Download Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Stevens-Johnson Syndrome and
Toxic Epidermal Necrolysis
Grant J. Anhalt, MD
Professor, Dermatology & Pathology
Johns Hopkins University, School of Medicine
Disclosures
Consulting for GlaxoSmithKline
No conflict of interest
No commercial sponsorship
Definition
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Rare, acute syndrome characterized by systemic
symptoms, mucosal ulcerations and blistering
skin lesions.
Spectrum of disease that includes:
Erythema multiforme
Stevens Johnson Syndrome
Toxic Epidermal Necrolysis
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Definition
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Differentiated by degree of body surface area
blistering observed :
10% BSA – SJS
10-30% - Overlap
 >30% BSA – TEN
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Clinical features
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Blisters and erosions of skin and mucous
membranes, directly affects only “stratified
squamous epithelium”
Histology shows lymphocytes (T cells) in the
epidermis, and epidermal cell death that can be
limited (EM) or confluent (TEN)
Blood work – unremarkable
Skin biopsy is required
Clinical features
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Internal organs can be damaged by secondary
events:
Infection / sepsis
Respiratory complications
Multi-organ failure due to massive cell death that
overwhelms salvage mechanisms
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Epidemiology
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Roughly 2-3 cases / million population / year in
Europe and USA
More frequent in adults than children
M : F ratio – equal (more to come on that….)
More frequent in HIV disease
HLA association only in select populations (e.g.
carbamazepine in Han Chinese).
Etiology
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In adults, almost always drugs (in some, no
identifiable cause)
Risk for highly associated drugs – 1/10,000 to
1/100,000 patients
In children, some are due to Mycoplasma
pneumonia infection (perhaps 20%), Herpes
simplex virus (less severe cases), and other
infections
Drugs in SJS / TEN
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Three major culprits:
1) Anti-infective sulfonamides (Bactrim)
2) Anti-epileptic drugs (Phenobarbital, dilantin,
carbamazepine, lamictal)
 3) Allopurinol
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Recent increasing interest in NSAIDs &
acetaminophen as potential causes
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Clinical Manifestations
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First exposure to drug – lag time to onset of
prodromal symptoms usually 4+ to 28 days.
Prodromal symptoms (~1-3 days) mimic a viral
infection - low grade fever, nausea, conjunctival
and oral suffusion and tenderness.
Then a morbilliform rash of the upper trunk,
head and neck area appears.
Clinical Manifestations
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Redness rapidly becomes confluent, turns dusky
and then the epidermis sloughs off in sheets.
Extensive, extraordinarily painful ulcerations of
oropharynx, conjunctiva and genital mucosa.
Patients should receive supportive care in a burn
facility and any suspect drugs should be stopped.
There is no drug or treatment that has proven to
halt the disease progression.
Pediatric SJS
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Adult TEN
Adult TEN
Outcome
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From blistering to healing – about 3-5 weeks.
Immediate complications include infection,
pulmonary complications and multi-organ
failure.
Mortality – overall ~ 20%, <10% in SJS and
>40% in TEN. Mortality can be predicted by
the SCORTEN scoring system. Poor outcomes
predicted by greater BSA involved, increasing
age and metabolic derangements.
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Late Complications
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Skin can heal without scarring but secondary
infection may cause areas of scar and loss of
nails.
Ocular scarring can be severe and lead to
blindness.
Strictures may form in the esophagus, bronchi,
genital mucosa and urethra.
Pathophysiology
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SJS / TEN results from activation of the
immune system.
The immune system has the capacity to
ruthlessly kill cells, as an important tool in viral
infections and suppressing cancer.
Viral infections are defeated by producing
antibodies that neutralize free virus, but also by
killing viral-infected cells, which are factories for
new virus.
T Cell Mediated Killing
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T cells kill other targeted cells by production of
many different cytokines and enzymes:
Granzyme / perforin / granulysin punch holes
in the cell membrane and induce apoptotic cell
death
Tumor Necrosis Factor – α and Fas / Fas
ligand interactions also trigger apoptosis
Nitrous Oxide induces cell necrosis
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The “Prodrome” in SJS/TEN
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Mimics a viral illness, because T cells also secrete
cytokines such as gamma-interferon, which
helps inhibit viral replication.
But gamma-interferon is the cause of the
symptoms (fever, nausea, myalgias, etc.) that
make one feel sick in viral illnesses.
Gamma interferon is used to treat HepC, but is
hard to tolerate because it makes patients feel
like the have “the flu” 24/7…
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Time to Onset
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It is biologically impossible to generate all of the
activated T cells required to kill off the whole
body’s epidermis in less than 4+ days.
The exception – if a patient has had previous
exposure to a drug, with a “generic” drug rash,
there will be a population of already sensitized T
cells waiting to be activated again, and this can
occur in just 2-3 days.
Time to Onset
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“More precise evaluation of time relationship
strongly suggests that SJS and TEN most often
begin more than 4 and up to 28 days after the
initiation of the responsible medication. We
advise to integrate these figures in the
algorithms used for assessing the causality of
medications in individual cases.”
Mockenhaupt et al, Euroscar study, 2008
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SJS/TEN Literature
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High quality studies are few, and due to rarity,
prospective studies or drug trials can’t happen.
Good data is found in the “EuroSCAR” studies
Case control series from several European countries
and Israel, encompassing 1800 hospitals and 100
million people over 4 years.
 379 confirmed cases and 1,505 controls
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Mockenhaupt M. J Invest Derm 2008:128, p35
SJS/TEN Literature
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However, the general medical literature is
polluted with many anecdotal case reports, small
case series, and even studies that confuse true
SJS/TEN with other drug reactions, like DRESS
syndrome (Drug Reaction with Eosinophilia and
Systemic Symptoms), and other far less severe
drug reactions.
It’s easy to find some reference to support any
claim.
Determining Causality
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“It is a problem in determining the etiology of
SJS-TEN that drugs taken during the prodromal
phase to alleviate symptoms cannot be
distinguished from those that actually caused the
disease.” (Fitzpatrick’s DIGM, 6th Ed, p.549)
Physicians are generally trained to expect that
the most recently introduced drug is the cause of
the drug reaction
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Acetaminophen (Tylenol)
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Recently – FDA required a Black Box warning
to be added re: the risk of SJS / TEN
EuroScar showed a weak association.
But, they felt that “antipyretic agents are used to
treat unspecific symptoms such as fever or pain”
To control for “confounding by indication” they
restricted the analysis to patients who took the
drug at least 4 days before the onset of the AE,
and the observed association “disappeared…”
Alden Algorithm
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Algorithm of Drug Causality in Epidermal
Necrolysis - 6 criteria to help identify or exclude
causative drugs (Sassolas B, Clin Pharm Ther 2010, 88:1, p 60).
2 major criteria - Drug intake to first symptoms
5-28 days is the most likely time frame
Notariety of drug – Drugs known to be strongly
associated get the highest score
Incorrect Diagnosis
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Many physicians have only a vague idea of the
precise definition of SJS/TEN
They know that it’s caused by drugs and patients
get really sick
Any “drug rash serious enough to require
hospitalization” can be misdiagnosed, and this
happens frequently. Once labeled as SJS/TEN,
the diagnosis carries through the medical record
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Incorrect Diagnoses
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DRESS – Drug Reaction with Eosinophilia and
Systemic Symptoms. Allergist Charlesworth
published on the beneficial effects of steroids in
SJS/TEN, but many of his cases were DRESS
AGEP – Acute generalized erythematous
pustulosis – also caused by drugs, dramatic in
appearance but no long term complications
Exfoliative Erythroderma – can also be caused
by drugs, but lacks mucosal involvement
Claims – Treatment Below
Standard of Care
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Small case series have shown benefit from many
treatments, including IVIg, systemic steroids,
cyclosporine, and others
For each publication promoting an effective
treatment, there is usually a similar number
showing no beneficial effect
Most agree that supportive care in a facility
experienced in burn treatment is the only helpful
treatment
IVIg
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High dose normal human immunoglobulins
1998 article showed up-regulation of Fas/Fas
ligand in TEN. IvIg can inhibit this interaction.
Viard I, Science 1998, 282:490
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However, there are multiple mechanisms
through which T cells kill their targets
It’s not reasonable to expect that inhibition of
just one pathway would have a net effect
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Example of claims
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Elderly patient, hospitalized for infected knee
prosthesis. On multiple antibiotics plus 2
associated drugs, allopurinol (months) and
vancomycin (7 days). New fever - abx changed
to ceftazidime – 24 hours later, first blisters
appeared. Eventually she died in the Burn Unit.
Claim – TEN caused by ceftazidime, due to
known h/o allergy to penicillin and crossreactivity.
Response
At trial we were successfully able to explain that
 24 hours is not enough time to develop the
disease after exposure to a new drug.
 She was on more highly implicated drugs, within
the appropriate time frame
 There is no cross-reactivity between penicillin
and 3rd generation cephalosporins.
 Penicillin allergies are Type I reactions, not Type
IV
Example of Claims
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Teenager develops cough, fever of 4 days
duration.
CXR shows infiltrate, started on azithromicin
for presumed Mycoplasma pneumonia.
2 days later, conjunctivitis, mucositis and
recurrent fever. 24 hours later first oral ulcers
and skin rash appears. Eventually develops SJS.
Claim – azithromicin caused her SJS.
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Response
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Although Mockenhaupt has written that
essentially all cases of SJS/TEN are due to
drugs, there are numerous decent case series that
show a convincing relationship with
Mycoplasma pneumonia.
The time line from drug exposure to prodromal
symptoms was too short to implicate
azithromycin.
Summary
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SJS/TEN is an unpredictable and rare event
It has a clearly defined set of signs and
symptoms, and clinical evolution
Causality can be determined by establishing
appropriate timing of drug administration and
drug notariety
Supportive care is the only recognized beneficial
treatment
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