Diagnosis and management of urticaria and angioedema for acute physicians

Sinisa Savic

Outline

Definition of urticaria and angioedema

Biology of mast cell activation

Diagnosis and classification of acute and chronic urticaria

Diagnosis and classification of angioedema

Treatment algorithm for acute urticaria and angioedema

Concluding remarks

3

The majority of patients presenting with urticaria and angioedema do

not have an allergy

4

Definition of Urticaria and Angioedema

Urticaria is a dermatological manifestation characterized by the sudden appearance of itchy hives (wheals), angioedema or both1

A hive consists of three typical features:

1. Central swelling of variable size, usually surrounded by a

reflex erythema

2. Associated itching (pruritus), or sometimes a burning

sensation

3. Usually resolves within a few hours and

always by 24 hours

1. Zuberbier T, et al. Allergy 2014;69:868–87

Hives: Superficial swellings with pale

centres surrounded by a red flare

Angioedema is typically characterized by:

1. Sudden, pronounced swelling of the lower

dermis and subcutis

2. Sometimes pain rather than itching

3. Frequent involvement below mucous membranes

4. Up to 72 hours for resolution

Angioedema of the lips: Pronounced swelling of soft

tissue in the mouth

The terms ‘itch/pruritus’, and ‘hive/wheal’ are interchangeable. For the purpose of this training

tool, itch and hive will be used to describe these key symptoms of urticaria

6

Biology of mast cell activation

Mast Cells

Primary effector cells in urticaria and angioedema

Widely distributed in skin, mucosa and other areas of the body

Have high-affinity IgE receptors

Degranulation leads to

• Rapid release of inflammatory mediators, e.g. histamine, leukotrienes and prostaglandins

• Vasodilation and leakage of plasma in/below skin

• Delayed (4-8 hour) secretion of inflammatory cytokines, e.g. tumor necrosis factor, interleukin 4/5

• Further inflammatory responses, longer lasting lesions

Case 1

Please see this 54 years old man who presented to A&E with anaphylaxis. He initially developed widespread urticaria, with lip swelling shortly after he was stung by a bee. He took an antihistamine tablet but despite this he developed further problems including difficulty breathing and felt woozy. He was taken to A&E where he was given IM adrenaline and corticosteroids, after which he made full recovery.

He is a bee keeper, and previously he was stung several times, but only ever use to develop localised swelling

Larché et al. Nature Reviews Immunology 6, 761–771

Cutaneous mast cells release

mediators in response to various

factors including drugs, peptides

and vasoactive amines

Trigger: Allergy

heat, cold,

exercise or

undefined

(CSU)

Symptom

manifestation

Symptom induction

via mediators, e.g.

interleukins,

histamine

Mast cell activation: overview

Mast cells are the key effector cells

in the induction of urticaria symptoms

Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M, editors. Berlin: Springer-Verlag, 2010

PRURITUS

ERYTHEMA

WHEAL

INFILTRATE

C

A

U

S

E

Activation

Vasodilation

Extravasation

Recruitment

MC

IgE SCF

IgG

LPS Complement

Anaphylatoxins

Neuropeptides Endothelin-1

Bacteria

Interleukins Chemokines

Oxytocine

Leukotriene POMCs

Prostaglandins Cannabinoids

Adenosine Urokinase

Capsaicin

?

FceRI Kit

FcR TLRs

CR1/2, CR3

C3aR, C5aR NK1

ETA/ETB

CD48

IL-3,4,15R

CCR3

OTRs

CysLT1R

MG1/MCS

EP1/EP3

CB1/CB2

A2b/A3

uPAR

VR

PIR A/PIR B

IL-1, IL-2,

IL-3, IL-4,

IL-5, IL-6,

IL-8, IL-10,

IL-13, TNF,

MIPs, IFN-

GM-CSF,

TGF-b,

bFGF,

VPF/VEGF,

PGD2, LTB4,

LTC4, PAF,

histamine,

serotonine,

heparin,

chondroitin,

sulfate,

chymase,

tryptase, CPA

MC, mast cell

IgE-mediated urticaria

Food allergy

Drug allergy

Insect venom allergy

Aeroallergies

Non-IgE-mediated urticaria

Infection

Medications (NSAID’s)

Stress (exercise)

Idiopathic

Acute urticaria causes

Anaphylaxis

An acute, potentially life-threatening, systemic mast cell degranulation

Allergic, or IgE mediated

Non-allergic (anaphylactoid), or non-IgE mediated

The Lancet, Volume 382, Issue 9905, 16–22 November 2013, Pages 1656–1664

Mast cell tryptase can be used to detect mast cell degranulation for diagnostic and medico-legal purposes and in order to define actions which will avoid future reactions

Samples required

•Basic requirements: 2mL EDTA plasma or serum sample

•Sample 1: As soon as possible after, or within one hour or, onset

of reaction.

•Sample 2: 3-6 h post-reaction (peak reaction time)

•Sample 3: 24h post-reaction (baseline)

Case 2

Please see this 34 years old woman who has become allergic to multiple foods. She describes developing widespread hives over the last two months which usually resolve within 24 hours. She has linked this to eating dairy and sometimes nuts. However there are some occasions when she was unable to find a cause.

She has taken occasionally taken over the counter antihistamines which she has found effective

Recently she also developed swelling of her face and lips and was treated in A&E for anaphylaxis

She is otherwise fit and well

Chronic spontaneous urticaria (CSU) can be defined as the spontaneous daily, or almost

daily, occurrence of itchy hives, angioedema or both, lasting for 6 weeks or more

Urticaria can be classified based on duration, frequency, and cause1

1. Adapted from: Zuberbier T, et al. Allergy 2014;69:868–87

Chronic spontaneous

urticaria

Chronic

Acute

Spontaneous

Inducible

Urticaria

Known causes (including autoimmune,

infection)

Unknown causes

Chronic spontaneous urticaria (CSU) can be defined as the spontaneous daily, or almost daily,

occurrence of itchy hives, angioedema or both, lasting for 6 weeks or more

Symptoms daily or

almost daily for ≥6

weeks

No obvious external

specific trigger

Symptoms for

<6 weeks

Symptoms induced

by a specific trigger,

e.g. temperature,

pressure, cholinergic

Diagnosis of CSU

Diagnosing CSU

A routine patient evaluation should comprise a thorough history and physical examination1

Obtaining a thorough history is the most important diagnostic procedure, and should include questions relating to the following1

1. Zuberbier T, et al. Allergy 2009;64:1417‒26

Timing, frequency, duration of attacks Shape, size, distribution and

associated symptoms of lesions

Family and medical history, including

allergies

Correlation to any triggers, e.g.

foods, exercise, drug use

Work, hobbies, smoking habits and

stress

Previous therapy and response to

treatment

Please note: models are for illustrative purposes only

Proportion of CSU patients presenting with hives, or angioedema only or both

Maurer M et al. Allergy 2011;66:317030 1. Maurer M et al. Allergy 2011;66:317–30.

What proportion of CSU patients presentwith hives and angioedema?

XSU16-C004sJune 2016

10–33%1<20%2

33–67%3>80%4

95%50

10

20

30

40

50

60

70

80

90

100

Hives and angioedema Hives only Angioedema only

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Frequency (range) of symptoms in patients with CSU1

Epidemiology

Urticaria is more common than previously thought1

CSU affects up to 1% of the population at any given time, accounting

for approximately two-thirds of cases of CU1–3

• Female:male ratio is 2:11

• All age groups can be affected, but peak incidence is between 20–40 years

of age1

No apparent relationship between urticaria prevalence and education, income, occupation, place of residence or ethnic background1

Evidence suggests that the prevalence of CU may be increasing4–8

CU = chronic urticaria

CSU = chronic spontaneous urticaria.

1. Maurer M, et al. Allergy 2011;66:317−30;

2. Kozel MM, et al. Arch Dermatol 1998;134:1575–80;

3. Saini SS. Curr Allergy Asthma Rep 2009;9:286–90;

4. Hellgren L. Acta Allergol. 1972;27:236–40;

5. Gaig P, et al. J Investig Allergol Clin Immunol. 2004;14:214–20;

6. Zuberbier T, et al. Clin Exp Dermatol. 2010;35:869–73;

7. Zazzali JL, et al. Ann Allergy Asthma Immunol. 2012;108:98–102;

8. Furue M, et al. J Dermatol. 2011;38:310–20.

CSU is a chronic disease whose duration is estimated to be 1–5 years in most cases1,2

1. Maurer M, et al. Allergy 2011;66:317–30;

2. Beltrani VS. Clin Rev Allergy Immunol 2002;23:147–69.

Time from symptom onset

Patients

initially

diagnosed

with CSU

50% will

continue to

suffer after

6 months2

30% will

continue to

suffer after

3 years2

10% will

continue to

suffer after

5 years2

8% will

continue to

suffer after

25 years2

22

CSU Pathogenesis

Strong rationale for targeting IgE as a means to alleviate symptoms in patients with CSU

The high-affinity IgE receptor (FcεRI) on mast cells plays a key role in activation of these cells and in the pathophysiology of CSU1,2

• Total IgE levels in patients with CSU are typically higher than in healthy individuals3,4

CU = chronic urticaria;

CSU = chronic spontaneous urticaria;

IgE = immunoglobulin E.

1. Vonakis BM, Saini SS. Curr Opin Immunol 2008;20:709–16;

2. Stone KD, et al. J Allergy Clin Immunol 2010;125(2 Suppl 2):S73–80;

3. Zuberbier T, et al. Allergy 2014;69:868–87;

4. Kaplan AP, Greaves M. Clin Exp Allergy 2009;39:777–87.

Antigen

FcεRI receptor

Histamine

(and other

inflammatory

mediators)

IgE

Reflex erythema

Itch Hives Angioedema

Key symptoms

of CSU

24

Bradykinin vs Histamine-mediated angioedema

25

Results form fluid extravasation into

deeper dermis and subcutaneous tissues

Non-pitting. non-dependent areas

Localised swelling

Involves skin and mucus membranes

Relatively rapid onset: minutes to hours

Frequently asymmetrical distribution

Clinical presentation of angioedema

26

27

Zuraw BL. N Engl J Med 2008;359:1027-1036.

C1inh regulates

4 serine proteases: • C1 complement component

• Factor XII

• Plasmin

• Kallikrein

29

Bernstein et al. International Journal of Emergency Medicine (2017) 10:15

Bernstein et al. International Journal of Emergency Medicine (2017) 10:15

Acquired C1inh ACE inh

34

Treatment of hereditary angioedema

Acute

• pdC1 inhibitor replacement concentrate

• Bradykinin (B2) receptor antagonist-icatibant

• Kalikreine inhibitor

Prophylaxis

• Attenuated androgens

• pdC1 inhibitor replacement concentrate

Bernstein et al. International Journal of Emergency Medicine (2017)

10:15

Conclusions

Mast cell degranulation can result from IgE (allergic) and

non-IgE (non-allergic) triggers

Clinically allergic and non-allergic anaphylaxis are

indistinguishable

Chronic urticaria is often mistaken for allergic disorder

Angioedema can be histamine or bradykine dependent

If angioedema is not responsive to antihistamine, steroids and adrenaline, consider bradykinin-mediated causes and treat accordingly