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 urticariaChronic urticaria

Physical urticaria

Ordinary chronic

urticari

a

Urticarial vasculitis

Contact urticari

a

Schnitzler’s

syndrome

Autoimmune

urticaria

Idiopathic chronic urticaria

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.

• 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)

Symptomatic dermatographism, cont.

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.

• 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

Delayed pressure urticaria, cont.

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.

• 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

Cholinergic urticaria, cont.

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)

• 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 contact urticaria, cont.

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 resultTreatment: 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 DekkerInc. New York, 2004, P. 171-214.

• 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 DekkerInc. New York, 2004, P. 171-214.

Rare physical urticarias: diagnosis, treatment, cont.

Chronic urticarias

1) Chronic ordinary urticaria:a) Idiopathicb) Autoimmune

2) Cutaneous vasculitis:a) Idiopathicb) Connective tissue diseasesc) Hypocomplementemic urticarial vasculitis

syndrome

3) Genetic autoinflammatory syndromes

4) Miscellaneous, e.g., Schnitzler’s Syndrome

Chronic ordinary urticariaThe 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 urticariaPatients with chronic urticaria are almost invariably over-investigated

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 pathogenesis1. 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.

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

Immune pathogenesis, cont.

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 ofautoimmune urticaria

Abnormal basophil responsiveness

1. Basophils of patients with chronic urticaria are hyporesponsive topolyclonal anti-IgE based on histamine release

2. Hyporesponsiveness in at least 50% of patients is due to increasedcytoplasmic phosphatases such as Src-homology-2 containing inositolPhosphatases (SHIP); Diminished phosphorylation of key signaltransduction molecules limits histamine release

3. Hyporesponsiveness of basophils is reversible as patients remit

4. Patients’ basophils are paradoxically hyperresponsive to a factorin 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 in- vitro 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.Clough B, Boutsiouki P, Church M. Allergy 56:985-988, 2001.

• 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: general

principles 2., cont.

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 anti-depressant, 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 blood-brain 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.

4. Leukotriene antagonists

5. Corticosteroids: limit to 10 mg/day for chronic use or 20-25mg q.o.d. Gradual taper with 1 mg tablets or 2.5mg increments

6. Cyclosporin

Therapy of chronic idiopathic/autoimmune urticaria

in adults, cont.

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.

• 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

Treatment of autoimmune chronic urticaria, cont.

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 diagnosisHypocomplementaemia: 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.Mehregan DR, Hall MJ, Gibson LE. J Am Acad Dermatol 26:441-448, 1992.

Chronic urticaria associated with systemic

diseaseWhen 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 syndromeThis 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.

• 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)

Autoinflammatory syndromes: CAPS (cryopyrin – associated periodic syndromes), cont.

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 andA.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

• 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: investigation sequence,

cont.

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)

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WAO Secretariat555 East Wells Street, Suite 1100

Milwaukee, WI 53202United States

Tel: +1 414 276 1791Fax: +1 414 276 3349

Email: info@worldallergy.org