The systemic vasculitides are characterized by immune inflammation affecting blood vessels, which can lead to organ and tissue damage. One study showed that 8% of Wegener's granulomatosis (WG) patients had some degree of AATD (Alpha-1 antitrypsin deficiency). It's perhaps wise for all WG patients to be tested for AATD, especially if they're having bronchiectasis or similar conditions affecting breathing. Some rheumatologists order a lab test for AATD whenever a WG patient is diagnosed. This presentation, reviews this topic and hypothesize the role of replacement therapy in patients affected by both conditions.

2.  “Vasculitis”… You what?????
 AAT deficiency and natural history
 Going through the pathogenic link
 Relevant studies
 Conclusions

3.  ““Vasculitis”… You what?????Vasculitis”… You what?????
 AAT deficiency and natural history
 Going through the pathogenic link
 Relevant studies
 Conclusions

4.  Non specific termNon specific term
 Systemic processSystemic process
 Non specific manifestationsNon specific manifestations
 Large & heterogeneous group of disordersLarge & heterogeneous group of disorders
characterized bycharacterized by
Inflammation of blood vesselsInflammation of blood vessels

8.  “Vasculitis”… You what?????
 AAT deficiency and natural historyAAT deficiency and natural history
 Going through the pathogenic link
 Relevant studies
 Conclusions

9. Genetic disorderGenetic disorder
AATDAATD
Liver disease
Others:
renal, vasculitis, etc
Lung disease
bronchiectasis
Airflow obstruction
Bronchial hiperresponssivenessasthmaCOPD
enphysema

10.  There is evidence of an associationThere is evidence of an association
between AATD & systemic vasculitis.between AATD & systemic vasculitis.
 AAT deficiency alone is not usuallyAAT deficiency alone is not usually
enough to cause sysitemic vasculitis inenough to cause sysitemic vasculitis in
the absence of other genetic andthe absence of other genetic and
environmental risk factors.environmental risk factors.

11.  “Vasculitis”… You what?????
 AAT deficiency and natural history
 Going through the pathogenic linkGoing through the pathogenic link
 Relevant studies
 Conclusions

12. Neutrophil elastase is released during times
of inflammation. This action is normally
helpful and is balanced (neutralized) by the
protein α-1 antitrypsin produced in the liver.
• One cause of damage to any tissue is that
elastase is produced by neutrophil but there
is a genetically lack of α-1 antitrypsin.

13. S. Stolk.S. Stolk. Eur Respir MonEur Respir Mon 2006; 34: 139-1502006; 34: 139-150
macrophage
Airwways
aneutrophils
activation
Elastase
LTB4
Neutrophile recruitment Destruction
area

14. • There are normal regulatory mechanismsThere are normal regulatory mechanisms
for control of secreted neutrophilfor control of secreted neutrophil
enzymes and control pathways to limitenzymes and control pathways to limit
the enzyme action bythe enzyme action by anti-proteases.anti-proteases.
• These are highly important forThese are highly important for
neutralization of the enzymatic activitiesneutralization of the enzymatic activities
of the neutrophil proteases.of the neutrophil proteases.

15. Anti-protease
shield
prevents degradation
of normal tissues
Then how can the neutrophilThen how can the neutrophil
perform its normal functions?perform its normal functions?

16. Subsequent to this
attack
on anti-proteases,
the neutrophil enzymes
are free to damage the
bacterial targets,
necrotic tissues, or in
pathological condition
normal tissues.

17.  “Vasculitis”… You what?????
 AAT deficiency and natural history
 Going through the pathogenic link
 Relevant studiesRelevant studies
 Conclusions

18.  It’s been described that ANCA activate
primed neurophiles and possibly induce
accelerate apoptosis of tumor necrosis
factor-primed neutrophils.
 Actually, the titer of ANCA is correlated with
the disease activity, and rises prior to
clinical manifestations .
Savage COS et al. Lancet 1987; 1: 1389-93Savage COS et al. Lancet 1987; 1: 1389-93

19.  The main antigenic targets for ANCA are
proteinase 3 (PR3) and myeloperoxidase (MPO).
Rao Nvet al. J Biol Chem 1991; 266: 9540-48Rao Nvet al. J Biol Chem 1991; 266: 9540-48

20.  Accordingly it is likely proteases play a role in
pathogenesis of systemic vasculitis 
protease/antiprotease imbalance,
which may be either :
genetically determined in AATDgenetically determined in AATD
 pathological acquire inactivation.pathological acquire inactivation.
Rao Nvet al. J Biol Chem 1991; 266: 9540-48Rao Nvet al. J Biol Chem 1991; 266: 9540-48

21.  In some cases the serum is negative for
ANCA, and it is apparent that other
something than PR3-ANCA plays a role
in releasing PR3.

22.  A subpopulation of AATD Pi*ZZ
associated with ANCA(+) plus systemic
vasculitis has been reported,
but it was demonstrated there is no
evidence that a Pi*ZZ patient carrying
ANCA against PR3 or MPO has a greater
risk of developing systemic vasculitis than
a Pi*MM patient carrying ANCA
Audrain MAP et al. Nephrol Dial Transplant 2001; 16: 31-44Audrain MAP et al. Nephrol Dial Transplant 2001; 16: 31-44

23.  Although the vasculitis associated with
AATD showed a more widespread and
worse prognosis than vasculitis,
in Pi*MM patients, there was no
difference in age at onset or relapse
tendency.
Audrain MAP et al. Nephrol Dial Transplant 2001; 16: 31-44Audrain MAP et al. Nephrol Dial Transplant 2001; 16: 31-44

24.  Previous reports have suggested an
association between certain ANCA(+)
vasculitis and AATD phenotypes .
 Esnault VEsnault Vet al. Kidney Intet al. Kidney Int 1993; 43: 1329-13321993; 43: 1329-1332

25.  However, other small studies have given
conflicting results, so it is unclear whether
this is a consistent association and, if so,
whether it is of significance as regards
disease manifestations.
 Elzouki AN et al.Elzouki AN et al. J Intern MedJ Intern Med 1994; 236: 543-5481994; 236: 543-548
 O'Donaghue D et al. In: Gross WL, ed.O'Donaghue D et al. In: Gross WL, ed. ANCA-AssociatedANCA-Associated
Vasculitides: Immunological and Clinical Aspects. PVasculitides: Immunological and Clinical Aspects. Plenum Press,lenum Press,
NY1993; 331-335NY1993; 331-335

26.  “Vasculitis”… You what?????
 AAT deficiency and natural history
 Going through the pathogenic link
 Relevant studies
 ConclusionsConclusions

27.  ANCAANCA  neutrophilneutrophil activationactivation
releasing proteases and ROS,releasing proteases and ROS,
whichwhich may resultmay result in systemic vasculitis.in systemic vasculitis.
 Since vasculitis didn’t result from theSince vasculitis didn’t result from the
production of ANCA in some patients,production of ANCA in some patients,
the evidence suggests…the evidence suggests…
AATD may be a serious genetic factorAATD may be a serious genetic factor
exacerbating the vasculitisexacerbating the vasculitis
regardless of the relation with ANCA.regardless of the relation with ANCA.