Allergy and immunology symposium Flashcards
What is C1 inhibitor deficiency also known as?
Hereditary angioedema
What is the characteristic feature of C1 inhibitor deficiency\?
Recurrent attacks of cutaneous and submucosal swelling
Also get abdominal attacks due to swelling in abdominal viscera
What is the prevalence of C1 inhibitor deficiency?
Between 1 in 25,000 to 1 in 100,00
What are some common causes of angioedema?
Spontaneous Autoimmune Drug-induced Physical Allergy
What other symptom is angioedema commonly associated with?
Urticaria
What is the genetic inheritance of C1 inhibitor deficiency?
Autosomal dominant
Describe the onset of C1 inhibitor deficiency
Infants and children are often asymptomatic or only mildly affected
Some people are symptomatic throughout their life
What can precipitate an attack?
Trauma (commonly dental or surgical)
Infection
Describe the role of C1 inhibitor protein
Binds to activated C1r and C1s which then dissociate from C1q
C1r and C1s are then free in solution and are no longer stable so they break down leading to inactivation
Only a strong stimulus that generates lots of C1s will lead to full activation
What happens in the absence of C1 inhibitor?
Excessive activation of classical complement pathway and low levels of C2 and C4
Describe type 1 HAE
Deletions / missense mutations in C1 inhibitor gene
Low C1 inhibitor protein levels
Describe type 2 HAE
Point mutations at active site
Normal / high levels of dysfunctional protein
How is HAE diagnosed?
Clinical history of attacks of swelling and/or abdominal pain without urticaria
Check serum C4 levels
- normal levels then HAE is excluded
- if low, proceed to test for C1 inhibitor protein levels and functional activity
What is acquired C1 inhibitor deficiency?
Very rare, non-genetic causes C1 inhibitor deficiency
Occurs in 2 settings: SLE, monoclonal B-cell disorders with paraproteins
How are acute attacks treated?
C1 inhibitor concentrate
How is C1 inhibitor concentrate produced?
Purified from plasma donor pools or produced by recombinant technology
What are the cons of C1 inhibitor concentrate?
Expensive
Must be given via IV
Human blood product
How can the bradykinin system be treated?
Ecallantide
Icatibant
Describe Ecallantide
Not licensed in UK
Subcutaneous injection given 3 times
Effective for acute attacks
1-2% suffer anaphylactic reaction
Describe Icatibant
Bradykinin B2 antagonist
Subcutaneous injection (suited to self-treatment)
Safe and effective for acute attacks
When should prophylactic treatment be considered?
If attacks are frequent, severe or very disruptive
What can be given for prophylaxis?
Tranexamic acid
Attenuated androgens
Regular C1 inhibitor injections
Where does tranexamic acid act?
Locally at tissues to prevent activation of kinin system
Give examples of attenuated androgens given for prophylaxis of HAE
Danazol
Stanozolol
What are the side effects of giving attenuated androgens for prophylaxis?
Weight gain Hirsutism Hypertension Hyperlipidaemia Acne
When are C1 inhibitor injections recommended for prophylaxis?
Pregnancy when disease may worsen and androgens can’t be used
Give examples of new drugs for HAE
BCX7353
HAEGARDA
Lanadelumab
Describe BCX7353
Small molecule inhibitor of pre-kallikrein
Early studies show 50% reduction in attacks
Describe HAEGARDA
Subcutaneous C1 inhibitor prophylaxis
Twice weekly S.C. injections
95% reduction in attacks
Describe Lanadelumab
Monoclonal antibody against Kallikrein
Monthly subcutaneous injection
95% reduction in attacks in phase 3 trials
