eas LONDON Hereditary angioedema — the best way to prevent attacks , Clive Grattan, MA, MD, FRCP (UK) St John’s Institute of Dermatology, London COO®Definition of angioedema A sudden, pronounced erythematous or skin-coloured | swelling of the lower dermis and subcutis, often below mucous | membranes and sometimes presenting with pain rather than itching. Its | resolution is slower than that for weals and can take up to 72 h.1 Angioedema can be anywhere on the skin or oropharynx. Often asymmetrical initially and resolve with no residual change Hereditary angioedema also involves severe swelling of the throat (glottis) and gastrointestinal tract € 700» 1. Zuberbier et al. Allergy 2014; Jul;69(7):868-87.Angioedema without weals ANGIOCOOMA yaTHoUT WHEALs Oo» {cramocraene |p Pera nonT |, [soto ane sites > Staring vo vunnre ene ane ed < Sa ‘eaunc ee ‘Dorman, > Maer wo owekcuse or |__| Mttes needs Aetna | —$> eos nd se retary cramoenceney }-—>. atic | readers wa Frusutanon ap, seman Nomad chant estry { unenown case Lop; stgorieme of Cicardi et al. Allergy 2014, 69; 602-616Angioedema pathogenesis HISTAMINERGIC * Occurs in 40-60% of patients with chronic spontaneous urticaria + 10% of CSU patients have angioedema without weals Urticaria (with angioedema) is due to MAST CELL DEGRANULATION with release of histamine (and f other mediators) \FOoo® BRADYKININERGIC + Weals NEVER seen (but prodromal erythema marginatum possible) + Excess tissue bradykinin due to — Increased generation — Reduced breakdown (ACEI) Bradykinin is the main mediator of hereditary angioedema HAE is NOT associated with mast cell degranulationHereditary angioedema * HAE 1 and 2 rare (1:50,000 people)! + Autosomal dominant inheritance (i.e. affects 50% of children) * Characterized by low C1 INH (Type 1) or non-functional C1 INH (Type 2) due to mutations in SERPING1 * HAE nC1 INH associated with mutations in genes for FXII, angiopoietin-1 and plasminogen or others unknown C1 INH inhibits complement proteases, plasmin and contact system proteases (kallikrein and coagulation FXII) r 1, Maurer et al, Allergy 2018; 73:1575-96 700%7 Scale of the problem + HAE is an unpredictable, painful and life-threatening condition + Patient survey in 2013! — 25% HAE patients with C1INH types1 and 2 reported 21 attack a week, and 48% reported 2 1 attack/month — Patients with HAE nCINH reported more frequent attacks — About 50% HAE patients had a delay in diagnosis of = 10 y * Goals for prevention — Early diagnosis — No more angioedema . 41. Banerji et al. Allergy Asthma Proc 2018, 39(3):212-23 »Why attacks need prevention 1. Courtesy of Professor Bork 2. Yakushiji al. Allergy 2018, 73:2244-7 . \ 3, Abuzakouk et ak. Case Reports in of 9 |, Immunology, 2018, Article ID 7435870 :fatal laryngeal oedema in Hereditary Angioedema Phase 1: onset of symptoms to onset of dyspnoea 2: onset of- dyspnoea to loss of consciousness Phase 3: onset of loss of consciousness to death Phase 2:10 49 minutes: range, 2 minutes to hours Phase 3: 8.9 t 5.1 minutes; range, 2-20 minutes FIG 4. Moan durations of the 3 phases of fatal loryngual attacks in 36 pationts with HAE C1.INK. AAs Bork K et al. J Allergy Clin Immunol 2012;130:692-7Biochemical characterization of HAE ANGIO- OEDEMA I, Angioedema ‘Angioedema WITH weals WITHOUT weals Diagnose as Angioedema with Angioedema for URTICARIA NORMAL C4 with LOW C4 ‘Spontaneous HAE Types | or Il Drug-induced Acquired C1 INH Non-histaminergic deficiency HAE Normal C1INH testing-ofychildren should be after 1 year oldBiochemical characterization of HAE ‘Angioedema WITHOUT weals an Drug Physic: ‘Angioedema with ‘Angioedema NORMAL C4 with LOW C4 ‘Normal G1 INH Yer INH Normal (G1 INH | #01 INH Normal function C1 INH function | ¥C1 INH function WC1 INH function are aon | SC 9. ACE! | testina of children should be after 1 vear old | vc1q Y cos Tye] [Tipe |Managem Avoidance of triggers — Drugs: oestrogen and ACE inhibitors — Mechanical trauma, especially oropharyngeal procedures — Psychological stress — Tiredness — Treatment of infections (? helicobacter) On-demand treatments (emergency for breakthroughs) — plasma derived (pd) or recombinant C1INH (IV) — Icatibant (bradykinin 2 receptor antagonist, s/c) — Ecallantide (recombinant kallikrein inhibitor, s/c plasma T %, 2 h)HAE prophylaxis (types 1 and i) + None required for some patients + Short term (e.g. dental procedures, surgery, pre-long haul flight) —pdC1 INH — danazol (5 days before, 2 days after) + Long term —oral (anabolic steroids, tranexamic acid) | —pdC1 INH twice weekly (IV or s/c’) | —lanadelumab fortnightly or monthly (s/c?) \ 1. Longhurst ot al. N Engl J Med 2017, 23;376(12):1131~ 1140 2, Banerji ot al. N Eng J Med 2017, 378:717-28Children and adolescents * 50% children have their first attack by 12-13 years old ~ no prophylaxis until then Long term prophylaxis: same as adults, BUT — androgens not recommended (masculinization and hypogonadism in boys; menstrual abnormalities in girls) — tranexamic acid (safer but ? benefit) — pdC1INH (usually on demand) — Action plans for schools (lifestyle and emergency management) e700»Pregnancy and breast feeding * Short term prophylaxis — pdC1 INH —[? FFP] * Long term prophylaxis —pd C1 INH — ? tranexamic acid — ? lanadelumab (limited data) * Contraindicated: androgensIndividualized patient plans Everyone’s illness is differe! Availability of treatment options depends on — Funding — Opportunities for self-administration — Access to medical supervision Disease activity (varies over lifetime) Wishes and expectations Self awareness and knowledge (patient support groups) — https://haei.org — https://www.haeuk.orgGOAL FOR PREVENTION ©