Urtikaria Andrews n Fitzpatrick Eng

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W. D. James, D.M. Elston, T.G. Berger. Andrews Diseases of the skin Dermatology 11 th

edition. 2011.

Urticaria is a vascular reaction o the s!in characteri"ed #$ the a%%earance o &heals

generall$ surrounded #$ a red halo or lare and associated &ith severe itching, stinging, or

%ric!ing sensations. These &heals are caused #$ locali"ed edema. 'learing o the central

region ma$ occur and lesions ma$ coalesce, %roducing an annular or %ol$c$clic %attern.

(u#cutaneous s&ellings )angioedema* ma$ accom%an$ the &heals. +ngioedema ma$ target

the gastrointestinal and res%irator$ tracts, resulting in a#dominal %ain, cor$"a, asthma, and

res%irator$ %ro#lems. es%irator$ tract involvement can %roduce air&a$ o#struction.

+na%h$la-is and h$%otension ma$ also occur.

Classification

+cute urticaria evolves over da$s to &ee!s, %roducing evanescent &heals that individuall$

rarel$ last more than 12 h, &ith com%lete resolution o the urticaria &ithin &ee!s o onset.

Dail$ e%isodes o urticaria and/or angioedema lasting more than &ee!s are designated

chronic urticaria. 'hronic urticarial %redominantl$ aects adults and is t&ice as common in

&omen as in men. onimmunologic mechanisms can %roduce mast cell degranulation.

'ommon triggers include o%iates, %ol$m$-in B, tu#ocurarine, radiocontrast d$e, as%irin,

other (+Ds, tartra"ine, and #en"oate. More than 03 o chronic urticaria is idio%athic.

4h$sical stimuli ma$ %roduce urticarial reactions and re%resent 56153 o cases o chronic

urticaria. The %h$sical urticarias include dermatogra%hic, cold, heat, cholinergic, a7uagenic,

solar, vi#rator$, and e-ercise8induced cases. 4h$sical urticaria commonl$ occurs in %atients

&ith chronic urticaria.

Etiologic factors

Drugs

Drugs are %ro#a#l$ the most re7uent cause o acute urticaria. 4enicillin and related

anti#iotics are the most re7uent oenders.+ re7uentl$ overloo!ed actor is that %enicillin

sensitivit$ ma$ #ecome so e-7uisite that reactions can occur rom %enicillin in dair$

%roducts. The incidence o as%irin8induced urticaria has allen, most li!el$ related to the

availa#ilit$ o alternative anti8inlammator$ agents. +s%irin8sensitive %ersons tend to have

cross8sensitivit$ &ith tartra"ine, the $ello& a"o8#en"one d$e, and other a"o d$es, natural

salic$lates, and #en"oic acid and its derivatives. These are common ood additives and

%reservatives. +s%irin e-acer#ates chronic urticaria in at least 903 o %atients. 4atients ma$

have allergic rhinitis or asthma, nasal %ol$%s, and oodinduced ana%h$la-is. Mite8

contaminated &heat lour has #een im%licated as an allergen. The nature o the association

#et&een as%irin intolerance and mite8induced res%irator$ allergies is un!no&n.

Food

:oods are a re7uent cause o acute urticaria, &hereas in chronic urticaria ood is a less

re7uent actor. The most allergenic oods are chocolate, shellish, nuts, %eanuts, tomatoes,

straerries, melons, %or!, cheese, garlic, onions, eggs, mil!, and s%ices. :ood allergens that


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ma$ cross8react &ith late- include chestnuts, #ananas, %assion ruit, avocado, and !i&i.

E-%osure to sael$ coo!ed ish and shellish %arasiti"ed #$ +nisa!is sim%le- can result in

angioedema and urticaria, suggesting that some seaood allergies ma$ #e related to e-%osure

to %arasite antigens. the urticaria is acute and recurrent, ood allerg$ ma$ #e suggested #$ a

ood diar$. (erum radioallergosor#ent tests )+(Ts* can #e used to detect s%eciic gE, andelimination diets can #e o #eneit in some %atients. ;ne such diet %ermits inclusion o the

ollo&ing< lam#, #ee, rice, %otatoes, carrots, string #eans, %eas, s7uash, a%%le sauce, ta%ioca,

%reserved %ears, %eaches, or cherries, $8=ris% crac!ers, #utter, sugar, tea &ithout mil! or

lemon, and coee &ithout cream. This diet is ollo&ed or 9 &ee!s. urticaria does not

occur, then sus%ected oods are added one #$ one and reactions o#served. t should #e noted

that %otatoes oten contain sulites, and that some %atients ma$ #e allergic to the oods

contained in the a#ove diet. t is #est tried onl$ ater a careul histor$. The use o ood

challenges and o scratch and intradermal tests can #e misleading. :alse8%ositive ood

challenges are common and an oending ood ma$ give a negative %ric! or intradermal test.

Moreover, ood additives and %reservatives ma$ #e res%onsi#le.

Food additives

:e&er than 103 o cases o chronic urticaria are caused #$ ood additives. atural ood

additives that ma$ #e im%licated in urticaria include $easts, salic$lates, citric acid, egg, and

ish al#umin. ($nthetic additives include a"o d$es, #en"oic acid derivatives, sulite, and

%enicillin. >east is &idel$ used in oods. When it is sus%ected o #eing the causative agent,

#read and #readstus, sausages, &ine, #eer, gra%es, cheese, vinegar, %ic!led oods, catsu%,

and $east ta#lets should #e avoided. :oods containing a"o d$es and #en"oic acid include

cand$, sot drin!s, ?ell$, marmalade, custards, %uddings, various ca!e and %anca!e mi-es,

ma$onnaise, read$8made salad dressings and sauces, %ac!aged sou%s, anchovies, and colored

tooth%astes. With the e-ce%tion o sulite and %enicillin, most ood additives can #e avoided

#$ eating onl$ meat, %roduce, and dair$ %roducts )the outer aisles o the grocer$ store*.

4ac!aged oods ound in the interior aisles are largel$ o limits.

Infections

+cute urticaria ma$ #e associated &ith u%%er res%irator$ inections, es%eciall$ stre%tococcal

inections. The incidence o stre%tococcal inection in %ediatric cases o acute urticarial varies

greatl$ in re%orted series. The %ossi#ilit$ o locali"ed inection in the tonsils, a tooth, thesinuses, gall#ladder, %rostate, #ladder, or !idne$ should #e considered as a %ossi#le cause in

cases o acute or chronic urticaria. n some %atients, treatment &ith anti#iotics or

@elico#acter %$lori has led to resolution o the urticaria. 'hronic viral inections, such as

he%atitis B and ', ma$ cause urticaria. +cute inectious mononucleosis and %sittacosis ma$

also #e triggering conditions. @elminths ma$ cause urticaria. +mong these are +scaris,

+n!$lostoma, (trong$loides, :ilaria, Echinococcus, (chistosoma, Trichinella, To-ocara, and

liver lu!e.

Emotional stress


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4ersons under severe emotional stress ma$ have more mar!ed urticaria, no matter &hat the

%rimar$ cause is. n cholinergic urticaria emotional stress is a %articularl$ &ell8documented

inciting stimulus. Urticaria secondar$ to he%atitis B.

Menthol

arel$, menthol ma$ cause urticaria. t is ound in mentholated cigarettes, cand$ and mints,

cough dro%s, aerosol s%ra$s, and to%ical medications.

Neoplasms

Urticaria has #een associated &ith carcinomas and @odg!in disease. 'old urticaria &ith

cr$oglo#ulinemia has #een re%orted as #eing associated &ith chronic l$m%hoc$tic leu!emia.

Inhalants

Grass %ollens, house dust mites, eathers, ormaldeh$de, acrolein )%roduced &hen r$ing &ithlard or #$ smo!ing cigarettes containing gl$cerin*, castor #ean or so$#ean dust, coo!ed

lentils, cottonseed, animal dander, cosmetics, aerosols, %$rethrum, and molds have #een

!no&n to cause urticaria.

Alcohol

Urticaria ma$ #e induced #$ the ingestion o alcohol. The mechanism o alcohol8induced

indirect mast cell stimulation is un!no&n. Wines generall$ contain sulites, &hich ma$

%roduce lushing or urticaria.

Hormonal imbalance

'hronic urticaria is a%%ro-imatel$ t&ice as common among &omen than men and lo& levels

o deh$droe%iandrosterone )D@E+*8( have #een noted, suggesting a %ossi#le role or

hormone im#alance.

Genetics

4ol$mor%hisms in the A2 adrenergic rece%tor ) ADRB2* gene have #een identiied in as%irin8

intolerant acute urticaria.

Pathogenesis/histopathology

'a%illar$ %ermea#ilit$ results rom the increased release o histamine rom the mast cells

situated around the ca%illaries. The mast cell is the %rimar$ eector cell in urticarial

reactions. ;ther su#stances #esides histamine ma$ cause vasodilation and ca%illar$

%ermea#ilit$, and there#$ ma$ %ossi#l$ #ecome

mediators o urticaria and angioedema. These include serotonin,

leu!otrienes, %rostaglandins, %roteases, and !inins.

The ma?or #asic %rotein o eosino%hil granules is a#normall$


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high in the #lood o more than 03 o %atients &ith chronic

urticaria, even &hen %eri%heral #lood eosino%hil counts are

normal, and there are e-tracellular de%osits o it in the s!in in

a#out the same %ro%ortion o %atients.

+#out one8third o %atients &ith chronic idio%athic urticaria

have circulating unctional histamine8releasing gG autoanti#odies

that #ind to the high8ainit$ gE rece%tor. (ome %atients

have gG that does not #ind the gE rece%tor, #ut causes mastcell

degranulation. Th$roid autoanti#odies are oten %resent

in &omen &ith chronic idio%athic urticaria, #ut clinicall$ relevant

th$roid disease is seldom %resent. Even in those &ith

th$roid disease, treatment o the th$roid disorder generall$

does not aect the course o the urticaria.

The histo%athologic changes in acute urticaria include mild

dermal edema and margination o neutro%hils &ithin %ostca%illar$

venules. Cater, neutro%hils migrate through the vessel

&all into the interstitium, and eosino%hils and l$m%hoc$tes

are also noted in the iniltrate. =ar$orrhe-is and i#rin de%osition

&ithin vessel &alls are a#sent, hel%ing to dierentiate

urticaria rom vasculitis.

+ su#set o %atients has long8lasting, reractor$ lesions and

this has #een du##ed neutro%hilic urticaria. Cesions in these

%atients oten %ersist or longer than 2 h, and #io%sies demonstrate

a neutro%hil8rich %erivascular iniltrate that lac!s

!ar$orrhe-is or i#rin de%osition &ithin vessels &alls.

Eosino%hils and mononuclear cells are noted in var$ing %ro%ortions.

4atients &ith neutro%hilic urticaria ma$ %resent &ith


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acute urticaria, chronic urticaria, or %h$sical urticaria. Cesional

s!in demonstrates increased e-%ression o T:8F and C89,

&hereas C8 e-%ression is onl$ minor. +s neutro%hils are

commonl$ %resent in urticaria in general, it is li!el$ that cases

o neutro%hilic urticaria sim%l$ re%resent urticaria &ith u%regulation

o some mast cell8derived c$to!ines.

Diagnosis

Diagnosis o urticaria and angioedema is usuall$ made on

clinical grounds. Cesions in a i-ed location or more than 2 h

suggest the %ossi#ilit$ o urticarial vasculitis, the urticarial

%hase o an immuno#ullous eru%tion, EM, granuloma annulare,

sarcoidosis, or cutaneous T8cell l$m%homa. individual

&heals last or longer than 2 h, a s!in #io%s$ should #e

%erormed.

Clinical evaluation

Ca#orator$ evaluation should #e driven #$ associated signs

and s$m%toms. andom tests in the a#sence o a suggestive

histor$ or %h$sical indings are rarel$ cost8eective. + %ractical

evaluation is limited to a detailed histor$ )oods, drugs,

including as%irin, %h$sical causes* and %h$sical e-amination.

+ngioedema in the a#sence o urticaria ma$ #e related to

hereditar$ angioedema or an angiotensin8converting en"$me

)+'E* inhi#itor. '1 esterase deicienc$ does not cause hives,

onl$ angioedema. there is a histor$ o sinus diiculties,

%articularl$ i there is %al%a#le tenderness over the ma-illar$

or ethmoid sinuses, radiologic sinus evaluation is recommended.

n areas &here %arasitic disease is common, a #lood


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count to detect eosino%hilia is an ine-%ensive screening test

&ith a air $ield. The #lood count ma$ #e unrelia#le i the

%atient has #een on a s$stemic corticosteroid.

n %atients &ith chronic urticaria, a revie& o medications,

including over8the8counter %roducts, su%%lements, as%irin, and other (+Ds, should #e

o#tained. the histor$ suggests a %h$sical urticaria, then the a%%ro%riate challenge test

should

#e used to conirm the diagnosis. Cesions that #urn rather than

itch, resolve &ith %ur%ura, or last longer than 2 h should

%rom%t a #io%s$ to e-clude urticarial vasculitis.

+ directed histor$ and %h$sical e-amination should elicit

signs or s$m%toms o th$roid disease, connective tissue

disease, changes in #o&el or #ladder ha#its, vaginal or urethral

discharge, other locali"ed inection, ?aundice, or ris!

actors or he%atitis or C$me disease. 4ositive indings should

%rom%t a%%ro%riate screening tests. +lthough sinus -8ra$

ilms, a 4anore- dental ilm, a stre%tococcal throat culture,

a#dominal ultrasonogra%h$, and urinal$sis &ith urine culture

)in men, &ith %rostatic massage* ma$ reveal the most common

occult inections triggering urticaria, %ositive cases are almost

al&a$s associated &ith some signs or s$m%toms suggestive o

the diagnosis. n %atients &ith chronic angioedema, &ithout

classic &heals or s$m%toms o %ruritus, a careul drug histor$

and evaluation o ' level should #e ordered. ' is lo&, an

evaluation o '1 esterase inhi#itor is a%%ro%riate.

Anaphylaxis

+na%h$la-is is an acute and oten lie8threatening immunologic

reaction, re7uentl$ heralded #$ scal% %ruritus, diuse


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er$thema, urticaria, or angioedema. Bronchos%asm, lar$ngeal

edema, h$%er%eristalsis, h$%otension, and cardiac arrh$thmia

ma$ occur. +nti#iotics, es%eciall$ %enicillins, other drugs, and

radiogra%hic contrast agents are the most common causes o

serious ana%h$lactic reactions. @$meno%tera stings are the

ne-t most re7uent cause, ollo&ed #$ ingestion o crustaceans

and other ood allergens. +to%ic dermatitis is commonl$ associated

&ith ana%h$la-is regardless o origin. 'ausative agents

can #e identiied in u% to t&o8thirds o cases and recurrent

attac!s are the rule. E-ercise8induced ana%h$la-is is oten

de%endent on %riming #$ %rior ingestion o a s%eciic ood, or

ood in general, and as%irin ma$ #e an additional e-acer#ating

actor.

Treatment

Acute urticaria

The mainsta$ o treatment o acute urticaria is administration

o antihistamines. n adults, nonsedating antihistamines %ose

a lo&er ris! o %s$chomotor im%airment. the cause o the

acute e%isode can #e identiied, avoiding that trigger should

#e stressed. n %atients &ith acute urticaria that does not

res%ond to antihistamines, s$stemic corticosteroids are generall$

eective. Cess re#ound is seen &ith a 98&ee! ta%ered

course o s$stemic corticosteroid thera%$ as com%ared &ith

shorter courses.

:or severe reactions, including ana%h$la-is, res%irator$ and

cardiovascular su%%ort is essential. + 0.9 mC dose o a 1 < 1000

dilution o e%ine%hrine is administered ever$ 10620 min as


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needed. n $oung children, a hal8strength dilution is used. n

ra%idl$ %rogressive cases, intu#ation or tracheotom$ ma$ #e

re7uired. +d?unctive thera%$ includes intramuscular antihistamines

)260 mg h$dro-$"ine or di%henh$dramine ever$

h as needed* and s$stemic corticosteroids )20 mg h$drocortisone

or 0 mg meth$l%rednisolone intravenousl$ ever$ h

or 26 doses*.

Chronic urticaria

The mainsta$ o treatment or chronic urticaria is, again,

administration o antihistamines. These should #e ta!en on a

dail$ #asisH the$ should not #e %rescri#ed to #e ta!en onl$ as

needed. The %atient should #e &arned a#out driving an automo#ile

&hen irst8generation antihistamines are used.

(econd8generation @1 antihistamines )cetiri"ine, levocetiri"ine,

amotidine, loratadine, acrivastine, and a"elastine* are

large, li%o%hilic molecules &ith charged side chains that #ind

e-tensivel$ to %roteins, %reventing the drugs rom crossing the

#lood6#rain #arrierH thus the$ %roduce less sedation in most

%atients. Cong8acting orms are availa#le, and the long hal8lie

o these antihistamines and reduced sedation result in

im%roved com%liance and eicac$. 'etiri"ine )I$rtec* and

some o the other second8generation antihistamines can cause

dro&siness in some individuals, %articularl$ in higher doses

or &hen com#ined &ith other antihistamines. Do-e%in, a tric$clic

antide%ressant &ith %otent @1 antihistaminic activit$,

ma$ #e useul and can #e added to the e-isting antihistamine.

Do-e%in is re7uentl$ dosed at #edtime, so much o the dro&siness


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and dr$ mouth are gone #$ morning. n stu##orn cases,

dosages o antihistamines that e-ceed drug la#eling are sometimes

re7uired. Even second8generation antihistamines ma$

#ecome sedating at higher doses. :e-oenadine is generall$

&ell tolerated, even at doses that e-ceed %roduct la#eling. The

authors have ound escalating doses o antihistamines to #e

hel%ul in management, #ut in one %u#lished stud$ o 22 adult

%atients &ith reractor$ urticaria, tri%ling the dose o cetiri"ine

resulted in ade7uate control in onl$ one %atient. The others

re7uired alternate s$stemic agents such as c$clos%orine. The

com#ination o @1 and @2 antihistamines, such as h$dro-$"ine

and cimetidine or ranitidine, ma$ #e eective in some cases.

'imetidine or ranitidine should not #e used alone or treatment

o urticaria, as the$ ma$ interere &ith eed#ac! inhi#ition

o histamine release. ;ther second8line treatments include

%hotothera%$, calcium channel antagonists )niedi%ine*, antimalarial

medications, leu!otriene and 8li%o-$genase inhi#itors,

gold, a"athio%rine, lo&8dose c$clos%orine, ter#utaline,

omali"uma#, and methotre-ate. Da%sone and colchicines ma$

#e hel%ul in neutro%hil8rich urticaria. Unortunatel$, although

s$stemic corticosteroids are eective in su%%ressing most

cases o chronic urticaria, their long8term side eects ma!e

their e-tended use im%ractical. +s soon as the corticosteroid

is sto%%ed, hives recurs. n addition, i an inection is the

trigger, this could #e e-acer#ated #$ long8term steroid thera%$.

To%ical corticosteroids, to%ical antihistamines, and to%ical

anesthetics have no role in the management o chronic urticaria.


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:or local treatment, te%id or cold tu# #aths or sho&ers

ma$ #e reel$ advocated. To%ical cam%hor and menthol can

%rovide s$m%tomatic relie. (arna lotion contains menthol,

%henol, and cam%hor.

n a#out one8third o cases o chronic idio%athic urticaria,

%atients have autoanti#odies that #ind to high8ainit$ gE

rece%tors. (uch %atients ma$ re7uire more aggressive management

to include chronic immunosu%%ressive thera%$, %lasma%heresis,

or intravenous immunoglo#ulin )G*.

Other urticarial variants

Angioedema

+ngioedema is an acute, evanescent, circumscri#ed edema

that usuall$ aects the most distensi#le tissues, such as the

e$elids, li%s ):ig. 581*, lo#es o the ears, and e-ternal genitalia,

or the mucous mem#ranes o the mouth, tongue, or lar$n-.

The s&elling occurs in the dee%er %arts o the s!in or in the

su#cutaneous tissues and as a rule is onl$ slightl$ tender, &ith

the overl$ing s!in unaltered, edematous, or, rarel$, ecch$motic.

There ma$ #e a diuse s&elling on the hands, orearms,

eet, and an!les. :re7uentl$, the condition #egins during the

night and is ound on a&a!ening.

There are t&o distinct su#sets o angioedema. The irst is

considered a dee% orm o urticaria and ma$ #e o#served

as solitar$ or multi%le sites o angioedema alone or in com#ination &ith urticaria. The action

o histamine or similar

su#stances creates vasomotor la#ilit$, and %ruritus ma$ #e a

signiicant eature. The second, angioedema associated &ith


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'1 esterase inhi#itor deicienc$, is not associated &ith hives

and there is no %ruritus. ($m%toms o %ain %redominate.

+ngioedema ma$ #e related to +'E inhi#itors.

Hereditary angioedema

+lso !no&n as Kuinc!e edema, hereditar$ angioedema )@+E*

&as originall$ descri#ed and named #$ ;sler in 1. @+E

characteristicall$ a%%ears in the second to ourth decade.

(udden attac!s o angioedema occur as re7uentl$ as ever$

2 &ee!s throughout the %atientLs lie, lasting or 26 da$s.

(&elling is t$%icall$ as$mmetrical, and urticaria or itching

does not occur. The %resentation ma$ overla% &ith that o the

autoinlammator$ s$ndromes.

4atients ma$ e-%erience local s&elling in su#cutaneous

tissues )ace, hands, arms, legs, genitals, and #uttoc!s*H a#dominal

organs )stomach, intestines, #ladder*, mimic!ing surgical

emergenciesH and the u%%er air&a$ )lar$n-*, &hich can #e liethreatening.

There is little res%onse to antihistamines, e%ine%hrine,

or steroids. The mortalit$ rate is high, &ith death

oten caused #$ lar$ngeal edema. Gastrointestinal edema is

maniested #$ nausea, vomiting, and severe colic, and it

ma$ simulate a%%endicitis so closel$ that a%%endectom$ is

mista!enl$ %erormed. The actors that trigger attac!s are

minor trauma, surger$, sudden changes o tem%erature, or

sudden emotional stress.

nherited in an autosomal8dominant ashion, @+E is estimated

to occur in 1 in 0 000610 000 %ersons. There are three

%henot$%ic orms o the disease. T$%e is characteri"ed #$ lo&


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antigenic and unctional %lasma levels o a normal '1 esterase

inhi#itor %rotein )'18E*. T$%e is characteri"ed #$ the %resence

o normal or elevated antigenic levels o a d$sunctional

%rotein. T$%e demonstrates normal '18E unction and

normal com%lement. t has #een descri#ed onl$ in emale

mem#ers o aected amilies. 'riteria or t$%e include a

long histor$ o recurrent attac!s o s!in s&elling, a#dominal

%ain, or u%%er air&a$ o#structionH a#sence o urticariaH amilial

occurrenceH normal '18E and ' concentrationsH and

ailure o treatment &ith antihistamines, corticosteroids, and

'18E concentrate.

The screening test o choice or t$%es and is a ' level.

' &ill #e lo& )03 o normal* as a result o continuous

Fig. 7!" +ngioedema o the li%s.

activation and consum%tion. n addition to de%ressed '

levels, %atients &ith t$%es and also have lo& '1, '17, and

'2 levels. the clinical %icture and screening tests are %ositive,

a titer o '18E should #e ordered. '18E is a la#ile %rotein and

sam%le deca$ is common. + lo& '18E in the %resence o

normal ' levels should raise the sus%icion o sam%le deca$,

rather than true @+E.

The treatment o choice or acute @+E t$%es and is

re%lacement thera%$ &ith concentrates or resh ro"en

%lasma. (hort8term %ro%h$la-is )e.g. or %atients undergoing

dental care, endosco%$, or intu#ation or surger$* can

#e o#tained rom stano"olol, an attenuated androgen.

Estrogens in oral contrace%tives, in contrast, ma$ %reci%itate


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attac!s. +ntii#rinol$tic trane-amic acid, a drug related to

e8aminoca%roic acid, has #een used to treat acute and chronic

disease. T$%e does not res%ond to '18E re%lacement,

#ut ma$ res%ond to dana"ol.

Acquired C esterase inhibitor deficiency

(ome %atients %resent &ith s$m%toms indistinguisha#le rom

@+E, #ut &ith onset ater the ourth decade o lie and lac!ing

a amil$ histor$. +s in @+E, there is no associated %ruritus

or urticaria. This condition is su#divided into ac7uired

angioedema8 and , and an idio%athic orm. +c7uired

angioedema8 is a rare disorder associated &ith l$m%ho%rolierative

diseases. These associations include l$m%homas

)usuall$ B8cell*, chronic l$m%hoc$tic leu!emia, monoclonal

gammo%ath$, m$eloma, m$eloi#rosis, WaldenstrNm macroglo#ulinemia,

and #reast carcinoma. (ome %atients have

detecta#le autoanti#odies to '18E. Worsening o sta#le hereditar$

angioedema has #een the %resenting sign o l$m%homa.

+c7uired angioedema8 is an e-tremel$ rare disease deined

#$ the %resence o autoanti#odies to '18E. t is im%ortant to

reali"e that autoanti#odies directed against '18E ma$ also #e

ound in ac7uired angioedema8, %articularl$ in %atients &ith

B8cell l$m%homas, so the diagnosis o ac7uired angioedema8

is made onl$ &hen no such underl$ing condition e-ists.

The %atho%h$siolog$ o ac7uired angioedema8 is un!no&n

#ut ma$ #e related to increased cata#olism o '18E, since

man$ %atients &ith the disorder have #een sho&n to %roduce

normal amounts o '18E. n ac7uired angioedema8, he%atoc$tes


14/74

and monoc$tes are a#le to s$nthesi"e normal '18EH

ho&ever, a su#%o%ulation o B cells secretes autoanti#odies to

the unctional region o the '18E molecule.

Management o acute attac!s in ac7uired angioedema8 is

directed to&ard re%lacement o '18E &ith resh ro"en

%lasma, %lasma8derived '1 inhi#itor, or recom#inant human

'1 inhi#itor. (ome %atients develo% %rogressive resistance to

the inusions. +ntii#rinol$tic agents, such as aminoca%roic

acid or trane-amic acid, ma$ #e #eneicial, and are more eective

than antiandrogen thera%$. ($nthetic androgens, such as

dana"ol, ma$ #e hel%ul in angioedema8H ho&ever, androgens

are ineective in treating %atients &ith ac7uired angioedema8

, stressing the im%ortance o identi$ing these %atients.

mmunosu%%ressive thera%$ has #een sho&n to #e eective

in the treatment o ac7uired angioedema8 #$ decreasing

autoanti#od$ %roduction. ($stemic corticosteroids ma$ #e

tem%oraril$ eective. 4lasma%heresis, the B2 #rad$!inin

rece%tor antagonist @;E810, and the !alli!rein inhi#itor

DO8 are %romising thera%ies or %atients reractor$ to other

treatments.

Episodic angioedema !ith eosinophilia

E%isodic angioedema or isolated acial edema ma$ occur &ith

ever, &eight gain, eosino%hilia, and elevated eosino%hil ma?or

#asic %rotein. The disorder is not uncommon, and there is no

underl$ing disease. ncreased levels o C8 have #een documented

during %eriods o attac!. Treatment o%tions include administration o s$stemic steroidal

medications, antihistamines,


15/74

and G.

"chnit#ler syndrome

The rare disorder, (chnit"ler s$ndrome, is a com#ination o

chronic, non8%ruritic urticaria, ever o un!no&n origin, disa#ling

#one %ain, h$%erostosis, increased er$throc$te sedimentation

rate, and monoclonal gM gammo%ath$. 4ruritus is

not generall$ a eature. The age o onset ranges rom 2P to 55

$ears, &ithout gender %redilection. n some cases the gM

gammo%ath$ %rogresses to neo%lasia, es%eciall$ WaldenstrNm

macroglo#ulinemia. Eective thera%$ has not #een determined,

although the #one %ain and urticarial lesions res%ond

to s$stemic corticosteroids in some %atients. ;thers have

res%onded to ana!inra.

$hysical urticarias

(%eciic %h$sical stimuli are the cause o a%%ro-imatel$ 203

o all urticarias. The$ occur most re7uentl$ in %ersons #et&een

the ages o 15 and 0. The most common orm is dermatogra%hism

ollo&ed #$ cholinergic and cold urticaria. (everal

orms o %h$sical urticaria ma$ occur in the same %atient.

4h$sical urticarias, %articularl$ dermatogra%hism, dela$ed

%ressure, cholinergic, and cold urticaria, are re7uentl$ ound

in %atients &ith chronic idio%athic urticaria.

Dermatogra%hism

Dermatogra%hism is a shar%l$ locali"ed edema or &heal &ith

a surrounding er$thematous lare occurring &ithin seconds to

minutes ater the s!in has #een stro!ed ):ig. 5815*. t aects

263 o the %o%ulation. Dermatogra%hism ma$ arise s%ontaneousl$


16/74

ater drug8induced urticaria and %ersist or months.

t has also #een re%orted to #e associated &ith the use o the

@2 #loc!er, amotidine. t ma$ occur in h$%oth$roidism and

h$%erth$roidism, inectious diseases, dia#etes mellitus, and

during onset o meno%ause. t ma$ #e a cause o locali"ed or

generali"ed %ruritus. +ntihistamines su%%ress this reaction.

The addition o an @2 antihistamine ma$ #e o #eneit.

'holinergic urticaria

'holinergic urticaria, %roduced #$ the action o acet$lcholine

on the mast cell, is characteri"ed #$ minute, highl$ %ruritic,

%unctate &heals or %a%ules 169 mm in diameter and surrounded

#$ a distinct er$thematous lare ):ig. 581*. These

lesions occur %rimaril$ on the trun! and ace. The condition

s%ares the %alms and soles. Cesions %ersist or 906P0 min and

are ollo&ed #$ a reractor$ %eriod o u% to 2 h. Bronchos%asm

ma$ occur. :amilial cases have #een re%orted.

Fig. 7!7 Dermatogra%hism.

Fig. 7!# 'holinergic urticaria, small %a%ules &ith surrounding large

er$thematous lare.

The lesions ma$ #e induced in the susce%ti#le %atient #$

e-ercise, emotional stress, increased environmental tem%erature,

or intradermal in?ection o nicotine %icrate or methacholine.

(ometimes an attac! ma$ #e a#orted #$ ra%id cooling

o the #od$, as #$ ta!ing a cold sho&er. + reractor$ %eriod

&ith no lesions occurs or a%%ro-imatel$ 2 h ater an attac!.

'holinergic dermatogra%hism is noted in some %atients.

Treatment &ith antihistamines is oten eective i dosage is


17/74

ade7uate. +ntihistamines have #een com#ined &ith other

agents, such as montelu!ast and %ro%ranolol. +ttenuated

androgens, such as dana"ol, ma$ #e o #eneit in reractor$

cases. 4rovocative tests include e-ercise, a &arm #ath to raise

core tem%erature #$ 0.561.0Q' )1.261.Q:*, or a methacholine

s!in test.

+drenergic urticaria

+drenergic urticaria ma$ occur #$ itsel or coe-ist &ith cholinergic

urticaria. Bouts o urticaria are mediated #$ nore%ine%hrine.

The eru%tion consists o small )16 mm* red macules

and %a%ules &ith a %ale halo, a%%earing &ithin 1061 min o

emotional u%set, coee, or chocolate. (erum catecholamines,

nore%ine%hrine, do%amine, and e%ine%hrine ma$ rise mar!edl$

during attac!s, &hereas histamine and serotonin levels

remain normal. 4ro%ranolol, in a dosage o 10 mg our times

a da$, is eectiveH atenolol has #een ineective. + %rovocative

test consists o intradermal administration o 9610 ng o

nore%ine%hrine.

'old urticaria

E-%osure to cold ma$ result in edema and &healing on the

e-%osed areas, usuall$ the ace and hands. The urticaria does

not develo% during chilling, #ut on re&arming. This heterogenous

grou% o disorders is classiied into %rimar$ )essential*,

secondar$, and amilial cold urticaria.

4rimar$ )essential* cold urticaria is not associated &ith

underl$ing s$stemic diseases or cold reactive %roteins.

($m%toms are usuall$ locali"ed to the areas o cold e-%osure,


18/74

although res%irator$ and cardiovascular com%romise ma$

develo%. :atal shoc! ma$ occur &hen these %ersons go s&imming

in cold &ater or ta!e cold sho&ers. This t$%e o cold

urticaria usuall$ #egins in adulthood. t is usuall$ ice cu#e

test8%ositive.

The treatment o %rimar$ cold urticaria is &ith do-e%in, in

doses rom 2 mg at #edtime to 0 mg t&ice a da$, or c$%rohe%tadine,

mg three times a da$. Good thera%eutic res%onses

to the second8generation antihistamines acrivastine and cetiri"ine

have #een re%orted, and these agents are less li!el$ to

result in sedation. 'etiri"ine and "airlu!ast in com#ination are more eective than either

drug given alone. =etotien ma$

also #e eective, #ut is not mar!eted in the U(. 'orticosteroid

medications are ineective.

Desensiti"ation #$ re%eated, increased e-%osures to cold has

#een eective in some cases. n one re%ort, successul desensiti"ation

&as induced in an 18$ear8old %atient &ith severe

cold urticaria. Tolerance in a small area o the s!in &as

achieved #$ re%eated a%%lications o an ice cu#e at 908min

intervals or 5 h, ollo&ed #$ orearm immersion in cold &ater

hourl$ or h. The other lim#s &ere then treated one at a time,

and inall$ the trun!. +ter a &ee!, the %atient &as a#le to

tolerate &hole8#od$ immersion in cold &ater or min &ithout

urticaria. @e maintained this desensiti"ation &ith a 8min

cold sho&er ever$ 12 h. @e &as ree rom urticaria or

months, continuing his dail$ cold sho&ers. This sort o regimen

is onl$ suita#le in rare cases. n man$ %atients cold urticaria


19/74

&ill resolve ater months, although a#out 03 o %atients have

s$m%tomatic disease or $ears.

+s a %rovocative test, a %lastic8&ra%%ed ice cu#e is a%%lied

to the s!in or 620 min. no &heal develo%s, the area should

#e anned or an additional 10 min. The use o a com#ination

o cold and moving air is, in some cases, more eective in

re%roducing lesions than cold alone. The %rovocative test is not

%erormed i secondar$ cold urticaria is #eing considered.

(econdar$ cold urticaria is associated &ith an underl$ing

s$stemic disease, such as cr$oglo#ulinemia. ;ther associations

include cr$oi#rinogenemia, multi%le m$eloma, secondar$

s$%hilis, he%atitis, and inectious mononucleosis. 4atients ma$

have headache, h$%otension, lar$ngeal edema, and s$nco%e.

+n ice cu#e test is not recommended, since it can %reci%itate

vascular occlusion and tissue ischemia.

:amilial cold urticaria is grou%ed &ith the other autoinlammator$

s$ndromes. The lesions %roduce a #urning sensation

rather than itching. The$ ma$ have c$anotic centers and surrounding

&hite halos, and last or 26 h. The$ ma$ #e

accom%anied #$ ever, chills, headache, arthralgia, m$algia,

and a#dominal %ain. + %rominent eature is leu!oc$tosis,

&hich is the irst o#serva#le res%onse to cold. :amilial cold

urticaria &ill $ield a negative result to an ice cu#e test.

(tano"olol thera%$ has #een sho&n to #e eective in treating

9 o %atients.

Heat urticaria


20/74

Within min o the s!in #eing e-%osed to heat a#ove 9Q' , the e-%osed area #egins to #urn

and sting, and #ecomes red, s&ollen, and indurated. This rare t$%e o urticarial ma$ also #e

generali"ed and is accom%anied #$ cram%s, &ea!ness, lushing, salivation, and colla%se. @eat

desensiti"ation ma$ #e eective. +s a %rovocative test, a%%l$ a heated c$linder, 06Q'

)1226191Q:*, to a small area o s!in on the u%%er #od$ or 90 min.

"olar urticaria

(olar urticaria a%%ears soon ater unshielded s!in is e-%osed to sunlight. t is classiied #$ the

&avelengths o light that %reci%itate the reaction. isi#le light can trigger solar urticaria, and

sunscreens ma$ not %revent it. +ngioedema ma$ occasionall$ occur. (olar urticaria ma$ #e a

maniestation o %or%h$ria, leu!oc$toclastic vasculitis, and the 'hurg6(trauss s$ndrome.

Treatment is sun avoidance, sunscreens, antihistamines, re%etitive %hotothera%$, and 4U+.

$ressure urticaria %delayed pressure urticaria&

4ressure urticaria is characteri"ed #$ the develo%ment o s&elling &ith %ain that occurs 9612

h ater local %ressure has #een a%%lied. t occurs most re7uentl$ on the eet ater &al!ing and

on the #uttoc!s ater sitting. t is uni7ue in that there ma$ #e a latent %eriod o as much as 2

h #eore lesions develo%. +rthralgias, ever, chills, and leu!oc$tosis can occur. The %ain and

s&elling last or 62 h. 4ressure urticaria ma$ #e seen in com#ination &ith other %h$sical

urticarias. +s a %rovocative test, a 1 l# &eight is a%%lied to the s!in or 20 min and the area

ins%ected ater 6 h. The com#ination o montelu!ast and an antihistamine has #een used

eectivel$. ($stemic corticosteroids are oten thera%eutic, #ut are generall$ unsuita#le or

long8term use. Trane-amic acid, high8dose G, or an anti8T: #iologic ma$ #e eective in

cases reractor$ to other treatment, and the disease has remitted ater eradication o

Blastocystis hominis.

E'ercise(induced urticaria

+lthough #oth cholinergic urticaria and e-ercise urticaria are %reci%itated #$ e-ercise, the$

are distinct entities. aising the #od$ tem%erature %assivel$ &ill not induce e-ercise urticaria,

and the lesions o e-ercise urticaria are larger than the tin$ &heals o cholinergic urticaria.

Urticarial lesions a%%ear 690 min ater the start o e-ercise. +na%h$la-is ma$ #e associated.

+to%$ is common in these %atients and some have documented ood allerg$. +voiding these

allergens ma$ im%rove s$m%toms. Thera%$ &ith @1 and @2 antihistamines ma$ #e %artiall$

eective. (el8in?ecta#le e%ine%hrine !its are recommended or those rare %atients &ith

e%isodes o ana%h$la-is maniesting &ith res%irator$ s$m%toms. E-ercise is a %rovocative

test, #ut ma$ re7uire %riming &ith the identiied ood allergens.

)ibratory angioedema

i#rator$ angioedema, a orm o %h$sical urticaria, ma$ #e an inherited autosomal8dominant

trait, or ma$ #e ac7uired ater %rolonged occu%ational vi#ration e-%osure. Dermatogra%hism,

%ressure urticaria, and cholinergic urticaria ma$ occur in aected %atients. 4lasma histamine

levels are elevated during attac!s. The a%%earance o the angioedema is usuall$ not dela$ed.


21/74

The treatment is antihistamines. +s a %rovocative test, la#orator$ vorte- vi#ration is a%%lied

to the orearm or min.

Aquagenic urticaria

This rare condition is elicited #$ &ater or sea&ater at an$ tem%erature. 4ruritic &healsdevelo% immediatel$ or &ithin minutes at the sites o contact o the s!in &ith &ater,

irres%ective o tem%erature or source, and clear &ithin 9060 min. (&eat, saliva, and even

tears can %reci%itate a reaction. +7uagenic urticaria ma$ #e amilial in some cases, or

associated &ith ato%$ or cholinergic urticaria. ($stemic s$m%toms have #een re%orted to

include &hee"ing, d$s%hagia, and res%irator$ distress. The %athogenesis is un!no&n #ut ma$

#e associated &ith &ater8solu#le antigens that diuse into the dermis and cause histamine

release rom sensiti"ed mast cells. Whealing ma$ #e %revented #$ %retreatment o the s!in

&ith %etrolatum. Man$ antihistamines have #een eective. 4U+ a%%ears to %revent s!in

lesions #ut ma$ not %revent the s$m%toms o %ruritus. The %rovocative test is to a%%l$ &ater

com%resses 9Q' to the s!in o the u%%er #od$ or 90 min.

Galvanic urticaria

Galvanic urticaria has #een descri#ed ater e-%osure to a galvanic device used to treat

h$%erhidrosis. The relationshi% o this condition to other orms o %h$sical urticaria remains

to #e esta#lished.

Chapter $# %% &rticaria an' Angioe'ema

%% +llen 4. =a%lan

UT'++ +D +G;EDEM+

+T + GC+'E

;ccurs acutel$ at some time in 203 o the %o%ulationH incidence o chronic urticaria/

angioedema is a%%ro-imatel$ 0.3. +cute urticaria/angioedema is caused #$ drugs, oods,

occasionall$ inection in

association &ith immunoglo#ulin E8de%endent

mechanisms )allerg$*, or meta#olic actors.

'hronic urticaria/angioedema is an

autoimmune disorder in 3 o %atients.

n the a#sence o urticaria, angioedema

can #e due to over%roduction or im%aired

#rea!do&n o #rad$!inin.


22/74

Treatment o acute urticaria/angioedema

relies on antihistamines and short courses o

corticosteroids, and identiication and elimination

o endogenous and e-ogenous causes.

Treatment o '1 inhi#itor deicienc$ includes

androgenic agents, antii#rinol$tic agents, and

'1 inhi#itor )'1 @* concentrates, a !alli!rein

inhi#itor, and #rad$!inin rece%tor antagonist.

Treatment o %h$sical urticaria/angioedema

includes high8dose antihistamine %ro%h$la-is,

e-ce%t or dela$ed %ressure urticaria.

Treatment o chronic idio%athic or

autoimmune urticaria/angioedema includes

antihistamines )nonsedating %re%arations

%rimaril$*, lo&8dose dail$ or alternate da$

corticosteroids, or c$clos%orine.

Urticaria is deined as a s!in lesion consisting o a

&heal8and8lare reaction in &hich locali"ed intracutaneous

edema )&heal* is surrounded #$ an area o redness

)er$thema* that is t$%icall$ %ruritic. ndividual

hives can last as #riel$ as 90 minutes to as long as

9 hours. The$ can #e as small as a millimeter or 6

inches in diameter )giant urticaria*. The$ #lanch &ith

%ressure as the dilated #lood vessels are com%ressed,

&hich also accounts or the central %allor o the &heal.

The dilated #lood vessels and increased %ermea#ilit$

that characteri"e urticaria are %resent in the su%ericial


23/74

dermis and involves the venular %le-us in that location.

+ngioedema can #e caused #$ the same %athogenic

mechanisms as urticaria #ut the %atholog$ is in

the dee% dermis and su#cutaneous tissue and s&elling

is the ma?or maniestation. The overl$ing s!in ma$ #e

er$thematous or normal. There is less %ruritus )e&er

t$%e ' nerve endings at the dee%er cutaneous levels*

#ut there ma$ #e %ain or #urning.

E4DEM;C;G>

Urticaria and angioedema are common. +ge, race, se-,

occu%ation, geogra%hic location, and season o the $ear

ma$ #e im%licated in urticaria and angioedema onl$

insoar as the$ ma$ contri#ute to e-%osure to an eliciting

agent. ; a grou% o college students, 136203

re%orted having e-%erienced urticaria, &hile 13693

o the %atients reerred to hos%ital dermatolog$ clinics

in the United =ingdom noted urticaria and angioedema.

n the ational +m#ulator$ Medical 'are

(urve$ data rom 1PP0 to 1PP5 in the United (tates,

&omen accounted or P3 o %atient visits. There &as

a #imodal age distri#ution in %atients aged #irth to P

$ears and 9060 $ears.1

Urticaria/angioedema is considered to #e acute i it

lasts less than &ee!s. Most acute e%isodes are due to

adverse reactions to medications or oods and in children,

to viral illnesses. E%isodes o urticaria/angioedema

%ersisting #e$ond &ee!s are considered


24/74

chronic and are divided into t&o ma?or su#grou%s< )1*

chronic autoimmune urticaria )3* and )2* chronic

idio%athic urticaria )3* &ith a com#ined incidence

in the general %o%ulation o 0.3.2 4h$sicall$

induced urticaria/angioedema is not included in the

deinition. arious t$%es o %h$sical urticaria/angioedema

ma$ last or $ears, #ut the individual lesions

last e&er than 2 hours )e-ce%t dela$ed %ressure urticaria*

and are intermittent. Whereas 3 o children

e-%erience urticaria in the a#sence o angioedema,

03 o adult %atients &ith urticaria also e-%erience

angioedema.

+%%ro-imatel$ 03 o %atients &ith chronic urticaria

)&ith or &ithout angioedema* are ree o lesions

&ithin 1 $ear, 3 &ithin 9 $ears, and 3 &ithin

$earsH e&er than 3 have lesions that last or more

than 10 $ears. +ngioedema alters the natural histor$,

and onl$ 23 o %atients e-%erience resolution o

lesions &ithin 1 $ear. There are no data regarding the

remission rate in %atients &ith onl$ angioedema. The

hereditar$ grou% is considered to #e lie long once

the diagnosis #ecomes clinicall$ maniest.

4+T@;GEE((

M+(T 'ECC +D @(T+ME ECE+(E

The mast cell is the ma?or eector cell in most orms

o urticaria and angioedema, although other cell t$%es

undou#tedl$ contri#ute. 'utaneous mast cells adhere


25/74

sure urticaria is a variant o a late8%hase reaction &hile

mast cell degranulation in most other %h$sical urticarias

has no associated late %hase. These include t$%ical

ac7uired cold urticaria, cholinergic urticaria, dermatogra%hism,

and t$%e solar urticaria.

+UT;MMUT> +D '@;'

UT'++

The irst suggestion that %atients &ith chronic

urticaria and angioedema might have an autoimmune

diathesis &as the o#servation that there is an

increased incidence o antith$roid anti#odies in such

%atients relative to the incidence in the %o%ulation at

large.P These include antimicrosomal )%erio-idase*

and antith$roglo#ulin anti#odies, as seen in %atients

&ith @ashimotoLs th$roiditis.10 4atients ma$ have

clinical h$%oth$roidism, #ut a small num#er might #e

h$%erth$roid i inlammation is at an earl$ stage &hen

th$roid hormone is released into the circulation. This

at$%ical %resentation should #e distinguished rom

the occasional %atient &ith GraveLs disease. evertheless,

most %atients are euth$roid. The incidence o

antith$roid anti#odies in chronic urticaria, as re%orted

in the literature, varies #et&een 13 and 23,11,12 #ut

the most recent data are closer to the latter igure12

and demonstrate segregation o antith$roid anti#odies

&ith chronic autoimmune urticaria rather than

chronic idio%athic urticaria. @o&ever, the association


26/74

is not a#solute. The incidence in the autoimmune

su#grou% &as 253, in the chronic idio%athic urticaria

su#grou% 113, &hile in the %o%ulation at large it is

5363. Gru#er et al )1P*19 considered the %ossi#ilit$

that %atients might have circulating and anti8gE anti#odies

that are unctional and did indeed ind these

in a#out 36103 o %atients. Gratten et al1,1 sought

anti#odies reactive &ith s!in mast cells #$ %erorming

an autologous s!in test and ound a 903 incidence

o %ositive reactions in %atients &ith chronic urticaria.

There &ere onl$ rare %ositive reactions in health$

control su#?ects or %atients &ith other orms o urticaria.

(u#se7uentl$, this level o %ositivit$ &as sho&n

#$ @ide et al1 to #e due to an gG anti#od$ reactive

&ith the F su#unit o the gE rece%torH in addition a

36103 incidence o unctional anti8gE anti#odies

&as conirmed )e:ig. 981.1 in online edition*.15

'ECCUC+ :CT+TE

Mast cell degranulation certainl$ initiates the inlammator$

%rocess in autoimmune chronic urticaria and

is assumed to also do so in idio%athic chronic urticaria.

Evidence or an increased num#er o mast cells

in chronic urticaria has #een %resented,9,95 #ut there

are also %u#lications indicating no signiicant dierences

rom normalH9 these studies did not discriminate

the autoimmune rom the idio%athic grou%s. @o&ever,

no alternative mechanisms or mast cell degranulation


27/74

in the idio%athic grou%s have #een suggested to date.

>et the histolog$ o the t&o grou%s diers onl$ in minor

&a$s. 'ommon to all #io%s$ s%ecimens is a %erivascular

to i#ronectin and laminin through the ver$ late activation

)C+* A1 integrins C+89, C+8, and C+8 and

to vitronectin through the FvA9 integrin. 'utaneous mast

cells, #ut not those rom other sites, release histamine

in res%onse to com%ound /0, 'a, mor%hine, and

codeine. The neuro%e%tides su#stance 4 )(4*, vasoactive

intestinal %e%tide )4*, and somatostatin, )#ut

not neurotensin, neuro!inins + and B, #rad$!inin, or

calcitonin gene8related %e%tide*, activate mast cells or

histamine secretion. Dermal microdial$sis studies o the

a%%lication o (4 on s!in indicate that it induces histamine

release onl$ at 10R M, &hich suggests that ater

%h$siologic nocice%tor activation, (4 does not contri#ute

signiicantl$ to histamine release.9 >et it is a ma?or

contri#utor to the lare reaction induced #$ histamine

stimulation o aerent t$%e ' i#ers )mediating %ruritus*

&ith release o (4 rom ad?acent nerve endings #$

antidromic conduction. @istamine is ound associated

&ith the &heal. ecentl$, the s%inal cord aerent i#ers

mediating %ruritis have, or the irst time, #een distinguished

rom %ain i#ers in the lateral s%inothalamic

tracts.

ot all %otential #iologic %roducts are %roduced

&hen cutaneous mast cells are stimulated. :or e-am%le,


28/74

(4 releases histamine rom cutaneous mast cells

a#ove 10R M #ut does not generate %rostaglandin D2

)4GD2*. ascular %ermea#ilit$ in s!in is %roduced %redominantl$

#$ @1 histamine rece%tors )3*H @2 histamine

rece%tors account or the remaining 13.

The current h$%othesis regarding cellular iniltration

that ollo&s mast cell degranulation suggests that

the release o mast cell %roducts )histamine, leucotrienes,

c$to!ines, chemo!ines* leads to alterations in

vaso%ermea#ilit$, u%regulation o adhesion molecules

on endothelial cells, and rolling and attachment o

#lood leu!oc$tes, ollo&ed #$ chemota-is and transendothelial

cell migration.

arious orms o %h$sical urticaria/angioedema

have %rovided e-%erimental models or the stud$ o

urticaria/angioedema #$ allo&ing the o#servation o

the elicited clinical res%onse, e-amination o lesional

and normal s!in #io%s$ s%ecimens, assa$ o chemical

mediators released into the #lood or tissues, and characteri"ation

o %eri%heral leu!oc$te res%onses.,5 The

intracutaneous in?ection o s%eciic antigen in sensiti"ed

individuals has %rovided an e-%erimental model

or anal$sis o the role o immunoglo#ulin )g* E and

its interaction &ith the mast cell. n man$ su#?ects,

the challenged cutaneous sites demonstrate a #i%hasic

res%onse, &ith a transient, %ruritic, er$thematous

&heal8and8lare reaction ollo&ed #$ a tender, dee%,


29/74

er$thematous, %oorl$ demarcated area o s&elling

that %ersists or u% to 2 hours. This is the late8%hase

res%onse &ith recruitment o varia#le num#ers o

neutro%hils, %rominent eosino%hils, monoc$tes, small

num#ers o #aso%hils, and 'D

S T8l$m%hoc$tes o the

T@2 su#class. 'hemo!ines )chemotactic c$to!ines*

strongl$ associated &ith Th2 l$m%hoc$te %redominance

include those reactive &ith chemo!ine rece%tors

''9, '', and '' on T l$m%hoc$tes. 'haracteristic

c$to!ines %roduced #$ Th2 l$m%hoc$tes include

interleu!ins )Cs* , , P, 19, 2, 91 and 99. The cellular

iniltrate seen in #io%s$ s%ecimens o dela$ed %res

iniltrate that surrounds small venules &ithin the

su%ericial and dee% venular %le-us, &ith a %rominence

o 'DS T l$m%hoc$tes and monoc$tes and

virtuall$ no B cells.9,9P Granuloc$tes are 7uite varia#le

#ut are %lentiul i the lesion undergoes #io%s$ earl$

in its develo%ment. eutro%hils and eosino%hils are

#oth %resent,0,1 although the degree o eosino%hils

accumulation varies greatl$.9P Even &hen eosino%hils

are not evident, ma?or #asic %rotein can #e identiied

&ithin lesions )in at least t&o8thirds o %atients*,

&hich most li!el$ re%resents evidence o %rior eosino%hil

degranulation.2 The %resence o #aso%hils has

also #een recentl$ demonstrated #$ using an anti#od$

)BB1* that is s%eciic or this cell t$%e.1 Thus, the iniltrate


30/74

resem#les that o an allergic late8%hase reaction,

as suggested %reviousl$,9 although the %ercentage o

each cell t$%es diers, &ith neutro%hils and monoc$tes

#eing relativel$ more %rominent in urticaria. Endothelial

cell activation is suggested #$ the %resence o intercellular

adhesion molecule 1 and E8selectin in #io%s$

s%ecimens o urticarial lesions. (ources o chemo!ines

include the mast cell and the activated endothelial cellH

the latter cells are stimulated not onl$ #$ c$to!ines

or mono!ines, such as C8, C81, and tumor necrosis

actor8F )T:8F*, #ut also #$ the vasoactive actors,

or e-am%le, histamine and leu!otrienes released rom

activated mast cells. 'om%lement activation and the

release o 'a results not onl$ in augmented mast cell

)and #aso%hil* histamine release, #ut 'a is also chemotactic

or neutro%hils, eosino%hils, and monoc$tes.

The %resence o 'a is one o the actors that &ould

distinguish this lesion rom a t$%ical allergen8induced

cutaneous late8%hase reaction. The %articular chemo!ines

released in chronic urticaria have not #een

studied. The %resence o increased %lasma C8 levels2

in %atients &ith chronic urticaria %rovides indirect evidence

o l$m%hoc$te activation, #aso%hil activation,

or #oth, and isolated 'DS l$m%hoc$tes o %atients

&ere sho&n to secrete greater amounts o #oth C8

and :8 com%ared &ith that seen in health$ control

su#?ects on stimulation &ith %hor#ol m$ristate acetate.


31/74

+ direct com%arison #et&een cutaneous late%hase

reactions and the histolog$ o chronic urticaria

revealed that iniltrating cells had characteristics o

#oth T@1 and T@2 cells, &ith %roduction o :8 #$

the ormer cells and C8 and C8 #$ the latter. +lternativel$,

this might re%resent activated T@0 cells )i.e.,

activated 'DS l$m%hoc$tes that are not dierentiated

to T@1 or T@2 cells*. When the histolog$ o autoimmune

and idio%athic chronic urticarias &as com%ared,1 the

autoimmune su#grou% had greater %rominence o

granuloc$tes &ithin the iniltrate, &hereas other iniltrating

cells &ere 7uite similar, &ith a small increment

in c$to!ine levels in the autoimmune grou% and greater

tr$%tase %ositivit$ ) less degranulation* in the autoanti#od$8

negative grou%. The %atients &ith autoimmune

chronic urticaria generall$ had more severe s$m%toms

than those &ith idio%athic chronic urticaria.5

B+(;4@C ECE+(BCT>

):igs. 981 and 982*

The #aso%hils o %atients &ith chronic urticaria

have #een sho&n to #e h$%ores%onsive to anti8gE,

an o#servation made #$ =ern and Cichtenstein long

#eore there &ere an$ clues to the %athogenesis o

this disorder.

These indings &ere c

a%%eared to #e associated &ith #aso%enia0 and to segregate

&ith the autoimmune su#grou%. ;ne o#vious

inter%retation is that there is in vivo desensiti"ation o


32/74

#aso%hils in the %resence o circulating anti8gE rece%tor.

ona!is et al have demonstrated that %atientsL

#aso%hil h$%ores%onsiveness to anti8gE is due to

augmented levels o (@4 %hos%hatase1 that limits

%hos%hor$lation reactions critical or histamine secretion.

+lthough maniest in a#out hal the %atients &ith

chronic urticaria )and not segregated &ith either the

autoimmune or idio%athic su#grou%s*, the a#normalit$

a%%ears to reverse &hen %atients remit. Thus, it

ma$ #e a mar!er o disease activit$. We have ound

a %arado-ical result &hen the isolated #aso%hils o

%atients &ith chronic urticaria &ere activated and com%ared

&ith the #aso%hils o health$ control su#?ects.

+lthough the #aso%hils o the %atients &ith urticaria

&ere clearl$ less res%onsive to anti8gE, the$ demonstrated

augmented histamine release &hen incu#ated

&ith serum and it did not matter &hether the sera

&ere ta!en rom normal su#?ects, other %atients &ith

chronic urticaria, or &as their o&n.2

;CE ;: T@E EOT('

';+GUC+T; '+('+DE

(tudies o the %lasma o %atient &ith chronic urticaria

demonstrate the %resence o d8dimer and %rothrom#in

1 and 2 ragments indicating activation o %rothrom#in

to throm#in as &ell as digestion o i#rinogen #$

throm#in.9 The reaction is not s%eciic or chronic

urticaria as similar o#servations have #een noted in


33/74

multi%le nonsteroidal h$%ersensitivit$ s$ndrome.

evertheless, the data are o considera#le interest and

activation o the coagulation cascade is de%endent on

tissue actor rather than actor O, i.e., the e-trinsic

coagulation cascade. +lthough activated endothelial

cells are a &ell8!no&n source o the tissue actor, histologic

studies suggest that eosino%hils are a %rominent

source. The relationshi% o these o#servations

to histamine release #$ #aso%hils or mast cells is not

clear. Whereas throm#in activation o mast cells has

#een re%orted, the amounts re7uired are large and the

o#servations thus ar are conined to rodent mast cells.

;ne %u#lication relating to eosino%hil to histamine

release ound gG anti#od$ to :ce in the serum o

%atients &ith chronic urticaria &hich activates eosino%hils

to release cationic %roteins. The$ %ro%ose #aso%hil

activation #$ these eosino%hil cationic %roteins

#ut do not demonstrate itH ho&ever, the$ oer an additional

mechanism or #aso%hil and %ossi#l$ mast cell

histamine release.

B+D>=< ;CE +G;EDEM+

=inins are lo&8molecular8&eight %e%tides that %artici%ate

in inlammator$ %rocesses #$ virtue o their a#ilit$

to activate endothelial cells and, as a conse7uence, lead

to vasodilatation, increased vascular %ermea#ilit$, %roduction

o nitric o-ide, and mo#ili"ation o arachidonic

acid. =inins also stimulate sensor$ nerve endings to


34/74

cause a #urning d$sesthesia. Thus, the classical %arameters

o inlammation )i.e., redness, heat, s&elling, and

%ain* can all result rom !inin ormation. Brad$!inin is

the #est characteri"ed o this grou% o vasoactive su#stances.

There are t&o general %ath&a$s #$ &hich #rad$!inin

is generated. The sim%ler o the t&o has onl$

t&o com%onents< )1* an en"$me tissue !alli!rein5

and )2* a %lasma su#strate, lo&8molecular8&eight

!ininogen.,P Tissue !alli!rein is secreted #$ man$

cells throughout the #od$H ho&ever, certain tissues

%roduce %articularl$ large 7uantities. These include

glandular tissues )salivar$ and s&eat glands and %ancreatic

e-ocrine gland* and the lung, !idne$, intestine,

and #rain.

The second %ath&a$ or #rad$!inin ormation is ar

more com%le- and is %art o the initiating mechanism

#$ &hich the intrinsic coagulation %ath&a$ is activated

)e:ig. 981.2 in online edition*.0 :actor O is the initiating

%rotein that #inds to certain negativel$ charged macromolecular

suraces and autoactivates )autodigests* to

orm actor Oa.1,2 This is s$non$mous &ith @ageman

actor as designated in the igure. There are t&o %lasma

su#strates o actor Oa, namel$ )1* %re!alli!rein9 and

)2* actor O,, and each o these circulates as a com%le-

&ith high8molecular8&eight !ininogen )@=*.,5 These

com%le-es also attach to initiating suraces, and the

ma?or attachment sites are on t&o o the domains o @=,


35/74

&hich there#$ %laces #oth %re!alli!rein and actor O in

o%timal conormation or cleavage to !alli!rein )%lasma

!alli!rein* and actor Oa, res%ectivel$. t is im%ortant

to note that %lasma !alli!rein and tissue !alli!rein

areonirmedP and se%arate gene %roducts and have little amino acid

se7uence homolog$, although the$ have related unctions

)i.e., cleavage o !ininogens*. Tissue !alli!rein

%reers lo&8molecular8&eight !ininogen #ut is ca%a#le

o cleaving @=, &hereas %lasma !alli!rein cleaves @=

e-clusivel$. The t&o !ininogens have an identical amino

acid se7uence starting at the N 8terminus and continuing

to 12 amino acids #e$ond the #rad$!inin moiet$P

#ut dier in C 8terminal domains #ecause o alternative

s%licing at the transcri%tion level.,P Both actor O and

@= #ind to endothelial cells )&hich ma$ unction as the

natural surace in the %resence o %h$siologic "inc

ion*, thus activation ma$ occur at the cell surace.50,51

+ scheme or #oth %roduction and degradation o

!inins is sho&n in e:ig. 981.2 in online edition. The

en"$mes that destro$ #rad$!inin consist o !ininases

and . =ininase is also !no&n as %lasma car#o-$%e%tidase

,52 &hich removes the C 8terminal arg rom

#rad$!inin or !allidin to $ield des8arg59 #rad$!inin or

des8arg5 !allidin, res%ectivel$.5 t is the same en"$me

that cleaves the C 8terminal arg rom the com%lement

ana%h$lato-ins '9a and 'a. =ininase is identical

to angiotensin8converting en"$me )+'E*.5 =ininase


36/74

is a di%e%tidase that cleaves the C 8terminal %hearg

rom #rad$!inin to $ield a he%ta%e%tide, &hich is

cleaved once again to remove ser8%ro and to leave the

%enta%e%tide arg8%ro8%ro8gl$8%he.5 the C 8terminal

arg o #rad$!inin is irst removed &ith !ininase , then

+'E unctions as a tri%e%tidase to remove ser8%ro8%he

and to leave the a#ove %enta%e%tide.55 Brad$!inin and

!allidin stimulate constitutivel$ %roduced B2 rece%tors,

5 &hereas des8arg598B= or des8arg5 l$s8B= #oth

stimulate B1 rece%tors,5P &hich are induced as a result

o inlammation. (timuli or B1 rece%tor transcri%tion

include C81 and T:8F.0,1

'C'+C :DG(

'ircumscri#ed, raised, er$thematous, usuall$ %ruritic,

evanescent areas o edema that involve the su%ericial

%ortion o the dermis are !no&n as urticaria ):ig. 989*H

&hen the edematous %rocess e-tends into the dee%

dermis and/or su#cutaneous and su#mucosal la$ers,

it is !no&n as angioedema. Urticaria and angioedema

ma$ occur in an$ location together or individuall$.

+ngioedema commonl$ aects the ace or a %ortion o

an e-tremit$, ma$ #e %ainul #ut not %ruritic, and ma$

last several da$s. nvolvement o the li%s, chee!s, and

%erior#ital areas is common, #ut angioedema also ma$

aect the tongue, %har$n-, or lar$n-. The individual

lesions o urticaria arise suddenl$, rarel$ %ersist longer

than 269 hours, and ma$ continue to recur or indeinite


37/74

%eriods. The$ are highl$ %ruritic.

MMU;C;G'< MMU;GC;BUC

E8 +D MMU;GC;BUC E

E'E4T;8DE4EDET UT'++/

+G;EDEM+

+T;4' D+T@E((. E%isodes o acute urticaria/

angioedema that occur in individuals &ith a %ersonal

or amil$ histor$ o asthma, rhinitis, or ec"ema are

%resumed to #e gE de%endent. @o&ever, in clinical

%ractice, urticaria/angioedema inre7uentl$ accom%anies

an e-acer#ation o asthma, rhinitis, or ec"ema.

The %revalence o chronic urticaria/angioedema is not

increased in ato%ic individuals.

(4E':' +TGE (E(TT>. 'ommon

e-am%les o s%eciic antigens that %rovo!e urticaria/

angioedema include oods such as shellish, nuts, and

chocolateH drugs and thera%eutic agents nota#l$ %enicillinH

aeroallergensH and @$meno%tera venom )see

:ig. 989*. Urticaria in %atients &ith helminthic inestations

has #een attri#uted to gE8de%endent %rocessesH

ho&ever, %roo o this relationshi% is oten lac!ing.

(%eciic allergens and nons%eciic stimuli ma$ activate

local reactions termed recall urticaria at sites %reviousl$

in?ected &ith allergen immunothera%$.

4@>('+C UT'++/

+G;EDEM+,

DEM;G+4@(M. Dermogra%hism is the most


38/74

common orm o %h$sical urticaria and is the one

most li!el$ to #e conused &ith chronic urticaria.

+ lesion a%%ears as a linear &heal &ith a lare at a

site in &hich the s!in is #ris!l$ stro!ed &ith a irm

o#?ect ):ig. 98*. + transient &heal a%%ears ra%idl$

and usuall$ ades &ithin 90 minutesH ho&ever, the

%atientLs normal s!in is t$%icall$ %ruritic so that an

itch6scratch se7uence ma$ a%%ear. The %revalence

o dermogra%hism in the general %o%ulation &as

re%orted as 1.3 and .23, res%ectivel$, in t&o studies,

and its %revalence in %atients &ith chronic urticaria

is 223. t is not associated &ith ato%$. The %ea!

%revalence occurs in the second and third decades.

n one stud$, the duration o dermogra%hism &as

greater than $ears in 223 o individuals and greater

than 10 $ears in 103. Elevations in #lood histamine levels have #een documented

in some %atients ater e-%erimental scratching,

and increased levels o histamine,2 tr$%tase, (4,

and 4, #ut not calcitonin gene8related %e%tide, have

#een detected in e-%erimental suction8#lister as%irates.

The dermogra%hic res%onse has #een %assivel$

transerred to the s!in o normal su#?ects &ith serum

or gE.9

n dela$ed dermogra%hism, lesions develo% 96

hours ater stimulation, either &ith or &ithout an

immediate reaction, and last 26 hours. The eru%tion

is com%osed o linear red indurated &heals.


39/74

This condition ma$ #e associated &ith dela$ed %ressure

urticaria and these t&o ma$, in act, re%resent

the same entit$. 'old8de%endent dermogra%hism is

a condition characteri"ed #$ mar!ed augmentation

o the dermatogra%hic res%onse &hen the s!in is

chilled.

4E((UE UT'++. Dela$ed %ressure urticaria

a%%ears as er$thematous, dee%, local s&ellings,

oten %ainul, that arise rom 9 to hours ater

sustained %ressure has #een a%%lied to the s!in.,

(%ontaneous e%isodes are elicited on areas o contact

ater sitting on a hard chair, under shoulder stra%s

and #elts, on the eet ater running, and on the hands

ater manual la#or. The %ea! %revalence occurs in the

third decade. Dela$ed %ressure urticaria ma$ occasionall$

#e associated &ith ever, chills, arthralgias,

and m$algias, as &ell as &ith an elevated er$throc$te

sedimentation rate and leu!oc$tosis. n one stud$,

it accom%anied chronic urticaria in 953 o %atients.

This is ar more commonl$ seen than %atients &ith

%ressure urticaria and no s%ontaneousl$ occurring

hives. +n gE8mediated mechanism has not #een

demonstratedH ho&ever, histamine and C8 have

#een detected in lesional e-%erimental suction8#lister

as%irates and in luid rom s!in cham#ers, res%ectivel$.

56P

B+T;> +G;EDEM+. i#rator$ angioedema


40/74

ma$ occur as an ac7uired idio%athic disorder,

in association &ith cholinergic urticaria, or ater

several $ears o occu%ational e-%osure to vi#ration.P0

t has #een descri#ed in amilies &ith an autosomal

dominant %attern o inheritance.P1 The herita#le orm

oten is accom%anied #$ acial lushing. +n increase

in the level o %lasma histamine &as detected during

an e-%erimental attac! in %atients &ith the hereditar$

orm and in %atients &ith ac7uired disease.P1,P2 +

t$%ical s$m%tom is hives across the #ac! &hen to&eling

o ater a sho&er )in the a#sence o dermatogra%hism*.

';CD UT'++. There are #oth ac7uired and

inherited orms o cold urticaria/angioedemaH ho&ever,

the amilial orm is rare. dio%athic or %rimar$

ac7uired cold urticaria ma$ #e associated &ith headache,

h$%otension, s$nco%e, &hee"ing, shortness o

#reath, %al%itations, nausea, vomiting, and diarrhea.

+ttac!s occur &ithin minutes ater e-%osures that

include changes in am#ient tem%erature and direct

contact &ith cold o#?ects. The elicitation o a &heal

ater the a%%lication o ice has #een called a diagnostic

cold contact test ):ig. 98*. This can #e %erormed &ith

thermoelectric elements &ith graded tem%eratures so

that the tem%erature threshold or %roducing a &heal

can #e determined and a dose8res%onse )sensitivit$* in

terms o stimulus duration can #e readil$ o#tained.P2

the entire #od$ is cooled )as in s&imming*, h$%otension


41/74

and s$nco%e, &hich are %otentiall$ lethal events

)#$ dro&ning*, ma$ occur. n rare instances, ac7uired

cold urticaria has #een associated &ith circulating

cr$oglo#ulins, cr$oi#rinogens, cold agglutinins, and

cold hemol$sins, es%eciall$ in children &ith inectious

mononucleosis.P96P

4assive transer o cold urticaria #$ intracutaneous

in?ection o serum or gE to the s!in o normal reci%ients

has #een documented.P,P5 @istamine, chemotactic

actors or eosino%hils and neutro%hils, 4GD2, c$stein$l

leu!otrienes, %latelet8activating actor, and T:8F

have #een released into the circulation ater e-%erimental

challenge.P610 @istamine, (4, and 4, #ut not

calcitonin gene8related %e%tide, have #een detected

in e-%erimental suction8#lister as%irates. @istamine

has #een released in vitro rom chilled s!in #io%s$

s%ecimens that have #een re&armed.10 eutro%hils

harvested rom the #lood o an e-%erimentall$ coldchallenged

arm maniested an im%aired chemotactic

res%onse suggesting in vivo desensiti"ation. Whereas

com%lement has no role in %rimar$ ac7uired cold urticaria,

cold challenge o %atients &ith cold urticaria

&ho have circulating immune com%le-es )such as

cr$oglo#ulins* can %rovo!e a cutaneous necroti"ing

venulitis &ith com%lement activation.10610P

are orms o ac7uired cold urticaria have #een

descri#ed mainl$ in case re%orts include s$stemic cold


42/74

urticaria, locali"ed cold urticaria,110 cold8induced

cholinergic urticaria, cold8de%endent dermogra%hism,

and locali"ed cold rele- urticaria.111,112 Three

orms o dominantl$ inherited cold urticaria have

#een descri#ed. :amilial cold urticaria &hich has #een

termed familial cold autoinflammatory syndrome and is

considered a t$%e o %eriodic ever.119 t is a disorder

sho&ing an autosomal dominant %attern o inheritance

&ith a genetic lin!age to chromosomes 17.

The res%onsi#le gene has #een identiied as CIASI ,

&hich codes or a %rotein involved in regulation o

inlammation and a%o%tosis.11 The eru%tion occurs as

er$thematous macules and inre7uent &heals and is

associated &ith #urning or %ruritus. :ever, headaches,

con?unctivitis, arthralgias, and a neutro%hilic leu!oc$tosis

are eatures o attac!s. The dela$ #et&een cold

e-%osure and onset o s$m%toms is 2. hours, and the

average duration o an e%isode is 12 hours. enal disease

&ith am$loidosis occurs inre7uentl$. (!in #io%s$

s%ecimens sho& mast cell degranulation and an iniltrate

o neutro%hils. esults o the cold contact test

and %assive transer &ith serum have #een negative.

(erum levels o C8 and granuloc$te colon$ stimulating

actor &ere elevated in one %atient. ;ther studies

suggest a %athogenic role or C81. Dela$ed cold

urticaria occurs as er$thematous, edematous, dee%

s&ellings that a%%ear P61 hours ater cold challenge.


43/74

Cesional #io%s$ s%ecimens sho& edema &ith minimal

num#ers o mononuclear cellsH mast cells are not

degranulatedH and neither com%lement %roteins nor

immunoglo#ulins are detected. 'old immersion does

not release histamine, and the condition cannot #e

%assivel$ transerred. ecentl$, a ne& orm o amilial

cold urticaria &ith dominant inheritance has #een

re%orted &ith %ruritus, er$thema, and urticaria &ith

cold e-%osure that can %rogress to s$nco%e. The ice

cu#e test is negative and it lac!s the ever, and lu8li!e

s$m%toms associated &ith amilial cold autoinlammator$

s$ndrome.11

'@;CEG' UT'++. 'holinergic urticaria

develo%s ater an increase in core #od$ tem%erature,

such as during a &arm #ath, %rolonged

e-ercise, or e%isodes o ever.11 The highest %revalence

is o#served in individuals aged 2962 $ears. The eru%tion

a%%ears as distinctive, %ruritic, small, 18 to 28mm

&heals that are surrounded #$ large areas o er$thema

):ig. 98*. ;ccasionall$, the lesions ma$ #ecome conluent,

or angioedema ma$ develo%. ($stemic eatures

include di""iness, headache, s$nco%e, lushing,

&hee"ing, shortness o #reath, nausea, vomiting, and

diarrhea. +n increased %revalence o ato%$ has #een

re%orted. The intracutaneous in?ection o cholinergic

agents, such as methacholine chloride, %roduces a

&heal &ith satellite lesions in a%%ro-imatel$ one8third


44/74

o %atients.115,11 +lterations in %ulmonar$ unction

have #een documented during e-%erimental e-ercise

challenge11P or ater the inhalation o acet$lcholine, #ut

most are as$m%tomatic.

+ ma?or su#%o%ulation o %atients &ith cholinergic

urticaria have a %ositive s!in test result and in vitro

histamine release in res%onse to autologous s&eat.120 t

is not clear &hether this is gE mediated and an$ antigen

%resent in s&eat is unidentiied. This is the same

su#%o%ulation &ith a %ositive methacholine s!in test

&ith satellite lesions and a nonollicular distri#ution

o the &heals. The remaining %atients had negative

results on autologous s&eat s!in tests or in vitro histamine

release. esults o the methacholine s!in test are

negative or satellite lesions and the hives tend to #e

ollicular in distri#ution.

:amilial cases have #een re%orted onl$ in men in

our amilies.121 This o#servation suggests an autosomal

dominant %attern o inheritance. ;ne o these

individuals had coe-isting dermogra%hism and a7uagenic

urticaria.

+ter e-ercise challenge, histamine and actors chemotactic

or eosino%hils and neutro%hils have #een released

into the circulation.PP,11P Tr$%tase has #een detected in

lesional suction8#lister as%irates. The urticarial res%onse

has #een %assivel$ transerred on one occasionH ho&ever,

most other attem%ts to do so have #een unsuccessul.


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'old urticaria and cholinergic urticaria are not

uncommonl$ seen together122,129 and cold8induced

cholinergic urticaria re%resents an unusual variant

in &hich t$%ical cholinergic a%%earing lesions

occur &ith e-ercise, #ut onl$ i the %erson is chilled,

or e-am%le, &ith e-ercise outside on a &interLs da$.

The ice cu#e test and methacholine s!in test are #oth

negative.12

C;'+C @E+T UT'++. Cocal heat urticaria

is a rare orm o urticaria in &hich &heals develo%

&ithin minutes ater e-%osure to locall$ a%%lied heat.

+n increased incidence o ato%$ has #een re%orted.

4assive transer has #een negative. @istamine, neutro%hil

chemotactic activit$, and 4GD2 have #een detected

in the circulation ater e-%erimental challenge.12 +

amilial dela$ed orm o local heat urticaria in &hich

the urticaria occurred in 162 hours ater challenge and

lasted u% to 10 hours has #een descri#ed.

(;C+ UT'++. (olar urticaria occurs as %ruritus,

er$thema, &heals, and occasionall$ angioedema

that develo% &ithin minutes ater e-%osure to sun or

artiicial light sources. @eadache, s$nco%e, di""iness,

&hee"ing, and nausea are s$stemic eatures. Most

commonl$, solar urticaria a%%ears during the third

decade.12 n one stud$, 3 o %atients had a histor$ o

ato%$. +lthough solar urticaria ma$ #e associated &ith

s$stemic lu%us er$thematosus and %ol$mor%hous


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light eru%tion, it is usuall$ idio%athic. The develo%ment

o s!in lesions under e-%erimental conditions

in res%onse to s%eciic &avelengths has allo&ed classiication

into si- su#t$%esH ho&ever, individuals ma$

res%ond to more than one %ortion o the light s%ectrum.

n t$%e , elicited #$ &avelengths o 26920 nm,

and in t$%e , elicited #$ &avelengths o 00600 nm,

the res%onses have #een %assivel$ transerred &ith

serum, suggesting a role or gE anti#od$. n t$%e , the

&avelengths are #loc!ed #$ &indo& glass.125,12 T$%e

, &hich is identical to er$thro%oietic %roto%or%h$ria,

is due to errochelatase )hemes$nthetase* deicienc$

)see 'ha%ter 192*.5 There is evidence that an antigen

on s!in ma$ #ecome evident once irradiated &ith the

a%%ro%riate &ave length o light ollo&ed #$ com%lement

activation and release o 'a.12P6191

@istamine and chemotactic actors or eosino%hils

and neutro%hils have #een identiied in #lood ater

e-%osure o the individuals to ultraviolet +, ultraviolet

B, and visi#le light.192,199 n some individuals,

uncharacteri"ed serum actors &ith molecular &eights

ranging rom 2 to 1,000 !Da, &hich elicit cutaneous

&heal8and8er$thema reactions ater intracutaneous

in?ection, have #een im%licated in the develo%ment o

lesions.

EOE'(E8DU'ED ++4@>C+O(. E-ercise8

induced ana%h$la-is is a clinical s$m%tom com%le-


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consisting o %ruritus, urticaria, angioedema

res%irator$ distress, and s$nco%e that is distinct

rom cholinergic urticaria.196195 n most %atients, the

&heals are not %unctate and resem#le the hives seen

in acute or chronic urticaria. The s$m%tom com%le-

is not readil$ re%roduced #$ e-ercise challenges as is

cholinergic urticaria. There is a high %revalence o an

ato%ic diathesis. (ome cases are ood de%endent, i.e.,

e-ercise &ill lead to an ana%h$la-is8li!e e%isode onl$

i ood &as ingested &ithin hours o the e-ercise.

The ood de%endenc$ is su#divided into t&o grou%s<

in the irst the nature o the ood eaten is not relevant,

&hereas in the second a s%eciic ood to &hich

there is gE8mediated h$%ersensitivit$ must #e eaten

or hives to a%%ear.19611 >et in these cases, eating the

ood &ithout e-ercise does not result in urticaria.

The ood8de%endent grou% is easier to treat #ecause

avoidance o ood )or a s%eciic ood* or 6 hours

#eore e-ercise %revents e%isodes. 'ases not related to

ood re7uire thera%$ or acute e%isodes and attem%ts

to %revent e%isodes &ith high8dose antihistaminics

or avoidance o e-ercise. esults o a 7uestionnaire

stud$ o individuals &ho had had e-ercise8induced

ana%h$la-is or more than a decade12 disclosed that

the re7uenc$ o attac!s had decreased in 53 and

had sta#ili"ed in 3. :ort$8one %ercent had #een

ree o attac!s or 1 $ear. are amilial orms have


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#een descri#ed. n e-ercise8induced ana%h$la-is,

#aseline %ulmonar$ unction tests are normal. Bio%s$

s%ecimens sho& mast cell degranulation, and histamine

and tr$%tase are released into the circulation

&hen s$m%toms a%%ear.

+DEEG' UT'++. +drenergic urticaria

occurs as &heals surrounded #$ a &hite halo that

develo% during emotional stress. The lesions can #e

elicited #$ the intracutaneous in?ection o nore%ine%hrine.

+KU+GE' UT'++ +D +KU+GE'

4UT(. 'ontact o the s!in &ith &ater

o an$ tem%erature ma$ result in %ruritus alone or,

more rarel$, urticaria. The eru%tion consists o small

&heals that are reminiscent o cholinergic urticaria.

+7uagenic urticaria has #een re%orted in more than

one mem#er in ive amilies.19 +7uagenic %ruritus

&ithout urticaria is usuall$ idio%athic #ut also occurs

in elderl$ %ersons &ith dr$ s!in and in %atients &ith

%ol$c$themia vera, @odg!inLs disease, the m$elod$s%lastic

s$ndrome, and the h$%ereosino%hilic

s$ndrome. 4atients &ith a7uagenic %ruritus should

#e evaluated or the emergence o a hematologic disorder.

+ter e-%erimental challenge, #lood histamine

levels &ere elevated in su#?ects &ith a7uagenic %ruritus

and &ith a7uagenic urticaria. Mast cell degranulation

&as %resent in lesional tissues. 4assive transer

&as negative.


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';T+'T UT'++

Urticaria ma$ occur ater direct contact &ith a variet$

o su#stances. t ma$ #e gE mediated or nonimmunologic.

The transient eru%tion a%%ears &ithin minutes,

and &hen it is gE mediated, it ma$ #e associated &ith

s$stemic maniestations. 4assive transer has #een documented

in some instances. 4roteins rom late- %roducts

are a %rominent cause o gE8mediated contact

urticaria.1 Cate- %roteins also ma$ #ecome air#orne

allergens, as demonstrated #$ allergen8loaded air#orne

glove %o&der used in inhalation challenge tests. These

%atients ma$ maniest cross8reactivit$ to ruits, such

as #ananas, avocado, and !i&i.1 +ssociated maniestations

include rhinitis, con?unctivitis, d$s%nea, and

shoc!. The ris! grou% is dominated #$ #iomedical

&or!ers and individuals &ith re7uent contact &ith

late-, such as children &ith s%ina #iida. +gents such

as stinging nettles, arthro%od hairs, and chemicals ma$

release histamine directl$ rom mast cells.

4+4UC+ UT'++

4a%ular urticari occurs as e%isodic, s$mmetricall$ distri#uted,

%ruritic, 98 to 108mm urticarial %a%ules that

result rom a h$%ersensitivit$ reaction to the #ites o

insects such as mos7uitoes, leas, and #ed#ugs. This

condition a%%ears mainl$ in children. The lesions

tend to a%%ear in grou%s on e-%osed areas such as the

e-tensor as%ects o the e-tremities.1


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UT'++/+G;EDEM+ MED+TED

B> B+D>=, T@E ';M4CEMET

(>(TEM ; ;T@E E::E'T;

ME'@+(M(

=( +D '1 @BT; DE:'E'>.

'1 inhi#itor )'1 @* is the sole %lasma inhi#itor o

actor Oa and actor O,15,1 and it is one o the

ma?or inhi#itors o !alli!rein1P as &ell as actor Oa.10

Thus, in the a#sence o '1 @, stimuli that activate

the !inin8orming %ath&a$ &ill do so in a mar!edl$

augmented ashionH the amount o active en"$me and

the duration o action o the en"$mes are %rolonged.

'1 @ deicienc$ can #e amilial, in &hich there is

a mutant C1 INH gene, or it can #e ac7uired. Both

the hereditar$ and ac7uired disorders have t&o su#t$%es.

:or the hereditar$ disorder, t$%e hereditar$

angioedema )@+E* )3* is an autosomal dominant

disorder &ith a mutant gene )oten &ith du%lication,

deletions, or rame shits* leading to mar!edl$ su%%ressed

'1 @ %rotein levels as a result o a#normal

secretion or intracellular degradation.11 T$%e 2 @+E

)13* is also a dominantl$ inherited disorder, t$%icall$

&ith a %oint )missense* mutation leading to s$nthesis

o a d$sunctional %rotein.12 The '1 @ %rotein

level ma$ #e normal or even el

Urtikaria Andrews n Fitzpatrick Eng

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