Transcript Part II: Contact Dermatitis & Drug Eruptions

Part II: Contact Dermatitis &
Drug Eruptions
Andrew’s Chapter 6
JoAnne M.LaRow, D.O.
Drug Reactions
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Adverse reactions occurs at low rate- 1/1000
exposures
Except for commonly used meds-semisynthetic
penicillins and sulfamethoxazole/trimethoprim –
30-50/1000
Presence of HIV disease or EBV infection
increases rate
One of the most common reasons pts visit
dermatologist
Pt evaluation
Three rules:
1.) stop all unnecessary meds
2.) ask about nonprescription
meds and meds delivered
by other meanssuppositories,eye drops,
implants, patches, etc
3.) no matter how atypical
the presentation always
consider pts meds as a
possible cause
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Diagnose cutaneous
eruption by clinical
pattern(ie urticaria,
exanthem, vasculitis,
erythema multiforme, etc)
 Ask two questions:
1.) which med can cause this
pattern of rxn?
2.) how commonly does this
med cause this rxn
pattern?
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Additional testing?
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Skin testing is most
useful in evaluating
type I (immediate)
hypersensitivity
Skin testing is most
frequently used in
evaluating adverse
rxn’s to penicillin,
local anesthetics,
insulin, and vaccines
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Radioallergosorbent
(RAST) tests have
20% false-neg rate in
penicillin type I
allergy
Therefore RAST must
be followed by skin
testing
RAST test cannot
replace skin testing
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Pathogenesis
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In most patterns
pathogenesis is
UNKOWN!!
Drug rxn’s are often
nonimmunologic
May result from normal
pharmacologic effects of
drug- ie urticaria
worsening from aspirin
ingestion
Rxn’s may be
immunologic, based on an
immune response by the pt
to the drug or its
matabolite
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The pts metabolism of
medication may determine
the likelihood of a rxn
occurring
As in anticonvulsant and
sulfonamide rxn’s, the P450 system of individuals
generates toxic
metabolites of the med
that binds to proteins and
stimulates an
immunologic rxn
This defect can be found
in family members and is
linked to HLA subtypes
Immune status and clinical
condition may be a factorAIDS pts-may be related
to glutathione deficiency
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Commonest form of
adverse cutaneous
eruption
Characterized by
erythema, often with
papules throughout
Tend to occur within the
first two weeks of tx, but
may occur later, even up
to 10 days after tx
Lesions first appear
proximally-especially
groin and axilla,
generalizing within 1-2
days
Pruritus is usually
prominent-a
distinguishing factor from
a viral exanthem
Exanthems
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Most common cause of
this rxn patternantibiotics, especially
semi-synthetic penicillins
&
sulfamethoxazole/trimetho
pirm
Ampicillin given during
infectious mononucleosis
and Bactrim given to
AIDS pts cause exanthems
in a large # of pts treated
Morbilliform rxn’s to
amoxicillin are likely
mediated by helper T cells
similar to ACD and
tuberculin rxn’s
Exanthems
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Morbilliform drug
eruption caused by
sulfonamide
Exanthems
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Simple exanthemssupportive tx
Eruption may resolve even
if offending med is
continued
Topical steroidal
medications and
antihistamines may allow
course of tx to be
completed
Rechallenge may or may
not result in reappearance
of eruption
In HIV infection and
rarely, in persons with
normal immune status
rechallenge may result in a
more severe blistering rxn
Treatment
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Complex exanthems or
hypersensitivity
syndromes are seen
mostly with
anticonvulsants, and longacting sulfonamides; less
commonly with
allopurinol, gold, dapsone,
and sorbinil
These present with fever,
rash, and variably , with
eosinophilia,
lymphadenopathy,
hepatitis, nephritis, and
rarely heart, lung & brain
Anticonvulsant Hypersensitivity
Syndrome
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Can be seen withdiphenylhydantoin,
phenobarbital,
carbamazepine, and
other anticonvulsants
Eruption may occur in
as many as 1 of 5000
pts tx with these meds
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Skin eruption is typically
initially morbilliform, but
may have various
morphologies in different
pts at different times
Histologic picture is
compatible with clinical
morphology
Syndrome begins with
fever between 2 and 6
weeks after agent is
started
Eruption begins with
prominent facial swelling
Anticonvulsant Hypersensitivity
Syndrome
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Associated findings:
pharyngitis,
lymphadenopathy,
hepatosplenomegaly
Lab abnormalities:
eosinophilia, atypical
lymphocytosis, elevated
liver function tests, and
occasionally nephritis
Untreated pts can lead to
death from hepatitis
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Pathogenesis is an
inability to detoxify arene
oxide metabolites of these
meds
Metabolites bind to
proteins and elicit an
immune response leading
to an adverse drug rxn
Cross-rxn with different
anticonvulsants are
common (because meds
are metabolized by same
pathway)
Management
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Ruling other infectious
etiologies
Discontinue offending
med
Supportive tx
If liver or renal
involvement or pt is ill
requires hospitalization,
systemic steroids may be
used
Sulfonamide Hypersensitivity
Syndrome
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Clinical syndrome similar
to anticonvulsants
Pts develop severe bullous
rxn like Stevens-Johnson
syndrome or TEN
Pts with this are almost
always slow acetylators
who produce toxic
hydroxylamine
metabolites during
metabolism of the
sulfonamide
Allopurinol Hypersensitivity
Syndrome
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Typically occurs in pts
with preexisting renal
failure, whose dose is not
adjusted for their renal
function
Weeks to months (average
7 weeks) after allopurinol
is begun, a morbilliform
eruption (50%) that often
evolves to an exfoliative
erythroderma(20%)
Bullous eruptions
including TEN’s may
occur(25%) may occur
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Associated with the
dermatitis is fever,
eosinophilia, sometimes
hepatitis, and typically
worsening renal failure
Syndrome may be steroid
responsive, but is slow to
resolve
Frequently lasts months
after allopurinol has been
stopped
About 25% of pts die as a
consequence
Dialysis does not
accelerate resolution of
this syndrome-
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Exfoliative dermatitis
caused by allopurinol
Drug-Induced
Pseudolymphoma
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True pseudolymphoma
rxn’s are rare
Histology must be
consistent with the
diagnosis of lymphoma
Exposure to a med will
result in cutaneous
inflammatory infiltrates
that resemble lymphoma
Most frequently MF
Usually other features like
keratinocyte necrosis and
dermal edema help to
distinguish these rxn’s
from true lymphoma
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T-cell receptor gene
rearrangements in skin
and blood may be positive
in these drug-induced
cases
More rarely, meds may
induce plaques or nodules,
usually in elderly white
men after months of tx
Lymphadenopathy and
circulating Szary cells
may also be present
Pseodolymphoma resolves
with discontinuation of the
med
Primary meds
responsible:anticonvulsant
s, sulfa drugs, dapsone,
and antidepressants
Urticaria
Urticaria
Urticaria
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Secondary to
amoxicillin
Urticaria
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Meds may induce urticaria
by immunologic and
nonimmunologic
mechanisms
Clinically lesions are
wheals or angioedema
Urticaria may be part of a
more severe anaphylactic
rxn with bronchospasm,
laryngospasm, or
hypotension
Immediate
hypersensitivity skin
testing and sometimes
RAST tests are useful in
evaluating risk for these
patterns of rxn
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Aspirin and nonsteroidal
anti inflammatory drugs
are the most common
cause of nonimmunologic
urticarial rxn’s
They alter prostaglandin
metabolism, enhancing
degranulation of mast
cells
They may also exacerbate
chronic urticaria of other
causes
Nonacetylated
salicylates(Trisisate and
salsalate) do not crossreact with aspirin in pts
experiencing
bronchospasm and may be
safe alternatives
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Immunologic urticaria is
most commonly
associated with penicillin
and related beta-lactam
antibioics
It is associated with IgE
antibodies to penicillin or
its metabolite
Skin testing is useful in
evaluating pts with a
history of urticaria
associated with penicillin
exposure
If pt is positive , an
alternative antibiotic must
be considered , or pt may
be given a desensitization
protocol
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Most pts with a history of
penicillin “ allergy”are
skin test neg
These pts ca be tx with a
low liklihood of a severe
adverse event
Pts with pen allergy have
an increased rate of rxn to
cephalosporins
Third-generation
cephalosporins are much
less likely to induce a rxn
in a pcn allergic pt than
the first- or second
generation ones
In the case of Cefaclor,
half of ana phylactic rxn’s
occur in pts with a history
of pcn allergy
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Angioedema is a known
complication of the use of
ACE inhibitors
Blacks are nearly five
times greater risk than
whites
Lisinopril and enalapril
produce angioedema more
commonly than captopril
Episodes may reqire
hospitalization 45% of the
time, ICU 27% of the
time, and intubation 18%
of the time
One quarter of pts give a
history of previous
angioedema
Captopril enhances the
flare rxn around wheals
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Angioedema is dose
dependent, as it may
resolve with decreased
dose
These factors suggest that
the angioedema may
represent a consequence
of a normal
pharmacologic effect of
the ACE inhibitors
Blocking of kininase II by
ACE inhibitors may
increase tissue kinin
levels, enhancing
urticarial rxn’s and
angioedema
Although dose dependent,
ACE inhibitor users with
one episode of
angioedema have a ten-
Angioedema
Angioedema
Photosensivity Reactions
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Meds may cause
phototoxic (sunburn-like)
reactions, lichenoid
reactions,
pseudoporphyria
Most drug-induced
photosensitivity is
triggered by radiation in
the UVA range
Most common drugs
implicated are: NSAIDs,
sulfamethoxazole/trimetho
prin, thiazide diuretics and
related sulfonylureas,
quinine and quinidine, and
certain tetracyclines
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Phototoxic reactions are
related to dose of both
med and UV irradiation
Does not require prior
exposure or participation
by the immune system
Rxn’s can appear from hrs
to days after to exposure
Tetracyclines(especially
demeclocyline),
amiodarone, and the
NSAIDs are common
culprits
Ts may include dose
reduction and
photoprotection
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Photoallergic reactions are
typically eczematous,
pruritic, and occur after
some period of drug
exposure
They involve the immune
system, and are confirmed
by positive photopatch
testing
In general, they are not as
drug dose dependent as
phototoxic reactions
Photosensivity both of the
phototoxic and
photoallergic types may
persist for some time after
the med has been d/cd
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Amiodarone
photosensitivity develops
in 75% of tx pts, and
occurs after a
cummulative dose of 40g
A reduced MED to UVA,
but not UVB occurs, and
gradually returns to
normal between 12 and 24
months after stopping the
med
Stinging and burning may
occur as soon as a half hr
after sun exposure
Clinically a dusky, bluered erythema of face and
dorsa of the hands is most
common, but a papular
rxn has been seen
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Desquamation, as seen
following sunburn, is
NOT observed following
amiodarone
photosensitivity rxn’s
NSAIDs, especially
piroxicam are frequently
associated with
phototsensitivity
Characteristic rxn is a
vesicular eruption of dorsa
of hands, sometimes
associated with
dyshidrosiform pattern on
the lateral aspects of hands
and fingers
Pts with photosensitivity
to piroxicam react on
initial exposure to the med
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These pts also react to
thiosalicylic acid, a
common sensitizer in
thimerosal
Half of pts having a
positive patch test result to
thimerosal with no prior
exposure to piroxicam are
photopatch test positive to
piroxicam
This suggests that
piroxicam rxn’s seen on
initial exposure to the med
may be related to prior
sensitization during
thimerosal exposure
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Sulfonamide antibiotics,
related hypoglycemic
agents, and the
sulfonylurea diuretics may
all be associated with
photoallergic rxn’s
These agents may all
cross-react
Also, pts may tolerate one
of these meds, but when
another member is added,
clinical photosensitivity
occurs
Typical pattern is:
erythema, scale, and in
chronic cases,
lichenification and
hyperpigmentation
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Photodistributed
kichenoid rxn’s have been
reported with thiazide
diuretics, quinide, and
NSAIDs
They present with
erythematous patches and
plaques
Sometimes, typical
Wickham’s stria are
observed in the lesions
Histologically,
photodistributed lichenoid
rxn’s are often
indistinquishable fron
idiopathic lichen planus
Photoallergic Reactions
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Pseudoporphyria is a
photodistributed bullous
rxn clinically and
histologically resembling
porphyria cutanea tarda
Hypertrichosis, skin
fragility, dyspigmentation,
and sclerodermoid
changes are not seen
Porphyrin studies are
normal and the rxn
resolves on
discontinuation of
provoking med
Naproxen is most
commonly reported cause
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Other meds causing
similar bullous rxn’s are:
tetracycline, furosemide,
nalidixic acid, dapsone,
nabumetone, and
pyridoxine
Histologically, a pauciinflammatory
subepidermal vesicle is
sen
DIF may show IgG and
complement deposition at
the d-e junction and
perivascularly, as seen in
PCT
The histo picture
resembling “cell poor”
pemphigoid has resulted
in these rxn’s being
reported as drug induced
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Anticoagulant-Induced Skin
Necrosis
Both warfarin and heparin
induce lesions of
cutaneous necrosis, but by
different mechanisms
Obese, postmenopausal
women are predispoded
secondary to the fact that
lesions tend to occur in
areas with abundant
subcutaneous fat(breast,
abdomen, or buttocks)
Warfarin necrosis occurs 3
–5 days after therapy is
begun(the higher the
initial dose, the higher the
risk)
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Lesions begin as red,
painful plaques that
become necrotic
Hereditary or acquired
deficiency of protein C
and less commonly
protein S is associated
Persons are usually
aysmptomatic
heterozygotes with protein
C deficiency
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Warfarin-induced
necrosis
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1-2 weeks after injection
of vitamin K, an allergic
reaction at the injection
site may occur
Most affected pts have
liver disease & are being
tx for elevated PPT’s
Lesions are pruritic, red
plaques-deep-seated
involving the dermis and
subcutaneous tissue
Occur most frequently on
posterior arm and over hip
or buttocks
Plaques on hip tend to
progress around the waist
and down thigh, forming a
“cowboy gunbelt &
holster” pattern
Vitamin K Reactions
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Generalized eczematous
small papules may occur
on other skin sites in
severe rxn’s
Rxn’s usually persist for
1-3 weeks or may be
longer, they may resolve
and reoccur
On testing, pts are positive
on intradermal testing to
vit K, not to components
of the material
In Europe, another pattern
of vit K has been reportedsubcutaneous sclerosis
with or without fasciitis
appears at the site many
months later
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Allergic reaction at
site of vitamin K
injection
Injection Site Reactions
 IM injection may produce
Cutaneous necrosis
may occur at sites of
med injections
 Two types:
1.) those associated with
IV infusions
2.) those related to IM
injections
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a syndrome calledembolia cutis
medicamentosa or Nicolau
syndrome
Immediately after
injection there is a local
intense pain, and ischemic
palor
Within mins-hrs site
develops an erythematous
macule that evolves into a
livedoid violaceous patch
with dendrites
This becomes
hemorrhagic, then
ulcerates, and eventually
heals with an atrophic scar
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Muscle and liver enzymes
may be elevated, and
neurologic symptoms and
sequela occur in a third of
pts
Circulation of the limb
may be affected, rarely
leading to amputation
Syndrome appears to be
related to periarterial
injection leading to
arterial thrombosis
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Tx-conservativedressing changes,
debridement, bed rest,
and pain control
Rarely surgical
intervention is needed
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Cutaneous reaction to
IV infusion and
extravasation of
chemotherapeutic
agent
Acute Generalized
Exanthematous Pustulosis
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90% of time is related to
medication
Not uncommon
Sudden onset on eruption
an average of 5 days after
med is started- about 50%
of cases occur within the
first 24 hrs
Mercury is sole cause in
13% of cases in France,
beta-lactams in 44%, and
macrolides in 17%
Sulfonamides have NOT
been reported to cause this
rxn
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17% of pts have a h/o
psoriasis
Course and evolution
are
different from true
pustular psoriasis,
although pts with
psoriasis may be at
increased risk for this
form of drug rxn
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Initially there is a
scarlatiniform erythema
Eruption evolves and
disseminates rapidly,
consisting of usually more
than 100 nonfollicular
pustules less than 5 mm in
diameter
Widespread desquamation
occurs after a few days
Edema of face, purpura,
and target lesions may
appear in the background
Mucous membranes are
involved in 22%
Fever is universal
Neutrophilia in 90%, and
eosinophilia in 30%
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Once inciting agent is
discontinued or removed,
eruption usually resolves
within 15 days without
sequelae
Patch tesing with the
suspected agent may
reproduce a pustular
eruption on an
erythematous base at 48
hrs
Histology
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Early lesions show
marked papillary
edema, neutrophil
clusters in dermal
papillae, and
perivascular
eosinophils
May be an associated
leukocytoclastic
vasculitis
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Well developed lesions
show intraepidermal or
subcorneal spongiform
pustules
If there is a background of
EM clinically, the
histology of EM may be
superimposed
Presence of eosinophils,
and marked papillary
edema help to distinguish
this eruption from pustular
psoriasis
Drug-Induced Pigmentation
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Postinflammatory
hyperpigmentation or
actual deposition of drug
in skin
Minocycline causes three
types of pigmentation:
1.) blue-black
discoloration in areas of
prior inflammation(not rel
ated total or daily dose
exposure)
2.)appearance of a similarcolored pigmentation on
normal skin of anterior
shims(is dose dependent)
3.) least common-total
generalized, muddy brown
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Chloroquine,
hydroxychloroquine, and
quinacrine all may cause a
blue-black pigmentation
of face, extremities,ear
cartilage, oral mucosa, and
nails
Pretibial
hyperpigmentation is
most common
Quinidine may also rarely
cause this pattern
Quinacrine is yellow and
is concentrated in
epidermis
Generalized yellow
discoloration of skin and
sclera
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Amiodarone after 3-6
months causes
photosensitivity in 3057% of pts tx
1-10% of pts a slate-gray
hyperpigmentation
develops in areas of
photosensitivity
Pigmentation fades after
med is discontinued
Clofazimine tx
reproducibly causes a pink
discoloration that
gradually becomes reddish
blue or brown
concentrated in lesions of
Hansen’s disease
This pigmentation is
disfiguring and a major
cause of noncompliance
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Zidovudine causes a blue
or brown
hyperpigmentation most
frequently in nails
Lunula may be blue, or
whole nail plate may be
dark brown
Diffuse
hyperpigmentation of
skin, pigmentation lateral
tongue, and increased
tanning are less common
Occurs in darkly
pigmented pts, is dose
dependent, clears after
med discontinued
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Purple pigmentation in
patient who had been
on high doses of
chlorpromazine
There is sparing of
deep creases of the
face
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Chlorpromazine,
thioridazine, imipramine,
and clomipramine may
cause a slate-gray
hyperpigmentation in sunexposed areas after long
periods of ingestion
Frequently, corneal and
lens opacities are present
Therefore all pts with
hyperpigmentation from
these meds should have
ophthalmologic exam
Pigmentation from
phenothiazines fades
gradually over yrs
Corneal, but not lenticular
changes resolve
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Heavy metals gold, silver,
and bismuth produce blue
to slate-gray
hyperpigmentation
Pigmentation occurs after
yrs of exposure, mainly in
sun-exposed areas
It is permanent
Bismuth also pigments
gingival margin
Arsenical melanosis is
characterized by black,
generalized pigmentation
or by pronounced truncal
hyperpigmentation that
spares the face
Fixed Drug Reactions
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Common
Named such because they
recur at same site with
each exposure to med
Six or less lesions occur;
frequently only one
Present anywhere on
body(50% occur on oral
and genital mucosa)
Represent 2% of all
genital ulcers evaluated at
clinics for STD’s
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Clinically begin as a red
patch that soon evolves to
an iris or target lesion
identical to EM
Eventually may even
blister and erode
Lesions of oral mucosa
and genitalia usually
present as erosions
Characteristically,
prolonged or permanent
postinflammatory
hyperpigmentation results
Fixed Drug Eruption
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Meds inducing fixed drug
eruptions are usually those
taken intermittently
Many NSAIDs, especially
pyrazolone derivatives,
naproxen, mefenamic
acid; sulfonamides,
trimethoprim, or
combination are
responsible mainly
Barbiturates, tetracyclines,
phenolphthalein(in
laxatives), and
erythromycin
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Unknown pathogenesis
Persons with fixed drug
eruptions to pyrazole
derivatives are much more
likely to be HLA-B22 pos
Occasionally fixed drug
rxn’s do not result in longlasting hyperpigmentation
The so-called
nonpigmented fixed drug
eruption is distinctive
It is characterized by
large, tender, often
symmetrical erythematous
plaques that resolve
completely within weeks,
only to recur on
reingestion of offending
drug
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Pseudoephedrine
hydrochloride is by far
most common culprit of
nonpigmented fixed drug
eruption
There is the so-called
“baboon syndrome” where
the buttocks, groin, and
axilla are preferentially
involved in this category
Bullous Drug Reactions
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Skin blistering may
complicate drug rxn’s in
numerous ways
The term bullous drug
reaction most commonly
refers to a drug rxn in the
EM group
Uncommon-0.4- 1.2 per
million person for TEN a
& 1.2 to 6.0 per million
person yrs for StevensJohnson syndrome druginduced EM is usually
more extensive than that
induced by infectious
agents
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Exact definitions of SJS
and TEN remain arbitrary
as a result of overlap in
some cases
SJS < 10% of body
surface area involved,
cases with 10-30% are
overlap cases, and 30%
involvement is TEN
Others classify: SJS as
cases that begin with skin
pain and simple erythema
rapidly followed by skin
loss
EM & SJS &TEN

Although definitions
remain controversial, SJS
and TEN are probably a
disease spectrum based on
the following: most
commonly induced by the
same meds; pts initially
presenting with SJS may
progress to extensive skin
loss resembling TEN;
histology is
indistinguishable; both are
increased by same
magnitude in HIV
infection; identical
metabolic abnormalities
are identified in cases
induced by sulfonamides
or anticonvulants
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> 100 meds have been
reported as a cause
Most
common:trimethoprim/sul
famethoxazole(13/100,000), Fansidar-R,
sulfadoxine
pluspyrimethamine(10/10
0,000), and
carbamazepine(14/100,00
0)
Antibiotics(especially
long-acting sulfa drugs
and penicillins), other
anticonvulsants,
antiinflammatories, and
allopurinol are also causes
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Fever and influenza-like
symptoms often procede
the eruption
Skin lesions appear on
face and trunk and spread
rapidly (within 4 days) to
their maximum extent
Initial lesions are macular
and remain so, followed
by desquamation, or may
form atypical targets with
purpuric centers that
coalesce, form bullae, the
slough
Virtually always more
than two mucosal surfaces
are also eroded, the oral
and conjunctiva being
most frequently affected
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There may be difficulty
with swallowing,
photophobia, painful
urination, and extensive
respiratory and alimentary
tract involvement
Skin bx usually performed
to exclude other diseases
Independent of extent of
slough, clinical
morphology or the clinical
diagnosis the histology is
alike
Paraneoplastic pemphigus
also shows changes of EM
and must be excluded with
DIF
Pts with graft-versus host
disease may also be alike
Histology
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A lymphocytic
infiltrate at the D-E
junction
Necrosis of
keratinocytes that may
be full thickness
Infiltrate may be
marked or very scant
Histology


Subepidermal
separation
Full thickness
epidermal necrosis
Management

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Similar to an extensive
burn
They suffer fluid and
electolyte imbalances,
bacteremia from loss of
protective skin barrier,
hypercatabolism, and
sometimes ARDS
Survival is improved if tx
in a burn unit
Pts who are very ill or
have > 30%- 50% loss of
epidermis should be
transferred to burn unit
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One recent report of IVIG
in 10 pts in doses up to
0.75 g/kg/day for 4 days
led to response in 48 hrs
and skin healing within 1
week
No adverse rxn’s where
observed
MOA of IVIG in this
condition was blocking
apoptosis through
blockade of the death
receptor FAS(CD 95)
Immunsuppressive
therapy is very
controversial
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Benefit of
immunosuppresives is to
stop the process very
quickly to reduce the
ultimate amount of skin
lost
Once most of skin loss has
occurred,
immunosuppresives only
add to morbidity and
perhaps mortality
If considering
immunosuppressive
therapy it should be done
quickly, in adequate doses,
given a short trial to see if
the process can be
arrested, and then tapered
rapidly
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As with burns, the host’s
age, severity of underlying
disease, and extent of skin
loss are the most
important factors
determining the outcome
rather than the use of
immunosuppressive
agents
In pts who survive, the
average time for
epidermal regrowth is 3
weeks
Most common sequelae
are ocular scarring and
vision loss
A sicca like syndrome
may also result
EM


Erythema multiforme
bullosum
Note predilection for
arms, sparing the trunk
unlike
EM/TEN/SJS
TEN

Desquamation in
sheets-leaving raw, red
surface
SJS
Radiation-Induced EM
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Occurs if phenytoin is
given prophylactically
in neurosurgical pts
who are receiving
whole-brain radiation
therapy and systemic
steroids
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Erythema and edema
initally on the head in the
radiation ports, as dose of
steroids is being reduced
Evolves over 1-2 days to
lesions clinically and
histologically similar to
EM
Eruption spreads caudad
and mucosal involvemant
may occur
Can rarely be seen with
radiation therapy alone,
but is more common if
phenytoin is administered
Urticarial EM
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Unusual rxn virtually
always associated with
antibiotic ingestion
Skin lesions consist of
urticarial papules and
plaques, some of which
clear centrally forming
annular lesions,but no true
iris lesions
Lesions can be
distinguished from true
urticaia in that they are
fixed for days
Pruritis is common
Bullae are absent, and
mucous membranes are
uninvolved
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Rarely, hypotension may
occur
Histologically, there is a
superficial and deep
dermal infiltrate
containing eosinophils
with dermal edema
Epidermis is not involved
Response to systemic
steroids is dramatic, with
clearing in 48-72 hrs
HIV Disease and Drug Reactions

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HIV-infected pts,
especially those with
helper T-cell counts
between 25 and 200, are at
increased risk for
development of adverse
rxn’s to meds
Morbilliform rxn’s to
Bactrim occurs in 45%of
AIDS pts
Associated hepatitis or
neutropenia may require
discontinuation of drug
A similar increased risk is
seen in HIV pts receiving
Augmentin
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If dermatitis is tx limiting,
but eruption is not life
threatening, low-dose
rechallenge/desensitizatio
n may be attempted
It is successful in 65%85% of pts short term, and
>50% long term
Most rxn’s occur in first
few days of rechallenge,
adverse rxn’s may appear
months after restatring
drug
MOA?? Many AIDS pts
are slow acetylators
Severe bullous rxn’s-SJS,
TEN are 100-1000 times
more common
Adverse Reactions to
Chemotherapeutic Agents
Radiation Enhancement &Recall
Reactions
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Radiation dermatitis in
form of intense erythema
and vesiculation may be
observed in radiation ports
Administration of many
chemotherapeutic agents,
during or in close
proximity to time of
radiation therapy, may
enhance this rxn
It is termed “radiation
recall” because it may
occur a week or more after
radiation therapy

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A similar rxn of
reactivation of a
sunburn after
methotrexate therapy
also occurs
This probably
represents synergistic
toxicity reactions
Chemo-induced acral erythema
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Common syndrome
induced most frequently
by 5-florouracil,
doxorubicin, cystosine
arabinoside
Rxn may occur in as many
as 40% of tx pts
Rxn is dose dependent
May appear with bolus
short-term infusions or
low-dose, long-term
infusions
May present weeks to
months after tx’s are
started
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May present days to
months after treatments
are started
Likely a direct toxic effect
of chemotherapeutic
agents on the skin
Large number of sweat
glands on the palms and
soles that may concentrate
the chemotherapeutic
agent explaining the
localization of the toxicity
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Initial manifestation is
often dysesthesia or
tingling of the palms and
soles
This is followed by
painful, symmetric
erythema and edema most
pronounced over the distal
pads of the digits
Rxn may spread to dorsal
hands and feet & may be
accompanied by a
morbilliform eruption
Erythema becomes dusky
develops areas of pallor,
blisters, desquamates, then
reepithelializes
Dequamation is often
prominent
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Blisters developing over
pressure areas is a variant
Pts usually recover
without complications
Although rarely, full
thickness ischemic
necrosis occurs in areas of
blistering
Histology is nonspecific
Most cases require only
local supportive care
Cold compresses and
elevation are helpful;
cooling of hands during tx
may reduce severity of rxn
Modification of dose
decreases the pain of
fluorouracil induced
syndrome
Neutrophilic Eccrine Hidradenitis
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Most cases occur in
neutropenic pts with
malignancies, usually
AML
Occurs in children and
adults-most commonly
associated with chemo,
especially cytoarabine
Appears about after 7-10
days of tx
Pts usually febrile
Erythematous papules,
plaques, or nodules
localized to trunk,
extremities, axillae, or
pubic area, but may be
generalized
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Clinical lesions are
nonspecific
Bx performed to exclude
infection
Histology-a neutrophilic
infiltrate involving
glandular and ductal
portions of the eccrine
gland
May be necrosis of eccrine
unit, and in later bx’s
syringometaplasia
Skin lesions resolve in 10
days, but in severe cases
may be tx with
corticosteroids
NEH
Histology-NEH

Infiltrate of
inflammatory cells
surrounding eccrine
coils
Chemotherapy-Induced

Hyperpigmentation
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Adriamycin causes
marked
hyperpigmentation of
nails, skin ,tongue
Most commonly seen in
black pts
Very similar to
Zidovudine-associated
pigmentation seen in
pigmented persons
Cyclophosphamide causes
transverse banding of nails
or diffuse nail
hyperpigmentation
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Bleomycin and 5FU
causes similar transverse
bands
Busulfan and 5FU in
duiffuse
hyperpigmentation that
may be photoaccentuated
Bleomycin induces
characteristic flagellate
erythmatous urticarial
wheals associated with
pruritis within hrs-days of
infusion
Fluorouracil causes a
serpentine
hyperpigmentation
overlying veins of
infusion
Acrodynia
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Caused by mercury
poisoning, usually in
infancy
Skin changes are
characteristic-almost
pathognomonic
Painful swelling of hands
and feet
Sometimes with pruritis
Hands & feet are dusky
red, pink, cold & clammy
Erythema is usually
blotchy but may be diffuse
Acrodynia
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Erythema is blotchy but
may be diffuse
Hemorrrhagic puncta are
sometimes evident
Over trunk, a blotchy
macular or papular
erythema is usually
present
Stomatitis and loss of
teeth may occur
Constitutional symptoms
consist of fever,
irritability, photophobia,
increased perspiration
Always moderate upper
respiratory inflammation
and sore throat
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May be hypertension,
hypertonia, anorexia,
and insomnia
Albuminuria and
hematuria are usually
present
Diagnosis is made by
finding mercury in the
urine
Etiology
Broken
thermometers
Teething
powders
Poisoned
fish
Broken
phosphorescent
bulbs
?Gas
heaters
Treatment
Chelating agents
-dimercaprol
Bromoderma
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Bromides commonly
produce distinctive
follicular eruptions
Most common is
acneform-with
inflammatory pustules in
hairy parts of body and
butterfly area of face(must
be differentiated from
rosacea)
Vesicular lesions and
bullae are common
Nodular lesions with a
violaceous color are
mistaken for malignant
lymphoma of skin
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A thick inflammatory
plaque, with pustules in its
border, resembling
blastomycosis, may also
occur
There is rapid resolution
of lesions when bromide is
stopped
It may occur after a small
dose or after protracted
use of bromides
A small child suffered
fatal bromoderma as a
result of one 50-mg dose
of methacholine bromide
by injection
Bromoderma
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Bromides are excreted
in breast milk
No correlation seems
to exist between
plasma levels and the
severity of cutaneous
lesions
Tx of bromoderma is
simply cessation of
bromide ingestion
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In acute intoxication 2 to 4
g of sodium chloride by
mouth, taken daily, rapidly
replaces the bromide in
body fluids
Ammonium chloride is
also helpful
In severe cases of
intoxication in which the
pt is badly confused,
ethacrynic acid rapidly
decreases the bromide
level, with clearing of
lesions
Bromoderma
Bromoderma

Bromide eruption on
shin; bullae and
granulomas
Iododerma
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Causes a wide variety of
skin eruptions
Most common-acneiform
eruption with numerous
acutely inflammed
follicular pustules,
surrounded by a ring of
hyperemia
Bullous lesions are also
common and may become
ulcerated and crusted
Pruitus and urticaria may
be only manifestations of
mild iodism
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Purpura, furnuncles,
erythema multiforme,
erythema nodosum,
polyarteritis nodosa may
also occur
Swelling, redness, and
scaling of eyelids occur
Acne vulgaris and rosacea
are worsened by iodine
Treatment is same as
bromoderma
Iododerma

Only brief duration
distinguishes it
clinically from basal
cell carcinoma
Iododerma
Topical Corticosteroids
Prolonged exposure
produces distinctive
changes
 Appearance of these side
effects depends on three
factors:
1.) strength of steroid
2.) area to which it is applied
3.) the individual’s
predisposition to certain
side effects

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Atrophy, striae,
telangiectasia, skin
fragility, and purpura most
frequent changes seen
Most striking
telangiectasias in fairskinned individuals using
fluorinated corticosteroids
on the face
Changes in skin are
enhanced with occlusion
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
When these side effects
occur, reduce strength of
steroid and add topicals
like doxepin, pramoxine,
or menthol and camphor
Telangiectasiases usually
disappear in a few months
after corticosteroid
applications are stopped
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When corticosteroid
preparations are applied to
face over a period of
weeks to months, persist
erythema with
telangiectases may occur
Perioral dermatitis and
rocacea may occur
Steroid rosacea has been
reported from long-term
use of 1% hydrocortisone
cream
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Repeated application of
corticosteroids to the face,
scrotum or vulva may lead
to marked atrophy of these
tissues
Tissue becomes
“addicted” to the topical
steroid, so that
withdrawing it results in
severe itching or burning
Difficult to manage
Best to apply judicious use
of topical steroid
preparations in these areas



Topical applications can
produce epidermal atrophy
with hypopigmentation
If used over a large area,
sufficient topical steroids
may be absorbed to
suppress the hypothalamic
pituitary axis
May affect growth of
children with atopic
dermatitis and has led to
Addisonian steroid
dependency and also
Cushing’s syndrome



Atopic children with more
than 50% body surface
area involvement have
short stature
This may be related to
their increased use of
potent topical steroids
Bone mineral density is
reduced in adults with
chronic atopic dermatitis
severs enough to require
steroids stronger than
hydrocortisone
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Paradoxically, topical
corticosteroids may induce
allergic contact dermatitis
Consider this complication
in any pt with an
eczematous dermatitis
who becomes worse or is
refractory to topical
steroid tx
Systemic corticosteroid
administration may be
tolerated, but in some pts
there is a cross reaction
manifested by whole-body
allergic dermatitis
Side effects…

Atrophy and purpura
caused by prolonged
applications of
corticosteroid
preparations

Atrophy and fragility
caused by chronic
corticosteroid
applications
Injected Corticosteroids




Intralesional injection may
produce subcutaneous
atrophy at site of injection
Injected steroid may
migrate along lymphatics
causing not only local side
effects but linear atrophic
hypopigmented hairless
streaks
These may take years to
resolve
To avoid these
complications-inject
directly into the lesion, not
into the fat, and use only
minimal concentration and
volume




Intramuscular steroid
injections should always
be given in the buttocks
with a long needle (at least
1.5 inches in adults)
Injection into deltoid
muscle sometimes causes
subcutaneous atrophy
Pt becomes aware of rxn
by noticing depression and
depigmentation at
injection site
Pt can be assured that this
will fill in but it may take
several yrs
Side effects corticosteriods:

Lipoatrophy of the
buttock resulting from
a corticosteroid
injection
Systemic Corticosteroids



Prolonged use may
produce numerous
changes of skin
Have a profound effect on
metabolism of many
tissues, leading to
preditable, and
preventable complications
Intramuscular injections
are not a safer delivery
method than oral
administration
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Purpura or ecchymoses
Cushingoid changes
Steroid acne
Striae
Hair loss in 50% of pts
Increased hair growth on
bearded areas and arms,
back(vellus hairs)
HTN,aseptic necrosis of
hip, osteoporosis
How to combat side effects…



Bone loss can occur early
in course of tx-so manage
preemptively-supplement
with calcium & vitamin
D(1.0-1.5 g calcium and
400-800 U of
cholecalciferol daily)
Stop smoking
Decrease alcohol
consumption



Obtain bone mineral
density at baseline (via
DEXA scan) & throughout
tx period (yrly?)
Hypogonadism which
contributes to osteoporosis
can be treated in men and
women with testosterone
and estrogen respectively
Calcitonin and
bisphosphonates may be
added to mangement as
needed
THE END- Thank you