GLORIA Module 12:
Urticaria
an educational program of
Updated: June 2011
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GLORIA Module 12:
Urticaria
Authors:
Allen P Kaplan
Malcolm W Greaves
Learning objectives
Following this presentation you should be able to:
• Distinguish the various forms of physical urticaria
• Formulate a differential diagnosis and treatment plan for acute
urticaria
• Describe the role of autoimmunity as a pathogenic mechanism
for chronic urticaria
• Describe a therapeutic approach for patients with severe chronic
idiopathic or chronic autoimmune urticaria.
• Distinguish urticarial vasculitis from other forms of chronic
urticaria
Urticaria and angioedema
Definition:
A wheal and flare reaction initiated at the level of the small
venules of the skin in response to substances that cause
vasodilatation, increase vascular permeability, and for
histamine, stimulate type C unmyelinated afferent cutaneous
neurons to release neuropeptides (axon reflex)
Definition of urticaria
(also called hives, nettle rash)
and epidemiology
• Urticaria affects up to 2% of the population at some time in a
lifetime
• Transitory (individual episodes < 24h duration) red skin
swellings with itching
• No desquamation, rarely affects mucous membranes
• Associated with angioedema in about 40% of cases
Pathophysiology of urticaria
• Most types of urticaria are due to promiscuous activation of
dermal mast cells, although basophils may also be involved
• Release of histamine and other mediators (including eicosanoids,
proteases, cytokines) causes local vasodilation, vasopermeability,
fibrin deposition, perivascular infiltration by lymphocytes,
neutrophils, and eosinophils, and pruritus
• There is minimal endothelial swelling and no leukocytoclasis
Substances that cause hive formation
when injected into the skin include:
• Histamine
• Leukotrienes C and D
• Platelet activating factor (PAF)
• Bradykinin
• Substance P
Skin rashes which mimic urticaria
(“pseudourticaria”)
• Maculopapular exanthems (viral, drug rashes)
• Urticarial dermatitis
• Erythema multiforme
• Insect bite reactions (“papular urticaria”)
• Leukocytoclastic vasculitis (including urticarial vasculitis)
• Polymorphic light eruption
• Some autoinflammatory syndromes (e.g., Muckle-Wells)
Classification of urticaria into acute
and chronic
• “Urticaria” is an umbrella term inclusive of diverse clinical
entities
• Conventionally (eg European guidelines: Allergy, 2004) it is
broadly divided into acute and chronic
• Chronic urticaria is conventionally defined as “daily or almost
daily urticarial eruptions occurring for 6 weeks or more”
• Chronic urticaria is further subclassified into several distinct
entities
Ordinary chronic urticaria
Classification of chronic urticaria
Chronic urticaria
Urticarial
vasculitis
Physical
urticaria
Autoimmune
urticaria
Ordinary
chronic
urticaria
Contact
urticaria
Idiopathic
chronic
urticaria
Schnitzler’s
syndrome
Acute urticaria
• All ages; common in childhood
• Abrupt onset of urticarial eruption usually pruritic and
widespread
• Angioedema common
• Systemic symptoms (fever, malaise) also common, depending
on cause
• Duration: usually hours or days
Zuberbier T, Ifflander J, Semmler C, et. al. Acta Derm Venereol 76:295-297, 1996.
Causes of acute urticaria
• Viral infections; particularly in children. In adults: prodrome of
Hepatitis B, infectious mononucleosis (EBV)
• Drugs (NSAIDS, penicillins and derivatives, radiocontrast
media)
• Foods non–allergic (e.g., scombroid fish poisoning) and allergic
(IgE–mediated) (e.g., nuts, shellfish)
• Immunization vaccines e.g., MMR, tetanus toxoid
Investigation of acute urticaria
• Many cases require no investigation - the cause is
evident to patient and doctor alike
• Skin prick tests may support the diagnosis (but avoid
SPT in severely affected patients, and in patients with
current angioedema or a history of angioedema)
• Serum IgE testing may also help confirm the culprit
Acute urticaria: prognosis and treatment
• Many attacks of acute urticaria are solitary, and the cause is evident
and avoidable
• Facial / labial / buccal angioedema should respond to Primatene mist
spray and / or subcutaneous adrenaline administered every 10-15 min
• Severe oropharyngeal angioedema should prompt overnight admission
• Chlorpheniramine 4 mg or diphenhydramine 50 mg by injection or by
mouth is usually sufficient to suppress even widespread urticaria
Zuberbier T, Greaves MW, Juhlin L, et. al. J Invest Dermatol Symp Proc 6:128-131, 2001.
Food allergy
• Mediated by binding of allergens that survive digestion,
and delivered to the skin to interact with IgE on
cutaneous mast cells
• Can be diagnosed by skin test or RAST assay – result
must be correlated with history and be reproducible
• Double-blind oral challenge represents the definitive test
for diagnosis
Drug reactions - 1
• Drug or drug metabolite causing hives by interaction with IgE
antibody on cutaneous mast cells
Example: Penicillin allergy
• Non-IgE mediated reactions that depend on drug metabolism
with resultant mast cell activation or direct interaction with
resultant mast cell activation or direct interaction with small
venules
Example: NSAID reactions
Drug reactions - 2
• Direct mast cell degranulation by drugs
Example: Opiates
• Osmotic cell degranulation and alternative complement
pathway activation
Example: Radiocontrast reactions
Physical urticarias: classification
Common:
• Symptomatic dermographism (also called factitious urticaria)
• Delayed pressure urticaria
• Cholinergic urticaria
Less common:
• Cold contact urticaria
Rare:
• Solar urticaria
• Heat contact urticaria
• Aquagenic urticaria
• Vibratory angioedema
Characteristics of physical urticarias
(except delayed pressure)
• Hives last less than 2 hours
• Stimulus (e.g., ice cube test, exercise, scratching) has no
late phase response
• Treated readily with antihistamines but may require high
doses
• Do not respond to corticosteroids
Soter N. Physical urticaria/angioedema. Seminar Dermatology 6:302, 1987.
Symptomatic dermatographism
• Common physical urticaria, frequently overlooked
• Generalized pruritus and red wheals, aggravated by
scratching, rubbing, tight or coarse clothing
• Mucous membranes unaffected, no angioedema
Greaves MW. Chronic Urticaria. J Allergy Clin Immunol 105:664, 2000.
Greaves M, Sundergaard. Arch Dermatol 101:418-425, 1970.
Symptomatic dermatographism, cont.
• Diagnosis: firm stroking of uninvolved skin causes almost
immediate linear red wheal and itch. A variable pressure
dermographometer which can be calibrated is commercially
available
• Investigations: none indicated
• Treatment: low sedation H1 antihistamines
(off-label dosage if necessary)
Dermatographism
27
Characteristics of dermatographism
• Patients complain of itch (even if hives not present), skin
“crawling” and worsening hives with scratching
• Particularly prominent over pressure points where
clothing is tight or rubbing
• Can be associated with lip swelling without other
evidence of angioedema
• When severe, may be confused with other types of
chronic urticaria
Therapy of dermatographism
• Non-sedating antihistamines; fexofendadine, cetirizine,
desloratidine, levocetirizine
• May combine agents for more severe cases, e.g.,
fexofenadine in the morning, levocetirizine midday and
bedtime
• For unresponsive cases to the above:
hydroxyzine or diphenhydramine at 25-50 mg q.i.d.
Shiarpe GR, Shuster S. Br J Dermatol 129:575-579, 1993.
Delayed pressure urticaria
• Concurrent with chronic ordinary urticaria in about 40% of
cases
• Common distribution sites: shoulders, waist, soles, palms
• Swellings are frequently of long duration (> 24h), often
tender and painful; arthralgia common
Estes S, Yung C. J Am Acad Dermatol 5:25-31, 1981.
Dover JS, Kobza Black A, Milford WA, et. al. J Am Acad Dermatol 18:1289-1298, 1988.
Delayed pressure urticaria, cont.
• Diagnosis: firm application of tip of a 3mm diameter rod to
uninvolved skin for 2 min; positive result – persistent firm red
papule developing in 3-5 hours
• Investigations: none indicated
• Treatment: antihistamines disappointing; salazopyrene,
dapsone, hydroxycholorquine should be tried. High dose
prednisolone is effective but the condition is chronic
Cholinergic urticaria
• Very common in older children, young adults
• Transitory pruritic symmetrical red maculopapular rash on
neck trunk, limbs after exercise, heat, emotion
• Associated bronchospasm in more severe cases, rarely
angioedema
Grant RT, Pearson RS, Comeau WJ. Clin Sci 2;253-272, 1936.
Soter NA, Wasserman SI, Austen KF, et. al. N Eng J Med 302:604-608, 1980.
Cholinergic urticaria, cont.
• Diagnosis: exercise challenge eg treadmill or jogging in place
usually elicits a positive response. Heat challenge e.g., hot bath
to evoke the rash
• Investigation: none indicated
• Treatment: usually responds well to H1 antihistamines,
anabolic steroids eg, danazol effective in severely affected cases
• Prognosis: usually resolves in months / a year or two
Grant RT, Pearson RS, Comeau WJ. Clin Sci 2;253-272, 1936.
Soter NA, Wasserman SI, Austen KF, et. al. N Eng J Med 302:604-608, 1980.
Cholinergic (generalized heat) urticaria
Characteristics of
cholinergic urticaria - 1
• Hives begin on neck, trunk, and spread to face and
extremities
• Triggered by exercise, sweating, hot showers, strong
emotion; Exercise induction is reproducible; requires
increase in core body temperature
• Small punctate urticarial lesions a few mm in diameter with
prominent erythema
• Occasional confluence of lesions and associated angioedema
• Histamine release demonstrated within circulation after
exercise challenge
Characteristics of
cholinergic urticaria - 2
• Sub-groups:
A. Positive skin test with autologous sweat, positive in vitro
histamine release with autologous sweat; positive methacholine
skin test with satellite lesions; non-follicular distribution of
wheals
B. Negative skin tests and in vitro histamine release with
autologous sweat; negative methacholine skin test; wheals tend
to be follicular
Kaplan A, Gray L, Shaff R, et. al. J Allergy Clin Immunol 55:394-402, 1975.
Fukunaga A, Bito T, Tsura K, et. al. J Allergy Clin Immunol 116:397-402, 2003.
Histamine release in serum of patient with cholinergic
urticaria challenged by exercise
Cold contact urticaria
• Redness, whealing itching on skin exposed to cold
surfaces, water, air
• Angioedema can occur e.g., lips, tongue after sucking
an iced-lolly
• If generalized (e.g., sea bathing), can be life threatening
(syncope)
Cold contact urticaria, cont.
• Diagnosis: place icepack on uninvolved skin for 15 min, remove
and inspect site for cold–evoked wheal 5 min after removal
• Investigations: cryoglobulins and cold agglutinins commonly
sought but rarely found
• Treatment: usually responds to avoidance + H1 antihistamines.
Cold tolerance treatment (“cold desensitization”) is effective in
selected cases
Cold urticaria
40
Cold urticarias - 1
• Hives due to contact with cold stimulus / object
• Predominance on unclothed areas – hands, face
• Can be generalized with anaphylactic-like symptoms
(hypotension) with swimming
Cold urticarias - 2
• A sub-group is IgE-mediated and can be passively
transferred
• Treated with oral antihistamines:
a) Try fexofenadine, cetirizine, levocetirizine,
desloratadine first
b) Cyproheptedine 4 mg t.i.d. up to 8 mg q.i.d. may be
particularly effective in resistant cases
Houser D, Arbesman C, Ito K, et. al. Am J Med 49:23-33, 1970.
Wanderer A, St-Pierre J, Ellis E. Arch Dermatol 13:1375-1377, 1977.
Kaplan A, Garofalo J, Sigler R, et. al. N Eng J Med 305:1074-1077, 1981.
Histamine release in cold urticaria
Rare physical urticarias:
diagnosis, treatment
• Solar urticaria:
Diagnosis: expose skin to direct sunlight, slide projector lamp; a local
pruritic wheal and flare reaction denotes a positive result
Treatment: avoidance, H1 antihistamines, light tolerance treatment in
selected patients
• Heat contact urticaria:
Diagnosis: place warm beaker base (45o C) on clinically uninvolved skin
for 5 min; a local pruritic wheal and flare reaction denotes a positive
result
Treatment: avoidance and H1 antihistamine
Kobza-Black A. In: Urticaria and Angioedema. Eds. M.W. Greaves and A.P. Kaplan. Marcel Dekker
Inc. New York, 2004, P. 171-214.
Rare physical urticarias:
diagnosis, treatment, cont.
• Aquagenic urticaria:
Diagnosis: expose face, neck upper trunk skin to tepid
water (eg squeezing a sponge); elicits a transitory pruritic
erythematous maculopapular eruption
• Vibratory angioedema:
Diagnosis: vibrate forearm with a laboratory vortex or rub a
towel vigorously across the back (assuming no
dermatographism).
Treatment: avoidance and H1 antihistamines
Kobza-Black A. In: Urticaria and Angioedema. Eds. M.W. Greaves and A.P. Kaplan. Marcel Dekker
Inc. New York, 2004, P. 171-214.
Chronic urticarias
1) Chronic ordinary urticaria:
a) Idiopathic
b) Autoimmune
2) Cutaneous vasculitis:
a) Idiopathic
b) Connective tissue diseases
c) Hypocomplementemic urticarial vasculitis syndrome
3) Genetic autoinflammatory syndromes
4) Miscellaneous, e.g., Schnitzler’s Syndrome
Chronic ordinary urticaria
The cause of many cases of chronic ordinary urticaria still remains
unclear, but the weight of available evidence indicates that the
following are not causative:
• Food allergy
• Chronic infections including Helicobacter pylori
• “Stress”
• Drug allergy
• Environmental pollution
Certain factors do exacerbate
pre-existing chronic ordinary urticaria
• Non-steroidal anti-inflammatory drugs (NSAIDS)
• Certain “pseudoallergens” in foods (controversial)
• Consumption of alcohol
• Intercurrent viral infections
• Stress / overtiredness
There are recognized associations with
chronic ordinary urticaria
• Angioedema: occurs in 40-80% of patients in different series,
mainly affecting the eyelids, lips or tongue. Although alarming it is
never fatal
• Physical urticarias: (usually symptomatic dermatographism, or
delayed pressure urticaria) occur in about 50%
• Functional thyroid disease: (hypo- or hyperthyroidism) occurs
in about 20% and Hashimoto’s disease is found in about 15%
Leznoff A, Sussman G. J Allergy Clin Immunol 84:66-71, 1989.
Greaves M. N Eng J Med 332:1767-1772, 1995.
Kaplan A. J Allergy Clin Immunol 114:465-474, 2004.
Chronic urticaria:
what if the patient has more than one
type concurrently?
• Patients with chronic urticaria frequently have both chronic
ordinary urticaria and a physical urticaria (usually delayed
pressure urticaria or symptomatic dermatographism)
• Which of these is the principle cause of the patient’s handicap
needs to be established by taking a detailed history, as the
patient’s investigations and treatment will depend on this
Barlow RJ, Warburton F, Watson K, et. al. J Am Acad Dermatol 29:954-958, 1993.
Chronic ordinary urticaria impacts
severely on quality of life
and has an economic cost
• Using a QOL instrument: the impairment of QOL due to
chronic urticaria has been shown to be equal in magnitude to
that experienced by patients with triple coronary artery
disease awaiting bypass surgery
• Chronic urticaria: is also a source of significant economic
cost due to absenteeism and cost of medications
Poon E, Seed PT, Greaves MW, et. al. Br J Dermatol 140:667-671, 1999.
Baiardini I, Giardini A, Pasquali M, et. al. Allergy 58:621-623, 2003.
Routine laboratory investigations in
chronic ordinary urticaria
Patients with chronic urticaria are almost invariably overinvestigated
Necessary investigations include:
• FBC, differential WBC, ESR, CRP
• Thyroid function and thyroid autoantibodies screen
• In-patients with a poor response to antihistamines, a skin biopsy
should be performed to exclude urticarial vasculitis (see slide 60)
An autoimmune process is causative in some
patients with
chronic ordinary urticaria
• 25-50% of patients with chronic ordinary urticaria have complement
activating IgG1 and IgG3 autoantibodies with histamine releasing
functional activity against the high affinity IgE receptor FcεR1 or
less commonly against IgE itself
• These autoantibodies dimerize IgE receptors expressed on dermal
mast cells leading to complement activation and dermal mast cell
activation
Niimi N, Francis D, Kermani F, et. al. J Invest Dermatol 106:1001-1006, 1996.
Soundararagan S, Kikuchi Y, Joseph K, et. al. J Allergy Clin Immunol 145:815-821, 2005.
O’Donnell B, O’Neill C, Francis D, et. al. Br J Dermatol 140:8530858, 1999.
An autoimmune process is causative in
some patients with
chronic ordinary urticaria, cont.
• Presence of these autoantibodies is commonly associated with
antithyroid autoantibodies, and less commonly other organ- and
non-organ-specific autoantibodies
• Also these autoantibodies have a significant association with HLA
DRB1*04 and DQB1*0302 - alleles recognized to be associated with
autoimmune disease
Niimi N, Francis D, Kermani F, et. al. J Invest Dermatol 106:1001-1006, 1996.
Soundararagan S, Kikuchi Y, Joseph K, et. al. J Allergy Clin Immunol 145:815-821, 2005.
O’Donnell B, O’Neill C, Francis D, et. al. Br J Dermatol 140:8530858, 1999.
Mast cell activation by bivalent cross-linking
of the high affinity IgE receptor by specific
IgG autoantibody
Autoimmune urticaria
56
Immune pathogenesis
1. IgG antibody to IgE receptor cross-links adjacent α subunits to
cause cutaneous mast cell (and basophil) activation
2. Predominant IgG antibody subclasses are IgG1 and IgG3 which
are complement fixing
3. Complement activation by two adjacent IgG-Fc regions (requires
4 IgE receptor α subunits)
4. Release of C5a anaphylatoxin from C5 which augments histamine
release
Hide M, Francis D, Grattan C, et. al. N Eng J Med 328:1599-1604, 1993.
Kikuchi Y, Kaplan A. J Allergy Clin Immunol 107:1056-1062, 2001.
Kikuchi Y, Kaplan A. J Allergy Clin Immunol 109:114-118, 2002.
Immune pathogenesis, cont.
5.
Release of mast cell histamine, leukotriene, cytokines, and
chemokines
6.
Activation of endothelial cells – vasodilation, increased
permeability, release of endothelial cell cytokines, and
chemokines
7.
Cellular infiltrate due to C5a chemotactic activity and
chemokines to yield perivascular distribution of cells
resembling a late phase allergic reaction
Hide M, Francis D, Grattan C, et. al. N Eng J Med 328:1599-1604, 1993.
Kikuchi Y, Kaplan A. J Allergy Clin Immunol 107:1056-1062, 2001.
Kikuchi Y, Kaplan A. J Allergy Clin Immunol 109:114-118, 2002.
Pathomechanism of
autoimmune urticaria
Abnormal basophil responsiveness
1. Basophils of patients with chronic urticaria are hyporesponsive to
polyclonal anti-IgE based on histamine release
2. Hyporesponsiveness in at least 50% of patients is due to increased
cytoplasmic phosphatases such as Src-homology-2 containing inositol
Phosphatases (SHIP); Diminished phosphorylation of key signal
transduction molecules limits histamine release
3. Hyporesponsiveness of basophils is reversible as patients remit
4. Patients’ basophils are paradoxically hyperresponsive to a factor
in serum
Greaves M, Plammer V, McLaughlan P. et. al. Clin Allergy 4:265-271, 1974.
Kern F and Lichteinstein L. J Clin Invest 57:1369-1377, 1976.
Luquin E, Kaplan A, Ferrer M. Clin Exp Allergy 35:456-460, 2005.
Vonakis B, Vasagar K, Gibbons J, et. al. J Allergy Clin Immunol 119:441-448, 2007.
Skin biopsy in chronic idiopathic
and chronic autoimmune urticaria
1.
Non-necrotizing perivascular infiltration
2.
Integrity of vessel wall maintained
3.
Predomination of CD4(+) lymphocytes with mixture of TH1
and TH2 cells. No basophils. Few CD8(+) cells
4.
Variable number of neutrophils and eosinophils – more
prominent in chronic autoimmune urticaria than chronic
idiopathic urticaria
Elias J, Boss E, Kaplan A. J Allergy Clin Immunol 78:914-918, 1986.
Ying S, Kikuchi Y, Meng Q, et. al. J Allergy Clin Immunol 109:694-700, 2002.
Autoimmune urticaria:
clinical and histological features
• Many cases are clinically and histologically indistinguishable
from non–autoimmune chronic urticaria
• Tend to run a more aggressive, treatment-resistant course
• Although these autoantibodies activate complement, there is
no hypocomplementaemia
• Histologically, activated eosinophils (EG2+) are more
prominent in older lesions of non-autoimmune patients
Sabroe R, Poon E, Orchard G, et. al. J Allergy Clin Immunol 103:484-493, 1999.
Diagnosis of autoimmune urticaria
• Autoimmune urticaria should be suspected if the response to regular
antihistamine treatment is poor
• Demonstration of serum thyroid antibodies is suggestive of
autoimmune urticaria
• An autologous serum skin test is helpful - a negative result effectively
rules out autoimmune urticaria, but a positive result requires
confirmation by in-vitro testing
• In-vitro testing consists of demonstrating the ability of the patient’s
serum to activate donor basophils* or cells of a rat basophil leukaemia
cell line by release of pharmacologic mediators such as histamine
* This test is now commercially available
Autologous serum skin test 1.
• Indicated only in patients with chronic ordinary urticaria who are
poorly responsive to routine treatment
• All H1 antihistamine treatment should be withdrawn at least 48h
prior to the test (2 weeks for systemic steroids)
• Serum is obtained from the patient during a period of disease
activity, and 0.05ml is injected intradermally into the forearm
skin on both sides. Similar control injections of saline and
histamine (10μg/mL-1) are performed
• A positive result, read at 30 min, is a red wheal at the serum sites
of diameter>1.5mm greater than the saline wheals
Grattan C, Wallington T, Warin R, et. al. Br J Dermatol 114:583-590, 1986.
Grattan C, Boon A, Eady R, et. al. Int Arch Allergy Immunol 93:198-204, 1990.
Autologous serum skin test 2.
• Significance of a negative ASST:
essentially rules out autoimmune
urticaria
• Significance of a positive ASST:
indicates the presence of
autoreactivity in the serum, but invitro confirmation is required
before this can be identified as due
to functional autoantibodies
serum
saline
histamine
A positive autologous serum test
Management of chronic ordinary
urticaria: general principles 1.
Avoidance of:
•
NSAIDS, alcohol, spicy foods
• Overtiredness and stress
• Wearing of tightly fitting garments, footwear
• Strenuous physical exercise
• Overheated ambient temperature
Therapy of chronic
idiopathic/autoimune urticarias
•
H1 receptor antagonists
•
H2 receptor antagonists
•
Leukotriene antagonists
•
Alternate-day corticosteroids
•
Cyclosporin
Management of chronic ordinary
urticaria: general principles 2.
• Tepid showering and frequent application of 1% menthol in
calamine cream if nocturnal pruritus is a problem
• Antihistamine treatment:
Low sedation antihistamines taken regularly - not on an “as
required” basis (desloratidine 5mg daily; levocetirizine 5mg daily;
fexofenadine 120-180mg daily)
Sedative antihistamine such as hydroxyzine 25mg taken before
sleep if nocturnal pruritus is a problem (warn about impairment
of cognitive function the following morning)
Finn AJ, Kaplan A, Fretwell R. J Allergy Clin Immunol 103:1071-1078, 1999.
Nelson H, Reynolds R, Mason J. Annals Allergy Asthma Immunol 84:517-522, 2000.
LaRosa M, Leonardi S, Marchese G, et. al. Annals Allergy Asthma Immunol 87:48-53, 2001.
Management of chronic ordinary
urticaria: general principles 2., cont.
• In resistant cases off-label doses of low sedation antihistamines
(e.g., 360mg fexofenadine daily) are effective and safe
• H2 antihistamines are of doubtful efficacy, but are useful in
patients with a history of corticosteroid toxicity
Management of chronic ordinary
urticaria: what to do if antihistamines
don’t work
• Add montelukast 10mg daily: It helps some but not all patients and
adverse effects are rarely a problem
• Add doxepin 25mg at night: This tricyclic is best known as an antidepressant, but is a very potent H1 and H2 antihistamine, causing
sedation. It should not be given with other antidepressants
• Prednisolone: short tapering courses commencing 30mg daily are
useful to deal with the occasional temporary flare-up
Management of chronic ordinary
urticaria: what to do if antihistamines
don’t work, cont.
• Cyclosporin: best known for its effectiveness in autoimmune
urticaria, is also effective in non–autoimmune chronic urticaria.
Dosage 4-6mg/Kg/day, with regular checks of renal function
and blood pressure, and a chest X-ray. It is especially valuable in
patients with chronic steroid toxicity
• Intolerance or ineffectivenes of cyclosporin: methotrexate
10-25mg orally once weekly, or mycophenolate mofetil 1-2g daily
can be tried
Antihistamines – H1 receptor
antagonists
Properties:
1. Bind to H1 receptors on endothelial cells and induce an
inactive conformation. Histamine binds to the same receptors
and induces an active conformation
2. Efficacy is proportional to receptor occupancy i.e., histamine
vs. antihistamine, varies with dose, half-life, distribution in the
skin, and receptor affinity
Simons F. N Eng J Med 351:2203-2217, 2004.
Sedation with antihistaminics
• Clearly more evident with first generation antihistamines and
more likely to adversely affect performance
• Second and third generation antihistaminics are more
specific for H1 receptor, are less likely to cross the bloodbrain barrier, and can be effective from 12-24 hrs
Weiler J, Bloomfield J, Woodwarth G, et. al. Ann Int Med 132:354-363, 2000.
Verster J, Volkerts E, van Oosterwijck et. al. J Allergy Clin Immunol 111:623-627, 2003.
Simons F, Fraser T, Reggin et. al. Clin Exp Allergy 26:1092-1097, 1996.
Verster J, Volkerts E Annals Allergy Asthma Immunol 92:294-303, 2004.
Sedation with antihistaminics, cont.
BUT
• Receptor occupancy may be greater with high dose first generation
antihistamines given q.i.d. for severe symptoms compared to current
recommended doses of second and third generation antihistamines
• No sedation or performance studies have ever been done in patients with
chronic urticaria - studies are short term using normal volunteers or patients
with allergic rhinitis
Schweitzer P, Muehlbach M, Walsh J . J Allergy Clin. Immunol 94:716-724, 1994.
Bender B, Berning S, Dudden R, et. al. J Allergy Clin Immunol 111:770-776, 2003.
Verster J, de Weert P, Bijtjes S, et. al. Psychopharmacol 169:84-90, 2003.
Cyclosporin
• Effective in chronic autoimmune urticaria with success rate of 75%
• Effectiveness demonstrated with two double-blind placebo controlled studies
• Anecdotal effectiveness in chronic idiopathic urticaria and delayed pressure
urticaria
• Is steroid-sparing
• Requires monitoring blood pressure, BUN, creatinine, and urinalysis every 6
weeks. Cyclosporin trough blood levels may be helpful to guage dosage
• Typical effective dose in adults in 200-300 mg/day
Toubi E, Blant A, Kessel A. Allergy 52:312-316, 1997.
Grattan C, O’Donnell B, Francis D, et. al. Br J Dermatol 143:365-372, 2000.
76
Therapy of chronic idiopathic/autoimmune
urticaria In adults
1.
Second (or third) generation antihistamines: one daily; double
dose if not sufficiently effective
2.
First-generation antihistamines given q.i.d.
- Hydroxyzine
- Diphenhydramine
3.
H2 receptor antagonists may augment antihistamine effect if H1
receptors are adequately blocked
Kaplan A. N Eng J Med 346:175-179, 2002.
Therapy of chronic
idiopathic/autoimmune urticaria in adults,
cont.
4.
Leukotriene antagonists
5.
or
Corticosteroids: limit to 10 mg/day for chronic use
20-25mg q.o.d. Gradual taper with 1 mg tablets or
2.5mg increments
6.
Cyclosporin
Kaplan A. N Eng J Med 346:175-179, 2002.
Treatment of autoimmune
chronic urticaria
• The options for treatment include all the therapies
mentioned above for non–autoimmune patients
• Most patients require off-label dosages of H1 antihistamines
• Cyclosporin is reputed to be more effective in autoimmune
than non–autoimmune chronic urticaria but this has not
been proven
Grattan CEH, Francis DM, Slater NGP, et. al. Lancet 339:1078-1080, 1992.
O’Donnell BF, Farr RM, Kobza-Black A, et. al. Br J Dermatol 138:101-106, 1998.
Kaplan A, Joseph K, Maykut R, et. al. J Allergy Clin Immunol 122:569-573, 2008.
Treatment of autoimmune
chronic urticaria, cont.
• Additionally, intravenous immunoglobulin and
plasmapheresis have proved highly effective in some selected
refractory cases
• There are now emerging reports of the effectiveness of the
anti-IgE monoclonal omalizumab in both autoimmne and
non-autoimmune chronic urticaria
Grattan CEH, Francis DM, Slater NGP, et. al. Lancet 339:1078-1080, 1992.
O’Donnell BF, Farr RM, Kobza-Black A, et. al. Br J Dermatol 138:101-106, 1998.
Kaplan A, Joseph K, Maykut R, et. al. J Allergy Clin Immunol 122:569-573, 2008.
Clinical features of chronic urticaria which
suggest urticarial vasculitis*
• Individual wheals persist for more than 24h, and may leave residual
staining
• Itching is inconsistent, and wheals may be tender and painful
• In a minority hypocomplementaemia is present associated with
systemic symptoms including arthralgia
• Response to antihistamine treatment is poor
• Morphology of urticarial eruption is often indistinguishable from
chronic ordinary urticaria
Urticarial vasculitis
Causes of urticarial vasculitis
• Autoimmune connective tissue disease: (Sjogren’s
syndrome, systemic lupus, rheumatoid arthritis)
• Viral hepatitis: (hepatitis B, C)
• Paraproteinaemia: (Schnitzler’s syndrome occasionally has
a vasculitic histology)
• Inflammatory bowel disease
McDuffie F, Sams JW, Maldonado J. Mayo Clin Proc 48:340-348, 1973.
Agnello V, Koffler D, Eisenberg J. J Exp Med 134:2285-2415, 1971.
Urticarial vasculitis:
confirmation of diagnosis
Hypocomplementaemia: is occasionally found, and is usually associated
with systemic involvement (arthritis, pulmonary hypertension)
Diagnosis is dependent on histological features of leukocytoclastic
vasculitis:
•
•
•
•
•
Endothelial swelling of post–capillary venules
Leukocytoclasis
Red cell diapedesis
Fibrin deposition
Direct immunofluorescence for immunoreactant deposition is usually
unhelpful
Soter N, Mihm MJ, Gigli, et. al. J Invest Dermatol 66:344-350, 1976.
Urticarial vasculitis:
histopathology
The photomicrograph shows endothelial cell swelling, perivascular fibrin deposition, neutrophil
perivascular infiltration, neutrophil granulocyte fragmentation (leukocytoclasia) and the presence of
nuclear dust
Urticarial vasculitis:
laboratory investigation
• Complement screen
• ESR, CRP
• Viral screen (hepatitis B, C)
• Plasma protein electrophoretic analysis
• ANF, rheumatoid factor, anti-Ro
• Chest X ray, ECG, Echocardiogram
Davis MDP, Daoud MS, Kirby B, et. al. J Am Acad Dermatol 38:899-905, 1998.
Treatment of urticarial vasculitis
Antihistamines are usually ineffective; the following may be effective:
• Dapsone (screen for G6-PD deficiency)
• Colchicine
• Hydroxychloroquine
• Prednisolone (especially in patients with systemic involvement)
• Intravenous immunoglobulin
• Plasmapheresis
Abookaker J, Greaves MW. Clin Exp Dermatol 11:436-444, 1986.
Athanasiadis GI, Pfab F, Kollman A. Allergy 61:1484-1485, 2006.
Lopez LR, Davis KC, Kohler PF, et. al. J Allergy Clin Immunol 73:600-603, 1984.
Chronic urticaria associated with
systemic disease
When chronic urticaria is associated with fever, two syndromes need to be
considered:
1.
Schnitzler’s syndrome
2.
Hereditary autoinflammatory syndromes - cryopyrin associated periodic syndromes (CAPS):
Muckle-Wells (urticaria amyloidosis and deafness)
FCAS (Familial cold autoinflammatory syndrome)
NOMID (neonatal onset mutisystem inflammatory disorder)
Schnitzler’s syndrome
This is the association of often non-pruritic but otherwise unremarkable chronic
urticaria with IgM (rarely IgG) kappa gammopathy on serum protein
electrophoresis
Other features include:
•
•
•
•
•
Fever
Bone pain
Neutrophilic urticaria (rarely vasculitis) on skin biopsy
Poor response to antihistamines
Good response to anakinra (interleukin-1 receptor antagonist)
(J Amer Acad Dermatol. 2007; 57: 361-4)
• Other treatments reported effective: cyclosporin, rituximab
• Occasional progression to B cell lymphoma
Berdy SS, Bloch KJ. J Allergy Clin Immunol 87:849-854, 1991.
deKoning HD, Bodar EJ, Van derMeer JW, et. al. Seminars Arthritis Rheum 37:137-148, 2007.
Saurat OH, Schifferli J, Steiger G, et. al. J Allergy Clin Immunol 88:244-256, 1991.
Autoinflammatory syndromes:
CAPS (cryopyrin – associated periodic
syndromes)
• CAPS: presents as persistent urticaria from birth, often worse in the
evenings, with minimal or no pruritus, fever and arthralgia; all are
associated with mutation in the CIAS1 gene leading to cryopyrins
• FCAS: (familial cold autoinflammatory syndrome) represents the mildest form
with atypical cold urticaria and febrile episodes
• Muckle-Wells syndrome: presents with chronic urticaria and
senorineural deafness from birth, with fever, and arthralgia and renal
amyloidosis may develop in adult life
Hoffman HM, Muellar JL, Broide DH, et. al. Nature Genetics 29:301-305, 2001.
Aganna E, Martinon F, Hawkins RN, et. al. Arthritis Rheum 46:2445-2452, 2002.
Autoinflammatory syndromes:
CAPS (cryopyrin – associated periodic
syndromes), cont.
• NOMID (neonatal onset multisystem inflammatory disorder) is more
severe, with sensorineural deafness, other CNS abnormalities
and arthropathy
• All three syndromes seem to respond well to anakinra
(recombinant IL-1 receptor antagonist)
Hoffman HM, Muellar JL, Broide DH, et. al. Nature Genetics 29:301-305, 2001.
Aganna E, Martinon F, Hawkins RN, et. al. Arthritis Rheum 46:2445-2452, 2002.
Contact urticaria:
definition, classification, mechanism
•
Eliciting substance causes local wheal and flare within
minutes of application to skin
•
May be associated with systemic symptoms: rhinitis,
conjunctivitis, bronchospasm, angioedema, anaphylaxis
•
Classified as immunological, non-immunological
•
Due to release of histamine and eicosanoids, especially
prostaglandin D2 from dermal mast cells
Kim E, Maibach H. Contact Urticaria. In: Urticaria and Angioedema. Eds. M.W. Greaves and
A.P. Kaplan. Marcel Dekker, New York. 2004. P. 149-169.
Causes of contact urticaria
Immunological:
• House dust mite
• Dairy products
• Fruits
• Nuts, especially peanuts
• Meats
• Sea foods
• Vegetables, esp. garlic, onion
• Fragrances
• Hair care products
• Medicaments, esp. antibiotics
• Plant products, esp. latex
Non-immunological:
• Foods, especially fish
• Fragrances, flavorings
• Medicaments
• Animals, esp. caterpillars,
jellyfish
• Plants, esp. nettles, corals
• Preservatives, antiseptics
• Ammonium persulphate
Contact urticaria:
investigation sequence
• Open elicitation test:
Apply to normal skin, then previously affected skin
• Prick test in normal skin:
Start with high dilution; include saline and histamine controls;
risk management (anaphylaxis): patient to remain on premises for
2hours, physician and resuscitation equipment on hand throughout
Contact urticaria:
investigation sequence, cont.
• Scratch test in normal skin:
Scratch skin lightly through drop of a dilution of candidate
culprit; controls and risk management as outlined.
Performance in control subjects to confirm positive result
may be required
• Latex contact allergy due to rubber gloves:
Place fragment of rubber glove in 5ml warm water and stir
20min, then use water for skin testing as above
Contact urticaria: treatment
• Treatment consists of identification of culprit, avoidance and
patient education
• Severe reactors (eg peanut contact urticaria) should wear an
inscribed bracelet listing the culprit plus cross reacting
substances, and should carry antihistamines and self
administration adrenaline (epinephrine)
World Allergy Organization (WAO)
For more information on the World Allergy
Organization (WAO), please visit
www.worldallery.org or contact the:
WAO Secretariat
555 East Wells Street, Suite 1100
Milwaukee, WI 53202
United States
Tel: +1 414 276 1791
Fax: +1 414 276 3349
Email: info@worldallergy.org