chronic urticaria presentation 2012

Chronic Urticaria & Chronic Urticaria & Angioedema Angioedema Assessment and ManagementAssessment and ManagementTimothy J. Sullivan, M.D.Timothy J. Sullivan, M.D.

• Pathophysiology of Urticaria Pathophysiology of Urticaria and Angioedemaand Angioedema

• Etiologic assessmentEtiologic assessment

• Conventional therapiesConventional therapies

• More intense therapiesMore intense therapies

May 5, 2012

UrticariaUrticaria

Chronic Urticaria Consultation Chronic Urticaria Consultation ResponseResponse

Fight of FlightFight of Flight

UrticariaUrticaria

• Intensely pruriticIntensely pruritic

• Sharply Sharply circumscribedcircumscribed

• RaisedRaised

• EvanescentEvanescent

Chronic Urticaria Chronic Urticaria • Daily or nearly daily lesionsDaily or nearly daily lesions

• 8 weeks or more in duration8 weeks or more in duration

• Frequently (15-50%) accompanied by Frequently (15-50%) accompanied by intermittent angioedemaintermittent angioedema

• Occasionally associated with acute Occasionally associated with acute episodes of anaphylaxisepisodes of anaphylaxis

The 7 Year ItchThe 7 Year Itch• Reports of the duration of CUA have provided Reports of the duration of CUA have provided

extremely variable estimatesextremely variable estimates

• Brief spontaneous remissions are commonBrief spontaneous remissions are common

• In most studies CUA has gone into durable In most studies CUA has gone into durable remission by a median of 4 years.remission by a median of 4 years.

• By 7 years ~80% of patients have remittedBy 7 years ~80% of patients have remitted

Chronic Urticaria & Chronic Urticaria & AngioedemaAngioedema

Parallel ObjectivesParallel Objectives• Pharmacologic Pharmacologic

controlcontrol• Relief from pruritusRelief from pruritus

• SleepSleep

• Suppression of visible Suppression of visible lesionslesions

• Planning to manage Planning to manage dangerous dangerous complicationscomplications

• Etiologic Etiologic assessmentassessment• Systematic evaluation Systematic evaluation

for known causesfor known causes

Assessment of Chronic Assessment of Chronic UrticariaUrticaria• History & physical examHistory & physical exam

• Challenges for physical urticariaChallenges for physical urticaria

• Laboratory studiesLaboratory studies

• Exclusion trial to assess exogenous Exclusion trial to assess exogenous causescauses

Etiologic AssessmentEtiologic Assessment

• A treatable or correctable cause can be A treatable or correctable cause can be found in ~35% (perhaps more if the new found in ~35% (perhaps more if the new Vitamin D data are cofirmed)Vitamin D data are cofirmed)

• Pathogenic antibodies to the IgE Pathogenic antibodies to the IgE receptor can be found in 30-50% of receptor can be found in 30-50% of patientspatients

• A probable explanation for the chronic A probable explanation for the chronic urticaria can be found in the majority of urticaria can be found in the majority of patientspatients

Causes of Chronic Urticaria & AngioedemaCauses of Chronic Urticaria & Angioedema323 consecutive patients323 consecutive patients

323

112

0

50

100

150

200

250

300

350

Studied Found

35%

The Mast Cell Theory The Mast Cell Theory of Chronic Urticariaof Chronic UrticariaKenneth Matthews, M.D.Kenneth Matthews, M.D.

• Mast cell mediators injected into the Mast cell mediators injected into the skin cause urticarial lesionsskin cause urticarial lesions

• Antigen-IgE activation of mast cells Antigen-IgE activation of mast cells causes urticaria causes urticaria

• Histopathologic exam of acute & chronic Histopathologic exam of acute & chronic urticaria shows mast cell degranulationurticaria shows mast cell degranulation

• Antihistamines and antileukotrienes Antihistamines and antileukotrienes suppress urticariasuppress urticaria

Chronic Urticaria Chronic Urticaria What enraged the mast What enraged the mast

cells?cells?• Physical stimuliPhysical stimuli

• Endogenous antigensEndogenous antigens

• Exogenous antigensExogenous antigens

• Metabolic factorsMetabolic factors

• Vitamin D deficiencyVitamin D deficiency

• Thyroid disordersThyroid disorders

• VasculitisVasculitis

• AutoantibodiesAutoantibodies

Physical UrticariasPhysical UrticariasConsistent stimulus-responseConsistent stimulus-response

DermatographismDermatographism

ColdCold

CholinergicCholinergic

Local heatLocal heat

Delayed pressureDelayed pressure

SolarSolar

AquagenicAquagenic

VibratoryVibratory

Stroke with tongue bladeStroke with tongue blade

Ice cube test 2 minutesIce cube test 2 minutes

Exercise 15-39 minutesExercise 15-39 minutes

44 C 5 minutes44 C 5 minutes

Sandbags 15 lbs 15 minutesSandbags 15 lbs 15 minutes

Specific wavelengthsSpecific wavelengths

35 C water compress35 C water compress

Vortex 4 minutesVortex 4 minutes

Can thyroid disease cause Can thyroid disease cause CUA?CUA?• HypothyroidismHypothyroidism

• HyperthyroidismHyperthyroidism

• Thyroid autoimmunityThyroid autoimmunity

• Antibody to thyroid peroxidaseAntibody to thyroid peroxidase

• Antibody to thyroglobulinAntibody to thyroglobulin

• ~30% of women with CUA~30% of women with CUA

• IgE to thyroid antigensIgE to thyroid antigens

• Remission with full thyroid hormone Remission with full thyroid hormone replacementreplacement

Chronic Urticaria Chronic Urticaria with Thyroid Autoimmunitywith Thyroid Autoimmunity• Association recognized for several yearsAssociation recognized for several years

• Rumbyrt et al JACI 1995;96:901-5.Rumbyrt et al JACI 1995;96:901-5.

• 7 patients with CUA & TA7 patients with CUA & TA

• 7 of 7 had complete remission with full 7 of 7 had complete remission with full thyroid hormone replacement therapythyroid hormone replacement therapy

• Variable results in subsequent studiesVariable results in subsequent studies

Thyroid SuppressionThyroid Suppression• Purpose is to minimize intravascular Purpose is to minimize intravascular

release of thyroid autoantigensrelease of thyroid autoantigens

• Supply TSupply T44 in amounts sufficient to in amounts sufficient to suppress endogenous secretionsuppress endogenous secretion

• 1 µg/pound of body weight/day1 µg/pound of body weight/day

• Initial response over 2-3 weeksInitial response over 2-3 weeks

• Check TSH, TCheck TSH, T44

Thyroid Suppression in CUA-Thyroid Suppression in CUA-TATA

61

54

41

32

73

0

10

20

30

40

50

60

70 TAT4 RxT4 ResponseT4 AloneT4+H1T4+More

76%

Can Helicobacter pylori cause Can Helicobacter pylori cause CUA?CUA?

• Immune responses uniformImmune responses uniform

• IgE to Hp antigensIgE to Hp antigens

• Remission with therapyRemission with therapy

IgE to IgE to Helicobacter pyloriHelicobacter pyloriAceti. Gastroenterology 1991;101:131-7Aceti. Gastroenterology 1991;101:131-7 • 26 patients with Hp associated gastritis26 patients with Hp associated gastritis

• 22 (84%) positive Basophil Histamine Release22 (84%) positive Basophil Histamine Release

• Acid elution removed response to HpAcid elution removed response to Hp

• Positive passive sensitization of normal Positive passive sensitization of normal basophilsbasophils

• Specific inhibition shownSpecific inhibition shown

• 18 (69%) positive Hp ELISA for IgE18 (69%) positive Hp ELISA for IgE

• 18 of 22 BHR positive patients ELISA18 of 22 BHR positive patients ELISA positivepositive

Systematic Review of Systematic Review of Studies of Hp Rx and Studies of Hp Rx and Chronic UrticariaChronic UrticariaFederman DG. J Amer Acad Dermatol 2003;49:861-4Federman DG. J Amer Acad Dermatol 2003;49:861-4

• 10 studies: CUA, Hp, adequate Rx10 studies: CUA, Hp, adequate Rx

• Remission RatesRemission Rates

• Hp eradication – 31%Hp eradication – 31%

• Hp not eradicated – 22%Hp not eradicated – 22%

• Hp- remission rate – 14%Hp- remission rate – 14%

• Hp eradication then remission OR 2.9 Hp eradication then remission OR 2.9 (95% CI 1.4 – 6.8) P=0.005(95% CI 1.4 – 6.8) P=0.005

H. pylori H. pylori Prevalence & Rx in Prevalence & Rx in CUACUA

0

50

100

150

200

250

300

350

TestedPositiveTreated

H. pylori H. pylori Rx in CUARx in CUA

39

10 9

0

5

10

15

20

25

30

35

40

TreatedCuredBetter

Onset of Allergic Drug Onset of Allergic Drug ReactionsReactionsPreviously Sensitized or UnsensitizedPreviously Sensitized or Unsensitized

0

2

4

6

8

10

12

14

16

18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Onset

What is the role of skin What is the role of skin testing in the evaluation of testing in the evaluation of CUA?CUA?

• Food can cause CUAFood can cause CUA

• Possible false positivePossible false positive

• Possible false negativePossible false negative

• Specific exclusion is Specific exclusion is easier and faster than easier and faster than an exclusion dietan exclusion diet

• IVT a potential IVT a potential alternativealternative

Exclusion TrialExclusion TrialIngested, topical, inhaled antigensIngested, topical, inhaled antigens

• Rice, chicken, & water (cooked fruit or juices)Rice, chicken, & water (cooked fruit or juices)

• Synthetic diet if acceptable to patientSynthetic diet if acceptable to patient

• One week, then re-challengeOne week, then re-challenge

• Food, seasoning, preservatives, toothpaste, Food, seasoning, preservatives, toothpaste, jewelry, OTC products, supplements, anti-jewelry, OTC products, supplements, anti-static sheets, air freshenersstatic sheets, air fresheners

• Everything that goes in or on the patient is a Everything that goes in or on the patient is a suspectsuspect

Can CUA be caused by Can CUA be caused by exogenous antigens?exogenous antigens?• PotatoPotato

• RiceRice

• PeanutPeanut

• SeasoningSeasoning

• ChocolateChocolate

• Anti-static sheetsAnti-static sheets

• LaxativeLaxative

• PreservativePreservative

• ToothpasteToothpaste

• SupplementsSupplements

• EarringEarring

• Air freshenerAir freshener

Causes of Chronic Urticaria & AngioedemaCauses of Chronic Urticaria & Angioedema323 consecutive patients323 consecutive patients

61

32

23

6

0

10

20

30

40

50

60

70CUA-TACUA-FACUA-HpCUA-PU

Can Vitamin D Deficiency Can Vitamin D Deficiency Cause or Exacerbate Cause or Exacerbate Chronic Urticaria?Chronic Urticaria?• Goetz, D. West Virginia Medical Goetz, D. West Virginia Medical

Journal.2011;107:14-20Journal.2011;107:14-20

• 57 patients with chronic urticaria & 57 patients with chronic urticaria & angioedema with 25-OH Vitamin D levels angioedema with 25-OH Vitamin D levels below 32 ng/mLbelow 32 ng/mL

• 11-80 yrs of age, 77% female11-80 yrs of age, 77% female

• With Vitamin D repletion, 40 (70%) had With Vitamin D repletion, 40 (70%) had complete resolution of CUA within 4 weekscomplete resolution of CUA within 4 weeks

Schnitzler SyndromeSchnitzler Syndrome• IgM monoclonal paraproteinemiaIgM monoclonal paraproteinemia

• Relatively nonpruritic urticariaRelatively nonpruritic urticaria

• Intermittent feverIntermittent fever

• Arthralgias, bone pain, hyperostosisArthralgias, bone pain, hyperostosis

• LymphadenopathyLymphadenopathy

• Anakinra (IL-1 RA) is beneficialAnakinra (IL-1 RA) is beneficial

Autologous Serum Skin TestAutologous Serum Skin Test• Intradermal injection of autologous Intradermal injection of autologous

serum causes a wheal and flare reaction serum causes a wheal and flare reaction at 30 minutes in some patients with CUAat 30 minutes in some patients with CUA

• Investigation of the mechanism revealed Investigation of the mechanism revealed autoimmune chronic urticariaautoimmune chronic urticaria

• Not all with active autoantibodies positiveNot all with active autoantibodies positive

• Not all with positive skin test have Not all with positive skin test have autoantibodiesautoantibodies

Autoantibody to theAutoantibody to the subunit of the IgE subunit of the IgEFcFcRI receptorRI receptor

• CUA 38%, PV 38%, DM 36%, SLE 20%, CUA 38%, PV 38%, DM 36%, SLE 20%, BP 13% BP 13%

• Basophil histamine release only with Basophil histamine release only with CUA seraCUA sera

• Blockade of C5a receptor blocked Blockade of C5a receptor blocked histamine releasehistamine release

• Decomplementation blocked histamine Decomplementation blocked histamine releaserelease

Fiebiger E. J Clin Invest 1998;101:243-51

Autoimmune Causes of Autoimmune Causes of Chronic Urticaria & Chronic Urticaria & AngioedemaAngioedema

• IgGIgG11 or IgG or IgG33 autoantibody to the autoantibody to the subunit of the IgEsubunit of the IgEFcFcRI receptorRI receptor

• Complement activation seems to be a Complement activation seems to be a necessary part of the activation processnecessary part of the activation process

• Present in 30% - 50% of CUA patientsPresent in 30% - 50% of CUA patients

• Less often an IgG antibody to IgELess often an IgG antibody to IgE

• Commercial laboratory assays availableCommercial laboratory assays available

Common Causes of Common Causes of Chronic Urticaria & Chronic Urticaria & AngioedemaAngioedema

40

25

7

15

13

AutoimmuneThyroidH pyloriFoodUnknown

Laboratory Studies to consider for Laboratory Studies to consider for Chronic UrticariaChronic Urticaria

• CBC, metabolic panelCBC, metabolic panel

• Antibodies to thyroid peroxidase & thyroglobulin, TSH, Antibodies to thyroid peroxidase & thyroglobulin, TSH, free T4free T4

• Helicobacter pylori stool antigenHelicobacter pylori stool antigen

• 25-OH Vitamin D level25-OH Vitamin D level

• Chronic urticaria indexChronic urticaria index

• CH 50CH 50

• Skin biopsySkin biopsy

• Other studies dictated by clinical assessmentOther studies dictated by clinical assessment

Hereditary AngioedemaHereditary Angioedema• C1-esterase inhibitor deficiencyC1-esterase inhibitor deficiency

• Inhibits activated C1Inhibits activated C1

• Inhibits activated factor XII and Inhibits activated factor XII and kallekreinkallekrein

• Isolated angioedema of skin, mucous Isolated angioedema of skin, mucous membranes, or gastrointestinal tractmembranes, or gastrointestinal tract

• Variable onset and frequency of episodesVariable onset and frequency of episodes

• Unresponsive to allergy medicationsUnresponsive to allergy medications

ACE Inhibitors & AngioedemaACE Inhibitors & AngioedemaClinical FeaturesClinical Features

• Variable interval from initiation of Variable interval from initiation of therapy to onset of angioedematherapy to onset of angioedema

• Isolated angioedema of skin, mucous Isolated angioedema of skin, mucous membranes, or gastrointestinal tractmembranes, or gastrointestinal tract

• Often progresses for hours and Often progresses for hours and resolves over daysresolves over days

• Usually Usually notnot responsive to allergy responsive to allergy medicationsmedications

ACE Inhibitors & AngioedemaACE Inhibitors & AngioedemaBrown NJ, JAMA 1997; 232-3Brown NJ, JAMA 1997; 232-3

• Incidence 1.6/1000 patient yearsIncidence 1.6/1000 patient years

• Recurrence with continued therapy Recurrence with continued therapy

• 18.7/100 patient years18.7/100 patient years

• Recurrence with discontinuation of ACE Recurrence with discontinuation of ACE inhibitorinhibitor

• 1.8/100 patient years1.8/100 patient years

AE can recur up to 3 months after discontinuation of ACEiAE can recur up to 3 months after discontinuation of ACEi

ACE Inhibitors & AngioedemaACE Inhibitors & AngioedemaManagementManagement

• Acute angioedemaAcute angioedema

• Assume allergy medications will not Assume allergy medications will not be effectivebe effective

• Intubation earlyIntubation early

• Cricothyrotomy if intubation not Cricothyrotomy if intubation not feasiblefeasible

• Discontinue ACE inhibitor therapyDiscontinue ACE inhibitor therapy

ACE Inhibitors & ACE Inhibitors & AngioedemaAngioedemaManagementManagement• Angiotensin receptor blocker (ARB) therapyAngiotensin receptor blocker (ARB) therapy

• Two recent meta-analyses (2009, 2012) Two recent meta-analyses (2009, 2012) indicate ARB therapy is associated with a indicate ARB therapy is associated with a higher risk of angioedema than placebo higher risk of angioedema than placebo or other antihypertensive therapyor other antihypertensive therapy

• Risk for confirmed angioedema 0-9.2% in Risk for confirmed angioedema 0-9.2% in patients with prior ACEi associated patients with prior ACEi associated angioedemaangioedema

XII XIIa

KallekreinPrekallekrein

Kininogen BradykininACE

Bradykinin & ACE

XII XIIa

KallekreinPrekallekrein

Kininogen BradykininACE

Bradykinin, HAE, & ACE

C1-INH

C1-INH

Chronic Urticaria & Chronic Urticaria & AngioedemaAngioedema

Parallel ObjectivesParallel Objectives• Pharmacologic Pharmacologic

controlcontrol• Relief from pruritusRelief from pruritus

• SleepSleep

• Suppression of visible Suppression of visible lesionslesions

• Planning to manage Planning to manage dangerous dangerous complicationscomplications

• Etiologic Etiologic assessmentassessment• Systematic evaluation Systematic evaluation

for known causesfor known causes

Conventional Rx for CUAConventional Rx for CUA• H1 antihistaminesH1 antihistamines

• Nonsedating, q.d. or b.i.d.Nonsedating, q.d. or b.i.d.

• Leukotriene receptor antagonistsLeukotriene receptor antagonists

• q.d. or b.i.d.q.d. or b.i.d.

• H2 antihistaminesH2 antihistamines

• Doxepin h.s.Doxepin h.s.

• Systemic glucocorticoidsSystemic glucocorticoids

Is Epinephrine Necessary?Is Epinephrine Necessary?• If there is a history If there is a history

of prior anaphylaxisof prior anaphylaxis

• If there have been If there have been prior acute severe prior acute severe exacerbationsexacerbations

• If the patient has If the patient has risk factors for risk factors for severe anaphylaxissevere anaphylaxis

Therapy of CUATherapy of CUARefractory DiseaseRefractory Disease

• Systemic glucocorticoidsSystemic glucocorticoids

• CyclosporineCyclosporine

• MycophenolateMycophenolate

• TacrolimusTacrolimus

• XolairXolair

• IVIgIVIg

• Hydroxychloroquine, othersHydroxychloroquine, others

Cyclosporine for CUA - Cyclosporine for CUA - 37 37 patientspatients

27

21

6

10

0

5

10

15

20

25

30CYA responseCYA aloneCYA +No response

73%

Cyclosporine for CUACyclosporine for CUA• 2 mg/kg once daily with the evening meal2 mg/kg once daily with the evening meal

• Congestion of the palms and solesCongestion of the palms and soles

• GI upsetGI upset

• Ice cream, antacids, split dosesIce cream, antacids, split doses

• Monitor BP, renal & hepatic functionMonitor BP, renal & hepatic function

• Mycophenolate (CellCept) or Prograf for Mycophenolate (CellCept) or Prograf for failuresfailures

IVIg for CUAIVIg for CUA• 400 mg/kg q1-3 months400 mg/kg q1-3 months

• Lesions regress over 1 weekLesions regress over 1 week

• Repeat infusion when lesions recurRepeat infusion when lesions recur

• Insurance will pay in GA if the patient Insurance will pay in GA if the patient has been shown to have mast cell or has been shown to have mast cell or basophil activating autoantibodiesbasophil activating autoantibodies

Steroid Dependent CUASteroid Dependent CUA

0

5

10

15

20

25

TotalH1+LTRACYAIVIgNo response

An Approach to CUAAn Approach to CUAETIOLOGIC STUDIESETIOLOGIC STUDIES

• Clinical AssessmentClinical Assessment

• Laboratory AssessmentLaboratory Assessment

• Therapeutic TrialsTherapeutic Trials

• Exclusion TrialExclusion Trial

NONSPECIFIC THERAPYNONSPECIFIC THERAPY

• H1-antihistaminesH1-antihistamines

• H1+H2 antihistaminesH1+H2 antihistamines

• H1+H2+LTRAH1+H2+LTRA

• +Cyclosporine+Cyclosporine

• IVIgIVIg

• OmalizumabOmalizumab

• Systemic steroidsSystemic steroids

Burst, q.o.d., q.d.Burst, q.o.d., q.d.

Identify CauseIdentify CauseProvide Pharmacologic Provide Pharmacologic

ReliefRelief

chronic urticaria presentation 2012

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