gene
Z most common gene that leads to AAT deficiency (Glu342Lys)
S milder cause of AAT deficiency (Val264Glu)
F normal quantity but dysfunctional protein

Thought to be about as common as cystic fibrosis, likely an under-recognized disease

Estimated 80-100 thousand patients with severe AAT deficiency in the US (symptomatic and non-symptomatic)
Diagnosis of AAT Deficiency
Family History Lung Disease
AAT deficiency Irreversible airflow limitation on spirometry
Emphysema Emphysema at age less than 45
Bronchiectasis Emphysema in a non-smoker
Liver disease Emphysema characterized by basilar changes
Panniculitis Unexplained bronchiectasis

Liver Disease Skin Disease

Neonatal hepatitis
Cirrhosis in both children and adults
Hepatocellular carcinoma
Hepatomegaly
Unexplained liver disease
Persistent mild/moderate increase in ALT & AST
Necrotizing panniculitis (thigh, buttocks)
Vasculitis
C-ANCA positive vasculitis
Abnormal Lab Tests
Low or two bands in alpha 1 globulin on SPEP
Vascular Disease
Vascular complications are less established consequence of PI*ZZ
A number of vascular abnormalities have been described
Includes abdominal and intracranial aneurysms
Arterial fibromuscular dysplasia

Mechanism is based on the principle that unopposed proteolytic activity damages vessel walls in
severely deficient individuals
ANCA Vasculitis
Association between c-ANCA vasculitis and AAT deficiency
Known association from small case-control studies; 5-27% have the most severe allele Z
2010 Arthritis Rheum published study of large cohort with 433 GPA
Both Z and S alleles display associated risk of GPA in a codominant pattern
Clinically significant odds ratio of 14.58 for ZZ, SS, or SZ genotypes

This polymorphism is the strongest genetic risk factor for anti-PR3 ANCA vasculitis so far
discovered
Nevertheless, population attributable risk is likely around 7%
Pathogenesis
Plausible pathogenetic mechanism
AAT has an important role as an inhibitor of proteinase-3
Proteinase-3 is a neutrophil elastase-like protease located in primary granules of the neutrophil
Unchecked, PR-3 exerts potent tissue destruction

Deficiency of AAT could trigger an auto-immune response by allowing increased extracellular

exposure to PR-3
Other theories include linkage disequilibrium for autoimmune genes along with abnormal AAT
genotypes or conceivably circulating Z or S polymers prompt a vasculitis response
Other Considerations
2003 suggestion from the joint American Thoracic Society and European Respiratory Society
(ERS) in favor of genetic testing for AAT deficiency in individuals with C-ANCA positive vasculitis
Multiple systems affected by vasculitis
Multidisciplinary team collaboration is beneficial
Individualized based on disease severity and specific organ involvement
Treatment
Any difference in treatment for AAT deficiency associated ANCA vasculitis? No
Induction: Cytoxan or Rituximab
Relapse: Rituximab
Maintenance: Rituximab or Imuran

Only specific treatment for AAT deficiency is augmentation therapy with weekly infusions of
human plasma-derived A1AT
Highly expensive
Recommended and approved only for patients with high-risk genotype, A1AT below protective levels
(11 microM), and evidence of obstructive lung disease
No evidence of benefit for extra-pulmonary manifestations
Future
Brief Report in June publication of Arthritis & Rheumatology
Examining the prevalence of AAT in rheumatoid arthritis
No statistical difference in AAT deficiency rates in RA vs general population
AAT heterozygous status in RA strongly associated with positive anti-CCP
May define a distinct subset of patients with increased disease severity
Conclusions
AAT deficiency vasculitis likely an underdiagnosed condition
Associated risk for PR-3 ANCA vasculitis with alleles Z and S demonstrated
Pulmonology recommendations for testing in GPA presented
No difference in treatment Rheumatologically
Potential association with RA explored
Resources
OMIM. 107400 SERPIN PEPTIDASE INHIBITOR, CLADE A, MEMBER 1; SERPINA1. Accessed 7/30/2017.
Mahr AD, Edberg JC, Stone JH, et al. Alpha-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's
granulomatosis. Arthritis Rheum. 2010;62(12):3760-7.
Esnault VL, Audrain MA, Sesbo R. Alpha-1-antitrypsin phenotyping in ANCA-associated diseases: one of several
arguments for protease/antiprotease imbalance in systemic vasculitis. Exp Clin Immunogenet. 1997;14(3):206-13.
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.
Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J
Med. 2010;363(3):221-32.
Petrache I, Hajjar J, Campos M. Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment
of patients with alpha-1-antitrypsin deficiency. Biologics. 2009;3:193-204.
McCarthy C, Orr C, Fee LT, et al. Brief Report: Genetic Variation of the 1 -Antitrypsin Gene Is Associated With
Increased Autoantibody Production in Rheumatoid Arthritis. Arthritis Rheumatol. 2017;69(8):1576-1579.
Mckinney EF, Willcocks LC, Broecker V, Smith KG. The immunopathology of ANCA-associated vasculitis. Semin
Immunopathol. 2014;36(4):461-78.