2. Definitions
• Angioedema is defined as a vascular reaction of deep
dermal/subcutaneous tissues or mucosal/submucosal
tissues with localized increased permeability of blood
vessels resulting in tissue swelling.
Maurer M, Magerl M, Ansotegui I, Aygören-Pürsün E, Betschel S, Bork K, et al. The international WAO/EAACI guideline
for the management of hereditary angioedema – the 2017 revision and update. World Allergy Organ J. 2018;11(5):5.
3. Hereditary angioedema (HAE)
• Hereditary angioedema (HAE) is a rare disease and a serious health
problem, globally and for affected patients and their families.
• The pathophysiological background is primarily a vascular reaction to an
overshooting local production of bradykinin.
• Quincke first described its clinical presentation, and Osler’s recognition of
the autosomal dominant inheritance pattern followed in 1888.
• Over the past 40 years, scientific investigations have identified the
fundamental defect of hereditary angioedema as a deficiency of functional
C1 inhibitor protein
• Bradykinin is the biologic mediator of swelling.
Busse PJ, Christiansen SC. Hereditary angioedema. N Engl J Med. 2020;382(12):1136–48.
4. Banerji A. The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2013;111(5):329–36.
5. Maurer M, Magerl M, Ansotegui I, Aygören-Pürsün E, Betschel S, Bork K, et al. The international WAO/EAACI guideline
for the management of hereditary angioedema – the 2017 revision and update. World Allergy Organ J. 2018;11(5):5.
Classification
6. • 1 in 10,000 and 1 in 150,000 individuals worldwide
• The overall prevalence of HAE related to C1INH deficiency is not well defined but
is estimated to range from 1:30,000 to 1:80,000 in the general population.
• Norway reported a prevalence of 1.75 per 100,000 inhabitants.
• Spanish registration study detected a minimal prevalence of 1.09 per 100,000.
• 1 in 50,000 individuals in the United States.
1.Lumry WR. Overview of epidemiology, pathophysiology, and disease progression in hereditary angioedema. Am J Manag Care. 2013;19(7 Suppl):s103-10.
2.Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
Epidemiology
7. Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
8. Zuraw BL. Hereditary angioedema with normal C1 inhibitor: Four types and counting. J Allergy Clin Immunol. 2018;141(3):884–5.
9. C1-esterase inhibitor
• C1-esterase inhibitor (C1-INH) belongs to the superfamily of
serine protease inhibitors.
• Plasma concentration of 0.25 g/L (3.5 µmol/L)
• It is among the most abundant protease inhibitors present in
the systemic blood circulation.
• C1-INH is the key regulator of the complement and contact
systems, and is also involved in the control of blood
coagulation and fibrinolysis
Kajdácsi E, Jandrasics Z, Veszeli N, Makó V, Koncz A, Gulyás D, et al. Patterns of C1-inhibitor/plasma Serine protease
complexes in healthy humans and in hereditary angioedema patients. Front Immunol. 2020;11:794.
10. Takimoto-Ito R, Kambe N, Izawa K, Yasumi T, Kabashima K. Hereditary angioedema with a novel mutation,
c.1481G>C, in the SERPING1 gene. J Cutan Immunol Allergy. 2021;4(3):73–4.
11. Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
12. Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
13. Rosi-Schumacher M, Shah SJ, Craig T, Goyal N. Clinical manifestations of hereditary angioedema and a systematic
review of treatment options. Laryngoscope Investig Otolaryngol. 2021;6(3):394–403.
14. Genetics of C1-INH-HAE
• The autosomal dominant mode of inheritance has been described for
C1-INH-HAE when one of the two alleles of the C1-INH gene
(SERPING1) is mutated.
Santacroce R, D’Andrea G, Maffione AB, Margaglione M, d’Apolito M. The genetics of hereditary angioedema: A review. J Clin Med. 2021;10(9):2023.
15. Santacroce R, D’Andrea G, Maffione AB, Margaglione M, d’Apolito M. The genetics of hereditary angioedema: A review. J Clin Med. 2021;10(9):2023.
16. • If one parent has HAE, the child has a 50% chance of
inheriting HAE and a 50% chance of not inheriting HAE.
• The disease does not skip generations.
25% of HAE patients do not have any family history of
the disease because the mutation is new, or
spontaneous.
https://www.cinryze.com/what-is-hereditary-angioedema
17. Santacroce R, D’Andrea G, Maffione AB, Margaglione M, d’Apolito M. The genetics of hereditary angioedema: A review. J Clin Med. 2021;10(9):2023.
19. Prodromal symptoms
• Several hours or up to a day in up to 50% of patients with HAE.
• The most common prodromal symptoms
• Erythematous non-urticarial rash (erythema marginatum)*
• Localized tingling
• skin tightness
• Malaise
• Fatigue
• Gastrointestinal symptoms
• Flulike symptoms
• Irritability
• Dysuria
• Mood changes
• Hyperactivity
• Thirst
1. Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
2. Rasmussen ER, de Freitas PV, Bygum A. Urticaria and prodromal symptoms including erythema marginatum in danish patients
with hereditary angioedema. Acta Derm Venereol. 2016;96(3):373–6.
3. Rasmussen ER, de Freitas PV, Bygum A. Urticaria and prodromal symptoms including erythema marginatum in danish patients
with hereditary angioedema. Acta Derm Venereol. 2016;96(3):373–6..
20. 1. https://dermnetnz.org/topics/rheumatic-fever
2. Majmundar VD, Nagalli S. Erythema Marginatum. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021.
• Evanescent, blanchable, nonpruritic macular rash
seen generally on the trunk and extremities.
• This was evidenced by the presence of dense
stromal and endothelial deposits of bradykinin in
skin biopsy specimens taken from lesions of
erythema marginatum in patients with hereditary
angioedema.
The clinical differential diagnosis for erythema marginatum include
1. Annular urticaria
2. Annular erythema of infancy
3. Erythema annulare centrifuged (EAC)
4. Autoinflammatory diseases such as TNF receptor-associated periodic
syndrome Still disease.
21. Hereditary Angioedema Related to
Decreased C1INH
Episodes of nonpruritic, nonpitting angioedema involving the
• Extremities* 50 %
• Abdomen* 50 %
• Genitourinary tract
• Face
• Oro-pharynx.
1. Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
2. https://www.discoverhae.com/what-is-hereditary-angioedema
22. • Over a lifetime, almost all patients with HAE experience both
extremity and abdominal attacks, and more than half of the patients
experience at least one laryngeal attack.
• Most often, patients with HAE begin swelling and experiencing
abdominal pain during child-hood.
• In 50% of the patients, swelling begins before the age of 10 years.
• Some patients manifesting angioedema by 1 year of age.
• Type 1 and type 2 HAE cannot be distinguished on clinical grounds.
Hereditary Angioedema Related to
Decreased C1INH
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
23. The typical course
• Gradual but relentless worsening over the first 24 hours, followed by an
even slower recovery over the next 48 to 72 hours.
Hereditary Angioedema Related to
Decreased C1INH
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
24. Subcutaneous attacks typically progress and
evolve over several hours, last for approximately
2 to 4 days if untreated.
1.https://www.ajmc.com/view/severity-of-hae-prevalence-and-diagnostic-considerations
2.Moreno AS, Valle SOR, Levy S, França AT, Serpa FS, Arcuri HA, et al. Coagulation factor XII gene mutation in Brazilian
families with hereditary angioedema with normal C1 inhibitor [Internet]. Unpublished; 2015
25. • Females
• It is less likely to manifest before puberty
• Patients tend to have fewer attacks,
with more attack-free intervals
• Distribution of attacks
• Higher percentage of facial and tongue episodes
• Lower percentage of abdominal episodes
• Fewer multiorgan attacks
Hereditary Angioedema With
Normal C1INH
1 .Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
2. https://www.discoverhae.com/what-is-hereditary-angioedema
26. The most striking clinical differences
• Onset at a relatively older age
• Lack of family history
• Underlying malignancy
Acquired C1INH Deficiency
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
27. • Strong predilection for involvement
• Face
• Lips
• Tongue
• Bowel or extremity angioedema is not commonly
• The first episode within the first month of treatment
• More than 25% of patients experience their first attack of
angioedema more than 6 months after beginning the ACE-I.
• Some patients have been on an ACE-I for years before their first episode.
• Discontinuation of the ACE-I leads to resolution of the problem, although it may
take many weeks before the risk of a recurrent attack is gone.
Angiotensin-Converting Enzyme
Inhibitor–Associated Angioedema
1 .Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
2. https://www.discoverhae.com/what-is-hereditary-angioedema
28. Hirose T, Kimbara F, Shinozaki M, Mizushima Y, Yamamoto H, Kishi M, et al. Screening for hereditary angioedema (HAE) at 13 emergency centers in
Osaka, Japan: A prospective observational study. Medicine (Baltimore). 2017;96(6):e6109.
Intestinal edema (arrow)
Ascites (arrowheads)
Laryngeal edema
29. Precipitating causes
• Trauma
• Prolonged sitting on a hard surface or clapping of the hands
• Dental work
• Medical procedures
• Surgery
• Emotional stress
• Postpartum period
• Birth control pills containing estrogen * contraindicated
• Estrogen replacement therapy * contraindicated
• ACE-I medications should be avoided in patients with HAE.
• Hormonal changes can affect disease severity.
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
31. PATIENT EVALUATION
Bradykinin-mediated angioedema usually is distinguished from
mast cell–mediated angioedema
• Slower evolution
• Longer duration
• Lack of urticaria
• Failure to respond to antihistamines or corticosteroids
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
33. Suspicious History
• Recurrent angioedema
• The absence of urticaria (wheals)
• Positive family history (although this may not be present in up to 25% of patients)
• Onset of symptoms in childhood/adolescence
• Recurrent and painful abdominal symptoms
• Occurrence of upper airway edema
• Failure to respond to antihistamines, glucocorticoids, or epinephrine.
• Presence of prodromal signs or symptoms before swelling.
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
34. Screening
• The C4 level is an excellent screening tool for C1INH deficiency in patients
older than 1 year.
• Reduced C4 level even between attacks in at least 95% of patients with
C1INH deficiency.
• Increasing to virtually 100% during angioedema attacks.
• A normal C4 level during an attack of angioedema strongly suggests a
diagnosis other than C1INH deficiency.
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
35. No significant differences observed in concentrations between age groups
Garcia-Prat M, Vila-Pijoan G, Martos Gutierrez S, Gala Yerga G, García Guantes E, Martínez-Gallo M, et al. Age-specific pediatric reference ranges for
immunoglobulins and complement proteins on the OptiliteTM automated turbidimetric analyzer. J Clin Lab Anal. 2018;32(6):e22420.
36. Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
37. Diagnosis of Hereditary Angioedema
Related to C1INH Deficiency
• Patients with recurrent angioedema who have a positive family history of
angioedema.
• Lack of a positive family history of angioedema cannot be used to exclude the
diagnosis, because 25% of patients presumably have a de novo mutation of the
C1INH gene.
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
38. Hereditary Angioedema With Normal
C1INH
• History of recurrent angioedema
• Strong family history
• Resistance to high-dose antihistamine therapy
• The C4, C1INH antigen, and C1INH functional assays are all normal.
• Genetic testing of suspected patients is recommended.
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
C4 level C1INH Antigen C1INH Function C1q level
Normal Normal Normal Normal
40. • The clinical presentation in acquired C1INH deficiency is very similar to that
in HAE, except that HAE tends to manifest during childhood, whereas
acquired C1INH deficiency tends to manifest in middle-aged or older
patients.
• Acquired C1INH deficiency is not associated with a positive family history
of angioedema.
• The C1q level is decreased in most cases of acquired C1INH deficiency but
should be normal in HAE, with rare exception.
• The finding of an underlying malignancy or C1INH autoantibodies would
strongly support the diagnosis of acquired C1INH deficiency.
Acquired C1INH Deficiency
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
41. • Acquired deficiency of C1 inhibitor
• Hyperactivation of the classical pathway -> C1 INH consumption
• Contact-kinin system -> Bradykinin
• C1-INH neutralizing antibodies (anti-C1-INH autoantibodies)
-> C1 INH inactivity and catabolism
Acquired Angioedema (AAE)
Cicardi M. et al. Allergy, Asthma and Clinical Immunol 2010, 6:14
42. Syndrome C4 level C1INH Antigen C1INH Function C1q level
Acquired C1INH
Deficiency
Low Low Low Low
Acquired C1INH Deficiency
Bruce L. Zuraw, Sandra C. Christiansen. Middleton's Allergy 8th edition
43. Associated disorders of
Acquired C1INH Deficiency
• Monoclonal gammopathy of undetermined significance / MGUS
• Non-Hodgkin lymphoma
• Anti-C1-INH autoantibodies
• Breast cancer
• Liver failure
Bork K, Staubach-Renz P, Hardt J. Angioedema due to acquired C1-inhibitor deficiency:
spectrum and treatment with C1-inhibitor concentrate. Orphanet J Rare Dis. 2019;14(1):65.
44. Maurer M, Magerl M, Ansotegui I, Aygören-Pürsün E, Betschel S, Bork K, et al. The international WAO/EAACI guideline
for the management of hereditary angioedema – the 2017 revision and update. World Allergy Organ J. 2018;11(5):5.
46. Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
HAE Treatment
On-demand Acute Therapy Early Treatment
Irrespective of Swelling
Sites
Long Term and Short Term
Prophylaxis
47. FDA-Approved On-demand Acute Therapy
Zuraw B. et al. Hereditary Angioedema. N Engl J Med 2008; 359:1027-36
• C1-INH concentrates
• Plasma derived
• Recombinant
• Kallikrein inhibitor
• Bradykinin B2 receptor
antagonist
48. • C1-INH concentrates (IV)
• Plasma derived (Cinryze)
• Cryodepleted human plasma
• Half life: > 30 hours
• Recombinant (Ruconest)
• Half life: 3 hours
• Contraindicated in patients with known rabbit derived products
On-demand Acute Therapy
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
Maurer M. et al. WAO J (2018) 11:5
49. Zuraw B. et al. Hereditary Angioedema. N Engl J Med 2008; 359:1027-36
• C1-INH concentrates
• Plasma derived
• Recombinant
• Kallikrein inhibitor
• Bradykinin B2 receptor
antagonist
FDA-Approved On-demand Acute Therapy
50. • Kallikrein inhibitor
• Ecallantide (Kalbitor)
• ≥ 12 years old
• Half life: 2 hours
• Severe HSR including anaphylaxis: 3-4%
On-demand Acute Therapy
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
Maurer M. et al. WAO J (2018) 11:5
51. Zuraw B. et al. Hereditary Angioedema. N Engl J Med 2008; 359:1027-36
• C1-INH concentrates
• Plasma derived
• Recombinant
• Kallikrein inhibitor
• Bradykinin B2 receptor
antagonist
FDA-Approved On-demand Acute Therapy
52. • Bradykinin B2 receptor antagonist
• Icatibant (Firazyr)
• ≥ 18 years old
• Half life: 1-2 hours
• Local injection site reactions (erythema, wheal, pruritus and burning sensation)
• No reported allergic reaction
On-demand Acute Therapy
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
Maurer M. et al. WAO J (2018) 11:5
53. Summary of FDA-Approved On-demand Acute Therapy
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
54. On-demand Acute Therapy
Zuraw B. et al. Hereditary Angioedema. N Engl J Med 2008; 359:1027-36
• C1-INH concentrates
• Plasma derived
• Recombinant
• Kallikrein inhibitor
• Fresh Frozen Plasma
• Bradykinin B2 receptor
antagonist
55. • Fresh Frozen Plasma
• Contains C1 INH
• Used if none of the FDA-approved on demand medications are available
• Efficacy -> not studied
• Dose: 2 units or 10 ml/kg, repeat within 4-6 hours
• HMWK, plasma prekallikrein and FXII -> Safe?
On-demand Acute Therapy
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
Maurer M. et al. WAO J (2018) 11:5
56. • Should have access to at least 2 standard doses of FDA-approved on-
demand medications for treatment of acute attacks
• Self administration: C1-INH concentrates or Icatibant
• Better response + Shorter time to resolution + Shorter total attack
duration regardless of attack severity
Early Treatment
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
57. Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
Prophylaxis
Short Term Prophylaxis
Long Term Prophylaxis
58. Long Term Prophylaxis
• Use of regular medication to reduce the burden of the disease by
preventing/attenuating attacks
• Indications -> Individualized
• Disease activity
• Frequency of attacks
• Patient’s QoL
• Availability of healthcare resource
• Failure to achieve adequate control with on-demand therapy
• Patient preference
• Patients with ongoing LTP should be assessed regularly for efficacy and safety of therapy, and dosage
and/or treatment
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
Maurer M. et al. WAO J (2018) 11:5
• Treatment goals
• Reduction in HAE attacks
• Well controlled -> Attack-free for > 6 months
59. Busse PJ. Et al. Ann Asthma immunol 121 (2018) 673-679
60. Long Term Prophylaxis
Busse PJ. N Engl J Med 2020; 382:1136-1148
• PD-C1-INH concentrates
• IV
• SC
• Kallikrein inhibitor
• Monoclonal antibody
• Antifibrinolytic
• Attenuated Androgen
61. • Kallikrein inhibitor
• Lanadelumab
• ≥ 12 years old
• Fully human monoclonal antibody
• Local side effects
• No known contraindications
• No study in pregnant and lactating women
Long Term Prophylaxis
Banerii A. et al. JAMA. 2018;320(20):2108-2121
62. Long Term Prophylaxis
Busse PJ. N Engl J Med 2020; 382:1136-1148
• PD-C1-INH concentrates
• IV
• SC
• Kallikrein inhibitor
• Monoclonal antibody
• Antifibrinolytic
• Attenuated Androgen
C1 INH
63. • Attenuated Androgen
• Danazol
• Alternative drugs (2nd line)
• Unknown mechanism -> Increase C1 INH synthesis from liver
• Lowest effective dose to minimize side effects
• Avoidance:
• Patients < 16 years of age, pregnant and breast feeding women
• High risk of thrombosis
• Drug interactions: Statin
Long Term Prophylaxis
Maurer M. et al. WAO J (2018) 11:5
64. Long Term Prophylaxis
Zuraw et al. J Allergy Clin Immunol Pract 2016;4:948-55
Maurer M. et al. JDDG; 2011
• Side effects
• Dose dependent
• Carefully follow potential drug side
effects
• 6 months
• CBC, LFT, Lipid profile, Urine
• Ultrasound of liver (>200 mg/day)
• Annually
• Ultrasound of liver (<200 mg/day)
65. Long Term Prophylaxis
Busse PJ. N Engl J Med 2020; 382:1136-1148
• PD-C1-INH concentrates
• IV
• SC
• Kallikrein inhibitor
• Monoclonal antibody
• Antifibrinolytic
• Attenuated Androgen
66. • Antifibrinolytic
• Tranexamic acid (TA)
• Alternative drugs (2nd line)
• Efficacy -> lacking data (less effecive)
• Minor side effects
• Gastrointestinal (nausea, vomit, diarrhea), headache, hypertension
• Retinal damage
• Possible increased risk of thrombosis (DVT, pulmonary embolism)
Long Term Prophylaxis
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
Maurer M. et al. WAO J (2018) 11:5
67. Long Term
Prophylaxis
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
68. Patient population Preferred agents Alternate agents Agents to be
avoided
Other notes
Pre-pubertal children • PD-C1 INH • Tranexamic acid • Androgen Lanadelumab not
studied for children
< 12 years of age
Adult women • PD-C1 INH
• Lanadelumab
• Tranexamic acid • Androgen
Adult men • PD-C1 INH
• Lanadelumab
• Tranexamic acid
• Androgen
Pregnant and
lactating women
• PD-C1 INH • Tranexamic acid • Androgen Lanadelumab not
studied for in
pregnancy
Specific Groups
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
Maurer M. et al. WAO J (2018) 11:5
69. • HAE attack triggers: trauma and stress
• Invasive medical, surgical or dental procedures
• Emergency procedures
• C1-INH concentrate 1000 units or 20 units/kg
• FFP or S/D (2nd line)
Short Term Prophylaxis
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
Maurer M. et al. WAO J (2018) 11:5
70. Short Term Prophylaxis
Busse PJ. Et al. Ann Asthma immunol 121 (2018) 673-679
High-risk procedures Low-risk procedures
Intubation, oral surgery (cutting of tissues), dental
procedures involving injections of anesthetics, general
surgery, other procedures that precipitated past
attacks
Routine dental cleanings
Option 1: PD-C1-INH concentrate 1 hour before
procedure, with 2 additional doses available on
demand
No additional treatment in advance but have
treatment for acute angioedema immediately
available (i.e. C1-INH concentrate, Ecallantide, or
Icatibant)
Option 2: Androgen for 5 days before and 3 days after
Example: Danazol 10 mg/kg/day up to 600 mg/day
71. • Individualized patient action and treatment plans (patient and family
education)
• Home therapy and self administration
• Avoidance of triggers
• Stress, surgery, infection, trauma, physical activities, fluctuating hormone,
ACEI, estrogen
• Family screening
• Follow up with experts
• Burden of illness -> physical and mental (anxiety and depression)
Other Management Considerations
Busse PJ. et al. US HAEA Medical Advisory Board 2020 Guidelines for the management of HAE. J. Allergy Clin Immunol Pract
Maurer M. et al. WAO J (2018) 11:5