C1 deficiency symposium

Question 1

describe the angioedema attack

Answer 1

Swelling
painless
not inflammation

fluid build up

Question 2

where do peripheral attacks occur

Answer 2

in hands

Question 3

danger to airways

Answer 3

swollen larynx which causes whisteling sound

Question 4

obstructive venous return

Answer 4

blocked venous return

finger tips are purple and necrotic

Question 5

what can happen in the abdomen

Answer 5

Swelling in large bowel and thickened abdominal wall

Question 6

why are most angioedema not HAE

Answer 6

Variety of other causes:

Spontaneous,

autoimmune,

drug-induced,

physical,

allergy

Often associated with urticaria

Question 7

what are the general features of AD

Answer 7

AD inheritance, but 20% of cases sporadic

Onset of symptoms may be delayed – infants and children often asymptomatic or mildly affected

Conversely, some people asymptomatic lifelong

Question 8

what are the general features

Answer 8

Episodic symptoms – patients well between

Attacks are usually paroxysmal

Trauma (often dental work) and infection may precipitate attacks

Delayed diagnosis very common

Historically around 10% mortality; 30% have family member who has died

Question 9

What is the classical complement pathway that causes disease

Answer 9

• C1q binding to antigen:antibody complexes activates C1r and C1s which

activates c4 and c2 forming C4b2a - C3 convertase

Question 10

what are the problems with the complement system

Answer 10

Antigen-antibody complexes are produced all the time during immune processes before removal in the spleen

It’s not always appropriate or desirable to activate inflammatory pathways in this setting

Various control mechanisms in place to prevent inappropriate activation

C1 inhibitor is the major negative regulator of classical complement

Question 11

describe c1 inhibitor

Answer 11

C1 inhibitor protein binds to activated C1r and C1s and makes them dissociate from C1q

Once free in solution, C1r and C1s are inactivated

Only a really strong stimulus that generates lots of C1s leads to full activation

Absence of C1 inhibitor protein will lead to excessive activation of the classical complement pathway and low levels of C2 and C4

Question 12

look at slide 10 for H&E mechanism

Answer 12

how was it

Question 13

genetics of H&E

Answer 13

C1 inhibitor protein encoded in 8 exons on C11

Now 283 mutations described*

Span all exons and exon-intron boundaries

Type 1 HAE
Deletions:

• missense mutations in C1 inhibitor gene
• Low C1 inhibitor protein levels

Type 2 HAE
Point :
-mutations at active site

-Normal/ high levels dysfunctional protein

Question 14

how do you make a diagnosis

Answer 14

Clinical history of attacks of swelling and/ or abdominal pain without urticaria

• Check serum C4 levels
• If very normal, HAE excluded
• If low, proceed to test for C1 inhibitor protein levels (type 1 HAE) and functional activity (type 1 and 2 HAE)

Tests perform poorly in infants<1yr old

Question 15

Acquired C1 inhibitor deficiency

Answer 15

Very rare non-genetic cause of C1 inhibitor deficiency

Occurs in two settings:

• Systemic lupus erythematosis
• -?Auto-antibodies against C1 inhibitor
• Monoclonal B cell disorders with paraproteins
• -Mechanism not known

Question 16

treatment of acute attacks

Answer 16

C1 inhibitor concentrate:

Purified from plasma donor pools , or produced by recombinant technology

Licensed for children and in pregnancy

Extremely effective, but:

• Expensive (usually £800+ per attack)
• Must be given iv
• Human blood product

Guidelines previously suggest treatment for severe attacks (facial, airway, abdominal)

New guidelines suggest treating any disabling attack

Self-treatment (home therapy) preferred

Question 17

Targeting Bradykinin system

Answer 17

Ecallantide (N America only)
Kallikrein inhibitor
Subcut injectionx3
Effective for acute attacks
1-2% anaphylactoid reactions

Icatibant
Bradykinin B2 antagonist
Subcut injection – very suited to self-treatment
Safe and effective for acute attacks

Question 18

what are the new drugs

Answer 18

-BCX7353
Small molecule inhibitor of pre-kallikrein
Approximately 50% reduction in attacks in early study

-HAEGARDA
Subcutaneous C1 inhibitor prophylaxis
Twice weekly subcutaneous injections
95% reduction in attacks
Licensed in North America, awaiting EU

-Lanadelumab
Monoclonal antibody against Kallikrein
Monthly subcutaneous injection
Not yet licensed; in Phase 3 reduced attacks by 95%

Question 19

prophylaxis

Answer 19

Consider if attacks frequent, severe or very disruptive

Tranexamic acid

-Believed to act locally at tissues to prevent activation of the kinin system

Attenuated androgens:

• Danazol/ stanozolol
• Stimulate the hepatic production of C1 inhibitor
• Very effective, but…….
• -Side-effects in some, especially at high doses (weight gain, hirsuitism, hypertension, hyperlipidemia, acne etc)
• -Not suitable for children/ in pregnancy

Regular C1 inhibitor injections:

• Effective, but requires venous access twice a week
• Cost >£100 000/ year
• Main indication is pregnancy, when disease may worsen and androgens cannot be used