Stevens–Johnson Syndrome Toxic Epidermal Necrolysis

1. Epidermal Necrolysis
Stevens–Johnson Syndrome
Toxic Epidermal Necrolysis
Ext. Siwaporn Khureerung
25/4/58

2. Introduction
• Toxic epidermal necrolysis (TEN) and Stevens–Johnson
syndrome (SJS) are acute life-threatening
mucocutaneous reactions characterized by extensive
necrosis and detachment of the epidermis.
• Both SJS and TEN are characterized by skin and mucous
membrane involvement. Because of the similarities in
clinical and histopathologic findings, risk factors, drug
causality, and mechanisms, these two conditions are
now considered severity variants of an identical
process that differs only in the final extent of body
surface involved.

3. Epidemiology
• The overall incidence of SJS and TEN was
estimated at 1 to 6 cases per million person-years
and 0.4 to 1.2 cases per million person-years,
respectively.
• The overall mortality associated with EN is 20% to
25%, varying from 5% to 12% for SJS to more
than 30% for TEN.
• Increasing age, significant comorbidity, and
greater extent of skin involvement correlate with
poor prognosis.

4. SCORTEN
Prognostic Factors Points
•Age >40 years 1
•Heart rate >120 beats/minute 1
•Cancer or hematologic malignancy 1
•Body surface area involved >10% 1
•Serum urea level >10 mM 1
•Serum bicarbonate level >20 mM 1
•Serum glucose level >14 mM 1
SCORTEN Mortality Rate (%)
0-1 3.2
2 12.1
3 35.8
4 58.3
5 90

5. Etiology
Medications and the Risk of Epidermal Necrolysis
High Risk Lower Risk Doubtful Risk No Evidence of Risk
Allopurinol
Sulfamethoxazole
Sulfadiazine
Sulfapyridine
Sulfadoxine
Sulfasalazine
Carbamazepine
Lamotrigine
Phenobarbital
Phenytoin
Phenylbutazone
Nevirapine
Oxicam NSAIDs
Thiacetazone
Acetic acid NSAIDs
(e.g., diclofenac)
Aminopenicillins
Cephalosporins
Quinolones
Cyclins
Macrolides
Paracetamol
(acetaminophen)
Pyrazolone analgesics
Corticosteroids
Other NSAIDs
(except aspirin)
Sertraline
Aspirin
Sulfonylurea
Thiazide diuretics
Furosemide
Aldactone
Calcium channel
blockers
β Blockers
Angiotensin-
converting enzyme
inhibitors
Angiotensin II receptor
antagonists
Statins
Hormones
Vitamins

6. Pathogenesis
• As explained previously, drugs are the etiologic factor in the majority of SJS/TEN
cases. However, it is still unknown, how a certain drug may actually induce
epidermal necrosis. T cells, especially CD8+ lymphocytes, have been identified to
play an important role in the process that is most likely mediated by cytokines.
CD8+ T cells from the blister fluid of patients with TEN induced by co-trimoxazole
were tested for their cytotoxic function and reacted without restimulation against
the parent drug (cotrimoxazole and sulfamethoxazole), but not against the
metabolite. This finding challenged the hypothesis that metabolites may be
directly involved in the process of epidermal cell death. In addition, these cytotoxic
T-cells killed autologous lymphocytes and keratinocytes in a drug-specific,
perforin/granzyme-mediated pathway restricted to MHC class I.[19] Later, the
cytolytic protein granulysin, which is produced by drug-specific CD8+ T cells and
natural killer (NK) cells, was identified as the most important factor for the
epidermal destruction. Its concentrations in the blister fluid of SJS/TEN patients
were two to four orders of magnitude higher than those of other cytotoxic
proteins such as perforin, granzyme B or soluble Fas ligand, and depleting
granulysin reduced the cytotoxicity. Furthermore, the concentration of granulysin
in the blister fluid was positively correlated with the clinical severity of the disease
(i.e. was higher in TEN as compared with SJS).[20]

7. • Recently, functionally active CD94/NKG2C+ cells were
detected in the blister fluid but also in the peripheral blood
of patients with SJS/TEN. This activating receptor might be
involved in triggering cytotoxic T cells in the acute stage of
the disease.[21]
• T-cell activation by drug antigens requires the interaction of
the T-cell receptor (TCR) with the MHC on antigen-
presenting cells. Thus, the drug may bind to the MHC
molecule, which is recognized by the TCR leading to specific
TCR activation, or the drug may bind first to a specific TCR
that then interacts with the MHC. Both ways are possible,
but drugs with a strong association to specific HLA alleles
are more suggestive to interact primarily with the HLA
molecule.[22]

8. • A genetic predisposition for SJS/TEN has long been discussed. After
preliminary data from Europe had suggested an association with certain
HLA types more than 20 years ago, a research group from Taiwan was the
first to demonstrate that 100% of Han-Chinese patients with SJS/TEN due
to the use of carbamazepine were positive for the allele HLA-
B*1502.[23] This finding could not be confirmed in Europe showing that
ethnicity matters more than previously thought in this context.[24] For
allopurinol-induced cases of SJS/TEN a 100% association with HLA-B*5801
could be demonstrated in a Han-Chinese population, whereas in the
European population the association was present in no more than
55%.[25,26] Strong associations such as those in Han-Chinese suggest that
these alleles must be involved in the presentation of a specific drug
antigen in a better way than other HLA alleles.[22] Thus, the risk of SJS/TEN
is not only related to the exposure with high-risk drugs, but also to a
genetic predisposition. In more homogeneous ethnic groups with a high
prevalence of reaction to a given medication strong genetic associations
may be easier to detect.[27]

9. Clinical Findings
Even in cases
requiring immediate
referral to
specialized wards,
the dermatologist
will have a specific
role in the
management of
patients with EN .

10. History
• EN clinically begins within 8 weeks (usually 4 to 30 days) after
the onset of drug exposure for the first time.
• Only in very rare cases with prior reaction and inadvertent
rechallenge with the same drug does it appear more rapidly,
within a few hours. Nonspecific symptoms such as fever,
headache, rhinitis, cough, or malaise may precede the
mucocutaneous lesions by 1 to 3 days.
• Pain on swallowing and burning or stinging of the eyes
progressively develop, heralding mucous membrane
involvement.
• The initial symptoms are, their rapid progression, the addition
of new signs, severe pain, and constitutional symptoms
should alert one to the onset of a severe disease.

11. Early exanthematous phase with Nikolsky's sign.
symmetrically distributed on the face, the upper trunk,
and the proximal part of limbs.The distal portions of the arms as
well as the legs are relatively spared, but the rash can rapidly
extend to the rest of the body within a few days and even within a
few hours.

12. • A. Early eruption. Erythematous
dusky red macules (flat atypical
target lesions) that progressively
coalesce and show epidermal
detachment.
• B. Early presentation with vesicles
and blisters, note the dusky color of
blister roofs, strongly suggesting
necrosis of the epidermis.
• C. Advanced eruption. Blisters and
epidermal detachment have led to
large confluent erosions.
• D. Full-blown epidermal necrolysis
characterized by large erosive areas
reminiscent of scalding.
Cutaneous Lesions

13. Blisters, erosions, and large areas of positive Nikolsky's sign
on the back of a patient with TEN. One aim of local treatment is to
protect “detachable” epidermis from being detached by using
antishear dressings.

14. Patients are classified into one of three
groups according to the total area in which the
epidermis is detached or “detachable” (positive
Nikolsky)
1. SJS, less than 10% of body surface area (BSA)
2. SJS/TEN overlap, between 10% and 30%
3. TEN, more than 30% of BSA
It is helpful to remember that the surface
of one hand (palm and fingers) represents a
little less than 1% of the BSA.

15. Evolution at days 4 (A), 7 (B), and 17 (C) after onset of
TEN. Note that repair of epidermis is delayed on previously
detached areas versus “detachable” ones that remained on
site at day 7.

16. A. Extensive erosions and necroses of the lower lip and oral mucosa.
B. Massive erosions covered by crusts on the lips. Note also shedding
of eyelashes.
Mucous Membrane Involvement

17. Extracutaneous Symptoms
• EN is associated with high fever, pain, and weakness.
• Visceral involvement is also possible, particularly with
pulmonary and digestive complications.
• Pulmonary complications occur in approximately 25% of
patients manifested by elevated respiratory rate and cough.
In most cases chest radiographs are normal on admission
but can rapidly reveal interstitial lesions that can progress
to acute respiratory distress syndrome (ARDS). It was
associated with poor prognosis.
• Gastrointestinal tract involvement is less commonly
observed, with epithelial necrosis of the esophagus, small
bowel, or colon manifesting as profuse diarrhea with
malabsorption, melena, and even colonic perforation.
• Renal involvement ,Glomerulonephritis is rare.

18. Laboratory Values
• There is no laboratory test to support the
diagnosis of EN.
• Laboratory examinations are essential to
evaluation of severity and daily management
as for all life-threatening conditions in
intensive care units.

19. Histologic appearance of toxic epidermal necrolysis.
A. Eosinophilic necrosis of the epidermis in the peak stage, with little
inflammatory response in the dermis. Note cleavage in the junction zone.
B. The completely necrotic epidermis has detached from the dermis and
folded like a sheet.

20. Differential Diagnosisnof Epidermal Necrolysis
Most Likely
•Limited EN (Stevens–Johnson syndrome)
• Erythema multiforme major
• Varicella
•Widespread EN
• Acute generalized exanthematous pustulosis
• Generalized bullous fixed drug eruption
Consider
Paraneoplastic pemphigus
Linear immunoglobulin A bullous disease
Pressure blisters after coma
Phototoxic reaction
Graft-versus-host disease
Always Rule Out
Staphylococcal scalded skin syndrome
Thermal burns
Skin necrosis from DIC or purpura fulminans
Chemical toxicity (e.g., colchicine intoxication, methotrexate overdose)

21. Complications and Sequelae
• During the acute phase, the most common
complication of EN is sepsis.
• The epithelial loss predisposes these patients to
infections, which are the main causes of mortality.
Staphylococcus aureus and Pseudomonas are the most
frequent pathogens, but about one-third of positive
blood cultures contain enterobacteriae not present on
the skin, a finding that suggests bacterial translocation
from gut lesions.
• Multisystem organ failure and pulmonary
complications are observed in more than 30% and 15%
of cases, respectively.

22. Posttraumatic stress disorder are not rare. Psychiatric
consultation and/or psychological support are probably
necessary in a majority of cases.
Late ophthalmic complications are mainly due to functional
alteration of the conjunctival epithelium with dryness and abnormal
lacrimal film. This leads to chronic inflammation, fibrosis, entropion,
trichiasis, and symblepharon. Long-term irritation and deficiency of
stem cells in the limbus may result in metaplasia of corneal
epithelium with painful ulcerations, scarring, and altered vision.

23. Nail changes, including change in pigmentation of the
nail bed, ridging, dystrophic nails, and permanent anonychia,
occur in more than 30% of cases .
Mouth sequelae are present in about one-third of
patients who complain of dryness, altered taste, and late
alterations of teeth.79

24. Vulvar and vaginal complications are
reported by about 25% of patients.Dyspareunia
is related to vaginal dryness, itching, pain, and
bleeding. Genital adhesions may lead to the
requirement for surgical treatment.
Esophageal, intestinal, urethral, and anal
strictures may also develop in rare cases.
Chronic lung disease can be observed after
EN, often attributed to bronchiolitis obliterans,
and occasionally requires lung transplantation.

25. Prognosis and Clinical Course
The epidermal detachment progresses for 5 to 7 days. Then,
patients enter a plateau phase, which corresponds to progressive
reepithelialization. This can take a few days to a few weeks, depending
on the severity of the disease and the prior general condition of the
patient. During this period, life-threatening complications such as
sepsis or systemic organ failure may occur. The overall hospital
mortality rate of EN is 22–25%, varying from 5% to 12% for SJS to more
than 30% for TEN. The prognosis is not affected by the type or dose of
the responsible drug or the presence of human immunodeficiency
virus infection
Prospective follow-up has shown an additional abnormally
increased mortality in the 3-month period following hospital discharge,
which seems to result from the negative impact of EN on prior severe
chronic conditions, for example, malignancies (RegiSCAR, unpublished
data).

26. Treatment
EN is a life-threatening disease that
requires optimal management:
• early recognition
• withdrawal of the offending drug(s)
• supportive care in an appropriate hospital
setting.

27. Symptomatic Treatment
There is no “specific” treatment of
demonstrated efficacy and supportive measures
are the most important.
Supportive care consists of maintaining
hemodynamic equilibrium and preventing life-
threatening complications. The aims are basically
the same as for extensive burns.

28. 1. Significant fluid loss from erosions, which results in
hypovolemia and electrolyte imbalance. Fluid replacement
must be started as soon as possible and adjusted daily.
2. Early nutritional support is preferentially provided by
nasogastric tube to promote healing and to decrease the risk
of bacterial translocation from the gastrointestinal tract.
3. Prophylactic antibiotics are not indicated. Patients should
receive antibiotics when clinical infection is suspected.
Prophylactic anticoagulation is provided during
hospitalization.
4. Do not recommend extensive and aggressive debridement
of necrotic epidermis in EN
5. Eyes should be examined daily by an ophthalmologist.
6. Mouth should be rinsed several times a day with antiseptic
or antifungal solution.

29. Specific Treatment in Acute Stage
Because of the importance of immunologic
and cytotoxic mechanisms, a large number of
immunosuppressive and/or anti-inflammatory
therapies have been tried to halt the
progression of the disease. None has clearly
proved its efficacy. The low prevalence of the
disease makes randomized clinical trials hard to
perform.

30. Corticosteroids
The use of systemic corticosteroids is still
controversial.

31. Intravenous Immunoglobulin
The proposal to use high-dose intravenous Ig
was based on the hypothesis that Fas-mediated cell
death can be abrogated by the anti-Fas activity
present in commercial batches of normal human Ig.
Benefits have been claimed by several studies
and case reports,but refuted by several others.
Thus, intravenous Ig cannot be considered the
standard of care,especially after recent findings that
the Fas-L/Fas pathway was not, or only marginally,
involved in the mechanisms of EN.

32. Cyclosporine A
Cyclosporine A is a powerful
immunosuppressive agent associated with
biologic effects that may theoretically be useful
in treatment of EN
activation of T helper 2 cytokines,
inhibition of CD8+ cytotoxic mechanisms, and
antiapoptotic effect through inhibition of Fas-L,
nuclear factor-κB, and TNF-α.

33. Plasmapheresis or Hemodialysis
The rationale for using plasmapheresis or
hemodialysis is to prompt the removal of the
offending medication, its metabolites, or
inflammatory mediators such as cytokines.

34. Antitumor Necrosis Factor Agents
Anti-TNF monoclonal antibodies have been
successfully used to treat a few patients.
Because a prior randomized controlled trial
of thalidomide, an anti-TNF agent, had to be
interrupted due to significantly increased
mortality,extreme caution is suggested in the
use of anti-TNF agents to treat EN.

35. Treatment of Sequelae
ocular sequelae, the literature contains
only case reports related to treating sequelae.
Photoprotection and cosmetic lasers may help
resolve the pigmentation changes on the skin.

36. Prevention
A list of the suspected medication(s) and
molecules of the same biochemical structure
must be given to the patient on a personal
“allergy card.” It is also very useful to provide a
list of drugs of common use that cannot be
suspected. Because of recent indications of
genetic susceptibilities to the development of
EN, prescription of the offending agent to family
members should also be avoided.

37. Chapter 40. Epidermal Necrolysis (Stevens–Johnson
Syndrome and Toxic Epidermal Necrolysis)
L. Valeyrie-Allanore; Jean-Claude Roujeau