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gloria module 12 urticaria

GLORIA Module 12:Urticaria

an educational program of

Updated: June 2011

global resources in allergy gloria
Global Resources in Allergy (GLORIA™)

Global Resources In Allergy (GLORIA™) is the flagship program of the World Allergy Organization (WAO). Its curriculum educates medical professionals worldwide through regional and national presentations. GLORIA modules are created from established guidelines and recommendations to address different aspects of allergy-related patient care.

slide4

World Allergy Organization (WAO)

The World Allergy Organization is an international coalition of 89 regional and national allergy and clinical immunology societies.

slide5

WAO’s Mission

WAO’s mission is to be a global resource and advocate in the field of allergy, advancing excellence in clinical care through education, research and training as a world-wide alliance of allergy and clinical immunology societies

gloria module 12 urticaria1

GLORIA Module 12: Urticaria

Authors:

Allen P Kaplan

Malcolm W Greaves

learning objectives
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
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
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
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
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
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
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
classification of chronic urticaria
Classification of chronic urticaria

Chronic urticaria

Ordinary chronic urticaria

Urticarial vasculitis

Physical urticaria

Contact urticaria

Schnitzler’s syndrome

Autoimmune urticaria

Idiopathic chronic urticaria

acute 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
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
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
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
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 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
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
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
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
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
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)

characteristics of dermatographism
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
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
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
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
Cholinergicurticaria

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.

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

cholinergic urticaria cont
Cholinergicurticaria, 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.

characteristics of cholinergic urticaria 1
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
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.

cold contact urticaria
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
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 urticarias 1
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
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.

rare physical urticarias diagnosis treatment
Rare physical urticarias: diagnosis, treatment

Kobza-Black A. In: Urticaria and Angioedema. Eds. M.W. Greaves and A.P. Kaplan. Marcel Dekker

Inc. New York, 2004, P. 171-214.

  • 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

rare physical urticarias diagnosis treatment cont
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
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
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 notcausative:

  • Food allergy
  • Chronic infections including Helicobacter pylori
  • “Stress”
  • Drug allergy
  • Environmental pollution
certain factors do exacerbate pre existing chronic ordinary urticaria
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
There are recognized associations with chronic ordinary urticaria

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.

  • 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%
chronic urticaria what if the patient has more than one type concurrently
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
Chronic ordinary urticaria impacts severely on quality of life and has an economic cost

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.

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

routine laboratory investigations in chronic ordinary urticaria
Routine laboratory investigations in chronic ordinary urticaria

Patients 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
An autoimmune process is causative in some patients with chronic ordinary urticaria

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.

  • 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
an autoimmune process is causative in some patients with chronic ordinary urticaria cont
An autoimmune process is causative in some patients with chronic ordinary urticaria, cont.

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.

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

slide55

Mast cell activation by bivalent cross-linking of the high affinity IgE receptor by specific IgG autoantibody

immune pathogenesis
Immune pathogenesis

IgG antibody to IgE receptor cross-links adjacent α subunits to cause cutaneous mast cell (and basophil) activation

Predominant IgG antibody subclasses are IgG1 and IgG3 which are complement fixing

Complement activation by two adjacent IgG-Fc regions (requires 4 IgE receptor α subunits)

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
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.

abnormal basophil responsiveness
Abnormal basophil responsiveness
  • Basophils of patients with chronic urticaria are hyporesponsive to
  • polyclonal anti-IgE based on histamine release
  • 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
  • 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
Skin biopsy in chronic idiopathic and chronic autoimmune urticaria

Non-necrotizing perivascular infiltration

Integrity of vessel wall maintained

Predomination of CD4(+) lymphocytes with mixture of TH1 and TH2 cells. No basophils. Few CD8(+) cells

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
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
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
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
Autologous serum skin test 2.

serum

saline

histamine

A positive autologous serum test

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

management of chronic ordinary urticaria general principles 1
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
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
Management of chronic ordinary urticaria: general principles 2.

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.

  • 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)

management of chronic ordinary urticaria general principles 2 cont
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
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
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 h 1 receptor antagonists
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
Sedation with antihistaminics

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.

  • 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
sedation with antihistaminics cont
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
Cyclosporin

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.

  • 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
therapy of chronic idiopathic autoimmune urticaria in adults
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
Therapy of chronic idiopathic/autoimmune urticaria in adults, cont.

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

Kaplan A. N Eng J Med 346:175-179, 2002.

treatment of autoimmune chronic urticaria
Treatment of 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.

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

treatment of autoimmune chronic urticaria cont
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
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
causes of 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
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.

slide85

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
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
Treatment of urticarial vasculitis

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.

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
chronic urticaria associated with systemic disease
Chronic urticaria associated with systemic disease

When chronic urticaria is associated with fever, two syndromes need to be considered:

  • 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
Schnitzler’s syndrome

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.

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
autoinflammatory syndromes caps cryopyrin associated periodic syndromes
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
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
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
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
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
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
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
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