Urticaria & Angioedema The Essentials for the ABAI Exam

David A. Khan, MDProfessor of Medicine & Pediatrics

Allergy & Immunology Training Program DirectorDivision of Allergy & Immunology

UT Southwestern Medical Center-Dallas

Disclosure

Research Grants NIH, Vanberg Family Fund

Speaker Honoraria Merck, Genentech

Organizations: Joint Task Force on Practice Parameters

Learning Objectives

Upon completion of this session, participants should be able to: Recognize differentiating features of physical

urticarias Recognize clinical, laboratory and treatment

differences for various types of hereditary angioedema

Overview

Mediators Etiologies Physical Urticaria Chronic Idiopathic Urticaria Urticarial Vasculitis Angioedema syndromes

Potential Mediators in Urticaria

Histamine Vasodilation, vascular

permeability Substance P

Released by type C fibers by antidromic conduction

Vasodilator PGD2

Vasodilator LTC4/LTD4

Vascular permeability

PAF Vascular permeability

C3a/C5a Bradykinin

Vasodilation Vascular permeability

Histamine releasing Factor (HRF)/-chemokine

Thrombin

Causes of Acute Urticaria/AE

Cause Example

Contact urticaria Pet dander

Early contact dermatitis Poison ivy

Exacerbation of physical urticaria Cholinergic

IgE-mediated food allergy Peanut allergy

Adverse reactions to immunotherapy

Adverse reactions to medications Opiates

Papular urticaria Fleas

Infection EBV

Toxin scombroid

Types of Chronic Urticaria & AE

Cause Example

Unknown Idiopathic

Autoimmune/Autoantibody associated + ASST

Physical urticarias Cold, dermographism, etc

Urticarial vasculitis Hypocomplementemic UV

Cryopyrin associated periodic syndromes (CAPS)

Pseudourticaria in familial cold autoinflammatory syndrome (FCAS)

Less established causes of CU: infections (e.g. H. pylori), celiac disease, malignancy

Connective Tissue Disease and Urticaria

SLE < 10% patients Most urticarial vasculitis

Sjogren’s Majority are urticarial vasculitis

Cryoglobulinemia Hepatitis C

Rheumatoid Arthritis?

In the absence of other symptoms/signs autoimmunity, routine serologies not required

Neoplasms and Urticaria Uncommon cause

B-cell Lymphomas and Hodkins Carcinomas

Lung, colorectal, liver Schnitzler Syndrome

IgM monoclonal paraproteinemia Nonpruritic urticaria (later may be pruritic) Intermittent spiking fever Arthralgias, bone pain, hyperostosis Leukocytosis and elevated ESR Neutrophilic dermal infiltrate on biopsy

Anti-IL-1 therapies effective

Parasites and Urticaria

Helminths Ascaris, Ancylostoma, Strongyloides,

Filaria, Echinococcus, Schistosoma, Trichinella, Toxocara, and Fasciola

Associated with eosinophilia

Helicobacter Pylori and Chronic Urticaria

Several studies have suggested an association of H pylori and CU

Evidence-based critical analysis (GRADE approach) of 19 studies evaluating H. pylori eradication for treatment of CU revealed conflicting results 10 studies with positive effect 9 studies with no effect All studies with low quality of evidence

The evidence that H. pylori eradication leads to improvement of CU outcomes is weak and conflicting leading to weak recommendation for H. pylori treatment in CU

Shakouri A. et al. Curr Opin Allergy Immunol 2010;10:362-9.

Physical Urticarias

Prime Board Exam Fodder

Cold Urticaria

Urticaria on cold-exposed areas of the body Systemic reactions can occur with shock

Patients with a history of oropharyngeal edema after cold drinks are at high risk for shock from swimming in colder water (Arch Dermatol 1998)

Diagnosis Ice cube test

“Drug of choice” Cyproheptadine Other antihistamines also work

Mechanisms of Idiopathic Cold Urticaria

Histamine peaks 4-8 minutes after cold exposure

Antibody mediated and passively transferred IgE, IgG, IgM

Other mediators NCF, PAF, PGD2, TNF-a

Cold Urticaria Syndromes

Idiopathic (most common) Secondary forms

Cold-dependent immunoglobulin diseases Cryoglobulinemia Cold agglutinin disease Cryofibrinogenemia Paroxysmal cold hemoglobinuria Cold hemolysis

Delayed Cold Urticaria Swelling 9-18 hrs after cold

exposure Not passively transferred

Cold Urticaria Syndromes -2

Localized cold urticaria Certain areas of body urticate with cold

exposure Predisposing factors

Cold injury Immunotherapy injection sites Insect bites

Localized cold reflex urticaria Ice cube test positive but only in the

vicinity of the contact site

Phospholipase C2-Associated Antibody Deficiency and Immune Dysregulation (PLAID)

Autosomal dominant Mutation in PLCG2

encoding phospholipase Cγ2, a signaling molecule expressed in B cells, NK cells, and mast cells

Cold urticaria at young age Negative ice cube test Positive evaporative cooling

Antibody deficiency Decreased B cells, switched memory B cells

and NK cells

Autoantibodies/autoimmune diseaseOmbrello MJ et al. N Engl J Med 2012;366:330-8.

Evaporative Cooling Test in PLAID

A: Air E: ethanolW: water C: covered water

Ombrello MJ et al. N Engl J Med 2012;366:330-8.

Ice Cube Test Negative Cold Urticaria

Cold-induced cholinergic urticaria Exercise in cold air causes urticaria resembling

cholinergic urticaria Requires systemic cold exposure

Systemic cold urticaria Generalized hives with systemic cold exposure Unrelated to exercise

Cold-dependent dermographism Accentuated hive formation if skin scratched and then

chilled

Familial cold autoinflammatory syndrome (FCAS) PLAID

Local Heat Urticaria

Very rare Test tube of water @ 44 ºC to arm for 5

minutes Hive forms few minutes later

Histamine and NCF released

Cholinergic Urticaria

Cholinergic urticaria

Occurs primarily in teenagers and young adults Pruritic, small macules and papules occur in

response to heat, exercise, or emotional stress May have other cholinergic symptoms

Lacrimation, salivation, diarrhea May occur with wheezing May occur without visible skin lesions

(cholinergic pruritus)

Cholinergic urticaria

Pathophysiologic Mechanisms Neurogenic reflex

Placing hand in warm water with proximal tourniquet does not cause local hives

Removal of tourniquet leads to generalized eruption

Central perception of temperature change Autologous sweat sensitivity

Sweat may cause basophil degranulation in sensitive subjects

Cholinergic Urticaria subtypes

Non-follicular Most common Hypersensitivity to autologous sweat Satellite wheals to acetylcholine skin test Negative ASST (autologous serum skin test)

Follicular Follicular wheals Weak to no response to autologous sweat No satellite wheals to acetylcholine Positive ASSTFukunaga A et al. J Allergy Clin Immunol 2005;116:397-402.

Cholinergic Urticaria

Diagnostic testing Challenge by exercise

15 minutes to point of sweating and 15 minutes beyond

Passive warming 42ºC full bath to achieve rise in body core temperature of 1.0ºC

Methacholine skin testing Poor specificity and sensitivity

Autologous sweat skin testing Positive in non-follicular subtype

Historical “drug of choice” hydroxyzine Abajian M et al. Immuno Allergy Clin N Am 2014;34:73-88.

Cholinergic Urticaria with Hypotension

Rare reports of patients with cholinergic urticaria with recurrent hypotension Increase in core body temperature > 0.7 ºC

with warming blankets or submersion in warm water causes urticaria, histamine release and anaphylactic symptoms

Patients with exercise-induced anaphylaxis will not react with passive heating

Delayed Pressure Urticaria (Angioedema)

Symptoms develop 4-6 hrs after pressure stimulus Hands, feet, buttocks

Usually associated with non-pressure induced chronic urticaria

“Sandbag” test 5-15 lb weight applied over forearm, shoulder, thigh

for 10-20 minutes Usually unresponsive to antihistamines Corticosteroids may be required

Delayed Pressure Urticaria

Dermographism

Dermographism

Clinical Features Stroking of the skin results in linear wheals which may

persist as long as 30 minutes Subtypes

Simple Dermographism (dermatographia) Very common- affects 2-5% of population Non-pruritic

Symptomatic Dermographism (factitious urticaria) Most common physical urticaria we see Patients may complain of generalized pruritus or “skin crawling”

Less common forms of dermographism cholinergic, cold-dependent, follicular, red, white

Dermographism

Pathogenesis Can be passively-transferred Some patients have elevated baseline histamine

Diagnosis Stroking skin (back preferable) with tongue blade with

with firm pressure and observing 1-3 minutes later Dermatographometer

can apply a defined, reproducible amount of pressure to the skin

Associations Psychological stressors, antibiotic therapy, contact

dermatitis, other physical urticarias, mastocytosis

Murphy GM, et al. Br J Dermatol 1987;116:801-4. Taskapan O et al. J Eur Acad Dermatol Venereol 2006;20:58-62.

Solar Urticaria

Solar Urticaria

Clinical Features Rare disorder (.08% of urticaria patients) exposure to UV radiation causes urticaria,

burning, and itching within 5-10 minutes Dermographism common Systemic symptoms including anaphylaxis

have been reported Several classification systems exist

Botto NC, Warshaw EM. Solar urticaria. J Am Acad Dermatol 2008;59:909-20.

Solar Urticaria I-VIType Eliciting

WavelengthComments

I 2800-3200 Å Passively transferred; protected by window glass

II 3200-4000 Å

III 4000-5000 Å

IV 4000-5000 Å Passively transferred

V 2800-5000 Å

VI 4000 Å Erythropoietic protoporphyria;Protoporphyrin IX acts as a photosensitizer;Porphyrin in urine is normal;Protoporphyrin and coproporphyrin in feces are increased

Harber LC et al. J Invest Derm 1963;41:439-43.

Solar Urticaria

Pathogenesis In some cases IgE to circulating photoallergen

(chromophore activated by light) Cases with underlying erthropoietic protoporhyria,

complement is activated via photoactivation

Diagnosis Phototesting with variable light sources used to

establish a diagnosis of solar urticaria

Therapy Sunlight exposure avoidance UVA therapy may be successful

Leenutaphong V et al. J Am Acad Dermatol 1989;21:237-40.

Aquagenic Urticaria Clinical Features

very rare form of urticaria (~30 reported cases) familial and localized forms

lesions identical to cholinergic urticaria that occur with water contact independent of temperature

systemic symptoms including headache and respiratory symptoms reported

association with dermographism Diagnosis

Tap/distilled water compress at 35° C applied to the skin

Baptist AP, Baldwin JL. Allergy Asthma Proc 2005;26:217-20.

Vibratory Angioedema

Clinical Features rare form of physical urticaria/angioedema hereditary and non-familial forms stimulus of angioedema is vibration

vibration results in local pruritus, erythema, and swelling occurring within minutes and resolving in 24 hours

Diagnosis Forearm on vortex mixer for 5 minutes

Dice JP. Immunol Allergy Clin North Am 2004;24:225-46.

Tests For Physical UrticariaCold Ice cube test

Localized Heat Test tube water 44ºC

Cholinergic Exercise for 15-20 min.Immersion in 42ºC bath

Delayed Pressure

Sand bag test: 15 lb weight for 15 minutes

Dermographism Stroking skin

Solar Specific wavelength light exposure

Aquagenic Water compress 35ºC

Vibratory Vortex for 4 minutes

Physical Urticaria:Passive Transfer by Serum

Cold IgE, IgM, IgG,

cryoglobulins

Solar Type I & IV

Dermographism IgE

Chronic Autoantibody Associated Urticaria

30-40% CIU associated with autoantibodies Thyroid autoantibodies > 20% of CU pts

anti-thyroid peroxidase > anti-thyroglobulin Ab IgG or IgM antibodies against high-affinity IgE

receptor chain Rarely anti-IgE antibodies

C5a augments histamine release by IgG anti-antibodies

Detected through autologous serum or plasma skin test and basophil histamine release assays

Basophils and CIU

Basopenia has been associated with CIU

CIU patients have 2 different basophil functional subtypes Basophil anti-IgE responders Basophil anti-IgE non-responders

Increased SHIP-2 Lower Syk kinase levels

Vonakis B, Saini SS. Curr Opin Immunol. 2008;20(6): 709–716.

Chronic Idiopathic Urticaria

After exclusion of acute urticaria and physical urticarias, identifiable etiologies may be found in < 2% cases according to Kaplan

Skin biopsy Nonnecrotizing perivascular mononuclear cell infiltrate Primarily lymphocytes Increased mast cells in some but not all studies Similar to late-phase allergic reactions except

Less basophils, variable eosinophils, prominent monocytes and lymphocytes

Urticarial Vasculitis

Prevalence ~5% CIU Female predominance Peak incidence 4th decade Histopathology can be indistinguishable from

leukocytoclastic vasculitis (palpable purpura) Leukocytoclasis Vessel wall damage +/- Fibrin deposits or RBC extravasation

Immunofluorescence Igs, Complement, fibrin within vessel wall

Davis MD, Brewer J. Immunol Allergy Clin N Am 2004;24:183-213.

Cutaneous Features of UV

Urticaria description Painful, tender, burning or pruritic

Duration of lesions 24-72 hrs (may be only present in ~40%*)

Lesions may resolve with purpura or hyperpigmentation

Angioedema in many patients Less common skin manifestations

e. multiforme, livedo reticularis, Raynauds*Tosoni C et al. Clin Exp Derm 2008;34:166-70.

Organ Involvement in Urticarial Vasculitis

Davis MD, Brewer J. Immunol Allergy Clin N Am 2004;24:183-213.

Common Arthralgias, myalgias

Less common Respiratory (obstructive lung disease) Renal, gastrointestinal

Rare Cardiac, ophthalmologic, splenomegaly,

lymphadenopathy

Very rare CNS, Jacoud’s syndrome

Subtypes of Urticarial Vasculitis

3 subtypes of UV Normocomplementemic (NUV) Hypocomplementemic UV (HUV) Hypocomplementemic UV syndrome (HUVS)

All types have many overlapping clinical, laboratory, and histologic features

NUV vs. HUV Clinical Features:

HUV Higher %: female gender, arthralgias/arthritis, episcleritis/uveitis

SLE: 54% HUV, 3% NUV Angioedema similar (13-23%)

Lab Features: HUV: higher % ANA+, dsDNA+ (<25%)

Skin Biopsy HUV: higher % dermal neutrophilia NUV: higher % dermal eosinophilia

HUV may be subset of SLE?

Davis MDP et al. J Am Acad Derm 1998;38:899-905.

Hypocomplementemic Urticarial Vasculitis Syndrome (HUVS)

HUVS (McDuffie syndrome) More severe and associated with COPD in 50%

Diagnostic criteria (Schwartz) major criteria (1)

urticaria > 6 months and hypocomplementemia minor criteria (2)

dermal venulitis, arthralgia/arthritis, uveitis/episcleritis, mild glomerulonephritis, recurrent abdominal pain, positive C1q precipitin test with a suppressed C1q level

Subset/unusual type of SLE? HUVS usually dsDNA negative

Patients with UV and low complement not fulfilling above criteria considered to have HUV

Laboratories in UV

All forms of UV ESR 50% ANA +

typically dsDNA –

HUV/HUVS C3 ,C4, CH50 C1q Anti C1q antibodies present in 100% of HUV

Also seen in Felty’s syndrome, SLE, Sjogren’s syndrome, and MPGN Kallenberg CG. Autoimmun Rev 2008;7:612-5.

Urticarial Vasculitis Etiology

Idiopathic most common SLE, Sjogren's, serum sickness Numerous other rare causes

Treatment Antihistamines (help with pruritus) Dapsone, colchicine, hydroxychloroquine, indomethacin,

corticosteroids, azathioprine, methotrexate, cyclosporine, cyclophosphamide, mycophenolate

Prognosis Average duration 3-4 years UV typically has benign course HUVS has a worse prognosis

COPD common cause of morbidity and mortality

Hereditary Urticaria & AE Syndromes

Hereditary Vibratory Angioedema Factor I Deficiency Hereditary Angioedema

Factor I Deficiency (C3b inactivator)

Rare disorder Autosomal recessive May present with urticaria Depressed C3 levels

May have liberation of C3a anaphylatoxin

Stepwise Approach to CU Therapy

Bernstein JA, et al. Urticaria Practice Parameters Update 2014

Angioedema

Angioedema occurs in ~ 50% of cases of urticaria

Presence of angioedema does not aid in classification, diagnosis, or treatment of urticaria

Angioedema in the absence of urticaria Consider bradykinin-mediated angioedema

C1-esterase inhibitor deficiency syndromes ACE-inhibitor angioedema

ACE-I Angioedema Occurs in 0.1-0.7%

more common in African-Americans Angioedema above neck most common

Rarely associated with urticaria Usually delayed in onset

Mean 1.8 yrs (Malde 2007) Likely des-Arg bradykinin induced

ACE (kinase II) activates bradykinin and angiotensin I

Usually tolerate ARBs but case reports of AE with ARBs too

C1-INH C1-INH belongs to family of serine protease

inhibitors (serpins) and inhibits: C1s and C1r (classical pathway) Mannin-binding lectin-associated serine proteases

(MASPs) FXIa (intrinsic pathway of coagulation) FXIIa and kallikrein (contact system) Weakly inhibits

Thrombin, plasmin, tissue-type plasminogen activator

C1-INH gene (SERPING1) Chromosome 11 > 250 mutations identified over entire length of coding

sequence

J Allergy Clin Immunol 2013;131:1491-3.

Hereditary Angioedema Clinical characteristics

Autosomal dominant Acute attacks

Symptoms progress over 24-48 hours and resolve over the next 48 hours

angioedema of extremities, face, throat abdominal pain, nausea, vomiting, diarrhea no urticaria or pruritus Symptoms not helped by antihistamines May be precipitated by trauma

dental work

Hormonal effects variable

Symptomatology of HAE

Symptoms Frequency

Extremity edema 96%

Abdominal Pain 93%

Nausea/vomiting 88%

Facial edema 85%

Oropharyngeal edema 64%

Laryngeal edema 50%

Diarrhea 22%

Khan DA. Allergy Asthma Proc 2011;32:1–10.

Prodromal Symptoms in HAE

96% HAE patients have had prodromal symptoms

Most common symptoms fatigue, rash, muscle aches

Timing variable 50% > 12 hrs before HAE attack

Prematta MJ et al. Allergy Asthma Proc 2009;30:506-11.

Hereditary Angioedema

Associated conditions SLE and autoimmune disorders (?) Other cutaneous findings (26% in

survey by Frank et al) Erythema marginatum Ertythema multiforme Erythematous mottling

Hereditary Angioedema

Type I ~ 85% patients with C1-INH deficiency Defective expression of 1 allele of C1-INH

gene Low C1 INH antigenic and function

Type II ~ 15 % patients with C1-INH deficiency Dysfunctional mutant protein C1-INH antigenic levels nl or high, functional

levels decreased

Hereditary Angioedema Pathophysiology

Bradykinin most likely mediator involved Evidence in both HAE and AAE

C2-kinin evidence weak to non-existent

Acquired Angioedema (AAE)

Clinical presentation similar to HAE except not hereditary and later onset (4th decade of life or later)

Increased consumption of C1-INH and hyperactivation of classical complement Consumption by neoplastic lymphatic tissue Autoantibodies to C1-INH impair C1-INH

function May enhance cleavage to non-functional

but antigenic protein In this case C1-INH levels are normal

Acquired Angioedema (AAE)

“Type I” (paraneoplastic) B cell lymphoproliferative disease MGUS (monoclonal gammopathy of

unknown significance) May also have autoantibody to C1-INH

at some time in course of disease

“Type II” (autoimmune) Autoantibody to C1-INH always present Otherwise healthy

Classification arbitrary given that both types may have autoantibodies

Laboratories in Hereditary and Acquired Angioedemas

C1-INH level

C1-INH function

C1q C4 C3

HAE-I ↓ ↓ N ↓ N

HAE-II N or ↑ ↓ N ↓ N

HAE-III N N N N N

AAE-I ↓ ↓ ↓ ↓ N or ↓

AAE-II ↓ or N ↓ ↓ or N ↓ N or ↓

Khan DA. Allergy Asthma Proc 2011;32:1–10.

Treatment Options for C1-INH Deficiencies

Management of Acute HAE Basics

Airway management Hydration Pain relief

HAE specific therapies (preferred) C1-INH concentrate, kallikrein inhibitor,

bradykinin B2 receptor antagonist

FFP (?) May worsen acute attack in small percentage

Treatment Options for C1-INH Deficiencies

Short-term prophylaxis C1-INH concentrate Androgens 5-10 days prior and 2 days after FFP

Long-term prophylaxis Attenuated Androgens

danazol, stanozolol, oxandrolone C1-INH concentrate Antifibrinolytics

-aminocaproic acid (Amicar) tranexamic acid (Lysteda)

Adverse Effects of HAE Therapy

Attenuated androgens Adverse effects

Hepatotoxicity (rarely liver carcinoma) Hyperlipidemia Weight gain, menstrual irregularities, libido,

virilization, acne, myalgias, fatigue, headache, hypertension

Contraindications Pregnancy, lactation, childhood*, prostate CA

Antifibrinolytics Thrombosis, postural hypotension, myalgias, myositis

Zuraw BL. N Engl J Med 2008;359:1027-36.

Therapy Indication Dose Adverse effects

Plasma-derived C1 INH (Cinryze®)

Long-term prophylaxis

1000 u IVq 3-4 days

Thrombotic events, anaphylaxis(rare)

Plasma-derived C1 INH (Berinert-P®)

Acute attacks 20 u/kg IV Thrombotic events, anaphylaxis(rare)

Kallikrein inhibitorEcallantide(Kalbitor®)

Acute attacks 30 mg subcutaneousMay repeat within 24 hrs

Anaphylaxis(uncommon)(black box warning)

Bradykinin-B2 receptor antagonistIcatibant(Firazyr®)

Acute attacks 30 mg subcutaneousMay repeat q 6hrs (max 3 doses/24 hrs)

Injection site reactions (97%)

HAE Specific Therapies

Therapy for AAE Treatment of underlying disease

May result in biochemical/clinical remission of AAE

Androgens AAE frequently resistant

Antifibrinolytics May be preferred over androgens

C1-INH concentrate May require higher doses and be more

resistant to treat than HAE

Rituximab

Hereditary Angioedema with nl C1INH(HAE-nml-C1INH)

Often referred to as HAE III Very rare Autosomal dominant Mutations in FXII gene identified in a

minority of patients, very rare in US Normal C1 INH levels and function Predominantly female with exacerbations

with estrogen Facial > extremity swelling

Bork K et al. J Allergy Clin Immunol 2009 Jul;124(1):129-34.

Hereditary Angioedema with nl C1INH(HAE-nml-C1INH)

Diagnostic criteria Recurrent AE in absence of hives or use if a

medication known to cause AE Normal or near normal C4, C1INH (antigen

and function) 1 of following

FXII mutation Positive family history & lack of efficiacy of

high dose antihistamine therapy for > 1 month and an interval expected to be associated with 3 or more attacksZuraw B et al. Allergy Asthma Proc 2012;33:S145-156.

HAE-C1INH def vs. HAE-nml-C1INH

Finding HAE-C1INH def HAE-nml-C1INH

Avg. age of Symptom onset

12 yr 27 yr

Gender M=F F > M

Attack location

abdominal ~100% 50%

facial occasional common

tongue not common common

Erythema marginatum common absent

Multiorgan attacks common uncommon

Disease-free intervals usually short may be long

Penetrance High, rare asymptomatic carrier

Low, may see asymptomatic carrier

Zuraw B et al. Allergy Asthma Proc 2012;33:S145-156.

Question 1 A 65 yo man presents with a 10 year history of a

non-pruritic urticarial rash, spiking fevers, bone pain, leukocytosis and an elevated sed rate. What laboratory abnormality is most likely?A. eosinophilic dermal infiltrateB. C1AS1 mutationC. monoclonal proteinD. thyroperoxidase antibodies

C: This presentation is classic for Schnitzler syndrome which is associated most frequently with an IgM monoclonal antibody. NOMID (mutation in C1AS1) may also have fevers and other symptoms but would present in childhood. Urticarial vasculitis may have non-pruritic urticaria and bone pain, but do not typically have spiking fevers or a long duration of disease and typically have a neutrophilic infiltrate. Thyroid peroxidase antibodies may be associated with chronic urticaria which would not have these other associated features.

Question 2

A patient presents with cold urticaria and a positive ice cube test. Which of the conditions is the most likely diagnosis ? A. Cold-induced cholinergic urticariaB. Systemic cold urticariaC. Cold-dependent dermographismD. Paroxysmal cold hemoglobinuria

D: Paroxysmal cold hemoglobinuria may be associated with a secondary form of cold urticaria due to cold-dependent immunoglobulins. The ice-cube test is positive in idiopathic and these secondary forms. The other 3 subtypes of cold urticaria have a negative ice cube test.

Question 3

What is the most sensitive diagnostic test for cholinergic urticaria?A. Autologous serum skin testB. Autologous sweat testC. Immersion in 42°C bathD. Methacholine skin test

C: Skin testing with autologous sweat is positive in patients with nonfollicular cholinergic urticaria while autologous serum skin tests are more common in the follicular subtype. Methacholine skin tests are not sensitive and also lack specificity. Immersion in warm water or exercise are the diagnostic tests of choice.

Question 4

Regarding most HUVS patients, which finding is typically true? A. Positive dsDNAB. Associated with rheumatoid arthritisC. Dermal eosinophiliaD. Positive anti-C1q autoantibody

D: Positive dsDNA is seen more often with HUV vs NUV, but the majority of patients are dsDNA negative. SLE is the most common autoimmune disease associated with HUVS. Neutrophilic infiltrates are typically seen with HUVS. Anti-C1q antibodies are detected in most all patients with HUVS.

Question 5 A patient with recurrent sinopulmonary infections

also notes lifelong cold urticaria. Several members of his family are similarly affected. What test would most likely be abnormal? A. C1AS1 mutationB. cryoglobulinsC. Evaporative cooling testD. Ice cube test

C: Patients with FCAS (C1AS1 mutation) certainly have lifelong cold urticaria and a family history, however they do not have recurrent sinopulmonary infections. Cryoglobulinemia would not have a family history, or sinopulmonary infections. This case is an example of Phospholipase Cγ2-Associated Antibody Deficiency and Immune Dysregulation (PLAID) in which case the evaporative cooling test is positive but the ice cube test is negative.

Question 6

What finding is more common in patients with HAE-nml-C1INH than HAE I ?A. Younger age of onsetB. Abdominal attacksC. Tongue swellingD. Male predominance

C: HAE-nml-C1INH typically present at an older age, is much more common in females, and have abdominal attacks at about ½ the rate as HAE I & II. Tongue swelling is more common in HAE-nml-C1INH than HAE I & II.