Chronic Urticaria & Angioedema Chronic Urticaria & Angioedema Assessment and Management Assessment and Management Timothy J. Sullivan, M.D. Timothy J. Sullivan, M.D. • Pathophysiology of Pathophysiology of Urticaria and Angioedema Urticaria and Angioedema • Etiologic assessment Etiologic assessment • Conventional therapies Conventional therapies • More intense therapies More intense therapies May 5, 2012
A review of causes and management of chronic urticaria and angioedema
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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
• 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
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
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
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
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70 TAT4 RxT4 ResponseT4 AloneT4+H1T4+More
76%
Can Helicobacter pylori cause Can Helicobacter pylori cause CUA?CUA?
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
• 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
• 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
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
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
Chronic Urticaria Chronic Urticaria What enraged the mast What enraged the mast
• Arthralgias, bone pain, hyperostosisArthralgias, bone pain, hyperostosis
• LymphadenopathyLymphadenopathy
• Anakinra (IL-1 RA) is beneficialAnakinra (IL-1 RA) is beneficial
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
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
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
• 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
• 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