Dermatology 2008 trial

dence supports the importance of bradykinin
ANGIOEDEMA in the clinical manifestations of angioedema.
Other kinins may also be pathogenic. The
specific trigger responsible for inducing the
release of these vasoactive peptides is un-
Angioedema,Acquired clear. Factor XII activation (Hageman factor)
may be secondary to phospholipid release
Synonyms and related keywords: AAE, from damaged or apoptotic cells and may be
Caldwell syndrome, acquired angioedema important in the generation of bradykinin
from endothelial activation. This hypothesis
Background encompasses the role of illness or tissue in-
jury in the generation of bradykinin. The pre-
Acquired angioedema (AAE) is characterized cise pathophysiology of AAE-I remains to be
by painless, nonpruritic, nonpitting swelling defined. Diminished levels of C1-INH are
of the skin that is classified into 2 forms: ac- due to its increased catabolism.
quired angioedema type I (AAE-I) and ac- In AAE-I, the associated disorders (usually
quired angioedema type II (AAE-II). AAE-I is lymphoproliferative malignancies) produce
associated with other diseases, most com- complement-activating factors, idiot-
monly B-cell lymphoproliferative disorders. ype/anti-idiotype antibodies, or other im-
AAE-II is an autoimmune process defined by mune complexes that destroy C1-INH func-
the presence of an autoantibody directed tion. Neoplastic lymphatic tissue has been
against the C1 inhibitor molecule (C1-INH). found to play an active role in the consump-
tion of C1-INH and the complement compo-
Pathophysiology nents of the classic pathway. The most com-
monly associated malignancy, B-cell lympho-
The gene for C1-INH (SERPING1) has been ma, has shown that anti-idiotypic antibody
mapped to chromosome 11 (11q12-q13.1). attached to immunoglobulin on the surface
C1-INH is a multifunctional serine protease of B-cells causes C1-INH deficiency. In-
inhibitor that is normally present in high con- creased consumption of C1q followed by C2
centrations in plasma. It is the only plasma and C4 results in subsequent release of vaso-
inhibitor of C1r and C1s, the activated pro- active peptides that act on postcapillary ven-
teases of the first component of complement. ules.
It is also the major plasma inhibitor of acti- In AAE-II, a normal 105-kd C1-INH molecule
vated Hageman factor, the first protease in is synthesized in adequate amounts, but, be-
the contact system. Additionally, C1-INH is cause of an unknown event, a subpopulation
one of the major inhibitors of plasma kallik- of B cells secretes autoantibodies to the
rein, the contact system protease that cleaves C1-INH molecule. This autoantibody, which
kininogen and releases bradykinin. may be any of the major immunoglobulin
Presumably, uncontrolled activation of the classes, binds to the reactive center of
contact system allows for release of kininlike C1-INH. After binding to C1-INH and alter-
mediators, resulting in vascular permeability ing its structure, its regulatory capacity is di-
with edema of subcutaneous and mucosal tis- minished or abrogated.
sues. Although the issue of which vasoactive In all reported cases of C1-INH deficiency
peptide is ultimately responsible for these caused by an autoantibody, C1-INH circu-
changes remain controversial, direct evi- lates in the blood in a form that has been

cleaved by target proteases from its native is not obtained, which distinguishes AAE
molecule to a 95-kd fragment. Because of the from HAE.
higher affinity of the autoantibody for native Regarding angioedema, symptoms are refer-
C1-INH, the 95-kd antibody/C1-INH com- able to 3 prominent sites: subcutaneous tis-
plex dissociates, and the freed antibody can sues (eg, face, hands, arms, legs, genitals, but-
bind to another native C1-INH molecule, al- tocks); abdominal organs (eg, stomach, intes-
lowing for the further depletion of C1-INH. tines, bladder), which may manifest as nau-
The distinction between AAE-I and AAE-II sea, vomiting, and/or colicky pain and
may be difficult to make at times and it is im- mimic a surgical emergency; and the upper
perative to stress that overlap does occur. For airway (eg, larynx), which may result in lar-
instance, cases of monoclonal gammopathy yngeal edema.
of undetermined significance ( MGUS) have Occasionally, patients may experience heat
shown the monoclonal immunoglobulin it- and pain in the affected areas.
self to be the C1-INH antibody. Regarding Other symptoms may be related to underly-
malignancies and/or other diseases associ- ing disorders, such as lymphoproliferative
ated with AAE-I, it has been demonstrated malignancies or connective tissue disease.
that these patients may initially present with
autoantibodies to C1-INH, or they may de- Physical
velop as the disease progresses. Physical signs include overt, noninflamma-
tory swelling of the skin and mucous mem-
Frequency branes.
International Although urticaria does not usually occur,
AAE is rare, with approximately 150 cases re- occasionally, erythema or mild urticarial
ported in the medical literature worldwide. eruptions may precede the edema.

Mortality/Morbidity Causes
Although mortality may occur because of lar- AAE-I is most frequently associated with B-
yngeal edema, it is more likely due to the cell lymphoproliferative disease. To date, on-
complications of the associated disorder. ly 2 reports of a T-cell lymphoma associated
with AAE-I have been documented. Other
Race disorders have included multiple myeloma,
Presumably, all races are affected. chronic lymphocytic leukemia, myelofibrosis,
Waldenström macroglobulinemia, non-
Sex Hodgkin lymphoma, MGUS, rectal carcino-
Men and women may be affected. ma, essential cryoglobulinemia, erythrocyte
sensitization, livedo reticularis, cold urtica-
Age ria, lupus anticoagulant, and infection with
The onset of AAE is most common after the Helicobacter pylori or Echinococcus granulosis.
fourth decade of life, whereas the onset of he- By definition, AAE-II is not associated with
reditary acquired angioedema (HAE) is in any specific disorder but rather by the pres-
the second decade. ence of the autoantibody directed against
C1-INH. However, the occasional existence
History of features of both AAE-I and AAE-II has
been noted, most notably with a MGUS.
A family history for hereditary angioedema One case of AAE with C1-INH deficiency

state was identified in association with liver Other Tests
transplantation. The status of the liver donor
was unknown, but it is speculated that the Other laboratory findings are related to asso-
donor may have been C1-INH deficient. ciated illnesses.
Another case of AAE was reported with
acute upper airway angioedema in associa- Histologic Findings
tion with the local anesthetic articaine.
Histologic features include reticular dermal,
DIFFERENTIALS subcutaneous, or submucosal edema without
infiltrating inflammatory cells. Vasodilation
Angioedema,Hereditary may be seen.
Drug Eruptions
Urticaria,Acute TREATMENT
Urticaria,Cholinergic
Urticaria,Chronic Medical Care
Urticaria,Contact Syndrome
Urticaria,Dermographism Depending on the symptoms and the site of
Urticaria,Solar the angioedema, intensive support may be
Urticarial,Vasculitis necessary, including intravenous fluids.
When possible, the underlying disorder
Other Problems to be Considered should be treated. The resolution of angioe-
dema has been reported with the treatment
ACE inhibitor–induced angioedema of underlying disease, although recurrences
Episodic angioedema with angioedema have occurred despite appropriate treatment
Leukocytoclastic vasculitis of the disorder.
Urticaria, cold In AAE-I, treatment of the associated lym-
phoproliferative process may result in correc-
Lab Studies tion of the abnormality.

AAE-I and AAE-II Surgical Care
Low C1-INH levels
Low C1q levels (except 1 reported case) Intubation may be necessary in cases of lar-
Low C4 levels yngeal edema.
Low C2 levels
AAE-II - Positive immunoblot assay find- MEDICATION
ings for 95-kd C1-INH cleavage product
AAE, therapy for acute attacks may be
Imaging Studies aborted with C1-INH concentrates or, if un-
available, fresh-frozen plasma. However,
Abdominal radiographs may demonstrate rapid catabolism of C1-INH occurs in AAE,
features of ileus. Other findings may be refer- so higher doses of C1-INH plasma concen-
able to an associated illness. trate may be needed.
Androgens, such as danazol or stanozolol,
may be beneficial in AAE-I but are of no val-
ue in AAE-II. Prostate cancer and pregnancy

preclude the use of androgens. neoplastic cells.
Antifibrinolytics, such as epsilon-aminocap-
roic acid and tranexamic acid, have been Adult Dose 500-750 mg/m2
found to be more effective for long-term pro-
Pediatric Administer as in adults
phylaxis in those with AAE.
Dose
Immunosuppressive therapy directed toward
decreasing autoantibody production may be Contraindi- Documented hypersensitivity;
of value in patients with AAE-II, which may cations severely depressed bone mar-
be accomplished by the use of plasmaphere- row function
sis with cyclophosphamide. Interactions Allopurinol may increase risk
A recent paper reported effective treatment of bleeding or infection and
of 3 severe AAE cases with a series of 4 enhance myelosuppressive ef-
weekly injections with rituximab (a chimeric fects; may potentiate doxoru-
monoclonal antibody to CD 20). After treat- bicin-induced cardiotoxicity;
ment with rituximab, normalization of may reduce digoxin serum
C1-INH and C4 levels and long-term remis- levels and antimicrobial ef-
sion of angioedema attacks was achieved. fects of quinolones; chloram-
New medications are currently being studied phenicol may increase half-life
for the treatment of AAE. One such treat- while decreasing metabolite
ment is a synthetic kallikrein inhibitor (DX- concentrations; may increase
88), which is thought to be able to stop the effect of anticoagulants; coad-
generation of bradykinin by inhibiting kallik- ministration with high doses
rein activation. This drug allows for a de- of phenobarbital may increase
crease in the rate of C1-INH catabolism, al- rate of metabolism and leuko-
lowing for C1-INH concentrate to be more ef- penic activity; thiazide diu-
fective. retics may prolong cyclophos-
Other new products in trial are genetically phamide-induced leukopenia
engineered C1 esterase inhibitor and bradyki- and neuromuscular blockade
nin B2 receptor antagonist. by inhibiting cholinesterase
activity

Drug Category: Alkylating agents Pregnancy D - Unsafe in pregnancy

Some agents in this class have potent immu- Precautions Regularly examine hemato-
nosuppressive activity. logic profile (particularly neu-
Drug Name Cyclophosphamide (Cytoxan, trophils and platelets) to mon-
Neosar) itor for hematopoietic sup-
pression; regularly examine
Description Chemically related to nitrogen
urine for RBCs, which may
mustards. As an alkylating
precede hemorrhagic cystitis;
agent, the mechanism of ac-
hematologic myelosuppres-
tion of the active metabolites
sion, primarily leukopenia, is
may involve cross-linking of
most common adverse effect;
DNA, which may interfere
thrombocytopenia and ane-
with growth of normal and
mia occur less frequently; gas-

trointestinal adverse effects in- Interactions Coadministration with estro-
clude anorexia, nausea, eme- gens may cause increase in
sis, and stomatitis; urologic clotting factors, leading to a
adverse effects include dysu- hypercoagulable state; coad-
ria, urgency, hematuria, blad- ministration with tretinoin my
der fibrosis, and necrosis; increase risk of both venous
death from hemorrhagic cysti- and arterial thrombosis
tis has occurred; encourage ex-
Pregnancy C - Safety for use during preg-
cessive fluid intake; interferes
nancy has not been estab-
with oogenesis and spermato-
lished.
genesis; may cause irreversi-
ble sterility in both sexes
Precautions Do not administer unless a
definite diagnosis of hyperfi-
Drug Category: Antifibrinolytic agents brinolysis has been made; cau-
tion in cardiac, hepatic or re-
Act through the inhibition of plasmin. nal disease; because amino-
caproic acid can be fatal in pa-
Drug Name Aminocaproic acid (Amicar)
tients with DIC, important to
Description Lysine analog that inhibits fi- differentiate between hyperfi-
brinolysis via inhibition of brinolysis and DIC; thrombi
plasminogen activator sub- that form during treatment
stances; to a lesser degree, are not lysed and effectiveness
through antiplasmin activity. is uncertain; associated ad-
Widely distributed. Half-life is verse effects are postural hy-
1-2 h. Peak effect occurs with- potension, thrombosis, and
in 2 h. Hepatic metabolism is muscular pain and weakness;
minimal. Can be used PO/IV. monitor CK levels; caution in
patients with upper urinary
Adult Dose 8 g q4h IV, then 16 g/d in
tract bleeding; caution with
acute attacks
rapid infusions; do not admin-
6-10 g/d PO maintenance
ister with factor IX complex
Pediatric 8-10 g/d PO concentrates or anti-inhibitor
Dose Not recommended in new- coagulant complexes; adverse
borns effects include bradyarrhyth-
Contraindi- Documented hypersensitivity; mia, drug-induced myopathy,
cations evidence of active intravascu- and hypotension
lar clotting process; coadmi-
nistration with factor IX com- Drug Name Tranexamic acid (Cyklokap-
plex concentrates or anti-in- ron)
hibitor coagulant complexes;
Description Alternative to aminocaproic
injection in premature neo-
acid. Inhibits fibrinolysis by
nates (injectable product con-
displacing plasminogen from
tains benzyl alcohol)
fibrin.

Adult Dose Up to 8 g PO/IV for acute at-
tacks Drug Category: Antigonadotropic agents
1-2 g PO for maintenance
3-4.5 g PO/IV qd divided These agents have immunosuppressive prop-
tid/qid pc; continue for peri- erties.
od long enough for at least 3-4 Drug Name Danazol (Danocrine)
attacks to have normally oc-
Description Increases levels of C4 compo-
curred
nent of complement and pre-
Pediatric 12-25 mg/kg/dose (not to ex- vents attacks associated with
Dose ceed 1.5 g) PO tid/qid for angioedema.
acute attack or as prophylaxis
Adult Dose 200 mg PO bid/tid initially; if
for 5 d
efficacious, taper dose by 50%
Contraindi- Documented hypersensitivity; over following 2-3 mo
cations active intravascular clotting
Pediatric Not established
process; acquired defective
Dose
color vision; subarachnoid
hemorrhage Contraindi- Documented hypersensitivity;
cations seizure disorders; renal or
Interactions Not established
hepatic insufficiency; cardiac
Pregnancy B - Usually safe but benefits disease; breastfeeding; condi-
must outweigh the risks. tions influenced by edema;
undiagnosed genital bleeding;
porphyria; carcinoma of the
Precautions Caution in renal impairment;
breast
adverse effects are not com-
mon but include headaches, Interactions Decreases insulin require-
nausea, abdominal pain, and ments and increases effects of
diarrhea; evidence of tumor anticoagulants; concomitant
formation in retina and liver administration with carbama-
found in experimental animal zepine may result in toxicity;
models after long-term use; coadministration with HMG-
although no evidence has sup- CoA reductase inhibitors may
ported these findings in hu- increase risk for rhabdomyoly-
mans, annual funduscopic ex- sis; cyclosporine and/or tacro-
aminations and LFT monitor- limus toxicity may increase if
ing recommended q6mo if on coadministered with danazol;
long-term therapy; perform concomitant use with carba-
baseline ophthalmologic ex- mazepine may increase risk of
amination before initiating carbamazepine toxicity; con-
therapy; caution in history of comitant administration with
thromboembolic disease and cyclosporine or tacrolimus
disseminated intravascular co- and anabolic steroids may re-
agulation sult in increased cyclosporine
or tacrolimus blood levels and

toxicity; may result in in- Pediatric <6 years: 1 mg/d PO
creased lovastatin plasma con- Dose 6-12 years: 2 mg/d PO
centrations when adminis- >12 years: Administer as in
tered concurrently (use only if adults
potential benefit justifies po-
Contraindi- Documented hypersensitivity;
tential risk of developing
cations nephrosis; breast or prostate
myopathy/rhabdomyolysis)
cancer
Pregnancy X - Contraindicated in preg-
Interactions Increases hypoprothrombine-
nancy
mic effects of oral anticoagu-
lants and hypoglycemic ef-
Precautions Caution in renal, hepatic, or fects of insulin and sulfonylur-
cardiac insufficiency and seiz- eas
ure disorders; peliosis hepati-
tis and benign hepatic adeno-
nancy
ma have been observed with
long-term therapy; throm-
boembolic events and pseudo- Precautions May cause peliosis hepatitis,
tumor cerebri reported; andro- liver cell tumors, and blood
genlike effects, including lipid changes with increased
weight gain, acne, hirsutism, risk of arteriosclerosis; caution
edema, hair loss, voice in cardiac, renal, or hepatic
change, and menstrual distur- disease or epilepsy; adverse
bances, occur; temporary al- effects include cholestatic
teration of lipoproteins may jaundice syndrome and/or
occur; consider the impact on hepatic necrosis (causing
the risk of atherosclerosis and death); may cause premature
coronary artery disease; se- epiphyseal closure in children;
rum total testosterone values caution in diabetic patients
may be falsely elevated if ra- and pediatric patients; may
dioimmunoassay done to cause suppression of clotting
measure testosterone in wom- factors II, V, VII, and X and an
en taking danazol increase in prothrombin time

Drug Name Stanozolol (Winstrol)
FOLLOW-UP
Description Synthetic androgen with im-
munosuppressive properties. Prognosis
Increases levels of C1 esterase
inhibitor and C4 component The prognosis is variable, but it predomi-
of the complement. nantly depends on control of the underlying
Adult Dose 2 mg PO tid and reduce to disorder.
maintenance dose of 2 mg/d Compared with the general population, pa-
or 2 mg qod after 1-3 mo tients with AAE have a higher incidence of
B-cell malignancies.

Patients with AAE and a concurrent diagno- Angioedema, Hereditary
sis of MGUS do not have an increased risk
for progression to malignancy compared Synonyms and related keywords: hereditary
with patients with a sole diagnosis of MGUS. angioedema, HAE, C1-INH, C1 inhibitor,
swelling of the skin
Patient Education

For excellent patient education resources, vis- Background
it eMedicine's Allergy Center and Skin, Hair, Hereditary angioedema (HAE) is an autoso-
and Nails Center. Also, see eMedicine's pa- mal dominant disorder of C1 inhibitor
tient education article Hives and Angioede- (C1-INH) deficiency manifested by painless,
ma. nonpruritic, nonpitting swelling of the skin.
Type I HAE is defined by low plasma levels
MISCELLANEOUS of a normal C1-INH protein. Type II HAE is
characterized by the presence of normal or
elevated levels of a dysfunctional C1-INH.
Special Concerns Type III HAE has been recently identified as
an estrogen-dependent inherited form of an-
Tranexamic acid may be used during preg- gioedema occurring mainly in women with
nancy. normal functional and quantitative levels of
C1-INH.

Pathophysiology
The gene for C1-INH (SERPING1) has been
mapped to 11q12-q13.1. C1-INH is a multi-
functional serine protease inhibitor that is
normally present in high concentrations in
plasma. It is the only known plasma inhibitor
of C1r and C1s, the activated proteases of the
first component of complement. It is also the
major plasma inhibitor of activated factor XII
(Hageman factor), the first protease in the
contact system. Additionally, C1-INH is one
of the major inhibitors of plasma kallikrein,
the contact system protease that cleaves kini-
nogen and releases bradykinin.
Presumably, uncontrolled activation of the
contact system allows for the release of kinin-
like mediators, resulting in edema of subcu-
taneous or submucosal tissues. Although the
issue of which vasoactive peptide is ulti-
mately responsible for these changes remains
controversial, direct evidence supports the
importance of bradykinin in the clinical man-
ifestations of angioedema. Other kinins may

also be pathogenic. The inciting factor re- Mortality/Morbidity
sponsible for inducing the release of these Mortality rates are estimated at 15-33%, re-
vasoactive peptides is unclear. Factor XII acti- sulting from laryngeal edema and asphyxia-
vation may be secondary to a genetic mutation.
tion or phospholipid release from damaged
or apoptotic cells and may be important in Race
the generation of bradykinin from endothe-
lial activation. This hypothesis encompasses Persons of any race can be affected, with no
the role of illness or tissue injury in the gener- reported bias in different ethnic groups.
ation of bradykinin.
HAE is due to mutations within the C1-INH Sex
gene (C1NH) and is transmitted as an autoso- Men and women are equally affected for
mal dominant trait. Approximately 150 dif- HAE types I and II. HAE type III was ini-
ferent genetic mutations have been described tially thought to occur only in women, but re-
in HAE, and a spontaneous mutation rate of cent family studies have described males
25% has been reported. The 2 variants of with HAE and normal C1 inhibitor levels.
HAE related to C1-INH function are type I Although a few male cases have been cited in
(85%) and type II(15%). the literature, HAE type III is still thought to
predominantly affect women.
Type I HAE is characterized by low antigenic
and functional plasma levels of a normal Age
C1-INH protein. Type II HAE is character-
C1-INH deficiency is present at birth,
ized by the presence of normal or elevated
although only a few patients have been re-
antigenic levels of a dysfunctional mutant
ported with perinatal angioedema. Symp-
protein together with reduced levels of the
toms usually become apparent in the first or
functional protein. C1-INH deficiency allows
second decade of life. Approximately 40% of
autoactivation of C1, with consumption of C4
people with HAE experience their first epi-
and C2. In type III HAE, the C1-INH protein
sode before age 5 years, and 75% present be-
is both qualitatively and functionally normal.
fore age 15 years. Patients typically experi-
The exact mechanism of action responsible
ence minor swelling in childhood that may
for the link between estrogen and angioede-
go unnoticed, with increased severity around
ma is unclear. One theory suggests that estro-
puberty. HAE is a lifelong affliction,
gen plays a role in up-regulating the produc-
although some report decreased symptoms
tion of bradykinin and decreasing its degra-
with age. Five percent of adults with HAE
dation by angiotensin-converting enzyme
are asymptomatic while carrying the C1NH
(ACE). A more recent theory suggests a mu-
mutation, and they are only identified after
tation in factor XII that allows for the inap-
their children are found to be symptomatic.
propriate activation of the kinin cascade.
CLINICAL
Frequency
History
International
HAE is estimated to occur in 1 in A family history of HAE is typically ob-
50,000-150,000 individuals. tained, although spontaneous mutations
may occur.
Symptoms are referable to 3 prominent

sites: subcutaneous tissues (face, hands, nal involvement.
arms, legs, genitals, and buttocks); ab-
dominal organs (stomach, intestines, blad- Physical
der, and kidneys), which may manifest as Physical signs include overt, noninflam-
vomiting, diarrhea, or paroxysmal colicky matory swelling of the skin and mucous
pain and mimic a surgical emergency; and membranes. Typical involvement includes
the upper airway (larynx) and tongue, the face, hands, arms, legs, genitalia, and
which may result in laryngeal edema and buttocks, although the edema can localize
upper airway obstruction. subcutaneously at any site. In some pa-
Attacks usually occur at a single site, but tients with severe edema, tension vesicles
simultaneous involvement of subcutane- or bullae may develop.
ous tissue, viscera, and the larynx is not In approximately 25% of patients, erythe-
uncommon. Nonpitting cutaneous swel- ma may precede the occurrence of edema.
ling is the most commonly reported symp- An estimated 30-50% of patients with
tom, and it mainly affects the extremities, HAE reportedly have erythema margina-
the genitalia, and the face. Acute abdomi- tum preceding or accompanying the at-
nal pain, nausea, and vomiting are the tacks. Urticaria is not usually associated
dominant symptoms in 25% of patients with HAE.
with HAE and are rarely seen in people Abdominal examination may reveal signs
with other forms of angioedema. The life- consistent with acute abdomen or abdomi-
time incidence of a laryngeal attack is esti- nal obstruction. Ascites is often present
mated at 70%. with an abdominal attack associated with
Mucosal edema of the bladder or urethra angioedema.
can result in urinary retention, stammer- Mucosal involvement with glossal, phar-
ing, pain, or anuria. yngeal, or laryngeal edema may cause res-
Episodes of severe headaches, visual dis- piratory obstruction and signs of distress.
turbances (eg, blurred vision, diplopia), Additional rare physical findings that
and ataxia have been reported. have been reported are pleuritic symp-
Cases of painful muscle swelling and uni- toms with pleural effusions, seizures and
lateral hip or shoulder involvement have hemiparesis secondary to cerebral edema,
also been cited. and bladder edema.
Attacks may be preceded several hours in Causes
advance by sudden mood changes, anxi-
ety, sensory changes, or exhaustion. Precipitating factors of attacks may in-
Patients often report episodes of swelling clude trauma (especially dental trauma),
worsening over a period of 12-24 hours, anxiety, menstruation, infection, exercise,
usually with resolution within 72 hours. alcohol consumption, and stress. Medica-
Symptoms can persist for up to 5 days, tions (eg, estrogen, ACE inhibitors, angio-
with migration of swelling to different tensin II type 1 receptor antagonists) have
sites. The edema is usually unresponsive also been shown to induce attacks.
to antihistamines. Attacks are usually peri- During pregnancy, symptoms may in-
odic and are commonly followed by crease or decrease for HAE types I and II.
weeks of remission. In HAE type III, studies have reported
Pediatric episodes are usually less fre- first episodes or recurrences associated
quent and commonly manifest as abdomi- with estrogen-containing oral contracep-

tives, estrogen replacement therapy, or Type II HAE
pregnancy. C1-INH level is normal or elevated but
As many as 2% of patients with HAE may dysfunctional.
have systemic lupus erythematosus. Less C4 and C2 levels are low.
commonly, other autoimmune disorders, C1q level is normal.
such as glomerulonephritis, rheumatoid Type III HAE
arthritis, thyroiditis, Sjögren syndrome, C1-INH level is normal.
and pernicious anemia, may be associated C1-INH functional assay is normal.
with HAE. C4 level may be normal.
Those HAE patients infected with Helico-
bacter pylori have been found to be more Imaging Studies
symptomatic than those who are not in- Abdominal radiographs may demonstrate
fected. features of ileus.
Abdominal ultrasonography or computed
DIFFERENTIALS tomography may show edematous thick-
Angioedema,Acquired ening of the intestinal wall, a fluid layer
Drug Eruptions around the bowel, and large amounts of
Urticaria,Acute free peritoneal fluid.
Urticaria,Cholinergic Chest radiographs may demonstrate pleu-
Urticaria,Chronic ral effusions.
Urticaria,Contact yndrome
Urticaria,Dermographism Histologic Findings
Urticaria,Pressure Histologic features include edema in the re-
Urticaria,Solar ticular dermis or subcutaneous or submu-
Urticarial Vasculitis cosal edema without infiltrating inflamma-
tory cells. Vasodilation may be present.
Other Problems to be Considered
TREATMENT
ACE inhibitor–induced angioedema
Episodic angioedema with eosinophilia
Vibratory- or pressure-induced angioedema Medical Care
Depending on the symptoms and the sites
WORKUP of the angioedema, intensive support may
Lab Studies be necessary, including intravenous fluids.
In cases of serious laryngeal edema caus-
Routine laboratory test results are usually ing respiratory obstruction, intubation or
normal, although a leukocytosis may occur tracheostomy should be performed. In
with gastrointestinal episodes. Elevation of HAE types I and II, the treatment of choice
the hematocrit value may be observed be- in acute attacks consists of replacement
cause of intravascular fluid loss. with commercially available C1-INH con-
centrates or, if unavailable, fresh-frozen
Type I HAE
plasma. In HAE type III, infusion of
C1-INH level is low.
C1-INH has proven to be ineffective.
C4 and C2 levels are low.
Prophylactic treatment is instituted if pa-
C1q level is normal.
tients are afflicted with frequent and/or

severe episodes. nin-2 receptor antagonist (icatibant), may
Danazol or stanozolol may be used at offer safer and more effective treatment
doses that prevent attacks; normalizing options. Several protease inhibitors have
the levels of C1-INH is not necessary. The been found to have functional overlap
most significant complication of long-term with C1-INH (eg, antithrombin III, beta-
use may be arterial hypertension. The macroglobulin, alpha1-antitrypsin) and
17-alpha-alkylated androgens rarely cause may be therapeutic options in the future.
hepatotoxicity and liver tumors, but they
should be used at the lowest effective dos- Surgical Care
age. Regular monitoring of liver function
test results, lipid levels, and liver ultraso- Intubation may be necessary in cases compli-
nography findings is recommended. cated by laryngeal edema.
Although virilization may be an issue with
women, keeping to the lowest possible MEDICATION
dose usually obviates this concern.
Contraindications to the use of androgens
include prostate cancer, pregnancy, child- The goals of pharmacotherapy are to reduce
hood, and breastfeeding. morbidity and to prevent complications.
Antifibrinolytic agents such as epsilon-
aminocaproic acid or tranexamic acid can Drug Category: Antigonadotropic agents
also be used for prophylaxis, although
they have not been found to be as effective These agents may be used at doses that pre-
as the androgenic agents. These agents are vent attacks.
the option for pregnant women. Drug Name Danazol (Danocrine)
Short-term prophylaxis for surgical proce- Description Increases levels of C4 compo-
dures, especially dental work, is neces- nent of complement and re-
sary. C1-INH infusions can be given 24 duces attacks associated with
hours before the procedure or just prior to angioedema. In HAE, danazol
it. Alternatives, such as antifibrinolytics or increases level of deficient C1
androgens, can be used, and they should esterase inhibitor.
be started 5 days before the procedure and
continued for 2 days afterwards. Adult Dose Short-term prophylaxis:
Eradication of the underlying cause of the 100-600 mg/d PO
attack, such as H pylori or another infec- Long term prophylaxis: 200
tious agent, may lead to resolution of mg PO tid; taper to lowest ef-
symptoms. Careful attention should be fective dose
given to medications being taken by the
patient that may have contributed to an at- Pediatric Not established
tack, such as contraceptives, hormone re- Dose
placement therapy, or ACE inhibitors.
Clinical trials are currently underway for Contraindi- Documented hypersensitivity;
several new therapies for acute attacks of cations seizure disorders; renal or
angioedema. The new therapies, such as hepatic insufficiency; cardiac
recombinant human C1-INH, recombinant disease; breastfeeding; condi-
kallikrein inhibitor (DX-88), and bradyki- tions influenced by edema;

undiagnosed genital bleeding; Interactions Increases hypoprothrombine-
porphyria mic effects of oral anticoagu-
lants and hypoglycemic ef-
Interactions Decreases insulin require-
fects of insulin and sulfonylur-
ments and increases effects of
eas
anticoagulants; may increase
carbamazepine levels Pregnancy X - Contraindicated in preg-
nancy
nancy
Precautions May cause peliosis hepatitis,
liver cell tumors, and blood
Precautions Caution in renal, hepatic, or
lipid changes with increased
cardiac insufficiency and seiz-
risk of arteriosclerosis; caution
ure disorders; peliosis hepati-
in cardiac, renal, or hepatic
tis and benign hepatic adeno-
disease or epilepsy; may in-
ma have been observed with
crease PT; phallic or clitoral
long-term therapy (>10 y);
enlargement, hirsutism, gyne-
thromboembolic events and
comastia, acne, edema, nau-
pseudotumor cerebri re-
sea, vomiting, and diarrhea
ported; androgenlike effects,
may occur
including weight gain, acne,
hirsutism, edema, hair loss,
voice changes, and menstrual
disturbances, occur Drug Category: Antifibrinolytic agents

Act through the inhibition of plasmin.
Drug Name Stanozolol (Winstrol)
Drug Name Epsilon-aminocaproic acid
Description Synthetic androgen with im- (Amicar)
munosuppressive properties.
Description Lysine analog that inhibits fi-
Increases levels of C1 esterase
brinolysis via inhibition of
inhibitor and C4 component
plasminogen activator sub-
of complement.
stances and, to a lesser degree,
Adult Dose 2 mg PO tid and reduce to through antiplasmin activity.
maintenance dose of 2 mg/d Widely distributed. Half-life is
PO or 2 mg PO qod after 1-3 1-2 h. Peak effect occurs with-
mo in 2 h. Hepatic metabolism is
Pediatric <6 years: 1 mg/d PO minimal. Can be used PO/IV.
Dose 6-12 years: 2 mg/d PO
>12 years: Administer as in Adult Dose Acute attack: 8 g q4h IV, then
adults 16 g/d
Contraindi- Documented hypersensitivity; Maintenance: 6-10 g/d PO
cations nephrosis; breast or prostate
cancer Pediatric 8-10 g/d PO
Dose Not recommended in new-

borns displacing plasminogen from
fibrin.
cations evidence of active intravascu- Adult Dose Acute attack: Up to 8 g PO/IV
lar clotting process; coadmi- Maintenance: 1-2 g PO
nistration with factor IX com-
plex concentrates or anti-in-
Pediatric 12-25 mg/kg/dose (not to ex-
hibitor coagulant complexes
Dose ceed 1.5 g) PO tid/qid recom-
Interactions Coadministration with estro- mended
gens may cause increase in
Contraindi- Documented hypersensitivity
clotting factors, leading to a
cations
hypercoagulable state
Interactions Not established
Pregnancy C - Safety for use during preg-
nancy has not been estab- Pregnancy B - Usually safe but benefits
lished. must outweigh the risks.

Precautions Do not administer unless a Precautions Caution in renal impairment;
definite diagnosis of hyperfi- adverse effects are not com-
brinolysis has been made; cau- mon but include headaches,
tion in cardiac, hepatic, or re- nausea, abdominal pain, and
nal disease; because amino- diarrhea; evidence of tumor
caproic acid can be fatal in pa- formation in retina and liver
tients with DIC (important to found in experimental animal
differentiate between hyperfi- models after long-term use;
brinolysis and DIC); thrombi although no evidence has sup-
that form during treatment ported these findings in hu-
are not lysed and effectiveness mans, annual funduscopic ex-
is uncertain; associated ad- aminations and LFT monitor-
verse effects are postural hy- ing recommended q6mo if on
potension, thrombosis, and long-term therapy; perform
muscular pain and weakness; baseline ophthalmologic ex-
monitor CK levels; caution in amination before initiating
patients with upper urinary therapy
tract bleeding; caution with
rapid infusions; do not admin- FOLLOW-UP
ister with factor IX complex
concentrates or anti-inhibitor
coagulant complexes Prognosis
Patients with an early onset of attacks
Drug Name Tranexamic acid (Cyklokap- have a worse prognosis than those with a
ron) late onset of attacks.
With appropriate use of prophylactic ther-
Description Alternative to aminocaproic apy, the prognosis for patients with HAE
acid. Inhibits fibrinolysis by is excellent.

Pathophysiology
Patient Education The pathophysiology of AD is poorly under-
stood. Several cell types seem to be involved,
For more information, visit the United including T lymphocytes, eosinophils, Lan-
States Hereditary Angioedema Associa- gerhans cells, and keratinocytes. Other fac-
tion. tors, including cytokines and IgE, are also im-
For excellent patient education resources, plicated.
visit eMedicine's Allergy Center and Skin, Laboratory findings suggest a number of dif-
Hair, and Nails Center. In addition, see ferent pathogenetic mechanisms. One in-
eMedicine's patient education article vokes an immune defect involving an abnor-
Hives and Angioedema. mality of T 2 cells that interacts with Langer-
H
hans cells and results in increased produc-
tion of interleukin (IL)–4, IL-5, IL-6, IL-10,
and IL-13. This leads to increased IgE and de-
creased gamma interferon levels. The imbal-
ance of T 2 cells occurs in the acute process,
Atopic Dermati- H
with a swing toward T 1 cells in the chronic
H

tis stages of the disease. Another theory in-
volves defective barrier function in the stra-
tum corneum leading to the entry of anti-
Synonyms and related keywords: infantile gens, which results in the production of vari-
eczema, Besnier's prurigo, intrinsic ecze- ous inflammatory cytokines.
ma, extrinsic eczema, atopiform eczema, Xerosis is known to be an associated sign in
asthma, food allergy, peanut allergy, allergic most AD patients. The xerosis is thought to
reaction involve defective lipid (particularly ceram-
ide) production. A third mechanism involves
environmental antigens from food (the gut),
INTRODUCTION
dust mites (the lungs), and other factors and
portals of entry that react with antibodies to
Background
produce increased levels of IgE and, possi-
Atopic dermatitis (AD) is a pruritic disease of bly, increased histamine reactions from mast
unknown origin that usually starts in early dells. Superimposed with these mechanisms
infancy and is typified by pruritus, eczema- is a genetic predisposition to react to various
tous lesions, xerosis (dry skin), and lichenifi- environmental allergens.
cation on the skin (thickening of the skin and
increase in skin markings). AD is associated Frequency
with other atopic diseases (eg, asthma, aller-
gic rhinitis, urticaria, acute allergic reactions
United States
to foods, increased immunoglobulin E [IgE]
The prevalence rate is 10-12% in children and
production) in many patients. It is a disease
0.9% in adults.
of great morbidity, and the incidence appears
to be increasing.
International
The prevalence rate is as high as 18% and is

rising, especially in developed countries. In beta-hemolytic group A Streptococcus.
China and Iran, the prevalence rate is ap- Urticaria and acute anaphylactic reactions
proximately 2-3%. The frequency is increased to food occur with increased frequency in
in patients who immigrate to developed patients with AD. The food groups most
countries from underdeveloped countries. commonly implicated include peanuts,
eggs, milk, soya, fish, and seafood.
Mortality/Morbidity Latex allergy is more common in patients
Incessant itch and work loss in adult life is a with AD than in the general population.
great financial burden. A number of studies Of patients with AD, 30% develop asthma
have reported that the financial burden to and 35% have nasal allergies.
families and government is similar to that of
asthma, arthritis, and diabetes mellitus. In Race
children, the disease causes enormous psy- AD may be more common among whites,
chological burden to families and loss of but it affects persons of all races.
school days. Mortality due to AD is unusual.
Sex
Kaposi varicelliform eruption (eczema her- The male-to-female ratio is 1:1.4.
peticum) is seen with some frequency in
patients with AD. It usually occurs with a Age
primary herpes simplex infection, but it al-
so may be seen recurrently. Vesicular le- In 85% of cases, AD occurs in the first year of
sions can begin at any location, but they life; in 95% of cases, it occurs before age 5
are particularly common in areas of ecze- years.
ma. The virus spreads rapidly to involve
all eczematous areas and healthy skin. Le- Disease is most prevalent in early infancy
sions may become secondarily infected. and childhood. The disease may have peri-
Although vaccination with the vaccinia ods of complete remission, particularly in
vaccine for the prevention of small pox is adolescence, and may then recur in early
now no longer mandatory, patients with adult life.
AD can contract eczema vaccinatum either In the adult population, the rate of AD fre-
from the vaccination of themselves or their quency diminishes to 0.9%. Rarely, onset
relatives. This condition had a high mor- may be delayed until adulthood, when the
tality rate (up to 25%). In the current cli- disease is more difficult to control.
mate of threats of bioterrorism, vaccina-
tion may once again become necessary
and physicians should be aware of eczema
vaccinatum in this setting. CLINICAL
With regard to bacterial infection (eg, with
Staphylococcus aureus or Streptococcus pyo- History
genes), note that the skin of most patients
Incessant pruritus is the only symptom.
with AD is colonized by S aureus. Clinical
Although pruritus may be present in the first
infection may occur and is worsened by
few weeks of life, parents become more
scratching and occlusion from medica-
aware of the itch as the itch-scratch cycle ma-
tions. Eczematous and bullous lesions on
tures when the patient is approximately age
the palms and soles are often infected with

3 months; children then scratch themselves Lesions become more diffuse with an
uncontrollably. underlying background of erythema. The
face is commonly involved and has a dry,
Physical scaling appearance.
Primary findings include xerosis, lichenifica- Xerosis is prominent.
tion, and eczematous lesions. The eczema- Lichenification is present.
tous changes are seen in different locations, A brown macular ring around the neck is
and the morphology changes with age. typical but not always present.
Hanifin diagnostic criteria: In 1980, Hani-
1
Infancy fin and Rajka developed criteria for the
AD may be noticed soon after birth. Xero- diagnosis of AD. They developed main cri-
sis also occurs in the neonatal period. Xe- teria and numerous minor criteria. Many
rosis involves the whole body but usually articles have questioned the validity of the
spares the diaper area. minor criteria, and the original criteria
The earliest lesions are often evident in the have been modified on numerous occa-
creases (ie, antecubital and popliteal fos- sions.
sae), where the lesions consist of erythema
with exudation. Over the following few Following are the criteria for 2001.
weeks, lesions localize to the cheeks and
forehead and extensors of the lower legs, Essential features: These features must be
but they may occur in any location on the present and, if complete, are sufficient for
body, often sparing the diaper area. Le- diagnosis.
sions are xerotic, erythematous, and scaly Pruritus
(eczematous) ill-defined patches and pla- Eczematous changes
ques. Typical and age-specific changes: Pat
The scalp is frequently involved with a terns in clude facial, neck, and
pruritic scaly dermatitis. extensor involvement in infants
Lichenification is seldom seen in infancy. and children, current or prior
Childhood flexural lesions in adults or per
Xerosis is often generalized. The skin is sons of any age, and sparing of
flaky and rough. the groin and axillary regions.
Lichenification is characteristic of child- Chronic and relapsing course
hood AD. It signifies repeated rubbing of Important features (seen in most
the skin and is seen mostly over the folds cases): These features are seen
and bony protuberances. in most cases and add support
Lesions are eczematous and exudative. to the diagnosis
Pallor of the face is common; erythema Early age of onset
and scaling occur around the eyes. Den- Atopy (IgE reactivity)
nie-Morgan folds (increased folds below Xerosis
the eye) are often seen. Flexural creases, Associated features (clinical associations):
particularly the antecubital and popliteal These changes help in suggesting the diag-
fossae, and buttock-thigh creases are often nosis of AD but are too nonspecific to be
affected. used for defining or detecting AD for re-
Excoriations and crusting are common. search and epidemiologic studies.
Adulthood Keratosis pilaris/ichthyosis/palmar

hyperlinearity aureus has been proposed as a cause of AD
Atypical vascular responses by acting as a superantigen.
Perifollicular changes AD flares occur in extremes of climate.
Ocular/periorbital changes Heat is poorly tolerated, as is extreme
Perioral/periauricular lesions cold. A dry atmosphere increases xerosis.
Exclusions: Note that a firm diagnosis of Sun exposure improves lesions, but sweat-
AD depends on excluding conditions such ing increases pruritus. All these external
as scabies, allergic contact dermatitis, se- factors may act as antigens, ultimately set-
borrheic dermatitis (SD), cutaneous lym- ting up an inflammatory cascade.
phoma, ichthyosis, psoriasis, and other pri- The role of food antigens in the pathogene-
mary disease entities. sis of AD is controversial, both in the pre-
vention of AD and by their effect with
Williams diagnostic criteria: According to withdrawal of certain foods in persons
the criteria of Williams et al, proposed di- with established AD. Most reported re-
agnostic guidelines include the following: search has methodologic flaws. One article
1. Patients must have an itchy skin condition showed improvement at 1 year with con-
(or parental report of scratching or rub- tinued breastfeeding. At 4 years, no differ-
bing in children). ence was noted in the incidence of AD be-
2. Patients also must have 3 or more of the tween the group that had not been exclu-
following: sively breastfed and the group that had.
A role for aeroallergens and house dust
History of involvement of the skin mites has been proposed, but this awaits
creases, such as folds of the elbows, behind further corroboration.
the knees, fronts of the ankles, or neck
Personal history of asthma or hay fever or
a history of atopic disease in a first-degree DIFFERENTIALS
relative in patients younger than 4 years
History of generally dry skin in the last Contact Dermatitis,
year Allergic Contact Dermatitis,
Visible flexural dermatitis or dermatitis in- Irritant
volving the cheeks or forehead and outer LichenSimplexChronicus
limbs in children younger than 4 years NummularDermatitis
Onset younger than age 2 years (not used Psoriasis,
if child is <4 y) Plaque
Scabies
Causes SeborrheicDermatitis
TineaCorporis
A genetic abnormality is possibly related
to bands 11q13 or 5q31.These findings Other Problems to be Considered
have yet to be corroborated; a family his-
tory of AD is common. Immunodeficiency
The skin of patients with AD is colonized Mycosis fungoides
by S aureus. Lesions flare following infec-
tion by S aureus, but they may occur with AD occasionally is indistinguishable from
any type of skin or systemic infection. S other causes of dermatitis. In infancy, the

most common difficulty is distinguishing it age of appearance, and an early onset (in
from SD. This entity is not seen with the AD) help distinguish between the 2 condi-
same frequency as a decade ago. Both AD tions.
and SD are associated with cradle cap (a
scale found on the vertex of the scalp), which
is greasy and yellow in individuals with SD WORKUP
and dry and crusted in individuals with AD.
Other areas of involvement in SD are the in- Lab Studies
tertriginous areas, where marked erythema
and a greasy scale can be seen over the eye-
brows and the sides of the nose. In AD, xero- Laboratory testing is seldom necessary.
sis of the skin and severe pruritus are seen, Allergy and radioallergosorbent testing is
which are not usually features of SD. Both of little value.
conditions should be distinguished from A platelet count for thrombocytopenia
psoriasis. helps exclude Wiskott-Aldrich syndrome,
Scabies manifests in infancy or childhood as and testing to rule out other immunodefi-
a pruritic eruption. Other members of the ciencies may be helpful.
family may be itchy, and the primary sites of Scraping to exclude tinea corporis is occa-
involvement are moist warm areas. The erup- sionally helpful.
tion is polymorphic with a dermatitis, nod-
ules, urticaria, and 6-10 burrows. Pustules on
the hands and feet are common in infancy. Histologic Findings
Facial involvement is rare, and xerosis does Biopsy shows an acute, subacute, or chronic
not occur. dermatitis, but no specific findings are dem-
Other causes of dermatitis, particularly con- onstrated.
tact dermatitis from nickel in infants, are
sometimes difficult to distinguish from AD.
A central area of dermatitis (from nickel TREATMENT
snaps in undershirts or snaps in jeans) is
helpful for making the diagnosis, although a
Medical Care
dermatitic eruption may occur as an Id reac-
tion in other areas, particularly the antecubi- Patients with AD do not usually require
tal fossae. Xerosis and facial involvement are emergency therapy, but they may visit the
absent. AD usually starts earlier than contact emergency department for treatment of acute
dermatitis. flares caused by eczema herpeticum and bac-
Children with a severe itch and generalized terial infections.
dermatitis in the setting of recurrent infec-
tions should be investigated for evidence of Moisturization
an immunodeficiency. Failure to thrive and Depending on the climate, patients may
repeated infections help distinguish the erup- benefit from short, cool showers or baths
tion from AD. followed by the application of a moistur-
Tinea corporis usually manifests as a single izer such as white petrolatum. Another
lesion, but inappropriate treatment with ste- regimen includes "soaking and greasing."
roids may cause a widespread dermatitis. Fa- Frequent baths with oil (1 capful of emulsi-
cial involvement, the presence of xerosis, the fying oil added to lukewarm bath water)

for 5-10 minutes comprise this regimen. In modulator and acts as a calcineurin inhibi-
infants, 3 times a day is not a great bur- tor. Studies have shown excellent results
den; in adults, once or twice a day is usu- compared with placebo and hydrocorti-
ally all that can be achieved. Leave the sone 1%. Little absorption occurs. A sting-
body wet after bathing. Oil and water are ing sensation may occur following applica-
kept in solution by an emulsifier in the oil, tion, but this can be minimized by apply-
thus preventing evaporation of water to ing the medication only when the skin is
the outside environment. very dry. The burning usually disappears
Advise patients to apply an emollient such within 2-3 days. Tacrolimus is available in
as petrolatum all over the body while wet, 2 strengths, 0.1% for adults and 0.03% for
to seal in moisture and allow water to be children, although some authorities rou-
absorbed through the stratum corneum. tinely use the 0.1% preparation in chil-
The ointment spreads well on wet skin. dren. Tacrolimus is an ointment and is in-
Topical steroids dicated for moderate-to-severe AD. The
Topical steroids are currently the mainstay latter is indicated for children older than 2
of treatment. In association with moisturi- years.
zation, responses to this regimen are excel- Pimecrolimus 1% is also an immunomodu-
lent. lator and calcineurin inhibitor. It is more
Ointment bases are preferred, particularly effective than placebo. Pimecrolimus is
in dry environments. produced in a cream base for use twice a
Patients with AD may develop a contact day; it is indicated for mild AD in persons
allergy to topical medications and moistur- older than 2 years.
izers. The allergy may be to a preservative A recent black box warning has been is-
or the active ingredient. Allergy to hydro- sued in the United States based on re-
cortisone is recognized with increasing fre- search that has shown an increase in ma-
quency. Preservatives are less commonly lignancy in associated with the calcineurin
present in ointments. inhibitors. While these claims are being in-
Initial therapy consists of hydrocortisone vestigated further, the medication should
1% powder in an ointment base applied 3 likely only be used as indicated (ie, for AD
times daily to lesions on the face and in in persons older than 2 y and only when
the folds. first-line therapy had failed).
A midstrength steroid ointment (desonide Other treatments, effective and ineffective
for milder areas or higher-strength ste- Probiotics have recently been explored as
roids such as triamcinolone or betametha- a therapeutic option for the treatment of
sone valerate for more severe areas) is ap- AD. The rationale for their use is that bac-
plied daily to lesions on the trunk until the terial products may induce an immune re-
eczematous lesions clear. sponse of the T 1 series instead of T 2
H H
Steroids are discontinued when lesions
and could therefore inhibit the develop-
disappear and are resumed when new
ment of allergic IgE antibody production.
patches arise.
This research, although garnering fairly
Flares may be associated with seasonal
convincing support, has yet to be proven.
changes, stress, activity, staphylococcal in-
UV-A, UV-B, a combination of both, psora-
fection, or contact allergy.
len plus UV-A (PUVA), or UV-B1 (narrow
Immunomodulators
band UV-B) therapy may be used. Long-
Tacrolimus (topical FK506) is an immuno-
term adverse effects of skin malignancies

in fair-skinned individuals should be Clothes should be washed in a mild deter-
weighed against the benefits. gent with no bleach or fabric softener.
In patients with eczema herpeticum, acy-
clovir is effective. Consultations
In patients with severe disease, and partic- Consulting an allergist may be necessary,
ularly in adults, phototherapy, methotrex- particularly if the patient develops asthma
ate (MTX), azathioprine, and cyclosporine and/or hay fever or an acute reaction to a
have been used with success. type of food.
Both hydroxyzine and diphenhydramine
hydrochloride provide a certain degree of
relief from itching but are not effective Diet
without other treatments.
Ketotifen (a calcium channel blocker) may Avoid foods that provoke acute allergic re-
be effective. actions (hives, anaphylaxis). Most fre-
Oil of evening primrose was believed to be quently, allergic reactions occur to peanuts
effective, but in a randomized controlled (peanut butter), eggs, fish and seafood,
study, it showed no benefit in children milk, soya, and chocolate.
and little improvement in adults. Advise patients to apply a barrier of petro-
Results with many other medications, leum jelly around the mouth prior to eat-
such as thymopentin, gamma interferon, ing to prevent irritation from tomatoes, or-
and Chinese herbs, have been disappoint- anges, and other irritating foods.
ing. Many medications are not practical to
use, and they can be expensive. Some Chi-
nese herbal preparations contain prescrip- Activity
tion medications, including prednisone. Advise patients to avoid activities that
Antibiotics are used for the treatment of cause excessive sweating.
clinical infection caused by S aureus or Swimming in an outdoor pool (or wading
flares of disease. They have no effect on pool for babies) in summer provides thera-
stable disease in the absence of infection. peutic benefit by exposing the person to
Laboratory evidence of S aureus is not evi- the sun but avoiding the heat.
dence of clinical infection because staphy-
lococcal organisms commonly colonize the MEDICATION
skin of patients with AD.
Nonmedical efforts
The basis of treatment is to provide moisturi-
Clothing should be soft next to the skin.
zation for dryness, allay pruritus, and man-
Cotton 100% is comfortable and can be lay-
age inflammation of the eczematous lesions.
ered in the winter.
Cool temperatures, particularly at night,
Drug Category: Anti-inflammatory agents
are better because sweating causes irrita-
tion and itch.
Provide relief of inflammation of eczematous
A humidifier (cool mist) prevents excess
lesions. Ointment base provides moisturiza-
drying and should be used in both winter,
tion. White petrolatum is useful to avoid po-
when the heating dries the atmosphere,
tential sensitization to preservatives in water-
and in the summer, when the air condi-
based moisturizers.
tioning absorbs the moisture from the air.

Drug Name Hydrocortisone (LactiCare and reversing capillary per-
HC, Cortaid, Westcort, Der- meability. Affects production
macort, DermaGel) of lymphokines and has inhib-
itory effect on Langerhans
Description Mild topical corticosteroid
cells.
mixed in petrolatum for facial
Use 0.05-0.1% ointment in
application. Has mineralocor-
adults and 0.05% ointment in
ticoid and glucocorticoid ef-
pediatrics.
fects, resulting in anti-inflam-
matory activity. Adult Dose Apply topically bid/tid until
Use 1% ointment daily. response; discontinue when
cleared
Adult Dose Apply sparingly to affected
areas bid/tid; discontinue Pediatric Administer as in adults
when cleared Dose
Pediatric Apply as in adults Contraindi- Documented hypersensitivity;
Dose cations skin infections
Contraindi- Documented hypersensitivity; Interactions None reported
cations clinical viral, fungal, and bac-
Pregnancy C - Fetal risk revealed in stud-
terial skin infections
ies in animals but not estab-
Interactions None reported lished or not studied in hu-
mans; may use if benefits out-
weigh risk to fetus
lished or not studied in hu-
mans; may use if benefits out- Precautions Do not use in skin with de-
weigh risk to fetus creased circulation; can cause
atrophy of groin, face, and ax-
illae; may cause striae disten-
Precautions Caution around eyes and in
sae in teenagers or rosacealike
stasis dermatitis, prolonged
eruption; may increase skin
use, and application over
fragility; rarely, may suppress
large surface areas; occlusive
HPA axis; if infection is
dressings may increase sys-
present, discontinue use until
temic absorption of corticoste-
infection is under control
roids

Drug Name Betamethasone valerate (Beta- Drug Category: Antihistamines
trex, Valisone, Luxiq)
Description Medium-strength topical cor- Provide symptomatic relief of pruritus.
ticosteroid for body areas. De- Drug Name Hydroxyzine hydrochloride
creases inflammation by sup- (Atarax)
pressing migration of poly-
Description Antihistamine with antiprur-
morphonuclear leukocytes
itic, anxiolytic, and mild seda-

tive effects. Antagonizes H1 Pediatric Cap
receptors in periphery. May Dose <10 years: Not recommended
suppress histamine activity in >10 years: 25 mg PO tid/qid
subcortical region of CNS. prn
Syrup available as 10 mg/5 Elix (12.5 mg/5 mL)
mL. 6-12 years: 5-10 mL PO q4-6h
prn; not to exceed 4 doses/d
Adult Dose 25-50 mg PO tid/qid prn
>12 years: Administer as in
Pediatric <6 years: 30-50 mg/d PO (2 adults
Dose mg/kg/d) in divided doses Children's liquid (6.25 mg/5
>6 years: 50-100 mg/d PO in mL)
divided doses <2 years: 2.5 mL q4-6h prn
Contraindi- Documented hypersensitivity 2-6 years: 5 mL q4-6h prn
cations 6-12 years: 10-20 mL q4-6h
prn; not to exceed 4 doses/d
Interactions CNS depression may increase or 5 mg/kg/d
with alcohol or other CNS de-
pressants Contraindi- Documented hypersensitivity;
cations children with chronic lung
Pregnancy C - Fetal risk revealed in stud- disease; glaucoma
lished or not studied in hu- Interactions Potentiates effect of CNS de-
mans; may use if benefits out- pressants; as a result of alco-
weigh risk to fetus hol content, do not administer
elix to patient taking medica-
tions that can cause disulfir-
Precautions Associated with clinical exac- amlike reactions
erbations of porphyria (may
not be safe for patients with Pregnancy C - Fetal risk revealed in stud-
porphyria); ECG abnormal- ies in animals but not estab-
ities (alterations in T waves) lished or not studied in hu-
may occur; may cause drowsi- mans; may use if benefits out-
ness; caution operating auto- weigh risk to fetus
mobiles and other dangerous
machinery; anticholinergic ef- Precautions May exacerbate angle-closure
fects (ie, dry mouth) may oc- glaucoma, hyperthyroidism,
cur peptic ulcer, or urinary tract
obstruction; xerostomia may
Drug Name Diphenhydramine (Benadryl) occur; caution operating auto-
mobiles and other dangerous
Description Antihistamine used for pruri- machinery because of possible
tus and allergic reactions. sedation; as a result of atro-
Adult Dose Cap: 25-50 mg tid/qid prn pinelike action, caution in his-
Elix: 10-20 mL (12.5 mg/5 mL) tory of bronchial asthma, in-
q4-6h; not to exceed 4 doses/d creased intraocular pressure,
hyperthyroidism, cardiovas-

cular disease, or hypertension cations uncontrolled hypertension or
malignancies; do not adminis-
ter concomitantly with PUVA
or UV-B radiation in psoriasis
because may increase risk of
Drug Category: Immunomodulators cancer
Interactions Carbamazepine, phenytoin,
For treatment of patients with severe disease isoniazid, rifampin, and phe-
in whom conventional therapy is ineffective. nobarbital may decrease con-
In more severe cases and particularly in centrations; azithromycin, itra-
adults, consider using both MTX and cyclo- conazole, nicardipine, ketoco-
sporine. The latter is more efficacious, but le- nazole, fluconazole, erythro-
sions recur when it is stopped. mycin, verapamil, grapefruit
Drug Name Cyclosporine (Neoral, San- juice, diltiazem, aminoglyco-
dimmune) sides, acyclovir, amphotericin
B, and clarithromycin may in-
Description Demonstrated to be helpful in
crease toxicity; acute renal fail-
a variety of skin disorders, es-
ure, rhabdomyolysis, myosi-
pecially psoriasis. Acts by in-
tis, and myalgias increase
hibiting T-cell production of
when taken concurrently with
cytokines and ILs. Like tacroli-
lovastatin
mus and pimecrolimus (asco-
mycin), cyclosporine binds to Pregnancy C - Fetal risk revealed in stud-
macrophilin and then inhibits ies in animals but not estab-
calcineurin, a calcium-de- lished or not studied in hu-
pendent enzyme, which, in mans; may use if benefits out-
turn, inhibits phosphorylation weigh risk to fetus
of nuclear factor of activated T
cells and inhibits transcription Precautions Evaluate renal and liver func-
of cytokines, particularly IL-4. tions often by measuring
Discontinue treatment if no re- BUN, serum creatinine, serum
sponse within 6 wk. bilirubin, and liver enzyme
Adult Dose 2 mg/kg/d PO divided bid; if levels; may increase risk of in-
no improvement within 1 mo, fection and lymphoma; re-
may be increased gradually; serve IV use only for patients
not to exceed 5 mg/kg/d who cannot take PO; develop-
As skin lesions improve, re- ment of malignancies (particu-
duce dose by 0.5-1 larly skin) has been reported;
mg/kg/d/mo; lowest effec- perform biopsy on skin sug-
tive dose for maintenance gestive of malignancy or pre-
malignancy and, if malignant,
Pediatric 3-5 mg/kg/d PO
discontinue
Dose

Drug Name Methotrexate (Folex PFS, Pregnancy D - Fetal risk shown in hu-
Rheumatrex) mans; use only if benefits out-
weigh risk to fetus
Description Antimetabolite that inhibits
dihydrofolate reductase,
thereby hindering DNA syn- Precautions Monitor CBC counts monthly
thesis and cell reproduction. and liver and renal function
Satisfactory response seen in q1-3mo during therapy (moni-
3-6 wk following administra- tor more frequently during in-
tion. itial dosing, dose adjustments,
Adjust dose gradually to at- or when risk of elevated MTX
tain satisfactory response. levels, eg, dehydration); has
toxic effects on hematologic,
Adult Dose 10-25 mg/wk PO/IM or
renal, GI, pulmonary, and
2.5-7.5 mg PO q12h for 3
neurologic systems; discon-
doses/wk
tinue if significant drop in
Pediatric Not established blood counts occurs; fatal re-
Dose actions reported when admin-
Contraindi- Documented hypersensitivity; istered concurrently with
cations alcoholism; hepatic insuffi- NSAIDs
ciency; documented immuno-
deficiency syndromes; preex- Drug Name Tacrolimus (Protopic)
isting blood dyscrasias (eg,
bone marrow hypoplasia, leu- Description Immunomodulator that sup-
kopenia, thrombocytopenia, presses humoral immunity (T-
significant anemia); renal in- lymphocyte) activity. Used for
sufficiency refractory disease.

Interactions Oral aminoglycosides may de- Adult Dose Apply a thin layer to affected
crease absorption and blood areas bid; continue for 1 wk
levels of concurrent oral MTX; after symptoms clear
charcoal lowers MTX levels; Pediatric <2 years: Not established
coadministration with etreti- Dose 2-15 years: Administer as in
nate may increase hepatotox- adults
icity of MTX; folic acid or its
derivatives contained in some
cations
vitamins may decrease re-
sponse to MTX; probenecid, Interactions Topical tacrolimus is mini-
NSAIDs, salicylates, procarba- mally absorbed; however, lev-
zine, and sulfonamides, in- els may increase with diltia-
cluding TMP-SMZ, can in- zem, nicardipine, clotrima-
crease MTX plasma levels; zole, verapamil, erythromy-
may decrease phenytoin plas- cin, ketoconazole, itracona-
ma levels; may increase plas- zole, fluconazole, bromocrip-
ma levels of thiopurines tine, grapefruit juice, metoclo-

pramide, methylprednisolone, acted on by DNA polymerase.
danazol, cyclosporine, cimeti- Patients experience less pain
dine, or clarithromycin; levels and faster resolution of cuta-
may reduce with rifabutin, ri- neous lesions when used with-
fampin, phenobarbital, pheny- in 48 h of rash onset. May pre-
toin, and carbamazepine vent recurrent outbreaks.
Early initiation of therapy is
imperative. Zoster dose is 4
times higher than that for her-
lished or not studied in hu-
pes simplex. Duration of ther-
mans; may use if benefits out-
apy varies.
weigh risk to fetus
Adult Dose 200-800 mg PO qid for 5-10 d
started within 24 h of appear-
Precautions Do not use with occlusive
ance of rash
dressings; may be associated
with an increased risk of vari- Pediatric 5-20 mg/kg PO qid for 5-10 d
cella zoster virus infection, Dose (susp 200 mg/5 mL) started
HSV infection, or eczema her- within 24 h of appearance of
peticum; increased risk for rash
myeloma development (if de-
velop lymphadenopathy, in-
cations
vestigate etiology); may cause
local burning sensation, sting- Interactions Concomitant use of probene-
ing, soreness, or pruritus (typ- cid or zidovudine prolongs
ically improve as lesions heal); half-life and increases CNS
for external use only; mini- toxicity
mize exposure to natural or Pregnancy C - Fetal risk revealed in stud-
artificial sunlight (eg, tanning ies in animals but not estab-
beds or UVA/B treatment); be lished or not studied in hu-
sure skin is completely dry be- mans; may use if benefits out-
fore application weigh risk to fetus

Precautions Caution in renal failure or
Drug Category: Antiviral agents
when using nephrotoxic
drugs; has caused mutagene-
For management of herpetic infections and to
sis in some studies at high
treat AD in patients who develop chicken-
concentrations
pox.
Drug Name Acyclovir (Zovirax)
Description Inhibits activity of both HSV-1 Drug Category: Antibiotics
and HSV-2. Has affinity for vi-
ral thymidine kinase and, Empiric antimicrobial therapy must be com-
once phosphorylated, causes prehensive and should cover all likely patho-
DNA-chain termination when gens in the context of the clinical setting. For

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