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
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
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.