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Hereditary angioedema &
Bradykinin-mediated
angioedema
Suda Sibunruang, M.D.
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Angioedema
Asymmetric, non-de...
Kulthanan K. et. al. Clinical and Developmental Immunology 2007; article ID 26438:1-6
Records of OPD patients  15 yr with...
Cicardi M. et. al. Classification, diagnosis, and approach to treatment for angioedema:
consensus report from the Heredita...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Epidemiology
Bork K. et. al. Lancet 2000;356:213–17
Hereditary angioedema with normal C1-inhibitor activity in women
• In 1985, Bork K....
Bork K, et. al. Br J Dermatol 2006;154:542-5
Hereditary angio-oedema with normal C1 inhibitor
in a family with affected wo...
Bork K. Immunol Allergy Clin North Am 2006;26:709-24
Bouillet L. et al. Immunol Allergy Clin N Am 2013;33:505–11
Caballero T. et. al. International consensus and practical gui...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Epidemiology
• Lymphoma
• CLL
• MGUS
• Myeloma
• W. macroglobulinemia
• Cryoglobulinemia
• Echinococcus
granulosus
• Rheumatoid arthrit...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Epidemiology
Polymorphisms in...
Abbas AK et al. Cellular and Molecular immunology. Eighth Edition
C1 INH: Regulation of complement activation
Pathogenesis...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
• Complement system proteases...
Davis AE. Clin Immunol 2005;114;3–9
Longhurst H. and Cicardi M. Lancet 2012;379:474–81
Overactivation of classical and lec...
Longhurst H. and Cicardi M. Lancet 2012;379:474–81
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practi...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Swelling in angioedema result...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
1. Activation B2 BKR initiate...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
2. Intracellular calcium flux...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Contraction, altogether with ...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
• Autosomal dominant
• More t...
G. Dewald and K. Bork. Biochemical and Biophysical Research Communications 2006;343:1286–9
Missense mutations in the coagu...
Bork K. Immunol Allergy Clin N Am 2013;33:457–70
Zingale LC, et. al. Immunol Allergy Clin North Am 2006;26:669-90
Acquired C1 INH def: Increased catabolism of C1INH
that o...
Picture from www.aaia.ca, access September 2015
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice....
Bork k. et. al. American Journal of Medicine 2006;119:267-74
Survey from 221 pts with C1 inhibitor deficiency with 131,110...
Picture from www.aaia.ca, access September 2015
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice....
US Hereditary Angioedema Association
Longhurst H. and Cicardi M. Lancet 2012;379:474–81
Erythema marginatum
Serpiginous, n...
Shiber JR. N Engl J Med 2005;353:e15
Angioedema of arytenoids; lisinopril
In HAE:
• Mortality rate due to laryngeal angioe...
Longhurst H. and Cicardi M. Lancet 2012;379:474–81
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practi...
Cicardi M. and Zanichelli A. Immunol Allergy Clin N Am 2013;33:449–56
Cicardi M. and Zanichelli A. Immunol Allergy Clin N Am 2013;33:449–56
Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
Triggers factors
Hereditary angioedema with
normal C1 INH
• More likely to affect females, men tend to
have milder symptoms
• Less likely t...
Bork K, et. al. Allergy 2015;70:1004-12
Hereditary angioedema with normal C1-INH
with versus without specific F12 gene mut...
Acquired C1 INH deficiency
• Onset at a relatively older age
• Lack of family history
Zuraw BL. and Christiansen SC. Middl...
Non-histaminergic idiopathic
angioedema
• Lack of response to usual treatments for mast
cell–dependent angioedema
Zuraw BL...
Laboratory criteria
After first year of age:
• C1 inhibitor antigen concentration <50% of normal
values obtained on 2 sepa...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Bradykinin-mediated angioedem...
Wagenaar-Bos I. et. al. Journal of Immunological Methods 2008;338:14–20
Functional C1-Inhibitor diagnostics in hereditary ...
Cugno M. et. al. Allergy 2009:64:254–7
Plasma biomarkers of acute attacks in patients with
angioedema due to C1-inhibitor ...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Syndrome C4 Level C1INH
Antig...
A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inh...
From www.aaia.ca, access September 2015
Castelli R. et. al. Immunopharmacology and Immunotoxicology 2013;35:181–90
FFP
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Earlier an attack is treated,...
Nanofiltered C1 inhibitor concentrate
• C1 inhibitor was purified from plasma by
a combination of cryoprecipitation,
ion-e...
Zuraw BL. et al. N Engl J Med 2010;363:513-22
2 RCT: 1. Compared nanofiltered C1 inh with placebo for
treatment of acute a...
Frank MM. Immunol Allergy Clin N Am 2013;33:495–503
Reduced in;
- Severity
- Shorter duration of attacks
- Lower total no....
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Earlier an attack is treated,...
Ecallantide
• Recombinant protein kallikrein antagonist that
is synthesised in Pichia pastoris
• In 3 double-blind placebo...
Ecallantide
However, administration outside a healthcare
facility is not recommended;
187 pts given to sc. ecallantide
• 4...
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Earlier an attack is treated,...
Van Veen HA. et. al. Journal of Biotechnology 2012;162:319–26
Recombinant human C1 inhibitor
Transgenic rabbits harbor the...
Craig T. et. al. WAO Journal 2012;5:182–99
They all appear to be highly effective, but data allowing direct comparisons ar...
Craig T. et. al. WAO Journal 2012;5:182–99
Plasma occasionally induce an acute exacerbation, presumably
because plasma con...
Prophylactic treatment
• Short term
Protect against the likelihood of experiencing attacks after
a stimulus known to preci...
Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
Long-term prophylaxis
Not all patients require, decision to provide
must be individualized;
• Attack frequency and severit...
Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
Optimal dose should be based on clinical response,
ra...
Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
-Both efficacy and side effects of
androgens are dose...
Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
Antifibrinolytic agents are effective and relatively ...
Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
Tourangeau LM, et. al. Int Arch Allergy Immunol 2011;157:417-24
Background: C1INH is most effective when administered earl...
Adjunctive strategies
• Avoid ACE-I drugs
• Avoid birth control pills containing estrogen
and estrogen replacement therapy...
Treatment of HAE with normal C1 INH
• No controlled treatment studies
• May respond to many of the same drugs as in
patien...
Treatment of acquired C1 INH
deficiency
• Treatment of underlying disorder
• C1INH autoantibodies require a higher dose of...
HAE and pregnancy
Diagnosis during pregnancy
• Rare for HAE-C1-INH manifestations to
present for the first time during pregnancy
• C1-INH te...
Prenatal diagnosis
• Is rarely requested
• No clear genotype-phenotype correlation
• It can only be performed if disease-c...
HAE in neonates and infant
Diagnosis
• C1-INH level in umbilical blood of neonates is
approximately 2/3 of normal adult
• ...
Clinical course
• Pregnancy can mitigate, aggravate, or have no
effect on HAE
• Frequency of attacks during previous
pregn...
Labor and delivery (1)
• Attacks can occur immediately or within
48 hrs of delivery, however rarely
• 80- 90% of births ar...
Labor and delivery (2)
• Routine prophylaxis before uncomplicated
deliveries is not recommended, but pdhC1INH
should be re...
Labor and delivery (3)
• pdhC1INH is recommended if forceps delivery
or vacuum extraction is performed
• After delivery, p...
Labor and delivery (4)
• Epidural anesthesia is recommended for
cesarean sections to avoid endotracheal
trauma
• STP is re...
Treatment
• pdhC1INH is the first line
• Antifibrinolytics can be administered if C1-INH
is not available
• Androgen are c...
Prophylaxis
• pdhC1INH appears to be safe and effective during
pregnancy and lactation
• Treatment is usually administered...
When they want to pregnant…
Before attempting conception
• Tranexamic acid should be stopped several days
(half-life 2-8 h...
Contraception
• Estrogens should be avoided
• Barrier methods, intrauterine devices, and
progestins can be used
Caballero ...
Take home messages
• HAE-C1-INH is a treatable disease with a
highly variable phenotype
• Effective management of heredita...
Thank you for your attention
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Hereditary angioedema and bradykinin-mediated angioedema

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Hereditary angioedema and bradykinin-mediated angioedema

presented by Suda Sibunruang, MD.

September18, 2015

Published in: Health & Medicine
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Hereditary angioedema and bradykinin-mediated angioedema

  1. 1. Hereditary angioedema & Bradykinin-mediated angioedema Suda Sibunruang, M.D.
  2. 2. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Angioedema Asymmetric, non-dependent, non-pruritic, swelling involving cutaneous or mucosal surfaces
  3. 3. Kulthanan K. et. al. Clinical and Developmental Immunology 2007; article ID 26438:1-6 Records of OPD patients  15 yr with angioedema between 2005-2006 were retrospectively reviewed • 105 patients, 82 cases (78.1%) were female • Mean age 39.4 ± 18.4 yrs (ranged 15-88 yrs) • 55 (52.4%) had angioedema without urticaria Bradykinin mediated angioedema 25 (23.8%)
  4. 4. Cicardi M. et. al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy 2014;69:602–16
  5. 5. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Epidemiology
  6. 6. Bork K. et. al. Lancet 2000;356:213–17 Hereditary angioedema with normal C1-inhibitor activity in women • In 1985, Bork K. assessed a large family, in which five women had recurrent angioedema with normal C1-inhibitor function • We assessed other families with similar cases at angioedema clinic from 1986 to 1999 • Results: - 10 women with recurrent angioedema and normal C1 INH - Family history disclosed another 26 affected women - Of those, 14 could be studied and had normal C1-inhibitor concentration and function • Occasional: - Onset after oral contraceptives (OC) started - Limited to time when OC are given or when patient is pregnant
  7. 7. Bork K, et. al. Br J Dermatol 2006;154:542-5 Hereditary angio-oedema with normal C1 inhibitor in a family with affected women and men
  8. 8. Bork K. Immunol Allergy Clin North Am 2006;26:709-24
  9. 9. Bouillet L. et al. Immunol Allergy Clin N Am 2013;33:505–11 Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20 Estrogens regulate B2 receptor gene expression and function
  10. 10. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Epidemiology
  11. 11. • Lymphoma • CLL • MGUS • Myeloma • W. macroglobulinemia • Cryoglobulinemia • Echinococcus granulosus • Rheumatoid arthritis • SLE • AIHA • Adenocarcinoma of gastric • Carcinoma of breast, pancreas, bladder, colon, rectum Literature on acquired C1 INH deficiency Zingale LC, et. al. Immunol Allergy Clin North Am 2006;26:669-90
  12. 12. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Epidemiology Polymorphisms in XPNPEP2/APP associated with higher risk
  13. 13. Abbas AK et al. Cellular and Molecular immunology. Eighth Edition C1 INH: Regulation of complement activation Pathogenesis: C1 INH deficiency
  14. 14. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 • Complement system proteases C1r and C1s • Mannose-binding lectin pathway proteases • Contact system proteases • Plasma kallikrein • Factor XIIa and factor XIIf • Intrinsic coagulation pathway protease factor Xia • Fibrinolytic pathway protease plasmin C1INH involves in regulating the activity of multiple proteases
  15. 15. Davis AE. Clin Immunol 2005;114;3–9 Longhurst H. and Cicardi M. Lancet 2012;379:474–81 Overactivation of classical and lectin pathways does not progress to common pathway and C3 concentration is typically normal, probably because reactions occur in fluid phase Abnormalities in complement pathway are important in diagnosis, but are probably not responsible for swellings
  16. 16. Longhurst H. and Cicardi M. Lancet 2012;379:474–81 Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Bradykinin can be released from kininogen through 2 distinct pathways 1. Cleaving of HMWK by plasma kallikrein 2. Cleaving of LMWK by tissue kallikrein (Carboxypeptidase N) (Aminopeptidase P) (Dipeptidyl-peptidase 4) (Neutral endopeptidase) 3. Bradykinins can be converted to their des-Arg products by CPN 4. Bradykinins are degraded into inactive peptides by other kininases B1 BKR is expressed after inflammatory stimuli. Physiological role is unclear, it might also have a role in pathogenesis of HAE
  17. 17. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Swelling in angioedema results from increased vascular permeability Paracellular fluid movement in endothelial cells is restricted by vascular endothelial cadherin (VE-cadherin) that make up adherens junction • Extracellular domains link adjacent endothelial cells • Intracellular domain binds β-catenin and p120-catenin, which stabilize VE-cadherin
  18. 18. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 1. Activation B2 BKR initiates a signaling cascade in which phospholipase C increases intracellular Ca2+
  19. 19. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 2. Intracellular calcium flux activates • endothelial nitric oxide synthase (eNOS) and phospholipase A2 (PLA2), which makes vasodilator and permeability-enhancing molecules • Protein kinase C 3. Protein kinase C: • Phosphorylates VE-cadherin, β-catenin and p120-catenin • Absence of stabilizing catenins, VE-cadherin is internalized and degraded • PKC activates GTPase RhoA, along with myosin light chain kinase • Contraction of actin cytoskeleton that leads to wider gaps between endothelial cells
  20. 20. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Contraction, altogether with a loss of VE-cadherin adherens junction and vascular dilatation >> fluid move from vascular to interstitial space
  21. 21. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 • Autosomal dominant • More than 280 mutations have been reported in patients with HAE • Type I HAE mutations, occur throughout SERPING1 gene, and may involve missense, nonsense, deletion, or insertion mutations. As a consequence, mutant C1INH protein is not secreted. • Type II HAE mutations, are almost always missense mutations involving region of gene at or near active site on reactive mobile loop, resulting in secretion of a protein that cannot form inhibitory complex with its target proteases • 25% of patients presumably have a de novo mutation of C1INH gene HAE type I & II are resulted from mutations in SERPING1 gene
  22. 22. G. Dewald and K. Bork. Biochemical and Biophysical Research Communications 2006;343:1286–9 Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor • Hypothesized that abnormal coagulation factor XII molecule may lead to inappropriate activation of kinin-forming cascade, therefore performed a search for mutations in F12 gene • Screened 20 index patients and 145 German blood donors served as controls • 2 missense mutations were identified in exon 9 of F12 gene in 6/20 patients • These mutation were absence in controls threonine-to-lysine substitution threonine-to-arginine substitution
  23. 23. Bork K. Immunol Allergy Clin N Am 2013;33:457–70
  24. 24. Zingale LC, et. al. Immunol Allergy Clin North Am 2006;26:669-90 Acquired C1 INH def: Increased catabolism of C1INH that outstrips normal capacity of host to synthesize C1INH
  25. 25. Picture from www.aaia.ca, access September 2015 Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Clinical Features Sites: face, oropharynx, extremities, abdomen, genitourinary tract Less frequent: brain, kidney, heart, and joints
  26. 26. Bork k. et. al. American Journal of Medicine 2006;119:267-74 Survey from 221 pts with C1 inhibitor deficiency with 131,110 episodes
  27. 27. Picture from www.aaia.ca, access September 2015 Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Clinical Features Sites: face, oropharynx, extremities, abdomen, genitourinary tract Less frequent: brain, kidney, heart, and joints Course: gradual worsening over the first 24 hrs, followed by an even slower recovery over the next 48 -72 hrs Variability in attack kinetics can be seen Severity is highly variable and can not be predicted at onset Frequency: twice per week to less than 1/yr Onset: 50% of patients begins before age of 10 yrs Worsening of symptoms around puberty Occasionally, begin in late teens or early adulthood Although some patients appear to decreased symptoms as they age, others continue to experience HAE attacks throughout their lives
  28. 28. US Hereditary Angioedema Association Longhurst H. and Cicardi M. Lancet 2012;379:474–81 Erythema marginatum Serpiginous, nonpruritic rash, characterized by red rings that appear on trunk and appendages Prodromal symptoms Precede an attack by several hours or day in up to 50% of patients Erythema marginatum, localized tingling, and a sense of skin tightness Others include fatigue, malaise, flu-like symptoms, irritability, mood changes, hyperactivity, thirst, and nausea
  29. 29. Shiber JR. N Engl J Med 2005;353:e15 Angioedema of arytenoids; lisinopril In HAE: • Mortality rate due to laryngeal angioedema of approximately 30% • More than half experience at least one laryngeal attack • All patients are at risk for potential laryngeal attack irrespective of prior disease severity
  30. 30. Longhurst H. and Cicardi M. Lancet 2012;379:474–81 Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Severe abdominal pain with intractable nausea and vomiting, and “third spacing” of fluid can induce hypotension Capsule endoscopy during abdominal attack Pain intensity during severe abdominal attack Symptoms are at maximum intensity for up to 24 h before spontaneously resolving in a further day
  31. 31. Cicardi M. and Zanichelli A. Immunol Allergy Clin N Am 2013;33:449–56
  32. 32. Cicardi M. and Zanichelli A. Immunol Allergy Clin N Am 2013;33:449–56
  33. 33. Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41 Triggers factors
  34. 34. Hereditary angioedema with normal C1 INH • More likely to affect females, men tend to have milder symptoms • Less likely to manifest before puberty • Tend to have fewer attacks • Higher percentage of facial and tongue episodes • No definitive lab to confirm • Diagnosis is one of exclusion Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
  35. 35. Bork K, et. al. Allergy 2015;70:1004-12 Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations HAE-FXII (n=69) HAE-unknown (n=196) Male: female 1: 68 1: 6.3 Mean age at onset (yr) 20.3 29.6 Impact of OC & pregnancy Higher - Incidence of asphyxiation due to angioedema Similar Similar No abnormalities were found for C1-INH protein, C1q, alpha2-macroglobulin, antithrombin III, and angiotensin-converting enzyme
  36. 36. Acquired C1 INH deficiency • Onset at a relatively older age • Lack of family history Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
  37. 37. Non-histaminergic idiopathic angioedema • Lack of response to usual treatments for mast cell–dependent angioedema Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
  38. 38. Laboratory criteria After first year of age: • C1 inhibitor antigen concentration <50% of normal values obtained on 2 separate occasions • C1 inhibitor function <50% (chromogenic assay) or <84% (ELISA assay; of normal values obtained on two separate occasions Mutation in C1-inhibitor gene that modifies protein synthesis or function Longhurst H. and Cicardi M. Lancet 2012;379:474–81
  39. 39. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Bradykinin-mediated angioedema • Slower evolution • Longer duration • Lack of urticaria • Failure to respond to antihistamines or corticosteroids C4 level is an excellent screening tool for C1INH deficiency in patients > 1 year • Reduced C4 level even between attacks in at least 95% of patients • Increasing to virtually 100% during attack Normal C4 level during an attack strongly suggests a diagnosis other than C1INH deficiency
  40. 40. Wagenaar-Bos I. et. al. Journal of Immunological Methods 2008;338:14–20 Functional C1-Inhibitor diagnostics in hereditary angioedema: Assay evaluation and recommendations Obj: evaluated performance of fC1- Inh assays in 15 different laboratories that are specialised in HAE diagnostics Chromogenic assay in 13 labs ELISA in 2 different labs • Chromogenic assay measures inhibition activity of target protease C1s by C1-Inh in the plasma sample to be tested • ELISA assay detects complexes formed between C1Inh and C1r or C1s following activation of C1 • Chromogenic assay: PPV 98 % NNV 100 % • fC1-Inh is more stable in plasma than in serum and samples should be stored at or below −20 °C
  41. 41. Cugno M. et. al. Allergy 2009:64:254–7 Plasma biomarkers of acute attacks in patients with angioedema due to C1-inhibitor deficiency Background: coagulation and fibrinolysis systems are activated during attack Obj: To investigate whether markers of thrombin generation (prothrombin fragment F1 + 2) and of fibrin degradation (D-dimer) can be used to diagnostic of angioedema from C1-INH deficiency, especially in abdominal attacks Participants: 28 pts with C1-INH deficiency during acute attacks and remission 35 pts without C1-INH deficiency during abdominal colics 20 healthy subjects During acute angioedema attacks, patients with C1-INH deficiency have high prothrombin fragment F1 + 2 and D-dimer levels
  42. 42. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Syndrome C4 Level C1INH Antigen C1INH Function C1q Level Type I HAE Low Low Low Normal Type II HAE Low Normal Low Normal HAE with normal C1INH Normal Normal Normal Normal Acquired C1INH deficiency Low Low Low Low ACE-I–associated Normal Normal Normal Normal Nonhistaminergic idiopathic Normal Normal Normal Normal
  43. 43. A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor–associated angioedema. J Allergy Clin Immunol 2013;131:1491-3 Treatment • Acute treatment (on demand) • Prophylaxis - short term - long term All patients with HAE have a management plan
  44. 44. From www.aaia.ca, access September 2015
  45. 45. Castelli R. et. al. Immunopharmacology and Immunotoxicology 2013;35:181–90 FFP
  46. 46. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Earlier an attack is treated, less fluid will have moved from plasma space into interstitial tissue, resulting in less morbidity and faster recovery
  47. 47. Nanofiltered C1 inhibitor concentrate • C1 inhibitor was purified from plasma by a combination of cryoprecipitation, ion-exchange chromatography, and polyethylene glycol precipitation • The resulting C1 inhibitor fraction was pasteurized, double nanofiltered with the use of 15-nm Planova filters and lyophilized Zuraw BL. et al. N Engl J Med 2010;363:513-22
  48. 48. Zuraw BL. et al. N Engl J Med 2010;363:513-22 2 RCT: 1. Compared nanofiltered C1 inh with placebo for treatment of acute attack of angioedema Primary end point: time to onset of relief 2. Crossover trial compared prophylactic twice-weekly injections of nanofiltered C1 inh with placebo during two 12-week periods Primary end point: number of attacks 22 subjects Results: 1st study: median time 2 hrs in C1 INH group 4 hrs in placebo group (p = 0.02) 2nd study: number of attacks /12 wks 6.26 in C1 INH 12.7 in placebo (p < 0.001) C1 INH significant reduced severity and duration of attacks, open-label rescue therapy, total number of days with swelling
  49. 49. Frank MM. Immunol Allergy Clin N Am 2013;33:495–503 Reduced in; - Severity - Shorter duration of attacks - Lower total no. of days of swelling - Fewer on-demand C1-inhibitor However, do not completely abolish attacks
  50. 50. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Earlier an attack is treated, less fluid will have moved from plasma space into interstitial tissue, resulting in less morbidity and faster recovery
  51. 51. Ecallantide • Recombinant protein kallikrein antagonist that is synthesised in Pichia pastoris • In 3 double-blind placebo-controlled studies, ecallantide was better than placebo in improving symptoms • Subcutaneous formulation of ecallantide improves convenience Longhurst H. and Cicardi M. Lancet 2012;379:474–81
  52. 52. Ecallantide However, administration outside a healthcare facility is not recommended; 187 pts given to sc. ecallantide • 4% had hypersensitivity events, including anaphylaxis in 2% • 8% of participants developed antibodies to either P. pastoris or ecallantide itself Longhurst H. and Cicardi M. Lancet 2012;379:474–81
  53. 53. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014 Earlier an attack is treated, less fluid will have moved from plasma space into interstitial tissue, resulting in less morbidity and faster recovery
  54. 54. Van Veen HA. et. al. Journal of Biotechnology 2012;162:319–26 Recombinant human C1 inhibitor Transgenic rabbits harbor the genomic C1INH gene rhC1INH expresses in milk Harvest and purification Therapeutic application of C1-Inh in inflammatory diseases like sepsis, acute myocardial infarction and vascular leakage syndrome seems promising, but large doses may be required. Therefore, a high-yield recombinant expression system for C1-Inh is very interesting. Bos I. et. al. Biochimica et Biophysica Acta 2003;1648:75– 83 Pichia pastoris Picture from 2013.igem.org, access September 2015 Different glycosylation results in a much reduced half-life of mean 3 h compared with 24 h or more for plasma-derived C1 inhibitors
  55. 55. Craig T. et. al. WAO Journal 2012;5:182–99 They all appear to be highly effective, but data allowing direct comparisons are lacking
  56. 56. Craig T. et. al. WAO Journal 2012;5:182–99 Plasma occasionally induce an acute exacerbation, presumably because plasma contains uncleaved HMWK in addition to C1INH Management of oropharyngeal-laryngeal attacks is primarily on maintaining the patency of airway
  57. 57. Prophylactic treatment • Short term Protect against the likelihood of experiencing attacks after a stimulus known to precipitate attacks • Long term Decrease frequency or severity of attacks Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
  58. 58. Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
  59. 59. Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
  60. 60. Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
  61. 61. Long-term prophylaxis Not all patients require, decision to provide must be individualized; • Attack frequency and severity • Location of attacks • Access to acute care • Presence of comorbid conditions • Patient preference Need for long-term prophylaxis may change in a particular patient over time Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
  62. 62. Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41 Optimal dose should be based on clinical response, rather than on C1INH level or C4 level
  63. 63. Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41 -Both efficacy and side effects of androgens are dose-related -If androgens are used, dosage must be titrated to lowest dose that provides effective control of attacks -Caution should be exercised if dose > 200 mg/day for long-term prophylaxis Relative contraindications: - Children - Breast or prostate cancer - Preexisting hepatic dysfunction - Pregnant
  64. 64. Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41 Antifibrinolytic agents are effective and relatively safe but generally is less effective than androgen
  65. 65. Caballero T. et. al. J Investig Allergol Clin Immunol 2011;21:422-41
  66. 66. Tourangeau LM, et. al. Int Arch Allergy Immunol 2011;157:417-24 Background: C1INH is most effective when administered early. Home infusion of C1INH allows for the earliest possible intervention since patients can initiate therapy at first sign of symptoms Method: 39 subjects with HAE utilizing 2 groups : one receiving on demand C1INH therapy in medical facility and the other self-managing on-demand C1INH therapy in home setting under supervision of a treating physician A registered nurse provided training in the majority of cases. Physician supervised the process Duration: 8 wks Safety and Efficacy of Physician-Supervised Self-Managed C1 Inhibitor Replacement Therapy Results - Attack frequency was similar - Significant decreases in attack duration (p < 0.0001) pain medication use (p < 0.0001) attack severity (p < 0.005) in subjects who received C1INH at home - Home group experienced more frequent injection-related side effects - Clinic group noted more severe adverse events from C1INH Severity of attacks Duration of attacks
  67. 67. Adjunctive strategies • Avoid ACE-I drugs • Avoid birth control pills containing estrogen and estrogen replacement therapy • Lifestyle modifications to address triggers such as stress Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
  68. 68. Treatment of HAE with normal C1 INH • No controlled treatment studies • May respond to many of the same drugs as in patients with HAE due to reduced C1INH • Some had improved on long-term prophylactic therapy with danazol, progesterone, or tranexamic acid Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
  69. 69. Treatment of acquired C1 INH deficiency • Treatment of underlying disorder • C1INH autoantibodies require a higher dose of pdC1INH or are even resistant to pdC1INH • Retuximab has induced remission in a small group of patients with acquired C1INH deficiency, C1INH autoantibodies, and severe frequent attacks • Antifibrinolytics appears to be more effective than androgens for long-term prophylaxis Zuraw BL. and Christiansen SC. Middleton’s Allergy Principle and Practice. 8th edition, 2014
  70. 70. HAE and pregnancy
  71. 71. Diagnosis during pregnancy • Rare for HAE-C1-INH manifestations to present for the first time during pregnancy • C1-INH testing for diagnosing should be interpreted with caution because C1-INH decrease during pregnancy in relation to the increase in plasma volume • Testing for C1-INH should be repeated postpartum to confirm diagnosis Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  72. 72. Prenatal diagnosis • Is rarely requested • No clear genotype-phenotype correlation • It can only be performed if disease-causing mutation of affected parent is known • Genetic testing for specific mutation is performed with cells from a chorion villus sample taken after GA 10th wk or from an amniotic fluid sample extracted after GA 15th wk. A chorion villus sample is preferable. • Preimplantation genetic diagnosis (PGD) might be more attractive Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  73. 73. HAE in neonates and infant Diagnosis • C1-INH level in umbilical blood of neonates is approximately 2/3 of normal adult • C1 INH reaches levels for mature adults at 6 - 36 months • C4 reaches levels at 2-3 yrs • False-positive and false-negative HAE-C1-INH test results can occur in infants < 12 months, additional tests to confirm should be performed at a later age • Genetic testing might be a safer and more direct way, however disease-causing mutation in family must be known Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  74. 74. Clinical course • Pregnancy can mitigate, aggravate, or have no effect on HAE • Frequency of attacks during previous pregnancies is not useful for predicting events in later pregnancies • Early onset of HAE-INH is associated with more frequent and more severe attacks during pregnancy • Abdominal attacks occur more frequently Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  75. 75. Labor and delivery (1) • Attacks can occur immediately or within 48 hrs of delivery, however rarely • 80- 90% of births are vaginal deliveries, rate of cesarean section is not higher than in general population (2008-2010) Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  76. 76. Labor and delivery (2) • Routine prophylaxis before uncomplicated deliveries is not recommended, but pdhC1INH should be readily available • Short-term prophylaxis is recommended when HAE-C1-INH is severe and frequently recurrent during 3rd trimester or medical history of genital edema caused by mechanical trauma Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  77. 77. Labor and delivery (3) • pdhC1INH is recommended if forceps delivery or vacuum extraction is performed • After delivery, patients with marked perineal swelling or other postpartum complications should be considered at higher risk for acute attacks, closely monitored for 72 hours after delivery, and treated with pdhC1INH when necessary Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  78. 78. Labor and delivery (4) • Epidural anesthesia is recommended for cesarean sections to avoid endotracheal trauma • STP is recommended with pdhC1INH Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  79. 79. Treatment • pdhC1INH is the first line • Antifibrinolytics can be administered if C1-INH is not available • Androgen are contraindicated Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  80. 80. Prophylaxis • pdhC1INH appears to be safe and effective during pregnancy and lactation • Treatment is usually administered during the 2nd half of pregnancy • Tranexamic acid is excreted into breast milk, therefore not recommended during breast-feeding • It is not known whether anabolic steroids are excreted into breast milk. Because of their potential side effects in children, it is recommended that mother cease breast-feeding before commencing androgen therapy Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  81. 81. When they want to pregnant… Before attempting conception • Tranexamic acid should be stopped several days (half-life 2-8 hours) • Androgen should be discontinued 2 months (half-life 9.44 hours) • pdhC1INH might continue during conception, pregnancy, and delivery • Ecallantide, Icatibant and rhC1INH have no data on use during pregnancy, and should be avoided before attempting conception Patients should stop taking them 1 wk prior Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  82. 82. Contraception • Estrogens should be avoided • Barrier methods, intrauterine devices, and progestins can be used Caballero T. et. al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308-20
  83. 83. Take home messages • HAE-C1-INH is a treatable disease with a highly variable phenotype • Effective management of hereditary angioedema requires careful physician-patient collaboration, with regular reassessments of patient status and individualization of therapy based on age, gender, comorbidity, and patient preference
  84. 84. Thank you for your attention

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