Chronic Urticaria and Angioedema

by the

Urticaria and Angioedema Committee

© AAAAI 2006

Angioedema vs Urticaria• Urticaria – involving the superficial dermis

– Most often characterized by intense pruritis due to histamine effect

• Angioedema – involving deeper dermal and subcutaneous layers– May be pruritic but often characterized as a

deeper and dull discomfort – burning quality

• Level of involvement may dictate detection and subsequent perception by patient

Chronic Urticaria/Angioedema(Mast cell driven)

0

10

20

30

40

50

60

70

80

% of Patients withChronic Urticaria

Women

Men40%50% 10 %

Urticaria& Angioedema

Urticaria Angioedema

Drug Induced Urticaria / Angioedema

Bradykinin responsible for swelling in angioedema in patients with HAE Kaplan A et al J Allergy Clin Immunol 2002;109:195-209

Angiotensin converting enzyme (ACE) inhibitors interfere with metabolism of bradykinin via interference with kininase Ii Gavras I Kidney Int 1992; 42:1020-29

Patients on angiotensin converting enzyme blockers (ARBs) may not be at risk for angioedema Gavras I Arch Int Med 2003; 163: 240-1

Hereditary Angioedema• Autosomal dominant with incomplete penetrance.

–Spontaneous mutations in 50%–Diminished C4 between attacks–Very low C4 during attacks

• HAE I–Low levels of C1 esterase inhibitor

• HAE II–Dysfunctional C1 INH

• HAE III (estrogen-dependent angioedema)–Normal C1 INH amount and function–Normal complement levels

Acquired Angioedema (AAE)

• Rare; Onset > 50 yo; negative familial history• AAE, type I

–Lymphoproliferative disorder–Monoclonal gamopathy, lymphoma,

lymphocytic leukemia• AAE, type II

–Autoantibodies to CI-INH• Low C1q levels in addition to depletion of C4

and C2.

Aspects cliniques

•Age de début•Localisation •Cinétique•Fréquence des crises•Facteurs déclenchants•Facteurs aggravants ( Inhibiteurs ACE, hormones)

• Inhibits C1r and C1s of the complement

system

• Inhibits activated factor XIIa and kallikrein

• An inhibitor of factor XIa and plasmin

• Inhibits activation of C1

C1 Inhibitor Functions

(Ecalantide)

Laboratory Tests for C1 Inhibitor Deficiency

• C4 low; C4d/C4 ratio always elevated

• C1 inhibitor protein low in about 85% of cases

• C1 inhibitor only functionally deficient in about

15%

• C1q antigen low in acquired deficiency

• Abnormal C1 inhibitor mobility (lower

molecular weight) on SDS gel electrophoresis

Treatment of Hereditary Angioedema• Patient education very important; test family• No regular medication needed in many cases• Prophylactic stanozolol or danozol• Epsilon aminocaproic acid (EACA) an option• Fresh frozen plasma before emergency

surgery• C1 inhibitor available in Europe but not in

the USA• Symptomatic treatment during attacks

Presentation of Urticaria• Patients typically present with pruritic and elevated papular

to plaque-like (plateau) elevations of skin• The duration of each lesion should help in defining the

type of urticaria and therapy– Less than 24 hours (each) suggestive of an IgE

mediated process and usually respond better with antihistamines

– Longer than 24 hours (each) implies cell mediated process (contact dermatitis, eczema), IgG/IgM antibody associated (i.e., serum sickness), or vasculitis that usually require steroids or other immuno-suppressants

Acute vs Chronic Urticaria• Acute Urticaria – lasts 6-8 weeks or less

– Viral syndromes (especially in young children)– Insect bites or stings (fire ants, scabies)– Food induced reactions (eat this- get that)– Medication related (antibiotics, NSAIDs, narcotics,

angioedema due to ACE inhibitors)• Chronic Urticaria – lasting longer than 8

weeks– Physical urticarias (dermographism, cholinergic,

cold)– Urticarial vasculitis – Urticaria/angioedema associated with

autoimmunity– Autoimmune urticaria– Idiopathic urticaria

Physical Urticarias• May occur so intermittently as to appear acute

but typically are chronic entities – most idiopathic

• Physical Urticarias– Symptomatic Dermatographism– Cholinergic– Cold Induced (Familial or Acquired)– Vibratory (angioedema)– Pressure – induced, Solar, Aquagenic

Physical urticaria

Symptomatic Dermatographism

• Simply scratching the skin promotes linear hives within minutes

• Delayed form described• Typically is short-lived in

duration (1/2 to 3 hours) and responds readily to antihistamines

Symptomatic Dermatographism

Cholinergic Urticaria

Cholinergic Urticaria

• Goal of raising body temperature (oral) by 0.7oC• Hot bath to 420C or having patient exercise

• Small pruritic papules result surrounded by erythema (but without hypotension) result

• Passive heat challenge may separate exercise-induced anaphylaxis from cholinergic urticariaCasale T et al. JAMA 1986; 255: 2049-2053

• Methacholine skin test insensitive (positive result in only 33% of patients with cholinergic urticaria)

Burrall B et al Western J Med 1990; 152: 268-76

Cholinergic urticaria

Cold-Induced Urticaria

• Familial (autosomal dominant) vs acquired (usually infection associated)

• Acquired form -positive ice-cube challenge

• Usually responds to cyproheptadine

Cold-induced urticaria

• Cold Stimulation Time Test (CSTT)– Positive in acquired cold-induced urticaria– Ice cubes and water in a plastic bag applied

to patient’s forearm up to 10 minutes– Urticaria results after warming of area– Timing of cold stimulus indirectly

proportional to severity (less time needed, worse symptoms upon exposure to cold)

• Many patients with good history for cold-induced urticaria may have negative CSTT

Diagnosis of cold-induced urticaria

Delayed Pressure Urticaria

Delayed Pressure Angioedema

• ~ 37% incidence of delayed pressure urticaria in chronic urticaria Barlow R et al. J Am Acad Dermatol 1993; 29: 954-8

• 15 pound weight suspended by thick strap over the shoulder and worn for 15 minutes– Typically, erythema with induration and

tenderness occurs at least 2 hours after the testSussman G et al J Allergy Clin Immunol

1982; 70: 337-42

Lawlor F et al Br J Dermatol 1989; 120: 93-99

Vibratory angioedema

Vortex to induce angioedema in a patient with swelling of hands while driving car

Solar Urticaria

• Phototesting performed with various light sources – sunlamp, blacklight, slide projector lamp

Horio T, Fukigaki K. J Am Acad Dermatol 1988; 18:

1189-93

• Differentiation from erythropoietic protoporphyria – lesions leave scarring– Analysis of red blood cells for

protoporphyrins– Stool for coproporphyrins

B Cell Lymphoma Associated with Symptomatic Dermatographism

Patient’s dermatographism resistant to fexofenadine and cetirizine sent a clue that something else may be causing her itching and hives.

Hypocomplementemic Urticarial Vasculitis Syndrome (HUVS)

Hypocomplementemic urticarial vasculitis syndrome

•Urticaria/angioedema depressed C4

•Depresseed C1q

•Various etiologies, autoimmune diseasses

•Medicine 1995 74 24-41

Antibodies associated with urticaria

IgG auto ab to IgE receptor 35-40%

Antithyroglobulin Ab 8%

Antimicrosomal Ab 5%

Autologous Serum Skin Test• Serum obtained from patient

– 0.05 ml injected intradermally– Examination of wheal response at 30 minutes– Positive test is extension of wheal response by at

least 1.5 mm greater than original

• Patients with positive skin test associated with histamine-releasing FceRI autoantibodies– Patients with sera with histamine releasing activity

had more severe urticaria compared to those without

Sabroe RA et al. J Allergy Clin Immunol 2002; 110:

494-9

Autologous serum skin test

• Therapy with antihistamines work best for most patients with acute-types of short-lasting urticaria

• Combination therapy should be attempted if H1 antagonists do not suffice (30% of cases)

• Steroids and other immunosuppressants should be reserved for severe urticaria associated with angioedema of oropharnyx or other systemic signs, moderate to severe drug reactions, urticarial vasculitis, and refractory cases of CIU

Therapeutic options