urticaria and angioedema 101 scot laurie, md allergy and asthma center at northpark assistant...

Urticaria and Urticaria and Angioedema 101Angioedema 101

Scot Laurie, MDScot Laurie, MD

Allergy and Asthma Center at Allergy and Asthma Center at NorthParkNorthPark

Assistant professor, University Assistant professor, University of Texas Southwestern of Texas Southwestern Medical CenterMedical Center

Case PresentationCase Presentation Jim S. is a 45 y/o who presented for evaluation Jim S. is a 45 y/o who presented for evaluation

of his urticaria. He has been suffering with hives of his urticaria. He has been suffering with hives for the past 4 months. He is unable to tell what for the past 4 months. He is unable to tell what triggers his hives.triggers his hives.

His hives are generalized and an individual hive His hives are generalized and an individual hive will last a few hours; he has had several will last a few hours; he has had several episodes of lip swelling as well.episodes of lip swelling as well.

He might have had a similar episode 10 years He might have had a similar episode 10 years ago and his doctor told him he was allergic to ago and his doctor told him he was allergic to penicillinpenicillin

Case presentationCase presentation

He has visited his primary care He has visited his primary care physician who suggested he take physician who suggested he take ClaritinClaritin

He returned when his hives He returned when his hives persisted and the doctor told him persisted and the doctor told him that he was allergic to something that he was allergic to something and suggested an allergy and suggested an allergy evaluation. evaluation.


Past medical historyPast medical history– HypothyroidismHypothyroidism

MedicationsMedications– levothyroxinelevothyroxine– Ibuprofen prnIbuprofen prn

Review of systemsReview of systems– Occasional headaches; otherwise Occasional headaches; otherwise

negativenegative Physical examPhysical exam


How would his hives be classified?How would his hives be classified? What is causing his hives?What is causing his hives? Are his medical conditions or Are his medical conditions or

medications contributing to his medications contributing to his hives?hives?

What tests should be done to What tests should be done to evaluate his hives?evaluate his hives?

How are his hives best treated?How are his hives best treated?

URTICARIA & ANGIOEDEMAURTICARIA & ANGIOEDEMA DESCRIPTIONDESCRIPTION

– UrticariaUrticaria Raised, erythematous, blanchingRaised, erythematous, blanching PruriticPruritic Lesions well-circumscribed; typically Lesions well-circumscribed; typically

coalescecoalesce

– AngioedemaAngioedema Subcutaneous swellingSubcutaneous swelling Predilection to areas of loose connective Predilection to areas of loose connective

tissue, such as the face or mucus tissue, such as the face or mucus membranes involving the lips or the tonguemembranes involving the lips or the tongue

Urticaria or “Hives”Urticaria or “Hives”

Urticaria and Urticaria and AngioedemaAngioedema Clinical features: UrticariaClinical features: Urticaria

– Repeated occurrence of short-lived Repeated occurrence of short-lived cutaneous wheals accompanied by cutaneous wheals accompanied by erythema and prurituserythema and pruritus

Wheals range in size from a few millimeters to Wheals range in size from a few millimeters to several centimetersseveral centimeters

Wheals may coalesce to form larger lesionsWheals may coalesce to form larger lesions Individual wheals typically last less than 24 hoursIndividual wheals typically last less than 24 hours Urticaria may occur anywhere on the skinUrticaria may occur anywhere on the skin

– Mucus membrane involvement is rareMucus membrane involvement is rare Lesions should resolve without any residual Lesions should resolve without any residual

markingmarking

Urticaria and Urticaria and AngioedemaAngioedema Clinical features: AngioedemaClinical features: Angioedema

– Approximately 50% of patients with Approximately 50% of patients with chronic urticaria have angioedema as wellchronic urticaria have angioedema as well

– Episodes of short-lived deep dermal and Episodes of short-lived deep dermal and subcutaneous or submucosal edemasubcutaneous or submucosal edema

– Like urticaria, symptoms generally last Like urticaria, symptoms generally last less than 24 hoursless than 24 hours

Larger swellings may take longer to resolveLarger swellings may take longer to resolve

– Pruritus does not consistently accompany Pruritus does not consistently accompany angioedema, and may not occur at all.angioedema, and may not occur at all.

Mediators of hives Mediators of hives and swellingand swelling

SourceSource FactorFactorMast cells (cutaneous)Mast cells (cutaneous) HistamineHistamine

Prostaglandin DProstaglandin D22

Leukotrienes C and DLeukotrienes C and D

Platelet Activating Platelet Activating FactorFactor

Complement systemComplement system Anaphylatoxins C3a, Anaphylatoxins C3a, C4a, C5a: histamineC4a, C5a: histamine

Hageman factor- Hageman factor- dependent pathwaydependent pathway

BradykininBradykinin

Mononuclear cellsMononuclear cells Histamine-releasing Histamine-releasing factors, chemokinesfactors, chemokines

Urticaria and Urticaria and AngioedemaAngioedema

ClassificationClassification– Acute: Acute: << 6 weeks 6 weeks

AllergicAllergic InfectiousInfectious IdiopathicIdiopathic

– Recurrent acuteRecurrent acute– Chronic: > 6 weeksChronic: > 6 weeks

IdiopathicIdiopathic AutoimmuneAutoimmune PhysicalPhysical

URTICARIA URTICARIA CLASSIFICATIONCLASSIFICATION

Acute: < 6 weeksAcute: < 6 weeks– Affects as many as 10-20% of the Affects as many as 10-20% of the

population at some point in their population at some point in their liveslives

– Etiology frequently identifiedEtiology frequently identified Food allergyFood allergy Drug allergyDrug allergy Stings/venomsStings/venoms InfectionInfection

– Viral infection leading cause of urticaria in Viral infection leading cause of urticaria in childrenchildren

Urticaria ClassificationUrticaria Classification

Recurrent acute (intermittent)Recurrent acute (intermittent)– Episodes of urticaria lasting days or Episodes of urticaria lasting days or

weeks with intervals of days, weeks, weeks with intervals of days, weeks, or months in between episodesor months in between episodes

Chronic: > 6 weeksChronic: > 6 weeks– IdiopathicIdiopathic– Physical urticariasPhysical urticarias

URTICARIA ETIOLOGIESURTICARIA ETIOLOGIES

CommonCommon– IdiopathicIdiopathic– MedicationsMedications– StingsStings– FoodsFoods– InfectionInfection– Physical Physical

urticariasurticarias

Rare CausesRare Causes– NeoplasmsNeoplasms– Collagen vascular Collagen vascular

diseasedisease– EndocrineEndocrine– Urticarial Urticarial

vasculitisvasculitis

Urticaria etiologiesUrticaria etiologies

Urticaria is rarely, if ever the Urticaria is rarely, if ever the presenting or sole symptom of an presenting or sole symptom of an underlying diseaseunderlying disease

A complete Review of Systems A complete Review of Systems will suggest or identify any will suggest or identify any systemic disease in which the systemic disease in which the urticaria occursurticaria occurs

URTICARIA ETIOLOGIESURTICARIA ETIOLOGIES MedicationsMedications

– Any drug has the potential to elicit Any drug has the potential to elicit an allergic reactionan allergic reaction Antibiotics in general, and penicillins Antibiotics in general, and penicillins

specifically, are most often indicatedspecifically, are most often indicated Aspirin/NSAID’sAspirin/NSAID’s

Considered second most common cause of Considered second most common cause of acute drug allergic reactionsacute drug allergic reactions

Frequently exacerbate chronic urticaria Frequently exacerbate chronic urticaria and angioedemaand angioedema

URTICARIA ETIOLOGIES URTICARIA ETIOLOGIES FoodsFoods

Important cause of acute urticariaImportant cause of acute urticaria– Primary allergens are peanuts, tree nuts, Primary allergens are peanuts, tree nuts,

shellfish, fish, eggs, milkshellfish, fish, eggs, milk Chronic urticaria typically unrelated to food Chronic urticaria typically unrelated to food

allergyallergy

InfectionInfection Common cause of acute urticariaCommon cause of acute urticaria

– Viral infection most common cause in childrenViral infection most common cause in children– Episodes are self-limitedEpisodes are self-limited

Rare cause of chronic urticariaRare cause of chronic urticaria

INSECT BITES & STINGSINSECT BITES & STINGS

Generalized urticaria/angioedemaGeneralized urticaria/angioedema– Indicates systemic reactionIndicates systemic reaction– Requires allergist evaluation for Requires allergist evaluation for

possible immunotherapypossible immunotherapy Urticaria in children does not require Urticaria in children does not require

immunotherapy immunotherapy

– HymenopteraHymenoptera bees, wasps, yellow jackets, hornetsbees, wasps, yellow jackets, hornets Fire antsFire ants

URTICARIA ETIOLOGIES URTICARIA ETIOLOGIES AeroallergensAeroallergens

– Rarely, if ever, cause urticariaRarely, if ever, cause urticaria Animals may cause contact urticariaAnimals may cause contact urticaria Inhaled latex may result in systemic Inhaled latex may result in systemic

allergic reactionallergic reaction ? seasonal pollens? seasonal pollens

Contact UrticariaContact Urticaria– NonimmunologicNonimmunologic

cinnamic acid, benzoic acidcinnamic acid, benzoic acid Diagnosed by open patch testDiagnosed by open patch test

– Immunologic (Allergic)Immunologic (Allergic) Latex, fruits, vegetablesLatex, fruits, vegetables Diagnosed by applying material to Diagnosed by applying material to

eczematous or scratched skin eczematous or scratched skin

Urticaria etiologiesUrticaria etiologies

Endocrine/autoimmuneEndocrine/autoimmune– Thyroid diseaseThyroid disease

Urticaria and angioedema has been Urticaria and angioedema has been associated with hypo- and associated with hypo- and hyperthyroidismhyperthyroidism

Possible association with the presence of Possible association with the presence of thyroid autoantibodies (antithyroid thyroid autoantibodies (antithyroid peroxidase and antithyroglobulin)peroxidase and antithyroglobulin)

– Thyroid autoimmunity has been demonstrated Thyroid autoimmunity has been demonstrated in 12-26 % of subjects with chronic urticariain 12-26 % of subjects with chronic urticaria

– Thyroid autoimmunity occurs in 3-6% of the Thyroid autoimmunity occurs in 3-6% of the populationpopulation

URTICARIA ETIOLOGIESURTICARIA ETIOLOGIES

Chronic urticariaChronic urticaria– Most common etiology is idiopathicMost common etiology is idiopathic– 30-60% of patients exhibit a wheal-and-30-60% of patients exhibit a wheal-and-

flare with autologous serum skin testing flare with autologous serum skin testing Thought to be due to a complement-activating, Thought to be due to a complement-activating,

histamine-releasing autoantibody (IgG) against histamine-releasing autoantibody (IgG) against the the αα-chain of the high-affinity IgE receptor -chain of the high-affinity IgE receptor (Fc(FcεRI)εRI)

– These autoantibodies are able to trigger mast cell These autoantibodies are able to trigger mast cell or basophil histamine release through direct or basophil histamine release through direct crosslinking of adjacent receptorscrosslinking of adjacent receptors

– Can cause histamine release in healthy subjectsCan cause histamine release in healthy subjects Treatment implications: urticaria may be more Treatment implications: urticaria may be more

difficult to controldifficult to control

Plasma of patients with chronic urticaria Plasma of patients with chronic urticaria shows signs of thrombin generation, and shows signs of thrombin generation, and its intradermal injection causes wheal-its intradermal injection causes wheal-and-flare reactions more frequently than and-flare reactions more frequently than autologous serumautologous serumJ Allergy Clin Immunol 2006;117:1113-7.J Allergy Clin Immunol 2006;117:1113-7.

Chronic urticaria: Chronic urticaria: etiologiesetiologies

51/96 (53%) patients had positive 51/96 (53%) patients had positive ASSTASST

61/71 (86%) patients had positive 61/71 (86%) patients had positive APSTAPST

Prothrombin fragment Prothrombin fragment FF(1+2) (marker (1+2) (marker of thrombin generation) was higher in of thrombin generation) was higher in patients than in controlspatients than in controls– Levels directly related to severity of Levels directly related to severity of

urticariaurticaria

Chronic urticaria: Chronic urticaria: etiologiesetiologies

ConclusionsConclusions– Suggests role of the activation of the Suggests role of the activation of the

extrinsic coagulation pathway with extrinsic coagulation pathway with thrombin generation in chronic thrombin generation in chronic urticariaurticaria Thrombin increases vascular Thrombin increases vascular

permeability (edema)permeability (edema) May trigger mast cell degranulationMay trigger mast cell degranulation

– Possible therapeutic use of Possible therapeutic use of anticoagulants (heparin/warfarin)anticoagulants (heparin/warfarin)

Natural history:Natural history:Chronic UrticariaChronic Urticaria Up to 50% patients resolve within 3-12 Up to 50% patients resolve within 3-12

monthsmonths Another 20% of patients resolve in 12-36 Another 20% of patients resolve in 12-36

months or 36-60 monthsmonths or 36-60 months Up to 1.5% of patients persist for 20+ Up to 1.5% of patients persist for 20+

yearsyears 50% of patients with chronic urticaria will 50% of patients with chronic urticaria will

have recurrenceshave recurrences Physical urticarias tend to last longer, as Physical urticarias tend to last longer, as

do more severe forms of chronic urticariado more severe forms of chronic urticaria

PHYSICAL URTICARIASPHYSICAL URTICARIAS

Symptomatic dermographismSymptomatic dermographism Cholinergic Cholinergic Delayed pressureDelayed pressure Cold Cold AquagenicAquagenic SolarSolar VibratoryVibratory adrenergicadrenergic


DermographismDermographism– Very common- affects 2-5% of Very common- affects 2-5% of

populationpopulation Small fraction of these patients will seek Small fraction of these patients will seek

treatmenttreatment

– Stroking of the skin results in linear Stroking of the skin results in linear wheals which may persist as long as wheals which may persist as long as 30 minutes30 minutes patients may complain of generalized patients may complain of generalized

pruritus or “skin crawling”pruritus or “skin crawling”


Cholinergic urticariaCholinergic urticaria– Likely the most common of the physical Likely the most common of the physical

urticarias- 30% of the physical urticariasurticarias- 30% of the physical urticarias– Occurs primarily in teenagers and young Occurs primarily in teenagers and young

adultsadults– Pruritic, small macules and papules Pruritic, small macules and papules

occur in response to heat, exercise, or occur in response to heat, exercise, or emotional stressemotional stress May occur with wheezingMay occur with wheezing May occur without visible skin lesions May occur without visible skin lesions

(cholinergic pruritus)(cholinergic pruritus)

Physical urticariasPhysical urticarias

Cold urticariaCold urticaria– Characterized by the rapid onset of Characterized by the rapid onset of

pruritus, erythema, and swelling after pruritus, erythema, and swelling after exposure to a cold stimulusexposure to a cold stimulus

Holding cold objects: hand swellingHolding cold objects: hand swelling Eating cold items: lip swelling/ oropharyngeal Eating cold items: lip swelling/ oropharyngeal

edemaedema Swimming, with total body immersion, can result Swimming, with total body immersion, can result

in massive mediator release, resulting in in massive mediator release, resulting in hypotensionhypotension

– Risk factor: oral symptoms with ingestion of cold Risk factor: oral symptoms with ingestion of cold itemsitems

URTICARIA EVALUATIONURTICARIA EVALUATION

Acute urticaria and angioedemaAcute urticaria and angioedema

– History to ascertain for possible History to ascertain for possible triggers: food, drug, sting, infectiontriggers: food, drug, sting, infection

– Exam to confirm diagnosisExam to confirm diagnosis– May refer to board-certified May refer to board-certified

allergist for select skin allergist for select skin testing/challenge tests to testing/challenge tests to suspected agents suspected agents

Urticaria evaluationUrticaria evaluation

Chronic urticariaChronic urticaria– History and physical examHistory and physical exam

Confirm diagnosis of urticaria/angioedemaConfirm diagnosis of urticaria/angioedema– Laboratory studiesLaboratory studies

Usually none requiredUsually none required– No relationship has been found between the No relationship has been found between the

number of identified diagnoses and the number number of identified diagnoses and the number of laboratory tests performedof laboratory tests performed

Consider thyroid evaluation (TSH, thyroid Consider thyroid evaluation (TSH, thyroid autoantibodies) in patients who fail initial autoantibodies) in patients who fail initial therapytherapy

If urticarial vasculitis suspected:If urticarial vasculitis suspected:– ANA, complement levelsANA, complement levels– Referral for skin biopsyReferral for skin biopsy

Skin biopsySkin biopsy

IndicationsIndications– Individual urticarial lesion persists Individual urticarial lesion persists

for >48 hoursfor >48 hours– Urticaria are less than moderately Urticaria are less than moderately

pruriticpruritic– Lack of significant response to Lack of significant response to

“maximum” doses of antihistamines“maximum” doses of antihistamines

URTICARIA MANAGEMENTURTICARIA MANAGEMENT GoalsGoals

– control symptoms & keep patient control symptoms & keep patient comfortablecomfortable

search for and treat underlying etiologies search for and treat underlying etiologies exclude serious diseasesexclude serious diseases

AvoidanceAvoidance– causative factor if identifiedcausative factor if identified– NSAID’s & ASANSAID’s & ASA– excessive heatexcessive heat

Supportive therapySupportive therapy– ReassuranceReassurance– Patient education is most importantPatient education is most important

Urticaria managementUrticaria management

Chronic idiopathic urticariaChronic idiopathic urticaria– Because there is no one specific Because there is no one specific

causative agent that can be causative agent that can be withdrawn, the hives cannot be withdrawn, the hives cannot be “cured”.“cured”.

– Treatment is considered palliative, Treatment is considered palliative, until the condition resolves on its ownuntil the condition resolves on its own Goal is to maintain a patient’s quality of Goal is to maintain a patient’s quality of

life, despite conditionlife, despite condition

INITIAL URTICARIA INITIAL URTICARIA PHARMACOTHERAPYPHARMACOTHERAPY

Antihistamines: HAntihistamines: H11 receptor antagonists receptor antagonists– Second generation (“Non-sedating”)Second generation (“Non-sedating”)

equal in efficacy to first generation without as equal in efficacy to first generation without as many side effectsmany side effects

– cetirizine, levocetirizine, desloratadine, cetirizine, levocetirizine, desloratadine, fexofenadine, loratadine fexofenadine, loratadine

– First generationFirst generation Generally administered on a daily basis for Generally administered on a daily basis for

preventative therapypreventative therapy– hydroxyzine, diphenhydramine, hydroxyzine, diphenhydramine,

chlorpheniramine, etc.chlorpheniramine, etc.– dose at qhs initially to reduce daytime dose at qhs initially to reduce daytime

somnolencesomnolence– May be used on a prn basisMay be used on a prn basis

SECONDARY URTICARIA SECONDARY URTICARIA PHARMACOTHERAPYPHARMACOTHERAPY

HH22 antagonists antagonists– 15% of histamine receptors in the skin are H15% of histamine receptors in the skin are H22 – May use in combination with HMay use in combination with H11 antagonists antagonists– Inhibits metabolism of hydroxyzine, resulting in Inhibits metabolism of hydroxyzine, resulting in

higher plasma concentration of hydroxyzinehigher plasma concentration of hydroxyzine

DoxepinDoxepin– Very potent HVery potent H1 1 antagonist antagonist – HH2 2 antagonist as wellantagonist as well– May be very sedating- generally use at nightMay be very sedating- generally use at night

Leukotriene antagonistsLeukotriene antagonists– Zafirlukast and montelukast superior to placebo in Zafirlukast and montelukast superior to placebo in

the treatment of chronic urticariathe treatment of chronic urticaria

Urticaria managementUrticaria management

Antihistamine “cocktail”Antihistamine “cocktail”– Begin with 2Begin with 2ndnd generation antihistamine generation antihistamine

once a day; if response unsatisfactory, once a day; if response unsatisfactory, – Double the dose (either split-dose twice Double the dose (either split-dose twice

daily, or full dose once daily); if response daily, or full dose once daily); if response unsatisfactory, ADDunsatisfactory, ADD

– Doxepin 10-50 qhs (titrate over time to Doxepin 10-50 qhs (titrate over time to reduce sedation)reduce sedation)

Levocetirizine/Levocetirizine/cetirizine>fexofenadine>desloratadine/cetirizine>fexofenadine>desloratadine/

loratadineloratadine


Oral corticosteroidsOral corticosteroids– Role of systemic steroids in the Role of systemic steroids in the

treatment of chronic urticaria is limitedtreatment of chronic urticaria is limited– Short-term use in special situations Short-term use in special situations

(e.g. control of symptoms prior to an (e.g. control of symptoms prior to an important event.)important event.)

– Prolonged treatment complicated by Prolonged treatment complicated by severe side effects along with severe side effects along with worsening of urticaria upon withdrawal worsening of urticaria upon withdrawal

Alternative agents for Alternative agents for refractory chronic refractory chronic

urticariaurticariaDrugDrug Level of Level of

evidenceevidenceLeukotriene modifiersLeukotriene modifiers IbIbDapsoneDapsone IIbIIbSulfasalazineSulfasalazine IIIIIIHydroxychloroquineHydroxychloroquine IbIbColchicineColchicine IIIIIICalcineurin inhibitorsCalcineurin inhibitors IbIbMycophenolateMycophenolate IIbIIbOmalizumabOmalizumab IIIIII


Immunomodulatory agentsImmunomodulatory agents– Limited studies demonstrate efficacy Limited studies demonstrate efficacy

of cyclosporine in improving urticaria of cyclosporine in improving urticaria along with decreasing dependence on along with decreasing dependence on prednisone.prednisone. Suppressive effect on basophil and mast Suppressive effect on basophil and mast

cell activationcell activation Requires monitoring of a patient’s blood Requires monitoring of a patient’s blood

pressure and renal functionpressure and renal function

CyclosporineCyclosporine

Patients with chronic, severe urticaria Patients with chronic, severe urticaria with positive autologous skin testwith positive autologous skin test– 3-month course of treatment resulted in 3-month course of treatment resulted in

80% totally or almost clearing their 80% totally or almost clearing their symptomssymptoms

– Upon medication withdrawal at 3 months:Upon medication withdrawal at 3 months: 1/3 remained clear1/3 remained clear 1/3 relapsed mildly1/3 relapsed mildly 1/3 relapsed to baseline1/3 relapsed to baseline

Br J Dermatol 2000;143:368.Br J Dermatol 2000;143:368.

Urticaria and Urticaria and angioedemaangioedema PearlsPearls

– Urticaria and angioedema frequently is not an Urticaria and angioedema frequently is not an allergic conditionallergic condition

– Urticaria does not respond to topical treatmentUrticaria does not respond to topical treatment– Urticaria in the setting of antibiotics use might be Urticaria in the setting of antibiotics use might be

due to the infection, rather than the antibioticdue to the infection, rather than the antibiotic– Almost all urticaria is responsive to antihistamines; Almost all urticaria is responsive to antihistamines;

if your initial dose does not work, use moreif your initial dose does not work, use more– When all else fails, refer to your favorite fellowship-When all else fails, refer to your favorite fellowship-

trained allergy and immunology specialisttrained allergy and immunology specialist– Treatment references: Treatment references: N Engl J MedN Engl J Med 2002;346:175- 2002;346:175-

99 or or Allergy and Asthma ProcAllergy and Asthma Proc 2004;25:143-149. 2004;25:143-149.

I Need an Allergist!!I Need an Allergist!!

urticaria and angioedema 101 scot laurie, md allergy and asthma center at northpark assistant...

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